Principles of Medical Physiology [2 ed.] 9382076646, 9789382076643

Table of contents :
Principles of Medical Physiology
Dedication
Title Page
Copyright
Preface to the Second Edition
Preface to the first Edition
Photo Acknowledgments
Sections
Table of Contents
Section 1 General Physiology
1. Principles of Physics in Physiology
2. Principles of Physical Chemistry in Physiology
3. Principles of Control Systems in Physiology
4. The Cell
5. Cell Membrane
6. Cell Cycle
7. Applied Genetics
Section 2 Nerve and Muscle
8. Functional Anatomy of Nerve and Muscle
9. Degeneration and Regeneration of Nerve and Muscle
10. Resting Membrane Potential
11. Membrane Excitation and Action Potential
12. Electrophysiology of Ion Channels
13. Conduction of Nerve Impulses
14. Neuromuscular Transmission
15 Mechanism of Striated Muscle Contraction
16. Characteristics of Skeletal Muscle Contraction
17. Electromyography and Electroneurography
18. Muscle Mechanics
19. Smooth Muscles
20. Cardiac Muscle
Section 3 Blood and Immune System
21. Body Fluids and Blood
22. Red Blood Cells
23. Hemoglobin
24. Hematinic Factors
25. Blood Grouping and Transfusion
26. Blood Platelets and Hemostasis
27. Hemostatic Balance
28. Granulocytes
29. Agranulocytes and Lymphoid Organs
30. Immunity, Tolerance, and Hypersensitivity
31. Immune Mechanisms
32. Hemopoiesis
Section 4 Cardiovascular System
33. Cardiac Excitation and the Electrocardiogram
34. Abnormalities of Cardiac Excitation
35. Cardiac Cycle
36. Cardiac Output
37. Circulatory Pathway
38. Hemodynamics
39. Capillary Circulation and Lymphatic Circulation
40. Chemical Control of the Cardiovascular System
41. Neural Control of the Cardiovascular System
42. Blood Pressure Regulation
43. Circulatory Shock
44. Coronary Circulation
45. Cerebral Circulation
46. Pulmonary and Pleural Circulation
47. Cutaneous, Muscle, and Splanchnic Circulation
Section 5 Respiratory System
48. Functional Anatomy of the Respiratory System
49. Mechanics of Pulmonary Ventilation
50. Measurement of Pulmonary Ventilation
51. Alveolar Ventilation, Perfusion, and Gas Exchange
52. Transport of Gases
53. Control of Respiratory Rhythm
54. Control of Pulmonary Ventilation
55. High- and Low-Pressure Breathing
56. Pulmonary Function Tests and Respiratory Disorders
Section 6 Renal System
57. Functional Anatomy of the Kidney
58. Glomerular Filtration and Tubular Reabsorption
59. Renal Handling of Sodium
60. Renal Regulation of Urine Volume and Osmolarity
61. Body Fluid and Electrolyte Balance
62. Renal Regulation of Acid–Base Balance
63. Renal Regulation of Potassium Balance
64. Renal Handling of Miscellaneous Substances
65. Hormones Acting on the Kidney
66. Quantitation of Renal Functions
67. Urine Analysis and Renal Function Tests
68. Renal Syndromes
69. Urinary Bladder and Micturition
Section 7 Gastrointestinal System
70. Events in the Mouth and Esophagus
71. Events in the Stomach
72. Events in the Duodenum
73. Events in the Small Intestine
74. Events in the Colon
75. Gastrointestinal Hormones
76. Gastrointestinal Disorders
Section 8 Nutrition and Metabolism
77. Dietary Nutrients and Fibers
78. Nutritional Assessment and Dietary Planning
79. Metabolic Pathways
80. Metabolic States and the Liver
Section 9 Endocrine System
81. Mechanism of Hormonal Action
82. Hypothalamic and Pituitary Hormones
83. Thyroid Hormones
84. Calcitropic Hormones
85. Adrenocortical Hormones
86. Adrenomedullary Hormones
87. Pancreatic Hormones
Section 10 Reproductive System
88. Testicular and Ovarian Hormones
89. Puberty and Gametogenesis
90. Menstrual Cycle
91. Sperm Transport and Fertilization
92. Sexual Differentiation of the Fetus
93. Pregnancy
94. Parturition and Lactation
Section 11 Central Nervous System
95. Anatomy of the Central Nervous System
96. Spinal Cord and Brain Stem
97. Cerebellum
98. Diencephalon
99. Basal Ganglia
100. Cerebral Cortex
101. Autonomic Nervous System
102. Synaptic Mechanisms and Neurotransmitters
103. Sensory Mechanisms
104. Regulation of Muscle Length and Tone
105. Motor Planning, Programming, and Execution
106. Thought, Emotion, and Conation
107. Electroencephalogram and Epilepsies
108. Sleep
109. Regulation of Body Temperature
110. Regulation of Food Intake
111. Memory and Learning
112. Language and Speech
Section 12 Special Senses
113. Functional Anatomy of the Eye
114. Visual Optics
115. The Retina and Phototransduction
116. Visual Pathways and Image Processing
117. Oculomotor Mechanisms
118. Auditory Mechanisms
119. Vestibular Mechanisms
120. Olfactory and Gustatory Mechanisms
Index

Citation preview

Sircar_Med-Physiology_9789382076537 1

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Principles of Medical Physiology 2nd edition

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Dedicated to the memory of my parents Who were the best teachers I have ever known

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Principles of Medical Physiology 2nd edition

Sabyasachi Sircar, MD Professor and Head of Department of Physiology All India Institute of Medical Sciences Jodhpur, Rajasthan India

811 Illustrations 116 Tables 19 Text Boxes

Thieme Medical and Scientific Publishers Private Limited A-12, Second Floor, Sector - 2 Noida, Uttar Pradesh - 201 301, India Email: [email protected] www.thieme.in Thieme Delhi • Stuttgart • New York • Rio

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Thieme Publishers Delhi A - 12, Second Floor, Sector - 2 Noida, Uttar Pradesh - 201 301, India Publishing Manager: Dr. Sonu Singh Development Editor: Dr. Gaurav Singh Head Editorial Services: Rachna Sinha Assistant Manager - Editorial Production: Kumar Kunal Sales and Marketing Director: Arun Kumar Majji Chief Executive Officer: Ajit Kohli Copyright © 2014 by Thieme Medical and Scientific Publishers Private Limited.

1st Edition Published in 2007. Principles of Medical Physiology / Sabyasachi Sircar, 2nd ed.

Published by Thieme Publishers Delhi A - 12, Second Floor, Sector - 2, Noida - 201 301, Uttar Pradesh, India, +911204556600 Email: [email protected] www.thieme.in Printer: Saurabh Printers Pvt Ltd 54321 ISBN 978-93-82076-53-7 eISBN: 978-93-82076-64-3

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Important note: Medical knowledge is ever changing. As new research and clinical experience broaden our knowledge, changes in treatment and drug therapy may be required. The authors and editors of the material herein have consulted sources believed to be reliable in their efforts to provide information that is complete and in accord with the standards accepted at the time of publication. However, in view of the possibility of human error by the authors, editors, or publishers of the work herein or changes in medical knowledge, neither the authors, editors, nor publishers, nor any other party who has been involved in the preparation of this work, warrants that the information contained herein is in every respect accurate or complete, and they are not responsible for any errors or omissions or for the results obtained from use of such information. Readers are encouraged to confirm the information contained herein with other sources. For example, readers are advised to check the product information sheet included in the package of each drug they plan to administer to be certain that the information contained in this publication is accurate and that changes have not been made in the recommended dose or in the contraindications for administration. This recommendation is of particular importance in connection with new or infrequently used drugs. Some of the product names, patents, and registered designs referred to in this book are in fact registered trademarks or proprietary names even though specific reference to this fact is not always made in the text. Therefore, the appearance of a name without designation as proprietary is not to be construed as a representation by the publishers that it is in the public domain.

This book, including all parts thereof, is legally protected by copyright. Any use, exploitation, or commercialization outside the narrow limits set by copyright legislation without the publisher’s consent is illegal and liable to prosecution. This applies in particular to photostat reproduction, copying, mimeographing or duplication of any kind, translating, preparation of microfilms, and electronic data processing and storage.

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VII

Preface to the Second Edition The second edition of Principles of Medical Physiology remains committed to the quartet of utility, lucidity, brevity, and contextual relevance of the text. The changes in this edition broadly fall in four categories: First, the errors that crept into the first edition are weeded out. Second, at the end of each chapter, revision questions are added. The questions, which somewhat define the “learning objectives” of the chapter, are mostly conceptual though some require only factual recall. Indeed, a quick look at these questions before going through the chapter should provide the necessary focus for appreciating the text. Third, several chapters have been substantially modified. Notable among them are the chapters on Membrane Excitation & Action Potential, Electrocardiography, Cardiac Output, Hemodynam-

ics, and Respiratory mechanics. Chapters 16 (Characteristics of Muscle Contraction) and 17 (Muscle Elasticity) of the previous edition are merged into a single chapter (Characteristics of Skeletal Muscle Contraction) while Chapter 38 (Circulatory Pathway & Hemodynamics) is split into two. Finally, if the first edition of the book was aimed at providing a text that is “easy to understand”, the second edition is aimed at making the text “easy to revise” by highlighting important parts of the text so that the rigorous structure of the text comes alive, making it even more suitable for reading at bedtime for relaxation! I welcome, indeed beseech, the feedback of readers which may be emailed to me at pmp.sircar@ gmail.com Sabyasachi Sircar January, 2014

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IX

Preface to the first Edition The real voyage of discovery consists not in seeking new landscapes but in having new eyes. Marcel Proust

About a decade ago, I set out to write a book of human physiology that undergraduate medical students could read at bedtime for relaxation, and the result is now in your hands! The four principal considerations that have shaped this book are utility, lucidity, brevity, and contextual relevance. Every sentence in this text has been carefully weighed for its utility before it was granted admission to this book. The utility could be its clinical relevance, conceptual elegance, or its importance in examinations. For deciding on the utility, I have used the simple test of time: Surely, any physiological fact that I fail to recall myself despite teaching physiology for more than two decades need not be taught to the student either. Admittedly though, I have erred and included in this book a lot more than what I can recall effortlessly. Lucidity has been attempted through numerous full-color illustrations and flow charts (which I have drawn myself ), tables, analogies, cartoons, anecdotes, and caveats, and by restricting the text to the basics. Brevity has been achieved, not by compromising on the elucidation of important facts and concepts but through a rigorous economy of words, elimination of introductory passages to chapters, avoiding repetitions, and substituting wherever appropriate a well-labeled picture in place of “a thousand words.” Ensuring contextual relevance has been the toughest of all and is also by far the most distinctive feature of this book. I have spent months planning as to what goes in where and mulling over the rubrics. Sundry facts that could not be woven into a flowing narrative have been omitted unless deemed especially important. Some topics do not fit nicely

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anywhere but are too small to be presented as a separate chapter. Others seem to be appropriate at too many places. There are still others that can be presented as a separate chapter only at the cost of extensive repetition. Hence, topics like exercise physiology or neonatal physiology are not presented as separate chapters but are discussed at several places throughout the book, wherever relevant. Conspicuous by their paucity or absence in this book are the references to the work of scientists, and the normal range of laboratory values. I do not discount the importance of these but leave them for students to find out from reference books. I have witnessed with dismay heated arguments among teachers on what should be considered the “normal” range of physiological parameters, often sidetracking vital conceptual questions, and would not like to join the fray! Rather, I would like to impress on the readers that there can be no global range of normal biological values and that in all such considerations, the context is important, as was strikingly brought out by the comment of the copy-editor of this book, “Are these data real?” referring to the 60 kg weight of a “reference man” (Table 78.3) that is well below western norms. Hence all “normal” values mentioned in this book should be taken as more illustrative than authoritative as they are drawn from myriad sources and altered slightly to make them easy to remember. I hope this book ushers in happier times for students interested in understanding medical physiology and doing well in competitive examinations. Sabyasachi Sircar August, 2007

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Photo Acknowledgments The following figures are reproduced/redrawn/adapted, with permission, from other sources.

From Thieme Publications Figs. 4.2, 8.5 Reproduced from Kuehnel W. Color Atlas of Cytology, Histology, and Microscopic Anatomy. Stuttgart-New York: Thieme ; 2003. Fig. 92.6 Reproduced from Passarge E. Color Atlas of Genetics. Stuttgart-New York: Thieme; 2007.

Reproduced from Schuenke M, et al. Thieme Atlas of Anatomy. Neck and Internal Organs. Stuttgart -New York: Thieme; 2006.

From Other Publications

Figs. 28.1, 28.3, 29.1, 29.2, 32.3, 32.5, 32.6 Reproduced from Theml N, Diem H, Haferlach T. Color Atlas of Hematology. Stuttgart-New York: Thieme; 2004.

Fig. 10.6A Redrawn, with permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc., from Curtis HJ, Cole KS: Membrane resting and action potentials from the squid giant axon . J Cell Comp Physiol, 1942,19:139.

Fig. 30.2 Reproduced from Burmester G-R, Pezzutto A. Color Atlas of Immunology. Stuttgart-New York: Thieme; 2006.

Fig. 11.4 Redrawn from Hodgkin AL, Katz B: The electrical activity of the giant axon of the squid. J Physiol (Lond), 1949, l09:245 .

Figs. 103.20, 105.2 Reproduced from Rohkamm R. Color Atlas of Neurology. Stuttgart-New York: Thieme; 2006.

Fig. 11.7 Redrawn from Mortimer JT: Motor prosthesis. In Brooks VB, editor: Handbook of Physiology. ed 2, Washington, 1981, Motor control, American Physiological Society.

Figs. 56.3, 56.4, 56.5, 76.4, 77.4, 84.4, 99.4 Reproduced from Riede U-N, Werner M. Color Atlas of Pathology. Stuttgart-New York: Thieme; 2005. Figs. 8.10, 49.19 Reproduced from Despopoulos A, Silbernagl. Color Atlas of Physiology. StuttgartNew York: Thieme; 2006 Figs. 45.7, 107.1, 107.3, 108.2, 120.2, 102.5 Reproduced from Mumenthaler M, Mattle H, Taub E. Fundamentals of Neurology. Stuttgart-New York: Thieme; 2006. Figs. 76.1, 76.3, 84.5 Reproduced from Eastman G, Wald C. Crossin J. Getting Started in Radiology. 2006, Thieme Stuttgart. Figs. 1.17, 8.2, 9.1, 9.7, 37.6, 37.8, 37.9, 38.5, 96.1. Reproduced from Schuenke M, et al. Thieme Atlas of Anatomy. General Anatomy and Musculoskeletal System. Stuttgart-New York : Thieme; 2006. Figs. 33.1, 35.1, 37.2, 44.1, 46 .1, 47.4, 48.2 , 49. 1, 57.1, 70.3, 71.1, 71.3, 72.1, 83.1, 84.2, 84.6, 85.1, 87.1, 89.6, 90.4, 91.1, 91.2, 91.4, 91.9, 93.2, 101.1

Sircar_Chapter FM_new.indd X

Fig. 12.8A Redrawn from Ackerman MJ, Clapham DE: Ion channels: Basic science and clinical disease. N Eng J Med 1997; 336:1575. Fig. 13.4 Redrawn from Rushton WAH: A theory of the effects of fiber size in medullated nerve. J Physiol (Lond), 1951,115:116. Fig. 16.1 Redrawn from Jewell BR, Wilkie DR: The mechanical properties of relaxing muscle. J Physiol (Lond), 1960, 152:30. Fig. 16.3B Redrawn from Gordon AM, Huxley AF, Julian FJ: The variation in isometric tension with sarcomere length in vertebrate muscle fibers. J Physiol (Lond), 1960, 152:30. Fig. 29.3, A, B. Redrawn, with kind permission of Springer Science and Business Media, from Faucett DW: A textbook of histology, ed 12, New York , 1994, Chapman & Hall. Fig. 38.10 Redrawn from O’Brien ET, O’Malley K: British Medical Journal, 1979, 2(6197), 1048.

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Fig. 42.6 Redrawn from O’Brien ET, O’Malley K: BMJ, 1979, 2(6198), 1126 Fig. 45.5 Courtesy Dr. M Abid Geelani, Professor of Cardiothoracic Surgery, GB Pant Hospital, Maulana Azad Medical College. New Delhi. Fig. 49.9 Redrawn from Rahn H, Otis AB, Chadwick LE, Fenn WO :The pressure-volume diagram of the thorax and lung. Am J Physiol, 1946,146:170. Fig. 49.15 Adapted from Sherman TF: A simple analog of lung mechanics. Am J Physiol, 1993, 265:S33.

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Fig. 52.3 Redrawn from Sircar SS: The oxygencarrying flask: A representational transform of oxygen dissociation curve of hemoglobin. Am J Physiol, 1994, 266:S34. Figs. 54.1, 58.3, 80.8, 80.9, 80.10, 82.5, 84.2, 92.5 Adapted from Ganong WF, Review of Medical Physiology. Boston. McGraw Hill; 2005. Fig. 55.2 Courtesy Lt. Col. (Dr.) DJ Chakrabarty, Army Medical Corps. Fig. 77.2 Redrawn from WHO/FCH/CAH/ lntegrated management of childhood illness.

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XIII

Sections

Section 1

General Physiology

Section 2

Nerve and Muscle

Section 3

Blood and Immune System

Section 4

Cardiovascular System

Section 5

Respiratory System

Section 6

Renal System

Section 7

Gastrointestinal System

Section 8

Nutrition and Metabolism

Section 9

Endocrine System

Section 10

Reproductive System

Section 11

Central Nervous System

Section 12

Special Senses

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XV

Table of Contents

Preface

vii

Section 1 General Physiology 1. Principles of Physics in Physiology

1

2. Principles of Physical Chemistry in Physiology

18

3. Principles of Control Systems in Physiology

24

4. The Cell

28

5. Cell Membrane

35

6. Cell Cycle

44

7. Applied Genetics

49

Section 2 Nerve and Muscle 8. Functional Anatomy of Nerve and Muscle

54

9. Degeneration and Regeneration of Nerve and Muscle

63

Section 3 Blood and Immune System 21. Body Fluids and Blood

132

22. Red Blood Cells

136

23. Hemoglobin

142

24. Hematinic Factors

151

25. Blood Grouping and Transfusion

158

26. Blood Platelets and Hemostasis

163

27. Hemostatic Balance

170

28. Granulocytes

176

29. Agranulocytes and Lymphoid Organs

182

30. Immunity, Tolerance, and Hypersensitivity

187

31. Immune Mechanisms

193

32. Hemopoiesis

200

Section 4 Cardiovascular System

10. Resting Membrane Potential

69

11. Membrane Excitation and Action Potential

76

12. Electrophysiology of Ion Channels

81

13. Conduction of Nerve Impulses

86

14. Neuromuscular Transmission

93

33. Cardiac Excitation and the Electrocardiogram

205

34. Abnormalities of Cardiac Excitation 217 35. Cardiac Cycle

224

36. Cardiac Output

231

37. Circulatory Pathway

245

38. Hemodynamics

252

97

39. Capillary Circulation and Lymphatic Circulation

262

16. Characteristics of Skeletal Muscle Contraction

101

40. Chemical Control of the Cardiovascular System

268

17. Electromyography and Electroneurography

111

41. Neural Control of the Cardiovascular System

273

18. Muscle Mechanics

117

42. Blood Pressure Regulation

280

19. Smooth Muscles

122

43. Circulatory Shock

286

20. Cardiac Muscle

127

44. Coronary Circulation

291

15

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Mechanism of Striated Muscle Contraction

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XVI 45. Cerebral Circulation

295

46. Pulmonary and Pleural Circulation

303

47. Cutaneous, Muscle, and Splanchnic Circulation 307 Section 5 Respiratory System 48. Functional Anatomy of the Respiratory System

313

49. Mechanics of Pulmonary Ventilation

318

50. Measurement of Pulmonary Ventilation

332

51. Alveolar Ventilation, Perfusion, and Gas Exchange

340

52. Transport of Gases

Section 7 Gastrointestinal System 70. Events in the Mouth and Esophagus 437 71. Events in the Stomach

442

72. Events in the Duodenum

448

73. Events in the Small Intestine

454

74. Events in the Colon

458

75. Gastrointestinal Hormones

462

76. Gastrointestinal Disorders

466

Section 8 Nutrition and Metabolism 77. Dietary Nutrients and Fibers

473

347

78. Nutritional Assessment and Dietary Planning

481

53. Control of Respiratory Rhythm

352

79. Metabolic Pathways

485

54. Control of Pulmonary Ventilation

358

80. Metabolic States and the Liver

494

55. High- and Low-Pressure Breathing

364

56. Pulmonary Function Tests and Respiratory Disorders

368

Section 6 Renal System

Section 9 Endocrine System 81. Mechanism of Hormonal Action

504

82. Hypothalamic and Pituitary Hormones

510

57. Functional Anatomy of the Kidney

376

83. Thyroid Hormones

517

58. Glomerular Filtration and Tubular Reabsorption

382

84. Calcitropic Hormones

525

85. Adrenocortical Hormones

534

59. Renal Handling of Sodium

387

86. Adrenomedullary Hormones

544

60. Renal Regulation of Urine Volume and Osmolarity

392

87. Pancreatic Hormones

547

61. Body Fluid and Electrolyte Balance

396

62. Renal Regulation of Acid–Base Balance

402

63. Renal Regulation of Potassium Balance

408

64. Renal Handling of Miscellaneous Substances

411

65. Hormones Acting on the Kidney

414

66. Quantitation of Renal Functions

418

67. Urine Analysis and Renal Function Tests

423

68. Renal Syndromes

427

69. Urinary Bladder and Micturition

431

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Section 10 Reproductive System 88. Testicular and Ovarian Hormones

554

89. Puberty and Gametogenesis

560

90. Menstrual Cycle

566

91. Sperm Transport and Fertilization

570

92. Sexual Differentiation of the Fetus

580

93. Pregnancy

585

94. Parturition and Lactation

591

Section 11 Central Nervous System 95. Anatomy of the Central Nervous System

595

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XVII 96. Spinal Cord and Brain Stem

606

110. Regulation of Food Intake

727

97. Cerebellum

615

111. Memory and Learning

731

98. Diencephalon

622

112. Language and Speech

740

99. Basal Ganglia

626

100. Cerebral Cortex

632

101. Autonomic Nervous System

642

102. Synaptic Mechanisms and Neurotransmitters

648

103. Sensory Mechanisms

660

104. Regulation of Muscle Length and Tone

677

Section 12 Special Senses 113. Functional Anatomy of the Eye

744

114. Visual Optics

749

115. The Retina and Phototransduction

760

116. Visual Pathways and Image Processing

766

117. Oculomotor Mechanisms

776

118. Auditory Mechanisms

783

105. Motor Planning, Programming, and Execution

685

119. Vestibular Mechanisms

794

106. Thought, Emotion, and Conation

699

120. Olfactory and Gustatory Mechanisms

799

107. Electroencephalogram and Epilepsies

706

108. Sleep

715

109. Regulation of Body Temperature

720

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Index

803

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Principles of Physics in Physiology

Several areas of physiology cannot be appreciated without an elementary knowledge of physics. If only to emphasize the point, selected principles of physics that are important in physiology are outlined below. Also discussed are mathematical principles that are inseparable from physics.

Mathematics

•

Vectors

Vectors are quantities that have a magnitude as well as a direction. A vector is represented with an arrow that indicates its direction. The length of the arrow gives a measure of the magnitude of the vector. A vector can be resolved into components. Conversely, two or more vectors can be combined into a resultant vector. Physiological applications of vectors are found in biomechanics, electrocardiography, motor control, and vestibular mechanisms, among others. The basic concepts of vector resolution are explained with the following examples. Suppose a person travels 150 km from point 0 to point P (Fig. 1.1A). In doing so, he travels 138 km to the south, 60 km to the east, and 140 km to the southeast. The distance he travels in a given direction can be calculated simply by dropping a perpendicular from point P onto the axis representing that direction. This basic method can be applied to any vector quantity. For example, if the person travels from point O toward point P with a velocity of 150 km/h, then he moves south with a velocity of 138 km/h, toward east with a velocity of 60 km/h, and toward southeast with a velocity of 140 km/h. Conversely, if it is known at what velocity he is moving toward south and east, the actual velocity and direction of his movement can be calculated graphically.

blood circulation gets nullified when the body is supine. In the supine position, the direction of gravity is perpendicular to the direction of blood flow in most of the large vessels. A special case of the vector principle is illustrated in Fig. 1.18. Suppose a person is standing at point O situated at the center of an equilateral triangle formed by points A, B, and C. When the person moves toward point P with a velocity of (say) 70 km/h, he is moving toward point A at 51 km/h, toward point Bat 16 km/h, and toward point C at -67 km/h. (The minus sign denotes that he is actually moving away from point c.) On adding the three velocities, we get zero. This principle forms the basis of the zero potential obtained by interconnecting the vertices of Einthoven triangle of electrocardiography.

A

60

E

140

138

SE

s

®

~ A

B

A vector does not have any component perpendicular to it. This is self-evident; a person traveling due south does not move toward east or west. The calculation of the mean electrical axis of the heart from the recorded voltages in the electrocardiogram (ECG) leads (see Fig. 34.11) is based on the same principle. It explains why an ECG wave that has the highest amplitude in lead I would have the lowest amplitude in lead augmented vector foot (aVF) which is perpendicular to lead I. Vector principles also explain why the effect of gravity on

-67

C

Fig. 1.1 Vector principles. [A] Resolution of a vector into its components. [B] Vector principles underlying Einthoven hypothesis of electrocardiography.

General Physiology

Calculus

A

10

Differential calculus makes it possible to cal-

Integral calculus makes it possible to calculate the area under the curve in a Cartesian plane. The area under the curve can be calculated by breaking up the area into rectangular blocks. However, if the curve is irregular, the blocks are not perfect rectangles and the result obtained is inaccurate. Greater accuracy is possible only if the width of blocks is infinitesimally small (dx) so that each block becomes a perfect rectangle. The area under the curve (A) is then given by: A = ∫ y dx

Or stated simply, A is the sum of areas of an infinite number of rectangles with an infinitesimally small width (dx) so that the area of each rectangle is given by y × dx. It should be readily apparent from Fig. 1.2B that ∫y dx is not the same as ∫x dy. The graphic calculation of the work done by the lung and heart, the pressure-time index of the heart and mean blood pressure, and the amount of dye flowing in the indicator dilution method of blood flow estimation are based on the principles of integral calculus.

δy δx

0 0

B

x

Sircar_Chapter01_001-017.indd 2

δx 0

δy x

dy x 10

∫ x dy

∫ y dx

0

y

0 0

10

x

0

dx

x

Fig. 1.2 [A] (Left) The slope (δy/δx) is the same in all segments of a straight line. (Right) For the same δx, the δy varies in different segments of the curve. Hence the slope (δy/δx) is different in all segments. [B] Areas defined by the terms ∫Xdy (left) and ∫Ydx (right).

just explained, the Nernst equation can be written in either way as follows: Em =

61 [C ] log o z [Ci ]

Em =

[C ] –61 log i z [Co]

or

An important application of logarithms is the logarithmic scale which is a convenient scale for describing certain types of data. Consider the sound pressure from various sources (Table 1.1). The inadequacy of a linear scale in representing these data graphically is obvious from Fig. 1.3. On the other hand, if the data are converted into their logarithms and then plotted, the advantage is instantly apparent. The logarithmic scale of sound intensity is called the decibel scale. Similarly, the logarithmic scale of acidity is the pH scale.

Table 1.1 Sound pressures at auditory threshold and in different situations Sound pressure in dyne/ cm2

Sound pressure as a multiple of threshold

Log of the multiple

0.002

1

0

Conversation

0.02

10

1

Factory noise

2

1,000

3

Discomfort

200

100,000

5

Logarithms The logarithm of a number is the exponent to which 10 must be raised so as to equal the number. Expressed mathematically, if 10a = N, then log N = a. For example, log 1,000 = 3 and log 0.001 = −3. It may be noted here that 1,000 and 0.001 are reciprocal numbers. In other words, if log N = a, then log 1/N = −a. Logarithms appear in the Nernst equation (p 19). In accordance with the logarithmic property

δy δx δy δx

0

y

culate the slope of a curve at any point. The slope of a line segment is expressed mathematically as δy/δx, where δy is the small vertical distance through which a point on the segment moves up as it shifts a small distance δx to the right. In the case of a straight line, this ratio remains the same anywhere along the line but in the case of a curved line, this ratio is different for every small segment of the line (Fig. 1.2A). Clearly, a precise description of the slopes of various parts of a curve requires that we break up the curve into infinitesimally small segments. The slope of each segment, which is small enough to be called a point, is denoted by the expression dy/dx.

δy y

δx δy δx

y

There are two broad branches of calculus: differential and integral. Both find applications in several areas of physiology.

y

2

Threshold

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Principles of Physics in Physiology

10,000

3

100,000

Sound pressure multiples (multiples of threshold)

10 8 6 4

Shearing force

2 1 Threshold

10

1,000

Conversation Factory noise

Discomfort

Logarithm of sound pressure multiples

5

Fig. 1.4 Shearing force.

4 3 2 1

Threshold

Conversation Factory noise

Discomfort

Fig. 1.3 Sound pressures expressed as multiples of hearing threshold are depicted graphically on a linear scale (above) and a logarithmic scale (below).

Mechanics Laws of motion The first law of motion states that a body continues to be stationary or to move in a straight line with uniform velocity until it is acted upon by an external force. The law helps in defining force itself (see below). The law is also known as the law of inertia. Because of inertia, a stationary body cannot start moving on its own and a moving body cannot stop on its own. The concept of inertia helps in understanding the effect of coup and counter-coup injuries of the brain and the working of the semicircular canals of the vestibular apparatus. The second law of motion tells us that the acceleration or retardation of a body is directly proportional to the force applied on it and inversely proportional to the mass of the body. The product of the mass and acceleration of a body gives the force acting on it. The third law of motion states that every action has an equal and opposite reaction. The third law has been put to use in ballistocardiography. It also helps in understanding muscle action (see Fig. 49.3).

Force Force is anything that changes or tends to change the uniform motion of a body in straight line. The SI 1

unit of force is the Newton (N). A force of 1 N, when applied to a 1 kg mass placed on a horizontal frictionless surface, produces an acceleration of 1 m/s2. A shearing force is a force that is directed tangentially to the surface of a body (Fig. 1.4). Under the effect of a shearing force, the constituent laminae of a body move through different distances. An understanding of the nature of shearing force is important in the context of otolith organs. Shearing force is also exerted by blood flow on the capillary endothelium. Gravitational force, as applicable on earth, is a special kind of force that has two remarkable features: (1) it is always directed toward the center of the earth and, thereby, defines the vertical. (2) It is directly proportional to the mass of the body. The acceleration produced by gravitational force is called acceleration due to gravity. A heavier body is pulled with a greater gravitational force (in accordance with Newton law of gravitation). However, for a given force, a heavier body has less acceleration (in accordance with Newton second law of motion). Therefore the acceleration due to gravity does not vary with the mass of a body and remains absolutely constant at 9.8 m/s2. This acceleration due to gravity, denoted by g, gives us the feel of weight. G forces are accelerative forces other than gravity that may act on the body in specific situations. The accelerative force is called Gx when it is directed anteroposteriorly, Gy when it is directed laterally, and Gz when it is directed superoinferiorly in reference to the body. Together, the Gx, Gy, and Gz forces are called G forces.1 The organs for sensing G forces are the otolith organs. The weight felt by a subject under the effect of Gz is called the apparent g. Changes in Gz have important effects on cardiac output, blood pressure, and

G conventionally denotes the universal gravitational constant. In certain special contexts, as in aerospace medicine, G denotes a variable whose value is expressed in multiples of g, for example, 2, –1, or 0 g. The term G-force is a misnomer because a change in G-force is almost always due to acceleratory forces other than gravitational force.

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4

General Physiology pulmonary ventilation that are described on p 257. High and low Gz are experienced when there is acceleration or deceleration along the long axis of the body. Very high Gz occurs when a space rocket takes off. More commonly, such changes in Gz are experienced during looping of airplanes and during parachute jumping when the parachute is suddenly opened out after a period of free fall: It is called the opening shock load. A slight feel of high and low Gz is experienced in an elevator when it starts or stops. Zero Gz is perceived by astronauts in orbiting satellites where the gravitational force is precisely counterbalanced by the centrifugal force generated by the orbiting satellite. On earth, zero Gz is experienced during free fall under the effect of gravity. Stated mathematically

A h P = hρg

Manometer tube

B

Mercury reservoir

Fixed scale h=0

Blood pressure cuff P=0

Gz = g – a

where Gz = apparent acceleration due to gravity a = actual acceleration in the direction of gravity g = 9.8 m/s2

When a = g, Gz becomes 0. In other words, a body falling under the effect of gravity is weightless (see Fig. 38.15).

Pressure Pressure is the force exerted per unit area. The pressure of a column of fluid is called hydrostatic pressure. It depends only on its vertical height; neither the width of the column nor its inclination makes any difference to the pressure exerted (Fig. 1.5A). This concept is of importance in understanding the measurement of jugular venous pressure and the direct manometry of blood pressure. The dependence of fluid pressure on the height of the fluid column also explains why the venous pressure is higher in the dependent parts of the body and why the atmospheric pressure decreases at high altitudes. Its knowledge helps in estimating the pressure at different depths of the sea, which is important in deep-sea diving. The SI unit of pressure is N/m2, which is also called Pascal (Pa). The atmospheric pressure at sea level is taken as 101.29 kilopascals (kPa). This pressure is also known as 1 atmosphere absolute (ATA). The value of 1 atmospheric pressure, when rounded off to 100 kPa, is called 1 bar. However, fluid pressure is often expressed simply in terms of the vertical height of a fluid column because the pressure of a fluid column is given by hρg where “h” is the height of the fluid column and “ρ” is the density of the fluid. The fluid of reference is usually

Sircar_Chapter01_001-017.indd 4

h Positive zero error P = hρg

Fig. 1.5 [A] Hydrostatic pressure depends only on the vertical height of a fluid column. It remains unaffected by the diameter and inclination of the tube. [B] A mercury manometer connected to a rubber cuff is used in sphygmomanometry. (Above) The cuff pressure is zero and the mercury levels in the reservoir and manometer tube are equal. (Below) As the cuff pressure increases, the mercury level in the tube rises while the mercury level in the reservoir falls. The difference h in the mercury levels gives the cuff pressure. Due to the fall in mercury level in the reservoir, the fixed scale gives a false-high reading due to positive zero error. The error can be reduced somewhat by scaling down the calibration. It can be verified that in a sphygmomanometer, the 1 cm calibration is actually a little less than 1 cm.

mercury but can be water, saline, or even blood, whichever is convenient. The pressure exerted by 1 mm of mercury column is called 1 Torr. Nearly all fluid pressures inside the body are a few millimeters of mercury above or below the atmospheric pressure, which makes the Torr a convenient unit for expressing physiological pressures. Since mercury is 13.6 times denser than water, 1 Torr equals 13.6 mm of water pressure. Even atmospheric pressure is commonly expressed in terms of the height of the mercury column that would counterbalance it. The height can

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Principles of Physics in Physiology be calculated, given that the density of mercury is 13.6 × 103 kg/m−3: Atmospheric pressure = h×ρ×g 101.29 × 103 = h × (13.6 × 103) × 9.8 ∴ h = 0.76 m = 760 mm

Dload

Deffort

L'

Distance moved by load

5

Class-I (High VR, high MR) F

L

E Distance moved by effort E'

L' Class-I (Low VR, low MR)

Hence, atmospheric pressure is also expressed as 760 mm of mercury, or 760 Torr. The mercury manometer (Fig. 1.5B) is commonly used for measuring pressure. One limb of the manometer is connected to the system whose pressure is to be measured. The other limb of the manometer is left open to the atmosphere. The difference in the mercury column in the two limbs indicates the pressure of the system in excess of the atmospheric pressure.

E

L F

E' Dload

Deffort

Class-II

E'

L' L F

E Dload

Deffort

Levers A lever is a rigid bar that is acted on by forces that tend to rotate the bar about its pivot or fulcrum. Levers are of three types depending on the relationship between the fulcrum, load (weight), and effort (force) applied. If the fulcrum (F) is central, it is a class-I lever. If the load (L) is central, it is a class-II lever. If the effort (E) is central, it is called a class-III lever. The mechanical advantage of a lever is the ratio of the load force to the effort force. The ratio is proportional to the ratio of effort arm to load arm (Fig. 1.6). The greater the mechanical advantage, the less will be the force required to move a load. Mechanical advantage =

Load Effort

The velocity ratio is the ratio of the distance moved by the effort to that moved by the load. The greater the velocity ratio, the greater is the distance through which an effort has to move for lifting a load. Distance moved by effort Velocity ratio = Distance moved by load

In a frictionless lever, mechanical advantage equals velocity ratio. Therefore, in all three classes, what is gained in excursion of the load is lost in the effective force acting on the load and vice versa. Class-II levers always produce force gains, and class-III levers always produce excursion gains. Class-I levers can produce either of the two. The principles of levers are essential to the understanding of the biomechanics of the musculoskeletal system (Chapter 18).

Sircar_Chapter01_001-017.indd 5

Class-III

L'

E' L F

E Deffort

Dload

Fig. 1.6 The physics of a lever (explanation in text).

Work and energy Work is done when the point of application of a force (F) moves through a certain distance (D). Stated mathematically, Work done (W) = F × D

The SI unit of work is the Joule. One joule of work is done when a force of 1 N moves a body through 1 m. Energy is the capacity for doing work and the unit of energy is the same as that of work, that is, Joule. The energy associated with motion is called kinetic energy (KE) and is given by the formula: KE =

1

2

mv 2

where m is the mass of the body and v is its velocity. The amount of kinetic energy that a body can gain by falling under the effect of gravity gives a measure of its potential energy (PE) and is given by the formula: PE = mgh

where m is the mass of the body, g is acceleration due to gravity, and h is the height through which the body can fall.

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General Physiology When work is done by a body by expending its own energy, the work done is said to be positive. For example, a body that falls through a certain height expends its potential energy and therefore the work done by the body is positive. Conversely, a body that is lifted against gravity gains in potential energy. Therefore, work is done on the body, and the work done is negative. When a fluid is compressed by application of pressure P, the fluid gains in energy, which is at least partly in the form of heat. The work done on the fluid is therefore negative and is given by:

lungs themselves do not expend any energy; rather, they are made to inflate by the inspiratory muscles. During inspiration, the lungs gain in elastic recoil energy. This recoil energy stored in the lungs is expended during expiration as the lungs deflate. Therefore, the work done by the lungs during expiration is positive. The work done on and by the lungs during inspiration and expiration are shown graphically in Fig. 1.7A. When the work done during both inspiration and expiration are added, there is a net small amount of negative work done that is represented by the area enclosed within the pressure–volume loop (called the hysteresis loop). The negative work signifies that at the end of one breathing cycle, work has been done on the lungs by the respiratory muscles which have expended their energy. The lungs have not spent energy of their own; rather, they have gained some energy. The energy gained is the heat energy that has been generated by the frictional (viscous) forces inside the lungs. In the same way, the area inside the ventricular pressure–volume loop of the cardiac cycle gives the positive work done by the ventricle in overcoming viscous resistance of blood flow (Fig. 1.7B).

Work done (W) = − ∫ PdV

where dV is the small decrement in volume through which it has been compressed. Conversely, for expanding against an incumbent pressure, the fluid has to expend energy and therefore it loses energy. The work done by the fluid is therefore positive and is given by: Work done (W) = +∫ PdV

These concepts help us understand why the work done by the lungs or the heart is given by the area enclosed in its pressure–volume loop. In the case of the lungs, the work done on the lungs is negative during inspiration because the

n ir a

In

sp In

sp

ir a

tio

Exp

n

ir a

ti o

n

i ra Ex p

n

tio ir a

sp

In

Total work done during a breathing cycle (on the lungs, negative)

n

Work done during expiration (by the lungs, positive)

ti o

ti o i ra

Exp

Tidal volume (mL)

When a body is immersed in a fluid, the fluid displaced pushes the body up so that the body loses weight. The loss in weight is called buoyancy and it

n

Work done during inspiration (on the lungs, negative)

A

Buoyancy

tio

6

Intrapleural pressure (mm Hg)

Work done during systole (by the ventricles, positive)

Work done during diastole (on the ventricles, negative)

Total work done during a cardiac cycle (by the ventricles, positive)

Pressure (mm Hg)

B

Ventricular Volume (mL)

Fig. 1.7 [A] Work done on the lung during breathing. [B] Work done by the ventricle during a cardiac cycle.

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Principles of Physics in Physiology is equal to the weight of the fluid displaced. Providing buoyancy to the brain is an important function of the cerebrospinal fluid.

Surface tension Surface tension is a property of liquids due to which a liquid surface behaves like a stretched membrane. Because of surface tension, a drop of fluid minimizes its surface area. It therefore assumes a spherical shape because the surface to volume ratio is minimum for a sphere. The fact that a bubble does not collapse indicates that the air inside it provides a distending pressure that exactly balances the collapsing pressure of the fluid shell. The law of Laplace states that tension (T) in the wall of a cylinder is equal to the product of the transmural pressure (P) and the radius (R). The formula has several variations (Table 1.2) depending on the geometry of the surface (spherical or cylindrical) and its composition (liquid drop, liquid bubble, or air bubble) (Fig. 1.8). Applications of Laplace law in physiology assume P = 2T/R as an approximation, which is the formula for a spherical air bubble in air. The law of Laplace helps explain several important physiological phenomena. (1) It explains how the thin-walled capillaries are able to withstand an internal pressure as high as 25 mm Hg, which is the normal capillary hydrostatic pressure. This is possible because capillaries have a very small radius R. Table 1.2 Formulas defining Laplace law Spherical

Cylindrical

Liquid drop in air

2T/R

T/R

Air bubble in liquid

4T/R

2T/R

Air bubble in air

2T/R

T/R

Even though the wall tension is low, the small value of R in the denominator makes a very high P possible. (2) The law of Laplace puts the dilated heart at a disadvantage. When the radius R increases, the wall tension T must go up proportionately if the ventricular pressure P is to be maintained. (3) In accordance with the Laplace law, the lower the functional residual capacity of the lungs, the more difficult it is to inflate it. (4) Because of Laplace law, the greater the gastric filling, the lower is the pressure that causes gastric emptying. This is obviously beneficial to the process of digestion. (5) Laplace law explains why a reduction in detrusor muscle tension prevents a rise of intravesical pressure even as the urinary bladder fills up to greater volume.

Viscosity Viscosity is fluid friction. When fluid moves along a tube, it does so in the form of multiple layers or laminae that slip on one another, moving at different velocities due to friction between the layers. The lamina at the middle of the blood vessel moves fastest while the one closest to the vessel wall does not move at all. Thus, there is a velocity gradient of laminae, which is called the shear rate. A fluid has 1 poise of viscosity if there is a frictional force of 1 dyne/cm2 between its layers when flowing at a shear rate of 1 cm/s. A Newtonian fluid is one in which the viscosity is independent of the shear rate. Blood is not a Newtonian fluid. Just as friction affects the velocity of a body, viscosity affects the velocity of fluid flow. In a long narrow tube of uniform radius, the relation of the flow rate (Q) with the pressure gradient (PA – PB), that is, the pressure difference at the two ends of the tube, fluid viscosity (η), tube radius (R), and tube length (L) is given by the Poiseuille-Hagen formula: Q = (PA – PB ) ×

Liquid drops in air

Air bubbles in liquid

Air bubbles in air

Liquid column in air

Fig. 1.8 The Laplace law is applicable to any of the above (see Table 1.2).

Sircar_Chapter01_001-017.indd 7

7

1 R4 π × × 8 η L

This law is important in the understanding of hemodynamics. Since resistance varies inversely with the fourth power of the radius, even small changes in the vessel diameter cause large variations in blood flow through it, enabling effective regulation of blood flow through vascular beds. The physiological relevance of the Poiseuille-Hagen formula is best brought out by the differences in the blood flow in the renal cortex and the renal medulla (see p 377), where blood viscosity, capillary length, and capillary diameter all have a role. At high velocities, the flow of fluid becomes turbulent and does not remain streamlined. The

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8

General Physiology probability of turbulence is related to the diameter of the vessel and the viscosity of the blood. This probability is expressed by the Reynolds number: Re =

A

ρDV η

where Re is the Reynolds number, ρ is the density of the fluid, D is the diameter of the tube (in cm), V is the velocity of the flow (in cm/s), and η is the viscosity of the fluid (in poise). The higher the value of Re, the greater the probability of turbulence. When Re < 2,000, flow is usually not turbulent whereas if Re > 3,000, turbulence is almost always present. Turbulence of blood is responsible for cardiac murmurs and the Korotkov sounds. The Poiseuille-Hagen formula can be rewritten as:

P1

P2

B

Constricted segment

C

L 8 (PA – PB ) = Q × π × η × 4 R

Thus when the flow rate, fluid viscosity, and tube radius remain constant, the pressure drop (PA – PB) along a tube is directly proportional to the length of the tube and inversely proportional to the tube radius, as explained in Fig. 1.9.

Bernoulli principle When a constant amount (Q) of fluid flows through a tube, the total fluid energy, that is, the sum of its kinetic energy, pressure energy, and potential energy, remains constant (Fig. 1.9). This is known as Bernoulli principle and it helps in understanding several important hemodynamic principles. It explains, for example, why the fluid pressure is low in a blood vessel at places where its radius is less2 (Fig. 1.9). It also explains the suction effect of venous blood flow on the thoracic duct terminating in the vein (see Fig. 39.7).

Heat Heat always flows from a higher temperature to a lower temperature. When the temperatures of two bodies are equal, no heat transfer occurs between them. (1) In conduction, transfer of heat occurs through a medium whose molecules cannot move about freely. Thus, when we hold an iron rod in fire, the iron atoms vibrate and transfer the heat from the fire to the hand through the rod. However, the

D

Fig. 1.9 A horizontal tube is fitted with uniformly spaced manometers for measuring the pressure drop. [A] The pressure falls uniformly with distance in accordance with the Poiseuille-Hagen formula. [B] The pressure falls in the constricted segment in accordance with Bernoulli principle. Beyond the constricted segment, the pressure rises again. The depiction is not entirely correct: the correct pressures are depicted immediately below. [C] The pressure in the constricted segment is low in accordance with Bernoulli principle and the pressure drop along the segment is steeper in accordance with the Poiseuille-Hagen formula. (D) The fluid rises higher in the last manometer because it captures a part of the fluid’s kinetic energy and converts it into pressure energy in accordance with Bernoulli principle.

iron atoms do not move from their fixed places. (2) In convection, the molecules of the medium transfer heat by actually moving about, carrying the heat with them. Evaporative cooling is an example: The water molecules vaporize and move away, carrying the heat with them. The caloric stimulation test for testing vestibular functions is based on the convective currents set up inside the vestibular apparatus. (3) In radiation, no medium is required. It is through radiation that heat from the sun travels through space and reaches us.

2

The fact that both Poiseuille-Hagen formula and Bernoulli principle give the effect of tube diameter on fluid pressure need not be cause for confusion. The two formulas deal with different aspects of fluid energy. The Poiseuille-Hagen formula deals with the conversion of fluid pressure into heat and the resultant loss of fluid pressure as the fluid flows through a long tube of uniform diameter. It does not deal with the other forms of fluid energy like kinetic energy or potential energy. On the other hand, Bernoulli principle deals with the interconversion of the three different forms of fluid energy and not with its conversion into heat energy.

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Principles of Physics in Physiology Heat transfer occurs through all possible modes. If a medium is present and the molecules are free to move about, heat will travel through convection. If the molecules cannot move about, heat will travel through conduction. Regardless of whether a medium is present or not, some heat will always travel through radiation. A knowledge of the modes of heat transfer is important to the understanding of thermoregulation in the body and explains our behavioral responses to changes in environmental temperature. For example, it is through convection that the circulating blood maintains a fairly uniform temperature throughout the body. The body is cooled through the evaporation of sweat (convection). We seek shade because it cuts off the radiation heat from the sun although we still feel the convective heat of hot air or the conductive heat of the ground we lie upon. We wear dark, coarse-textured clothes in winter because dark surfaces absorb radiated heat. We wear light-colored clothes in summer because they light surfaces reflect back heat radiation. Thick woolen clothes that trap air in them reduce conductive and convective losses of body heat in winter.

Light Light bends as it passes from air into a denser medium or when it emerges out of the medium into air. This bending is known as refraction and the extent to which it bends while passing in and out of the medium is given by the refractive index (μ) of the medium. The refractive index of water is 1.33. The refractive indices of the various compartments of the eye are shown in Fig. 114.1. Refraction of light underlies the formation of an image by the lens. A knowledge of how lenses work helps in understanding the refraction in the eye. The basic formula for lenses is: 1 1 1 = – f v u

where u is the distance of the object from the lens, v is the distance of the image from the lens, and f is the focal length of the lens. The distances u, v, and f may be positive or negative, depending on whether the measurements are made along the direction of the light or against it (Fig. 1.10). The focus is the point where parallel rays passing through the lens would converge (in the case of a convex lens) or appear to diverge (in the case of a concave lens). The focal length of a convex lens is positive while the focal length of a concave lens is negative.

Sircar_Chapter01_001-017.indd 9

9

F

F

–15

–10

–5

0

+5

+10

+15

Fig. 1.10 Ray diagrams showing the focal point of a convex lens (above) and a concave lens (below). In the examples illustrated here, the focal length of the convex lens is +6 cm and the focal length of the concave lens is –6 cm.

The power of a lens is expressed in diopter (D) and is the reciprocal of its focal length in meters. Thus the power of a convex lens with focal length of + 25 cm is + 4 diopter, whereas the power of a concave lens of −50 cm is −2 diopter. The power of the intraocular lens can be increased by contracting some of the intraocular muscles. This phenomenon is called accommodation. When two coaxial lenses are placed together, their diopteric powers are added algebraically. This forms the basis of correction of refractory errors by using external lenses. The physics of image formation is best understood by integrating it with the physiology of sensory perception, because whatever we see around us is essentially the sensory projection of images formed on our retina. Consider a point object (O) and its point image I formed by a convex lens L (Fig. 1.11). A point image is formed when all the rays diverging from a point object are made to converge at a single point using a convex lens. In Fig. 1.11A, the image Ir (r for real) is formed in front of the eye. After converging at Ir, the rays diverge again and therefore the point image (the point of convergence of rays) behaves like a point object (the point of divergence of rays). Hence the image is called a real image. The diverging rays from Ir converge on the retina after passing through the convex lens of the eye. Past sensory experience of the observer’s brain tells it that the rays forming the retinal image are originating from point Ir and, therefore, the brain “sees” an image at point Ir. This “calculated guess” made by the brain is known as sensory projection. In making the projection, the brain takes into consideration, among other factors, the extent of accommodation required by the intraocular muscles. In Fig. 1.11B, the convex lens L bends the divergent rays from the object but not enough to

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General Physiology

A

L in al i m a g e

10

Ir

Ret

O

B

in al i m a g e

L Iv

Ret

O

Fig. 1.11 The optics of image formation of point objects.

make them converge in front of the eye. It is the intraocular lens that finally converges the rays on to a point on the retina. As in the previous case, the brain projects the retinal image to the point where the divergent rays incident on the eye seem to be originating from. Hence, the brain “sees” an image at point Iv. Unlike Ir, no rays are actually diverging from Iv; they only appear to do so due to sensory projection. Hence, Iv is called a virtual image (virtual = amounting to). Stated simply, an image is real if it is formed by the convergence of rays. The image is virtual if it is visible at a site where there is no convergence of rays. Going by this definition, the image formed on the retina of the eye is a real image. The images formed when the object is located at different distances from the lens are shown in Fig. 1.12. These ray diagrams can be easily

constructed by remembering that (1) rays parallel to the principal axis converge at the focus after passing through the lens and (2) the rays passing through the optical center (3) of the lens do not deviate. How big does an object appear to the observer? The answer is that the nearer an object is to the eye, the bigger is the retinal image and the bigger it appears to the observer. However, how close we can bring an object to our eyes is limited by the power of our accommodation. Short-sighted people (myopes) see bigger images because they can bring the object nearer to the eye and still see it clearly. Another question arises here. Given two objects of different sizes placed at different distances from the eye, which one will appear bigger? The answer lies in the visual angle subtended by the two objects: The object that subtends a greater visual angle looks bigger (Fig. 1.13). The visual angle forms the basis of the testing of visual acuity. The visual angle subtended by an object is given by the formula: Visual angle = tan–1

Height of the object Distance of the object from the eye

Thus, if an 8.75 cm high object3 is kept at a distance of 60 m (i.e., 6,000 cm), the visual angle subtended by it will be: = tan−1 [8.75/6,000] = tan−1 [0.00145] = 0.0835 degree = 0.0835 × 60 minutes = 5.01 minutes

O F 2F

Principal axis

F Optical I center (C)

O F 2F

F I

O F Infinity

Fig. 1.12 The optics of image formation of objects placed greater than two focal lengths away (above), at twice the focal length (middle), and at focal length (below). 3

The retina is normally situated at the focus of the intraocular lens (see Fig. 114.4) and therefore when there is no accommodation, only objects at infinity are clearly visible, for example, the stars in a night sky. Anything nearer appears hazy. This can be verified by putting atropine (a cycloplegic) on the eye, which abolishes the power of accommodation. For the same reason, we see the maximally magnified images without straining our eyes when the object is kept at the focus of a magnifying glass and its virtual image is formed at infinity.4 Due to sensory projection, parallel rays falling on the eye result in a virtual image that is infinitely large and is formed at infinity. How big does an infinitely large image located at infinity appear to the eye? As already explained, the answer depends on the visual angle subtended at the eye by the virtual image.

In the Snellen chart, the topmost letter is 8.75 cm high, which is readable by a normal person from a distance of 60 m (see Fig. 114.12).

4

This point is stressed here because several textbooks of high school physics mention that when an object is kept at the focus of a convex lens, the rays become parallel and therefore no image is formed. That is incorrect.

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Principles of Physics in Physiology

11

Object located a long distance away from the eye Small retinal image

O Visual angle

Object at the near point of the eye O Large retinal image

Visual angle Maximum accommodation

Object nearer than the near point of the eye O Blurred retinal image

No further increase in accommodation (Accommodation failure)

Fig. 1.13 The visual angle increases as the object is brought nearer to the eye. Note that the greater the visual angle, the larger is the retinal image. When the object comes nearer than the near point, the retinal image becomes blurred.

Because the eyes do not have to be strained (accommodated) for seeing a virtual image at infinity, all optical instruments, including microscopes, are so designed that the image formed is virtual and is situated at infinity. A commonly observed virtual image at infinity is the red eye well known to photographers: The pupil appears red in a photograph that has been shot in dim light using flashlight (Fig. 1.14). Because the pupils are dilated in dim light, the red choroid layer beneath the retina is illuminated by the flashlight and gets photographed. The illuminated choroid, which is situated at the focus of the intraocular lens, sends out

parallel rays from the pupil. These parallel rays are captured by the camera even from a distance of several meters. Image formation when the object is at focus is also of importance in understanding direct ophthalmoscopy and retinoscopy. Fig. 1.12 also shows that the nearer an object is to the focal point F, the greater the distance between the image and the lens. In the eye, the distance between the lens and the retina is fixed at 17 mm and the maximum power of the lens that can be attained after full accommodation is 69 diopters which is equivalent to a focal length of 14.5 mm. Substituting these values in the lens formula, we get u = 10 mm, which is as close the object can get to our eyes without blurring the retinal image and is called the near point.

Waves and sound

Fig. 1.14 Red eye (Bruckner) reflex in a photograph shot in the dark using flashlight. The principle of direct ophthalmoscopy is similar.

Sircar_Chapter01_001-017.indd 11

A wave propagates through a medium when the particles of the medium oscillate rhythmically about their mean position. The wave is called transverse or longitudinal depending on whether the plane of oscillation of the particles is perpendicular or parallel to the direction of wave motion. A transverse wave has alternate crests and troughs (Fig. 1.15). The ocean waves or the ripples in a pool of water or the fluttering of a flag in the wind are examples of transverse waves. Transverse waves

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12

General Physiology

Crest

A

of phase. The term phase difference or phase lag has been used in this book in the context of fluctuations in blood gases in Cheyne–Stokes breathing and in the ionic basis of cardiac pacemaker potentials. Two waves with different frequencies and amplitudes can summate to produce a complex wave. Such complex waves form the basis of the quality or timbre of sound waves (Fig. 1.15D). The characteristics of a sound wave, namely, its pitch, loudness, and timbre, are discussed below.

Wavelength

Trough Wavelength Condensation

Rarefaction

B

Pitch The pitch (or tone) of the sound is what is perceived by the human ear as higher or lower musical notes: It is directly related to its frequency. The greater the frequency, the higher is the tone. Pitch discrimination by the human ear is best in the range of 1,000 to 3,000 Hz.

C

O

0

O

O

O

O

90 180 270

O

O

90 180 270

O

0

0

O

O

90

O

O

O

O

180 270

O

90 180 270

O

0

O

0

O

90

O

O

90 180

D

Intensity and loudness A sound wave is essentially a traveling pressure wave and therefore the amplitude of a sound wave is expressed as the maximum pressure variation in it. The intensity of a sound wave is the amount of energy (in joule) transported by the sound wave in unit time (1 s) per unit area (1 m2), across a surface perpendicular to the direction of propagation. The intensity of a sound wave is directly proportional to the square of its pressure amplitude. The pressure amplitude of the faintest sound that can be heard is about 3 × 10−5 Pa and the corresponding intensity is 10−12 J/s/ m2. A more convenient unit for expressing sound intensity is the decibel (dB). Number of dB = 10 log

Fig. 1.15 Characteristics of wave motion. [A] Transverse and longitudinal waves. [B] Waves with different frequency and amplitude. [C] Waves with a phase difference. [D] Wave summation. Note that the wave in red color is formed by the summation of the two waves shown in blue, one of which has a lower frequency (fundamental wave) and the other has double the frequency (harmonic wave). The shape of the summated wave is different from the component waves, and gives the wave a characteristic sound quality or timbre.

are also set up on the basilar membrane of the cochlea (see Fig. 118.6). A longitudinal wave has alternate zones of condensation and rarefaction. Sound waves in air are longitudinal waves. The frequency of a wave is the number of waves produced in 1 second and is expressed in Hertz (Hz). It is inversely related to its wavelength. Two waves with the same frequency can have a phase difference or phase lag (Fig. 1.15C). For example, if at any point of time, one wave is at its crest (i.e., at 90 degrees) and the other is at its trough (i.e., at 270 degrees), the two waves are 180 degrees out

Sircar_Chapter01_001-017.indd 12

Intensity of the sound Intensity of barely audible sound

The term loudness refers to the listener’s subjective perception of the magnitude of a sound sensation. Loudness increases with intensity, and the relation between the two is empirical, which is given by the Weber–Fechner law or any of its modifications (see Fig. 103.17). Since the decibel scale is a logarithmic scale, every 10 dB represents a 10-fold increase in sound intensity. The threshold of hearing (i.e., the intensity of the faintest audible sound) is zero decibel. A sound is 10 times louder than threshold at 10 dB, 100 times louder at 20 dB, a million times louder at 60 dB, and 10 billion times louder at 100 dB. The usual loudness of speech is 65 dB. A 100 dB sound damages the peripheral auditory apparatus while 120 dB causes pain, and 150 dB causes permanent damage to the hearing apparatus. Timbre or quality Most musical sounds are made

of complex waves formed by the summation of a high-amplitude wave (fundamental frequency) with several other waves of smaller amplitudes whose

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Principles of Physics in Physiology frequencies are multiples of the fundamental frequency (harmonics or overtones). The fundamental frequency determines the pitch of the sound while the overtones give the sound its characteristic timbre or quality. Variations in timbre enable us to distinguish tones of the same pitch produced by different musical instruments. A mathematical theorem called the Fourier transform makes it possible to express any wave with a given frequency and amplitude as the sum of a fundamental frequency and its numerous harmonics. Fourier transform has tremendous application in engineering. A well-known example is the musical synthesizer in which the tone of any musical instrument can be synthesized by mixing several multiples of a fundamental frequency in appropriate proportions of their amplitudes. Fourier transform has been applied to biological signals too, for example, for data reduction in electroencephalogram. Finally, it is interesting to note that the basilar membrane of the cochlea works out the Fourier transform of the sound waves: The sound wave breaks up into its component frequencies on the basilar membrane and each component registers its maximum amplitude at a different site of the basilar membrane. This information is conveyed separately to the brain which is then able to “synthesize” the quality of the sound.

Electricity Electrical charge Atoms are made of protons, neu-

trons, and electrons. A proton has a unit positive charge, an electron has a unit negative charge, and neutrons do not have any charge on them. A body containing equal numbers of protons and electrons is electrostatically neutral. When the number of electrons in a body exceeds the number of protons in it, the body develops a negative charge. Conversely, it develops a positive charge when the number of electrons is less than the number of protons in it. The SI unit of charge is the Coulomb which equals the charge of 6.242 × 1018 electrons.

the body is said to be 1 V, which is the SI unit of potential. Two charged bodies have 1 V potential difference if 1 J of work is done in moving a charge of +1 C from one body to the other. Resistance The resistance of a conductor determines how much current it allows to pass through it when a potential difference is applied across it: for a given potential difference across a conductor, the current flowing through the conductor is inversely proportional to its resistance. This is known as the Ohm law. If the current is 1 A when the potential difference is 1 V, the resistance is said to be 1 Ω, which is the SI unit of resistance. Conductance is the reciprocal of resistance and its SI unit is Mho. Voltage = Current × Resistance

An important derivation of Ohm law is that when resistances (R1, R2, R3…) are connected in series (Fig. 1.16A), the total resistance (R) is given by: R = R1 + R2 + R3 ……

When R1, R2, and R3 are connected in parallel (Fig. 1.16B), the total resistance is given by the formula: 1/R = 1/R1 + 1/R2 + 1/R3 ……

The resistance of a conductor varies directly with its length and inversely with its cross-sectional area. This principle is important in the understanding of nerve conduction and explains why nerve conduction velocity increases with axon diameter. Capacitance The potential of a body is directly

proportional to the amount of charge it contains. The greater the amount of charge a body contains,

A

Current The flow of charged particles is called an

electric current. The SI unit of current is the Ampere. A flow of 1 C of charge every second is 1 A current. Electricity is the flow of negatively charged electrons from a negative to positive potential. Conventionally, however, electricity is assumed to be the flow of positively charged particles from a positive to negative potential. Potential The potential of a body is the work done

when a charge of +1 C approaches the body from infinity under the effect of its attractive or repulsive force. If the work done is 1 J, the potential of

Sircar_Chapter01_001-017.indd 13

13

R1

R2

R3

B R1 R2 R3

Fig. 1.16 Resistances in series [A] and parallel [B].

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14

General Physiology

Box 1.1 What is Zero Potential? Although earth is a stable reference for all electric potentials, it is impractical to express all potentials with reference to ground potential. Consider Fig. 55.2 showing the Warila pass. Its altitude is shown as 17,300 feet. The reference point here is the sea level. A more stable reference would be the center of the earth but that is unnecessary and inconvenient. Similarly, it is more convenient to measure the heights of the local peaks in reference to the average altitude of the surrounding terrain. Thus, all bioelectric potentials are expressed in reference to the potential of adjacent areas of the body, or to the average potential of the body.

the greater is its potential. However, the extent to which the potential rises when a given amount of charge is imparted to it will differ for different bodies. A body that can hold a large amount of charge without much rise in its potential is said to have a high capacitance. Stated mathematically, Capacitance =

Charge Potential

Larger bodies have higher capacitance and, therefore, the earth has almost an infinite capacitance. Thus the potential of earth (ground potential) remains unchanged no matter how much charge enters it. This stable ground potential is assumed to be zero and serves as a convenient reference for all electrical measurements (Box 1.1). For the same reason, any charged body, when grounded, loses all its charge to the earth and its potential becomes zero. A device that can store a large amount of charge is called a capacitor. A capacitor can hold a lot of charge and yet its potential remains low. On the other hand, a body with a low capacitance develops a high potential when it is charged. At high potentials, charge tends to “leak out” and hence a body with low capacitance cannot hold much charge. A capacitor can be built by sandwiching a thin sheet of dielectric (nonconducting material) between two parallel metal plates. Such a capacitor is called a parallel plate capacitor. When a potential difference is applied to the plates, a large amount of charge is stored in the plates. The nerve membrane behaves like a dielectric, and when both its surfaces are layered with ions of opposite charges, it acts like a parallel plate capacitor (see Fig. 10.1). Membrane capacitance is an important determinant of membrane excitability and conduction velocity of nerve membranes.

Sircar_Chapter01_001-017.indd 14

Electricity and fluid dynamics The concepts of electricity are relevant to fluid dynamics too and help in understanding several important hemodynamic phenomena. Conversely, simple analogies of fluid mechanics help in understanding certain electrical phenomena like capacitance. These analogies are explained below. Fluid pressure is analogous to electric potential and fluid usually flows from high pressure to low pressure just as electric current flows from high to low potential. The amount of fluid flowing in unit time is analogous to electric current. Fluid resistance is quite similar to electrical resistance. The relationship between resistance, pressure drop, and flow rate in the blood vessels is similar to the relationship between the resistance, potential difference, and current:

Resistance = Pressure drop/flow rate

A similar formula is employed for defining blood flow resistance in vascular beds in terms of flow rate and perfusion pressure. Even the formulas for electrical resistances in series and parallel are valid for fluid dynamics and have important implications in hemodynamics. For example, most capillary beds are disposed in parallel to the heart while the portal beds are in series (Fig. 1.17). The physics of parallel circuits explains the phenomena of circulatory “steal” like coronary steal or subclavian steal: The electrical analogy is that when multiple resistors are connected in parallel, more current flows through resistors with lower resistance and vice versa. The electrical analogy also helps in understanding why the blood pressure falls when the resistance in any of the capillary beds decreases. The electrical capacitance of a body can be compared with the fluid capacity of a container. A container with a large base is similar to a capacitor because it can store a large amount of fluid (analogous to charge) without its hydrostatic pressure (analogous to potential) increasing too much. On the other hand, the pressure in a narrow tube rises quickly when filled with fluid. For the same reason, leakage of charge is higher when the capacity is low (Fig. 1.18A). Another similarity between electricity and fluid dynamics pertains to the measurement of potential. Consider two containers with fluid filled to different levels. For measuring their average potential, the two containers are connected to a graduated measuring tube as shown in Fig. 1.18B. The height of the fluid column in the graduated

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Principles of Physics in Physiology

15

Cerebral capillaries

Anterior pituitary capillaries

Hypothalamic capillaries

Pulmonary capillaries

Right ventricle

Left ventricle

Coronary capillaries

Muscle capillaries

Uterine capillaries

Lymph node

Portal vein

Lymphatic vessels

Peritubular capillaries

Glomerular capillaries

Hepatic sinusoids Mesenteric capillaries

Fig. 1.17 Circulatory beds in series and parallel with the heart. Note that the capillary beds that are in series constitute a portal system. A

B

Fig. 1.18 Fluid analogy of electricity. [A] Fluid pressure and capacity are analogous to electric potential and capacitance. Shown here are two containers containing the same volume of fluid and with both having a small hole near their base. The container on the left has a broader base and therefore the hydrostatic pressure is low and leakage is much less. The container on the right has a narrow base. Hence the hydrostatic pressure is high and leakage is more. [B] A graduated tube interconnects two fluid-filled containers and is equidistant from both. The fluid pressure in the tube gives the mean of the fluid pressures in the two containers. However, the pressures in the two containers soon equalize unless the connecting limbs have high resistance to fluid flow.

Sircar_Chapter01_001-017.indd 15

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16

General Physiology tube gives the average fluid pressure in the two containers. The problem with this method is that since the two containers are interconnected, their pressures equalize very soon. The problem can be tackled by increasing the resistance of the connecting limbs. This analogy helps in understanding why it is important in electrocardiography to interconnect the three limb electrodes only through a high (5,000 Ω) resistor for obtaining zero potential (see Fig. 34.4).

the lines of the electric field, resulting in the flow of an electric current. This happens in body fluid where an electric field is set up by the heart. A dipole is a pair of opposite charges lying close together. The electric field set up by a dipole is more complex. Each dipole results in the flow of current between the opposite charges along multiple pathways as shown in Fig. 1.19B. Although the conventional current flows from the positive to the negative charge, to a recording electrode placed at a distance, the current appears to flow along a vector directed from the negative to the positive charge. Multiple dipoles located along a line result in a large resultant current. Each dipole generates a large field around it as shown in Figs. 1.19C and 1.19D. Only currents that travel straight along the axis of the dipole add up and become strong enough to be picked up by a distant recording electrode. A knowledge of dipoles and their fields is essential to the understanding of electrocardiography and electroencephalography.

Electric field of dipoles Electric field refers to the area of influence of

an electric charge (or charges). The electric field of a single charged particle is depicted in Fig. 1.19A. Each vector in the diagram represents the direction and force with which a positive charge of 1 C moves (or tends to move) under the effect of the electric field. If an electric field is applied to a medium containing mobile charged particles, the charged particles start moving along

A

C

B

D

Fig. 1.19 [A] The electric field of a positive charge (pink) and a negative charge (blue). Each line represents the direction of the repulsive or attractive force exerted on a charge of +1 C. [B] The lines of force around a dipole. [C] The lines of force when two dipoles are placed side by side. [D] When several dipoles are lined up, the current flowing along the long axis of the dipoles summate and is recordable by a distant electrode.

REVISION QUESTIONS 1. Gravity affects the blood pressure when the subject is standing but not when he is supine. Why? 2. When the vertices of the Einthoven triangle is connected together, the nodal point is at zero potential. Which branch of mathematics explains it?

Sircar_Chapter01_001-017.indd 16

3. What is the difference between gravitational force and g-force? What are Gx, Gy and Gz? What is zero Gz and when is it experienced? 4. In a sphygmomanometer, the 1 cm calibration is actually a little less than 1 cm. Why?

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Principles of Physics in Physiology 5. The total work done on the lung during the breathing cycle is said to be negative. Why? 6. The lower the functional residual capacity of the lungs, the more difficult it is to inflate it. This observation is in accordance with which law of physics? 7. Is blood a Newtonian fluid? Give reasons. 8. Even small changes in vessel diameter cause large variations in blood flow through it. This observation is in accordance with which law of physics? 9. What are the factors that (1) affect the flow rate of a fluid, and (2) tend to make the flow of a fluid turbulent? 10. Circulation of blood maintains a fairly uniform temperature throughout the body? Which mode of heat transfer is at work in this case? 11. During near-vision, short-sighted people (myopes) see things bigger and better. Give reasons. 12. If the eye is photographed in dim light using flashlight, the pupil appears red. Why? 13. If the distance between the intraocular lens and retina is 17 mm and the power of the intraocular lens after maximum accommodation is 50 diopter, what will be the near point of the eye?

Sircar_Chapter01_001-017.indd 17

17

14. Which physical characteristic of sound determines its (1) pitch, (2) intensity or loudness, and (3) quality or timbre? 15. The basilar membrane of the cochlea performs a Fourier transform on the sound waves. What is Fourier transform? 16. How does the diameter of a conductor affect its resistance? 17. What is zero potential? 18. What is the product of fluid resistance and the flow rate of the fluid? 19. True or false: System capillary beds are disposed in parallel while portal capillary beds are disposed in series. 20. What is circulatory steal? 21. True or false: if two capacitors contain the same amount of charge, the one with lower capacity will have lower potential. Give reasons. 22. In electrocardiography, the zero potential for reference is obtained by interconnecting the three limb electrodes through a high resistor. Why is a high resistor used?

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2

Principles of Physical Chemistry in Physiology

Gases Gas laws Universal gas law The volume of a gas is directly

proportional to the absolute temperature (T) of the gas (Charles’ law) and inversely proportional to the pressure (P) applied upon it (Boyle’s law). The volume is also directly proportional to the number of moles of gas (n). Stated mathematically, V (volume) = n ×

(and not 500 mL each). In accordance with Boyle law, the pressure of each gas will drop to 380 mm Hg. Finally, in accordance with Dalton law of partial pressure, the pressure of the mixture will be 380 + 380 = 760 mm Hg. In the above example, the pressure of 380 mm Hg will be called the partial pressure of each of the constituent gases. It is calculated by the formula: Volume of the Partial pressure Total pressure gas at STP (500 mL) ⫽ × Volume of the of gas (380 mm Hg) (760 mm Hg) mixture at STP (1 L)

T P

or PV 5 nRT

where R is the proportionality constant and is called the universal gas constant. The variability in gas volume with temperature and pressure makes it imperative to express all gas volumes at standard temperature and pressure (STP). The standard temperature is 0°C (273 Kelvin) and the standard pressure is 1 atmosphere (760 mm Hg.) In physiology, gas volumes are often expressed at body temperature (37°C) and 1 atmosphere pressure, or BTP for short.

Taking another example: the concentration of O2 in atmospheric air = 21%. Therefore, its partial pressure in atmospheric air will be 760 × 21% = 160 mm Hg. The partial pressure of a gas dissolved in a liquid is equal to the partial pressure of the gas in a gaseous mixture that is in equilibrium with the liquid.

Dalton law of partial pressure When two or more

Aqueous tension When water vapor saturates a gas

gases are mixed, the total pressure exerted by the mixture is equal to the sum of the pressures exerted by the constituent gases when occupying the same volume. Suppose 500 mL of O2 and 500 mL of N2 at 0°C and 760 mm Hg are mixed together to make a 1 mL gaseous mixture (Fig. 2.1). What will be the pressure exerted by the mixture? Since the final volume of the gaseous mixture is 1 L, both the gases will come to occupy 1 L each

or a gas mixture, it exerts an additional pressure of 47 mm Hg at 37°C. This pressure is called the saturated vapor pressure or the aqueous tension. When air is saturated with water vapor, the concentration of all the constituent gases decreases. However, the percentage composition of a gas mixture is always expressed assuming that there is no moisture in it. For example, when we say that O2 constitutes 21% of atmospheric air, we actually mean 21% of “dry” atmospheric air. If the air is saturated with

500 mL O2 at 0oC and 760 mm Hg

500 mL N2 at 0oC and 760 mm Hg

⫽ Total pressure ×

Concentration of a gas in a gaseous mixture

1 L O2 at 0oC and 380 mm Hg

+ 1 L N2 at 0oC and 380 mm Hg

Fig. 2.1 An example of Dalton law of partial pressures.

Sircar_Chapter02_018-023.indd 18

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Principles of Physical Chemistry in Physiology water vapor, the saturated vapor pressure has to be deducted from the atmospheric pressure before calculating the partial pressure of constituent gases individually. For example, the partial pressure of O2 (Po2) in humidified atmospheric air (at 37°C) is (760 – 47) × 21% = 150 mm Hg. In physiology, it is a common practice to record the volume of gases saturated with water vapor at body temperature and at atmospheric pressure. Volumes thus recorded are denoted as BTPS (“S” for saturated).

Side B

K+ = 150 mEq /L

K+ = 5 mEq /L

Na+ = 10 mEq /L

Na+ = 140 mEq /L

Cl– = 5 mEq /L

Cl– = 100 mEq /L

Fig. 2.2 Ionic distribution in two compartments for illustrating the principles of Nernst potential.

Solutions Diffusion of solutes Simple diffusion If there are two solutions of dif-

ferent solute concentrations separated by a membrane, the solutes diffuse from higher to lower concentration. This is because the molecules in solution, due to their constant random motion, spread out to fill all of the available volume. The greater the concentration of a substance in solution, the greater is its tendency to spread out. Hence, although solutes in both the solutions are diffusing farther apart, there is a net flux of solutes from higher to lower concentration. The diffusion of a solute from one region to another is directly proportional to the crosssectional area across which the diffusion takes place and the concentration gradient, which is the difference in concentration of the diffusing substance divided by the thickness of the partition (Fick law of diffusion). Thus, J = –DA

Δc Δx

where J is the net rate of diffusion, D is the diffusion coefficient, A is the area of the partition that separates the two solutions, and Δc/Δx is the concentration gradient, that is, the rate of change of concentration with distance. The minus sign is a sign convention that indicates the direction of diffusion. When solutes diffuse from higher to lower concentration, Δc/Δx is negative and therefore multiplying by –DA gives a positive value of J. Nernst potential When two ionic solutions A and

B of different concentrations (CA and CB) are separated by a permeable membrane, the ions tend to diffuse along their concentration gradient. Since ions are charged particles, their diffusion can be stopped by an appropriate electrical potential (E) applied across the membrane. The magnitude and polarity of the potential that must be applied to

Sircar_Chapter02_018-023.indd 19

Side A

19

side A of the membrane for stopping the diffusion of ions (EA) are given by the Nernst equation: EA =

61 [C ] log B z [CA ]

where z is the valence of the ion. This equation can be also written as: EA =

–61 [C ] log A z [CB ]

In the example illustrated in Fig. 2.2, the application of Nernst equation to the concentration of K+ on side A (150 mEq/L) and side B (5 mEq/L) gives a value of –90 mV. This potential is called the Nernst potential for K+ (EK): EK =

–61 150 log +1 5

It has two implications. (1) It means that –90 mV applied to side A will prevent any outward diffusion of the K+. (2) It also means that if the K+ concentrations are equal on both sides of the membrane, a potential difference of –90 mV applied to the membrane will produce the same rate of diffusion as an ionic concentration ratio of 30 (i.e., 150 ÷ 5). Similarly, the diffusion of Na+ will be prevented by a potential of +70 mV (ENa) applied to side A and the diffusion of Cl– (ECl) will be prevented by applying a potential of –80 mV to side A: ENa =

–61 10 log +1 140

ECI =

–61 5 log –1 100

Thus, every ion distributed asymmetrically across the membrane has its own Nernst potential (E) that will prevent its diffusion. In other

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20

General Physiology words, the Nernst potential of an ion gives the electrical equivalent of its diffusion energy. Gibbs-Donnan equilibrium If two compartments

are separated by a semipermeable membrane and one of the compartments contains diffusible ions, the ions will soon distribute themselves equally across the two compartments. If, however, one of the compartments contains impermeable ions (Fig. 2.3), the typical equilibrium (with equal numbers of ions on both sides of the membrane) as observed in simple diffusion will not occur. Instead, a different type of equilibrium called the Gibbs-Donnan equilibrium will occur in which two conditions must be satisfied: (1) both the compartments must be electroneutral and (2) the product of diffusible ions (anions and cations) must be equal in both compartments. The solution is shown in Table 2.1. At equilibrium, compartment A will have a larger concentration of solutes (18) than compartment B (12). As a result, water will move from B to A due to osmosis and, thereby, decrease the solute concentration in compartment A. However, since the impermeable anion continues to be present in compartment A, the GibbsDonnan equilibrium is reestablished. As a result, compartment A would continue to have a higher solute concentration, no matter how much osmosis occurs! A living cell contains impermeable protein anions. This imposes the Gibbs-Donnan equilibrium, so that

Compartment A

10 NaCl

5 Na[A]

Compartment A

Compartment B

How much will diffuse into this compartment?

Compartment B

9 Na+

6 Na+

4 Cl-

6 Cl-

5 [A-]

Fig. 2.3 Ionic distribution in two compartments for illustrating the principles of Gibbs-Donnan equilibrium. [A–] denotes an impermeable anion.

Sircar_Chapter02_018-023.indd 20

Table 2.1 Ionic distribution at Gibbs-Donnan equilibrium Inside

Outside

Total +ve charge

9 (Na )

Total –ve charge

9 (4 Cl– + 5A– )

Product of diffusible ions [Na+] × [Cl–]

36 (9 Na × 4 Cl )

36 (6 Na+ × 6 Cl–)

Total number of ions

18 (9 + 4 + 5)

12 (6 + 6)

+

6 (Na+)

+

6 (Cl–) –

there are more ions inside the cell than outside it. As a result, water continuously moves into the cell by osmosis, which will inevitably rupture the cell. To survive, a cell must continuously pump out excess ions. It does so with the help of the adenosine triphosphate (ATP)-driven Na+–K+ pump. When a cell dies, the pump stops and the cell swells up, the microscopic appearance of which is known to pathologists as the cloudy swelling.

Diffusion of solvent Osmosis is the movement of solvent across a semipermeable membrane that separates two solutions of different solute concentrations and restricts the movement of solutes across it. For osmosis to occur, it is not necessary for the membrane to be totally impermeable to the solute. A solute with limited permeability also produces osmosis, though to a lesser extent. The solute permeability is given by the reflection coefficient, which varies between 0 (freely permeable) and 1 (totally impermeable). The reflection coefficient is the probability of a solute molecule reflecting back from the membrane instead of passing through it. The reflection coefficient of a solute is not an absolute constant but varies with the type of membrane. It will be zero for all solutes if the membrane has very large pores in it. Osmosis is proportional to the reflection coefficient as well as to the concentration gradient. Osmosis does not occur when the reflection coefficient is zero, that is, when the membrane is freely permeable to the solute. Osmotic pressure The osmosis from a dilute to a concentrated solution can be prevented by increasing the hydrostatic pressure of the concentrated solution. The hydrostatic pressure necessary to prevent the osmosis is called the osmotic pressure of the solution (Fig. 2.4). Osmotic pressure, like freezing-point depression and boiling-point elevation, is a colligative property, that is, it depends on the number rather than the size or type of particles

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Principles of Physical Chemistry in Physiology

1

3

2 Osmotic pressure

Solution A (10)

Solution B (5)

21

Osmotic pressure

Solution A (30)

Solution B (30)

Solution A (60)

Solution B (65)

Fig. 2.4 A membrane separates two solutions, A and B, containing ions of three different sizes. Solution A contains 60 particles: 10 large, 20 medium-sized, and 30 small. Solution B contains 65 particles: 5 large, 25 medium-sized, and 35 small. The tonicity of the solutions depends on the membrane pore size. The figures below each solution indicate the number of osmotically active particles in it. (1) The pores allow only the medium-sized and small particles to pass through, making solution A hypertonic. (2) The pores allow only the small particles to pass through, making the two solutions isotonic. (3) The pores are impermeable to particles of all sizes, making solution B hypertonic.

in a solution. It is given by the Van’t Hoff relationship: π = RT × φ nC

where π is the osmotic pressure, R is the universal gas constant, T is the absolute temperature, φ is the osmotic coefficient, n is the number of ions yielded by the dissociation of a solute molecule, and C is the molar concentration (moles/L) of the solute. The Van’t Hoff equation shows that at a constant temperature, osmotic pressure is proportional to the number of particles in solution per unit volume of solution (given by n × C in the formula). The osmotic coefficient (φ) in the formula is not the same as the reflection coefficient. The osmotic coefficient does not depend on membrane characteristics: It is constant for a solute molecule and is assumed to be 1.0 in all approximate calculations. Osmoles, osmolarity, and osmolality One mole1 of osmotically active particles is called one osmole (Osm). Thus, a molar solution of glucose contains 1 osmole, a molar solution of NaCl contains 2 osmoles (1 mole of Na+ and 1 mole of Cl−), while a molar solution of CaCl2 contains 3 osmoles (1 mole of Ca2+ and 2 moles of Cl−). The osmolar concentration of a solution in Osm/L is called osmolarity. When expressed in Osm/kg of solution, it is called osmolality. Osmolarity is affected by temperature, which changes the volume of solution. Also, dissolution of solutes is associated with a slight rise in the

volume of the solution. This increase is different for different solutes. Hence, when 1 mole of glucose is dissolved in 1 L of water, the osmolarity will be slightly less than 1 Osm/L. However, osmolality is unaffected by temperature or the increased volume of the solution that accompanies dissolution. The measurement of osmolarity (nC) is based on the principle that the freezing point of a solution is depressed in proportion to the number of osmoles present in it. It is given by the formula: nC = ΔΤf ÷ 1.86

where ΔTf is the reduction in the freezing temperature. The freezing point of normal human plasma averages –0.54°C, which corresponds to an osmolal concentration in plasma of 290 mOsm/L. This is equivalent to an osmotic pressure against pure water of 7.3 atm. Two solutions having identical osmolarity are called isoosmolar. They exert the same osmotic pressure and are therefore also called isoosmotic. If one of the two has greater osmolarity, it is said to be hyperosmolar or hyperosmotic in comparison to the other, which is called hypoosmolar or hypoosmotic. Except immediately after a sudden change in composition, all fluid compartments of the body are in osmotic equilibrium. Tonicity When a membrane with unknown char-

acteristics separates two solutions with different osmolarity, it does not necessarily mean that there

A “mole” is just a number. Just as a dozen equals 12 and a score equals 20, a mole equals 6.023 × 1023. The weight of 1 mole of atoms or molecules of any element or compound is exactly equal to the atomic or molecular weight of the element or compound expressed in grams. For example, the molecular weight of NaCl is 58.5. Therefore, 6.023 × 1023 molecules (i.e., 1 mole) of NaCl weighs exactly 58.5 grams.

1

Sircar_Chapter02_018-023.indd 21

2/7/14 11:19 AM

General Physiology will be osmosis from the hypoosmolar to the hyperosmolar solution. This is made clear by the example illustrated in Fig. 2.4 which explains why the magnitude and direction of osmosis cannot be predicted without knowing the pore size of the membrane. In real-life situations, the complexity of biological membranes makes it impossible to accurately predict whether a solute particle will pass through it. Moreover, body fluids contain innumerable types of solutes, which is another reason why their tonicity cannot be predicted. Therefore, the only way of estimating the tonicity is to determine it experimentally. In clinical parlance, the word tonicity always refers to the tonicity of a solution with respect to an erythrocyte. In other words, it is the erythrocytic cell membrane across which the tonicity is tested. If the erythrocyte shrinks in a solution by losing water through osmosis, the solution is hypertonic. If the erythrocyte swells up in a solution by gaining water through osmosis, the solution is hypotonic. If the erythrocyte neither shrinks nor swells in the solution, the solution is called isotonic. The fluid used in clinics for intravenous transfusion is both isotonic and isoosmolar to the plasma. A 0.9% saline solution is most often used for the purpose. The 0.9% NaCl solution is roughly isoosmolar (308 mOsm/L) to the body fluids (290 mOsm/L) as can be calculated easily.2 A 5% glucose solution is also isotonic initially when infused intravenously, but as the glucose is metabolized, the solution gradually becomes hypotonic. An isoosmolar solution of urea will not be isotonic since urea rapidly diffuses into the erythrocytes. Oncotic pressure Colloid osmotic pressure is also called oncotic pressure. The following example explains the necessity of distinguishing osmotic and oncotic pressures. If a hypertonic electrolyte solution (solution-A) is added to an isotonic colloid solution (solution-B), the mixture (solution-C) will have a higher osmotic pressure but a lower oncotic pressure than solution-B.

pK+2 pK+1 pK pK–1 pK–2 pK–3

0

0.5 mmol of alkali added

Fig. 2.5 The titration curve of a buffer mixture with alkali. The buffering power is maximum at pK.

where k is the dissociation constant. [H+] = k ×

[HA] [A–]

–log [H ] = –log k − log

[HA] [A–]

pH = pK + log

[A–] [HA]

+

The above equation is known as the HendersonHasselbalch equation. The buffering power of the system is the number of moles of acid or base that must be added to 1 mole of the buffer to change its pH by 1 unit. The maximum buffering power of any buffer is 0.575. The buffering power of a buffer is maximal when the pH of the solution equals the pK. From the HendersonHasselbalch equation, it is seen that when pH = pK, [A−] = [HA]. Hence for maximum buffering power, a buffer solution should contain a weak acid and its conjugate base in equimolar proportion. The buffering power also depends on the concentration of the buffer.

Chemical equilibrium

Buffers The pH of a solution is maintained at near constant levels with the help of buffers (Fig. 2.5). Most body buffers comprise weak acids [HA] with their conjugate bases [A–]. By the law of mass action: [H+ ][A– ] k= [HA] 2

pK+3 pH of buffer mixture

22

All chemical reactions are potentially reversible but they tend to proceed unidirectionally if one of the reactants or products is removed from the field of reaction. Consider the reaction shown below: CO2 + H2O

Carbonic anhydrase

H2CO 3

H+ + HCO 3–

Molecular weight of NaCl = 58.5. ∴ 58.5 g of NaCl contain 1 mole of NaCl molecules. ∴ A solution containing 58.5 g NaCl will contain 2 osmoles (1 osmole of Na+ and 1 osmole of Cl−). ∴ A solution containing 9 g of NaCl contains (2 × 9) /58.5 moles = 0.308 osmoles (or 308 milliosmoles). ∴ The osmolarity of a 9 g/L (0.9 g%) solution = 308 mOsm/L.

Sircar_Chapter02_018-023.indd 22

2/7/14 11:19 AM

Principles of Physical Chemistry in Physiology The reaction proceeds unidirectionally if at least one of the products is quickly removed, for example, if the H+ is buffered. On the other hand, if the CO2 escapes from the reaction mixture, the reaction will proceed in the backward direction. Another important example is the ionization of calcium in acidic solution, which is explained by the following reaction: Ca2+ + 2e− = Ca

+

23

-

Acids are electron acceptors. When the acid mops up electrons, the above reaction proceeds backward, causing ionization of calcium.

Electrophoresis Electrophoresis is the migration of charged solutes or particles in a liquid medium under the influence of an electrical field (Fig. 2.6). Cations migrate toward the cathode and anions migrate toward the anode. An ampholyte (earlier called zwitterion) takes on a positive charge in an acidic solution and a negative charge in a basic solution. Depending on its pH, therefore, an ampholyte will migrate toward the anode or cathode. At a particular pH called the isoelectric pH, an ampholyte will be neutral and therefore will not move in an electric field. Proteins contain ionizable amino (NH2) and carboxyl (COOH) groups and, therefore, they behave as ampholytes in solutions. Nucleic acids too are ampholytes. The rate of electrophoretic migration depends on (1) the net electrical charge of the molecule, (2) the size and shape of the molecule, (3) electrical field

Fig. 2.6 (Above) Electrophoresis apparatus. (Below) Major components of plasma proteins separated out through electrophoresis.

strength, (4) properties of the supporting medium, and (5) temperature of operation. Electrophoretic mobility is defined as the rate of migration (cm/s) per unit field strength (V/cm). Since electrophoretic mobility depends, among other things, on the size and shape of the molecule, electrophoresis is used for the separation of different proteins in a solution.

REVISION QUESTIONS 1. In physiology, gas volumes are expressed in BTP. What is BTP? 2. If the air is saturated with water vapor, the saturated vapor pressure has to be deducted from the atmospheric pressure before calculating the partial pressure of constituent gases. Why? 3. If a permeable membrane separates two NaCl solutions having Na+ concentrations of 100 and 10 mEq/L, calculate the potential that will prevent the diffusion of Na+ across the membrane. Calculate also the potential that will be produced if the membrane is permeable only to Na+ ions.

Sircar_Chapter02_018-023.indd 23

4. When a cell dies, it swells Why? 5. Osmosis does not occur when the reflection coefficient is zero. What is reflection coefficient? 6. If two solutions are isosmotic, will they be isotonic too? Give reasons. 7. What is meant by an “isoelectric pH”?

2/7/14 11:19 AM

3

Principles of Control Systems in Physiology

To control means to change something in a desired manner. A control system can therefore be defined as “a system with a goal.” The factors that have to be controlled to achieve the goal are called variables. The goal of a control system may be to increase or decrease a variable. The goal may also be to maintain the variable within a narrow range, in which case it is a regulatory control. Thus, a regulatory control can be defined as a special type of control meant for maintaining the constancy of a variable. On the other hand, a servo control sets the variable at any predetermined level that is not necessarily within a narrow range. The above concepts can be understood easily by considering the example of a fan regulator. The regulator controls (increases or decreases) the speed of the fan (a variable), which in turn controls the amount of evaporation (another variable) of our sweat. The final result is the regulation of our body temperature (a third variable) that is maintained within physiological limits. The regulation is achieved through the servo control of the fan. Similarly, there is a control system in our body that controls the cardiac output (increases or decreases it) in order to regulate (maintain constant) tissue oxygenation. Other physiological examples are the regulation of blood pressure, regulation of blood glucose, regulation of body temperature, regulation or control of posture, control of heart rate, and control of breathing. Homeostasis A special type of regulation is homeostasis, which refers to the regulation of the internal environment or milieu intérieur of the body. The importance of homeostasis becomes apparent when we consider the environmental adversities faced by a unicellular organism like the ameba with the cozy environment of any human cell. The human cell enjoys a steady supply of oxygen at 100 mm Hg partial pressure and glucose at a concentration of 100 mg/dL. Its metabolites are promptly washed away from its immediate vicinity. It basks in the cozy comfort of 37°C and is secure in the protective cover of an elaborate defense system. All this is made possible by the cooperation of all the cells that constitute a multicellular organism in which each cell plays its part and, together, ensure the maintenance of a steady internal environment. For example, when the body temperature falls it is sensed by a group of cells in the brain that signals to the muscles to step up their activity so that the

Sircar_Chapter03_024-027.indd 24

Electric signal Air flow Messenger

Control Room

Hall

AC Plant

Fig. 3.1 A manually controlled temperature-regulatory system in a large hall can explain several principles of a control system.

temperature can be restored. Likewise, each parameter that is held at a constant level by the body is the result of a unique homeostatic mechanism.

Regulatory mechanisms Several broad principles of regulatory system can be appreciated by considering the example of an air-conditioned hall (Fig. 3.1). The temperature inside the air-conditioned hall is regulated so that it remains constant (say, at 25°C). Whenever the temperature of the hall rises, the message is signaled to the control room. In a few minutes, an extra blast of cold air cools the hall. Conversely, when the hall temperature falls below 25°C, the cooling power of the air conditioner is reduced. All the essential elements of a regulatory system are present in the above example. There is a sensor or receptor that senses the variable (temperature inside the hall). There is an input that signals the information to the control center and there is an output (electrical power supply to the air-conditioning plant) that acts on the motor or the effector (the pump delivering the cold blast) that restores the variable to its original level. Closed-loop (guided) control The control system

described above is an example of a closed-loop control. The loop begins with the sensing of any change in the variable and ends with the correction of the same variable. In other words, a closed-loop control system begins and ends with the controlled variable. Such a system can be a crude one, manned by an untrained janitor who would only know when to increase or decrease the cooling power but not by

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Principles of Control Systems in Physiology

Students sweat and complain AC plant slowly cools down the air 35°c Cold air flows into classroom

30°c

Students comfortable again

25°c Janitor turns on AC plant

20°c

15°c Students comfortable

Students chilled and complain

Fig. 3.2 Genesis of temperature oscillations in an airconditioned hall. The temperature regulatory system is shown in Fig. 3.1.

how much. Hence, it is likely that each time the temperature drifts from the set point, it gets overcorrected resulting in temperature oscillations (Fig. 3.2). Despite its simplicity and its obvious propensity for oscillations, this system guarantees through repeated corrections that the hall temperature will hover around the desired temperature. It is called guided control and requires virtually no knowledge of the factors that affect the variable. Open-loop (parametric, anticipatory) control Not all control systems have closed loops. Consider the same example of an air-conditioned hall. A brilliant engineer decides that he will not let the hall temperature drift at all so that there is no need whatsoever of correcting the temperature. So he derives a complex formula for calculating the amount of heat lost from the hall each minute and the amount of body heat produced by the students present in the hall. From this formula, he calculates the exact amount of cold air that is to be delivered to the hall each minute so that the hall temperature does not change. The engineer realizes that his formula needs to incorporate the number of students present in the hall (and therefore the amount of heat produced in the hall). He therefore installs at the door a sensor that counts the number of students entering the lecture hall. This type of control system is an open-loop control system. Here, the controlled variable (hall temperature) is not the same as the feedback (number of students) provided by the sensor. The control system tries to cool the hall “in anticipation” even before it starts warming up. The system

Sircar_Chapter03_024-027.indd 25

25

is extremely prompt but not accurate since it does not have any temperature sensors to judge if the hall temperature has been properly corrected. The open-loop control system is also called a parametric control system since it is heavily dependent on parameters and calculations based on them. Parametric control might appear to be only a theoretical proposition that is impracticable. That is not true. The vestibuloocular reflex (p 777) is an example of parametric control in which the vestibular apparatus (sensor) detects jerky head movements and reflexly corrects ocular gaze (controlled variable). Normally, a parametric control system does not depend on information related to the controlled variable. However, if the same information is provided to it, parametric control becomes more efficient and is called parametric feedforward control. However, it still will never match the accuracy of a guided control system. This can be explained by extending the example of the airconditioned hall as follows. Suppose at the end of a lecture, the students present in the hall complain to the engineer that the temperature of the hall was warmer than it should have been. The engineer realizes that he needs to revise his temperature-correcting formula. He therefore goes back to the hall and does a detailed survey of the hall to find out the reasons for the failure of his formula. He realizes that the projector used by the professor was generating a lot of heat and therefore incorporates this factor too in his new revised formula which turns out to be better and the students are satisfied. It is important to realize that the feedback regarding the controlled variable was not a continuous feedback and, therefore, is essentially different from guided control. In parametric feedforward control, the control system learns and becomes wiser with time and the control formula becomes more and more accurate. What happens if the engineer is unable to detect the cause of failure to maintain the hall temperature at the set point? After all his efforts to detect the cause have failed, he will probably increase the cooling power a little above that suggested by his formula. He does so without understanding why his formula has failed, which could be an undetected leak in the air-conditioning duct. Such a system is called parametric feedback control. Combined control Finally, there will always be

certain factors, known or unknown, that are so unpredictable and random that no adjustments in the formula are possible for them. Such disturbances are called noise, which is an unavoidable component of any control system. Parametric control systems have no way

2/6/14 12:03 PM

26

General Physiology of dealing with noise. Only guided control systems can deal with noise. Hence, parametric and guided control systems can be integrated into a remarkably efficient control system in which the parametric control ensures quick and nearperfect correction of the variable to its set point while the guided control slowly but surely corrects any residual error that is attributable to noise. A physiological example of this type of combined control is found in the synergistic action of the vestibuloocular reflex which provides parametric control, and the optokinetic reflex, which provides guided control. Static versus dynamic sensors In the air-condition-

ing example, it is important to know how much the temperature has drifted from the set point if feedback correction is to be instituted. Another crucial piece of information required for the correction is the rate at which the hall temperature is changing. If the hall temperature is increasing at an alarming rate, the air-conditioning plant has to be turned on fullblast. On the other hand, if the hall temperature is rising slowly, the blast needs only to be gently turned on, or the temperature will overshoot. To acquire this information, it is important to install in the hall two types of sensors: static sensors that will signal the extent of temperature drift and dynamic sensors that will signal the rate of temperature change. A static sensor is ideal for detecting very small, slow changes in the variable, whereas a dynamic sensor is suited for detecting rapid fluctuations in the variable. If receptors with dynamic sensitivity are absent, regulation will fail whenever there are rapid fluctuations in the variable. Conversely, in the absence of receptors with static sensitivity, a large change in the variable can go undetected if the change occurs extremely slowly (Fig. 3.3). It is therefore advantageous to adjust the static and dynamic sensitivity of the receptors depending on how the variable tends to change. If the variable is changing extremely rapidly, the dynamic sensitivity needs to be increased. If the variable is changing extremely slowly, the static sensitivity needs to be increased. Where the rate of change in the variable is assuredly slow, dynamic sensitivity of receptors is not required. This is true for the chemical composition of body fluids and therefore chemoreceptors do not show dynamic sensitivity. However, mechanoreceptors mostly have two subtypes with static and dynamic sensitivity (see muscle spindle, p 677). The total time taken by the afferent sensory information to reach the control center and the time taken by the efferent corrective measures to take effect constitute the feedback correction time. An excessive delay in the feedback correction

Sircar_Chapter03_024-027.indd 26

Signal Dynamic response Static response Time

Signal Dynamic response Static response Time

Fig. 3.3 Static versus dynamic sensitivity of receptors. (Above) A signal that rises slowly to a high amplitude remains undetected by receptors with dynamic sensitivity but stimulates receptors with static sensitivity. (Below) Low-amplitude fluctuations go undetected by receptors with static sensitivity but cannot escape detection by receptors with dynamic sensitivity. Note that the density of the vertical lines (action potentials) indicates the intensity of receptor stimulation.

makes the regulatory system susceptible to oscillations (see below). The gain of feedback control may be defined as the ratio of the intensity of the corrective response to the intensity of the sensory input to the control center. In simpler words, when the control center overreacts to the sensory information, the gain is high; when it underreacts, the gain is low. If the gain is low, the regulatory system will fail when there are rapid fluctuations in the variable. Conversely, a high gain will overcorrect a slowly changing variable, making the regulatory system prone to oscillations. Gain =

Intensity of corrective response Intensity of sensory information

Oscillations in a regulatory system A regulatory mechanism is sometimes prone to overcorrection, as is exemplified by the airconditioning-plant analogy. When the hall warms up, the lecture-hall attendant goes to the control center to cool it down. However, by the time he returns to the hall, he might find all the students shivering with cold, especially, if the control has a

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Principles of Control Systems in Physiology

Control center Receptor

Diaphragm (ventilator)

Tidal vol.

high gain. The attendant again sets off for the airconditioning plant to turn down its cooling power. The oscillations resulting from such a regulatory system are depicted in Fig. 3.2. The oscillations can be prevented if the change in the variable can be detected early and the corrective measure is instituted quickly. In other words, (1) the receptor sensitivity has to be high and (2) the feedback correction time has to be short. Another factor that will dampen oscillation is (3) the size of the hall. A large hall will have a fairly stable temperature: It will not warm up or cool down quickly. Physiological example of oscillations are the Cheyne-Stokes breathing (p 355) and the Mayer waves in blood pressure (p 286). The CheyneStokes breathing is discussed here to exemplify the factors that predispose a system to rhythmic oscillations, as shown in Fig. 3.4. Its causes are briefly mentioned here for illustrating the factors that make a regulatory system oscillate in a physiological situation. In the chemical control of breathing, the partial pressure of CO2 (PCO2) in alveolar air is regulated by controlling the rate and depth of breathing. When breathing slows down, PCO2 rises in blood. Simultaneously, the alveolar PCO2 rises due to its equilibration with blood. The flow of blood acts as a slow messenger, conveying the information on blood PCO2 to the receptors located in the brain in a little over 7 seconds. The message then passes to the control center in the brain itself. The control center initiates corrective changes in pulmonary ventilation in order to bring down the alveolar PCO2 and, thereby, the blood PCO2. The regulatory system is shown schematically in Fig. 3.4. This regulatory system starts oscillating in three types of situations, and indeed, these are the three factors that are known to predispose to CheyneStokes breathing. (1) Any prolongation of the time taken by the blood to flow from the lungs to the

27

Time

Fig. 3.4 Cheyne-Stokes breathing. (Above) The circulatory and neural pathways that underlie the oscillations in the respiratory regulatory system. These oscillations are analogous to the oscillations that would occur in an air-conditioning regulatory system shown in Fig. 3.1. (Below) The spirogram in Cheyne-Stokes breathing.

brain increases the feedback correction time. This allows the alveolar PCO2 to rise to high levels before the information reaches the brain receptors, and thereby sets off oscillations. (2) A reduction in the sensitivity of the receptors in the brain to blood PCO2 allows the alveolar PCO2 to rise to high levels before correction is instituted, and the system starts oscillating. (3) A reduction in the functional residual capacity of the lung (analogous to the hall size) results in rapid changes in PCO2. This predisposes to oscillations in ventilation.

REVISION QUESTIONS 1. What is the difference between “regulatory” and “servo” control?

5. What is noise? Which type of control system best deals with noise?

2. What is homeostasis?

6. Which is more sensitive: static or dynamic sensors? Give reasons.

3. What are the advantages and disadvantages of (1) closed loop control and (2) open loop control. Give a physiological example wherein the two work together. 4. What is the difference between parametric feedback control and parametric feedforward control?

Sircar_Chapter03_024-027.indd 27

7. What are situations in which a regulatory system starts oscillating? Give reasons. 8. A reduction in the functional residual capacity of the lungs predisposes to oscillations in the depth of ventilation. Why?

2/19/14 9:35 AM

4

The Cell

The cell is the structural and functional unit of living organisms. It consists of a protoplasm enclosed within a membrane, and contains many biomolecules such as proteins and nucleic acids.

DNA double-helix

Cell organelles An organelle is a membrane-limited subcellular entity that can be isolated by centrifugation at high speeds. It includes the nucleus, mitochondria, endoplasmic reticulum (ER), Golgi apparatus, peroxisome, lysosome, and the plasma membrane. The nucleolus, ribosomes, and cytoskeleton proteins are not organelles because they are not membranebound. Although not organelles, the nucleolus and ribosome are considered here with the nucleus for functional reasons. The various subcellular fractions can be separated by differential centrifugation. Low-speed centrifugation precipitates the nuclei. Intermediate-speed centrifugation separates out the mitochondria, lysosomes, and peroxisomes. High-speed centrifugation precipitates the free ribosomes and ER both smooth and rough. These precipitates are collectively called microsomes, a term of common clinical usage. For example, the commonly used term hepatic microsomal enzymes refers to the enzymes contained in the smooth endoplasmic reticulum (SER) in liver cells. These enzymes are important for several important physiological reactions and for detoxification of drugs and poisons.

Apparatus for protein synthesis The nucleus consists mainly of the chromosomes. Except in germ cells, the chromosomes occur in pairs, one originally from each parent. Each chromosome consists of a single long strand of DNA (see Fig. 7.1). It is wrapped at intervals around a core of histone proteins to form a nucleosome (Fig. 4.1). Thus, a chromosome is like a string of beads. The whole complex of DNA and proteins is called chromatin. When the cell is not dividing, only clumps of chromatin can be discerned in the nucleus. The chromosomes become distinct during cell division as the coiling around histones loosens, probably due to acetylation of the histones. The nucleus is enclosed in a double membrane bearing the nuclear pores through which mRNA can pass out and some of the proteins synthesized

Sircar_Chapter04_028-034.indd 28

Histones

Rough endoplasmic reticulum mRNA

Golgi apparatus

1

DNA 4 2

3

Free ribosomes

Outer membrane

Transport vesicle

Inner membrane

Intracristal space Matrix Crista

Fig. 4.1 Peptides synthesized on the rough endoplasmic reticulum mostly end up in the Golgi apparatus (1) while those synthesized by the free ribosomes either end up as cytoplasmic proteins (2) or find their way into the mitochondria (3) or the nucleus (4). The DNA is magnified above, showing it as a “string of beads.” DNA forms the strings while nucleosomes form the beads. The mitochondrion is magnified below, showing the outer and inner membranes, the matrix, and the intracristal spaces. in the cytosol can enter back into the nucleus. The nuclear pores are guarded with two rings that open and close to regulate the passage of large molecules. The transport through the nuclear pore requires proteins called importins and exportins. Nucleolus The nucleus of most cells, especially the

growing cells, contains one or more nucleoli. The nucleolus is the site of ribosome synthesis. It contains the genes for ribosome synthesis along with a considerable amount of RNA and proteins representing ribosomes in various stages of production. Cells that are active in protein synthesis have prominent nucleoli. Ribosomes are the sites of protein synthesis (Fig. 4.1). They are small granules of RNAs. Ribosomes may be present free in the cytosol or

2/11/14 5:12 PM

The Cell

Fig. 4.2 (Above) Mitochondria, rough endoplasmic reticulum, and peroxisomes (× 10,000). (Below) Golgi body (× 33,000).

on the surface of the rough ER. The free ribosomes synthesize cytoskeletal proteins and other cytoplasmic proteins such as hemoglobin. The proteins synthesized by them also find their way into the nucleus, mitochondria, and peroxisomes (Fig. 4.2). The bound ribosomes are located on the rough ER. They synthesize all membrane proteins and most of the secreted proteins. The proteins synthesized are extruded into the rough ER. Bound and free ribosomes are structurally identical and interchangeable, and the cell can adjust the relative number of each as its metabolism changes. Both types of ribosomes usually occur in clusters called polyribosomes attached to one mRNA molecule, an arrangement that increases the rate of polypeptide synthesis. The ribosomes of eukaryotes and prokaryotes are entirely dissimilar. Hence in bacterial infections, drugs like tetracycline and streptomycin are able to selectively inhibit the prokaryotic ribosomes of the bacteria but not of the human cells.

Secretory (exocytic) apparatus The rough endoplasmic reticulum (ER), whether

rough or smooth, is made of a series of membra-

Sircar_Chapter04_028-034.indd 29

29

nous tubules in the cytoplasm of the cell (Figs. 4.1 and 4.2). The rough ER has ribosomes attached to its cytoplasmic side. It is concerned with protein synthesis and the initial folding of polypeptide chains. After the polypeptide chain is formed, there is posttranslational modification before the protein is finally formed: It involves chemical modifications of the amino acid residues, cleavage of the polypeptide chain, and folding and packaging of the protein into its ultimate, often complex configuration. Most proteins synthesized in the ribosomes have at their amino terminal a special sequence of 15 to 30 amino acids called the signal peptide. As the protein enters the rough ER, the signal peptide remains at the leading end and, hence, it is also called the leader sequence. The signal peptide, and with it, the rest of the peptide, is guided into the ER by the signal recognition particle (SRP) present in the cytosol. The process is analogous to a needle guiding the thread. The SRP binds to receptors present on the surface of the ER and thereby anchors the signal peptide to the ER. Thereafter, the signal peptide dissociates from the SRP and binds to translocon, the protein that forms the pores of the endoplasmic reticulum. The signal peptide is then cleaved from the rest of the peptide by a signal peptidase. In the case of hormones, removal of the signal peptide results in the conversion of preprohormone to prohormone. Before secretion, additional amino acid residues are removed in the Golgi apparatus, resulting in the formation of the hormone. The final step in posttranslational modification is protein folding. The way the protein gets folded is determined by the sequence of the amino acids in the polypeptide chain. Special protein molecules called molecular chaperones are sometimes required for ensuring a proper protein folding. A fully formed polypeptide chain may fold up and therefore fail to enter the ER. Such failure does not occur because the polypeptide chain enters the ER well before it is completely synthesized. Thus, while the signal protein is entering the ER, the other end of the polypeptide is still lengthening due to continuing translation. The process is called cotranslational insertion. The polypeptide chain anchors the ribosome on which it is synthesized to the ER. When a large number of ribosomes are anchored to the ER, it is called a rough ER. The Golgi apparatus is a stack of six or more mem-

brane-enclosed sacs (cisterns). The cell contains one or more Golgi apparatuses, usually near the nucleus. Each Golgi apparatus is a polarized structure with a cis (convex) side and a trans (concave) side. Membranous vesicles containing newly synthesized proteins bud off from the rough ER and

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30

General Physiology fuse with the cis side of the Golgi apparatus. The proteins are then passed from cistern to cistern, finally reaching the trans side. Protein-containing vesicles bud off from the trans side into the cytoplasm and are finally exocytosed (Figs. 4.1 and 4.2). The passage of the vesicle from the Golgi body to the exterior can be along nonconstitutive or constitutive pathways. In the constitutive or unregulated pathway, the contents of the secretory vesicles are exocytosed immediately. The exocytosis results not only in secretion but also in the incorporation of bits of new membrane into the existing cell membrane. Vesicles are also pinched off from the cell membrane by endocytosis. These vesicles, called endosomes, eventually become lysosomes (see below). In the nonconstitutive or regulated pathway, the secretory vesicles are released in a regulated fashion only on appropriate external stimulation, as in glandular cells and neuronal endings.

Apparatus for metabolic reactions Mitochondria are sausage-shaped structures made of an outer membrane and an inner membrane that is folded to form shelves or cristae. The space between the two membranes is called the intracristal space (or intermembrane space) and the space inside the inner membrane is called the matrix space (Figs. 4.1 and 4.2). The outer membrane of each mitochondrion is studded with the enzymes concerned with biologic oxidations, providing raw materials for the reactions occurring in the matrix space. The matrix space contains enzymes of the citric acid cycle and enzymes required for β-oxidation of fatty acids. The inner membrane contains succinate dehydrogenase and adenosine triphosphate (ATP) synthetase. The intracristal space contains adenyl kinase and creatine kinase. The enzymes in the matrix, inner membrane, and intermembrane space are marker enzymes for mitochondria, that is, they are found nowhere else. Mitochondria have their own mitochondrial genome, which suggests that mitochondria were once autonomous organisms that came to develop a symbiotic relation with eukaryotic cells. Compared to the nuclear genome, the mitochondrial genome contains much less DNA. The mitochondrial DNA codes certain key enzymes of oxidative phosphorylation. All the mitochondria in the zygote come from the ovum and therefore the inheritance of mitochondrial DNA is entirely maternal. Mitochondrial DNA mutates far more frequently than nuclear DNA. Mutations in mitochondrial DNA cause a large number of relatively rare diseases.

Sircar_Chapter04_028-034.indd 30

Peroxisomes are cellular storehouses of metabolic enzymes. The peroxisome matrix contains nearly 50 enzymes that catalyze a variety of metabolic reactions. Peroxisomes in the liver detoxify alcohol and other harmful compounds. The marker enzymes for peroxisomes are catalase and urate oxidase. Peroxisome membrane also has an elaborate mechanism for importing several enzymes into its matrix. An autosomal mutation that produces a defect in peroxisome membrane transport is the cause of Zellweger syndrome, which is fatal in infancy. Conversely, clofibrate, the drug used for lowering blood lipids, causes an increase in the number of peroxisomes. It is only one of the several peroxisome proliferators that are known to increase the number of peroxisomes. The smooth endoplasmic reticulum (SER) is the

site of steroid synthesis. Steroid-secreting cells are rich in SER. The enzymes responsible for the synthesis of membrane phospholipids reside in the cytoplasmic sur face of the cisterns of the SER. As phospholipids are synthesized at that site, they self-assemble into bimolecular layers, thereby expanding the membrane and promoting the detachment of lipid vesicles from it. These vesicles then travel to other sites, donating their lipids to other membranes (Fig. 4.3). SER is also the site of detoxification of drugs and poisons in other cells, especially liver cells. Hepatic detoxification has important implications in pharmacology and medicine. Liver cell SER is also the

5

6

4

1

3

2

Fig. 4.3 Phospholipid transfer from vesicle to membrane. The smooth endoplasmic reticulum contains enzymes for phospholipid synthesis on its cytoplasmic surface (1). The phospholipids synthesized are inserted into the membrane of the endoplasmic reticulum (2) and subsequently bud off (3) to form lipid vesicles (4) that can get inserted into other membranes, for example into the cell membrane (5 and 6).

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The Cell site where glucose-6-phosphate is stripped of its phosphate radical before releasing glucose into the blood. Glucose-6-phosphatase is the marker enzyme for SER. In striated (skeletal and cardiac) muscle, the SER is called the sarcoplasmic reticulum. It stores Ca2+ in high concentration and plays an important role in muscle contraction.

A

α-tubulin

Digestive apparatus Lysosomes are membranous bags containing hydrolytic enzymes. Lysosomes bud off from the trans face of the Golgi apparatus. Lysosomal enzymes are synthesized in the rough ER and then processed by the Golgi apparatus. The cell employs lysosomal enzymes for digesting large molecules of proteins, polysaccharides, fats, and nucleic acids. The marker enzyme for lysosome is acid phosphatase. The lysosomal membrane has a hydrogen-ion pump that pumps in H+ from the cytosol and lowers the lysosomal pH to 5.0, which is the optimum pH for the lysosomal enzymes. The granules of the granulocytic leukocytes are lysosomes. Phagocytic vacuoles fuse with the lysosome, whose enzymes digest the phagocytosed matter. The products of enzymatic digestion are absorbed into the cytosol while the rest is exocytosed. The lysosomes also engulf worn-out components of the cell in which they are located, forming autophagic vacuoles, and return the digested products for reuse by the cell. When a cell dies, lysosomal enzymes cause autolysis of the remnants. Apoptosis (p 47) by lysosomal enzymes is often important in the process of development. For example, in the embryonic stage, the hands are webbed till lysosomes digest the tissues between the fingers. Small amounts of enzymes that leak out of lysosomes into the cytosol normally get inactivated due to the absence of acidic pH. However, large leakages cause destruction of the cell. In gout, phagocytes ingest uric acid crystals and such ingestion triggers the extracellular release of lysosomal enzymes that contribute to the inflammatory response in the joints. When a lysosomal enzyme is congenitally absent, it results in a rare but well-known group of disorders called the lysosomal storage disorders. In this, the lysosomes become engorged with indigestible substrates. For example, in Tay–Sachs disease, a lipid-digesting enzyme is missing. It leads to brain dysfunction due to engorgement of brain cells with lipids.

Cytoskeletal apparatus The cytoskeleton comprises three types of filaments: Microtubules, microfilaments, and intermediate filaments. All the three are made of protein

Sircar_Chapter04_028-034.indd 31

31

β-tubulin B Vesicle

Kinesin (Molecular motor)

C Depolymerization

Polymerization

Direction of movement

D

Myosin (Molecular motor) mentous actin Fila

G-actin

Fig. 4.4 Microtubules and microfilaments. [A] A microtubule is made of α-tubulin and β-tubulin. Thirteen of these subunits form rings that stack up to form a hollow tubule. [B] A kinesin molecule carrying a vesicle is moving on a microtubule. [C] The microtubules themselves can move about in the cytoplasm by depolymerizing at one end and polymerizing at the other. [D] Two strands of F-actin are intertwined and are moved by the myosin molecule.

subunits. They not only maintain the structure of the cell but also permit it to change shape and move. Microtubules and microfilaments are long polymers that “move about” by depolymerization at one end (the minus end) and polymerization at the other (the plus end). Both serve as “railroads” on which certain proteins called molecular motors can “walk” (Fig. 4.4B). Both lend some amount of

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32

General Physiology structural solidity to the cell. However, there are differences too. Microtubules are tubular structures, about 15 to 20 nm in diameter. A microtubule is made of α-tubulin and β-tubulin subunits that form stacks of rings containing 13 subunits (Fig. 4.4A). Microtubules enable intracellular transport of secretory granules, vesicles, and mitochondria: one end of its molecular motor binds to the transport vesicle while the other end “walks” on the microtubule. The molecular motors for microtubule are kinesin and dynein. Microtubules also form the mitotic spindles, which move the chromosomes in mitosis. The anticancer drug paclitaxel binds to microtubules and makes them so stable that organelles cannot move and mitotic spindles cannot form, leading to cell death. Microtubule assembly is prevented by anticancer drugs like colchicine and vinblastine. Microfilaments are filamentous structures, about 3 to 5 nm in diameter. They are made of two F-actin (filamentous actin) strands that are coiled helically (Fig. 4.4D). Each F-actin strand is a polymer of G-actin (globular actin) subunits. The molecular motor of microfilaments is myosin. Microfilaments enable cell motility. The most well-known function of microfilaments is their role in muscle contraction: The actin filaments in muscle are microfilaments. Microfilaments are anchored to the plasma membrane by anchoring proteins. Together with anchoring proteins, microfilaments form a dense matrix beneath the cell membrane, which is particularly abundant at the zonulae adherentes (intercellular junctions). Microfilaments are abundant in lamellipodia, the processes that cells put out when they crawl along surfaces. Bundles of microfilaments are also present in the core of microvilli, where they lend structural support. Microfilaments are necessary for cytokinesis: When a cell divides, it is pinched into two by a constricting band of microfilaments. Intermediate filaments have a diameter (8–10 nm) that is between that of microtubule and microfilament. They are more abundant than either microtubule or microfilament. They are made of cytokeratin. Unlike microtubule or microfilaments, these proteins are very stable and remain mostly polymerized. They serve as the “bones” of the cell, giving structural strength to it. For example, the nucleus sits in a cage made of intermediate filaments. In axons, the intermediate filaments are called neurofilaments: they maintain the axonal diameter. Intermediate filaments are also present in desmosomes (intercellular junctions). The centrosome is located near the nucleus. It is

made of a pair of centrioles which are short cylinders

Sircar_Chapter04_028-034.indd 32

arranged at right angles to each other (Fig. 4.5). Microtubules in groups of three run longitudinally in the walls of each centriole. There are nine of these triplets spaced at regular intervals around the circumference. The centrioles are surrounded by a small amount of γ-tubulin. Microtubules grow out of this γ-tubulin in the pericentriolar material and, hence, the centrosome is also called the microtubuleorganizing center. When a cell divides, the centrosomes duplicate themselves and the pairs move apart to form the poles of the mitotic spindles, which are made of microtubules. Cilia and flagella are motile processes of cell. Cilia

usually occur in large numbers on cell surface while flagella are usually limited to one or a few per cell. Both have the same diameter but flagella are about 10 times longer. They also differ in their pattern of beating. Dynein is the molecular motor responsible for the beating of flagella and cilia. The propulsion of a sperm is an example of flagellar action. The mucokinesis in the respiratory tract is brought about by ciliary action. Both flagella and cilia resemble the centriole in having an array of nine tubules in their wall, but they have an additional pair of microtubules in the center (Fig. 4.5). Also, there are two rather than three microtubules in each of the nine circumferential structures. The microtubule assembly of a cilium or flagellum is anchored in the cell by a basal body, which is structurally identical to the centriole. It is from the basal body that the cilium or the flagellum starts to grow. A congenital form of ciliary inactivity is Kartagener syndrome, in which the axonemal dynein, the molecular motor that produces ciliary beating,

Triplet

Pair

Fig. 4.5 (Above) A pair of centrioles lying at right angles to each other. Each centriole is made of nine circumferential triplets of microtubules. (Below) A cilium or a flagellum is made of nine circumferential pairs and one central pair of microtubules.

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The Cell is absent. Patients with this condition suffer from bronchiectasis, an irreversible, chronic dilatation of the bronchioles. They often have situs inversus, presumably because the cilia necessary for rotating the viscera are nonfunctional during embryonic development. There is infertility in males because they lack motile sperm. However, female patients are able to conceive normally, proving that ciliary motility is not essential for transport of the ovum to the site of fertilization.

Intercellular junctions Intercellular junctions (Fig. 4.6) fasten cells to each other and to the basement membrane. They are of four types: zona occludens, zona adherens, desmosomes, and gap junction. Gap junctions not only fasten cells together but more importantly, they

Zona occludens (tight junctions)

Desmosomes Basal membrane

Zona occludens (tight junctions)

Desmosomes

Microfilaments Intermediate filaments

Hemidesmosomes

Basal membrane

Fig. 4.6 Intercellular junctions. (Above) The zona occludens and zona adherens form a continuous ring around the cell. The desmosomes form an interrupted ring around the cell. (Below) Longitudinal section of two cells showing intercellular junctions. The zona occludens forms the tightest junctions and usually does not permit movement of electrolytes across them.

Sircar_Chapter04_028-034.indd 33

permit passage of water, electrolytes, and ionic currents through them. The zona occludens or tight junction is a band-like ridge just below the apex of a cell. It lends a polarity to the cells: Membrane proteins in the apical region of the cell cannot float across the band of zona occludens. The membranes of the adjacent ridges are apposed tightly, leaving little space in between. Some are so tight that they do not allow water and ions to pass through them and are therefore called “tight” tight junctions. Others that are more permeable are called “leaky” tight junctions: These have important functions in the renal tubules. The zona adherens is another band immediately below the zona occludens. It does not form a ridge and therefore the membranes of adjacent cells are apposed less tightly here, leaving a gap of about 20 nm. It is formed by microfilaments running under the surface of the cell membrane. The microfilaments firmly stitch together the adjacent cells. Like zona occludens, they lend polarity to the cell by preventing the drift of integral membrane proteins. However, they are quite permeable to water and ions. The desmosome or macula adherens is not a band

Z o n a ad h ere n s

Zona adherens

33

but a row of junctional patches below zona adherens (macula = spot). Like zona adherens, these spot junctions leave 20 nm gaps between adjacent membranes. Intermediate filaments of the two adjacent cells converge on their respective side of the junction. The desmosome therefore not only attaches adjacent cells but also anchors together the cytoskeleton of the adjacent cells, lending structural stability to the entire epithelium. A hemidesmosome (one-half of a desmosome) attaches a cell to the basement membrane. The gap junction consists of a pair of hemichannels or connexons inserted into the membrane of adjacent cells (Fig. 4.7). Each connexon is made of six identical protein subunits called connexins which enclose a central channel. When the corresponding connexons of adjacent cells link up end to end, they form a continuous channel that permits cell-to-cell passage of substances and even ionic currents, enabling ephaptic conduction (see p 91) which is their preeminent physiological role. They also contribute to the binding of cells together. Mutant connexons produce the Charcot–Marie–Tooth disease, a form of peripheral neuropathy. The pore size of a gap junction decreases when intracellular Ca2+ is high or pH is low, both of which are commonly associated with cell damage. Closure of gap junctions in response to these stimuli isolates damaged cells so that the Ca2+ and H+ do not spread from the damaged to the normal cells.

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General Physiology

Cell adhesion molecules

NH2

Connexon

COOH

Connexin

Fig. 4.7 Gap junctions connecting adjacent cells are designed to permit free communication through them. A gap junction is made of two connexons, each of which is made of six connexins. Each connexin is made of a long peptide chain that traverses the membrane four times.

Cell adhesion molecules (CAMs) are surface glycoproteins present on the cell membrane. They are important for binding to other cells as well as to the extracellular matrix where they bind to laminins (see Fig. 8.8B). Apart from holding the tissues together, CAMs have important roles in inflammation and wound healing, embryonic development, axonal growth, and tumor metastasis. There are four important groups of CAMs: Selectins are required for capturing the freeflowing neutrophils and making them roll along the endothelial wall (see Fig. 29.2). Integrins and the IgG superfamily immunoglobulins are present on the endothelium. They bring about a firm adhesion of the neutrophil with the endothelium. Neutrophilic migration through the endothelial wall (diapedesis) requires dissociation of intercellular cadherin contacts.

REVISION QUESTIONS 1. Which is the site of ribosome synthesis in the cell? 2. What are the proteins synthesized by the free ribosomes and the bound ribosomes? 3. The ribosomes of eukaryotes and prokaryotes are entirely dissimilar. What is its clinical implication? 4. What are molecular chaperones? 5. What is the difference between constitutive and nonconstitutive pathways for passage of vesicles from the Golgi body to the exterior? 6. What are the characteristics of the mitochondrial genome? 7. Which organelle is the site of steroid synthesis?

Sircar_Chapter04_028-034.indd 34

8. Apoptosis by lysosomal enzymes is often important in the process of development. Give an example. 9. What is the role of phagocytes in the inflammation of joints in gout? 10. Which group of disorders is caused by the congenital absence of lysosomal enzymes? 11. Of microtubule, microfilament and intermediate filament, which is associated with (1) intracellular transport of secretory vesicles, (2) formation of mitotic spindles, (3) actin filaments, (4) zonulae adherentes, (5) microvilli, and (6) desmosomes? 12. What are “tight” tight junctions? 13. Which cell adhesion molecule is required for capturing flowing neutrophils and making them roll along the endothelial wall?

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5

Cell Membrane

Membrane composition Membranes are complex structures composed of lipids, proteins, and carbohydrates. The cell membrane contains proteins and lipids in a 50:50 ratio. This ratio refers to the ratio of their masses and not numbers. An average membrane protein is several times larger than the average lipid molecule but lipid molecules are about 50 times more numerous than protein molecules. The ratio is not absolute and varies from membrane to membrane. The exact ratio between the two varies with the function of the cell. For example, the myelin sheath of nerves has about 75% lipids and 25% proteins, whereas membranes involved in energy transduction, such as the inner mitochondrial membrane, have 75% proteins and 25% lipids. The major membrane lipids are phospholipids, glycosphingolipids, and cholesterol. Membrane phospholipids (Fig. 5.1) are broadly of two types: The phosphoglycerides, which are relatively more abundant, and the sphingomyelins, which are prominent in myelin sheath. Glycosphingolipids present in the membrane include cerebrosides and gangliosides. Both are derivatives of sphingosine. Cholesterol exists mainly in the plasma membranes of cells. It is also found in small quantities in mitochondria, Golgi complexes, and nuclear membranes. The membrane proteins comprise enzymes, transport proteins, structural proteins, antigens (e.g., for histocompatibility), and receptors for various molecules. The external side of membrane proteins mostly has oligosaccharide chains (carbohydrates) attached to them. The plasma membrane contains over a hundred different proteins.

Membrane structure Lipid bilayer Membrane lipids are amphipathic, that is, they contain both hydrophobic and hydrophilic regions. The hydrophilic (polar) region is their globular head while the hydrophobic (nonpolar) regions are their fatty acid tails. The membrane lipids are organized into a closed bilayer (Fig. 5.2A) in which the hydrophobic regions of the phospholipids are protected from the aqueous environment while the hydrophilic regions are immersed in water. Proteins are found inserted into this lipid bilayer and

Sircar_Chapter05_035-043.indd 35

O

Phosphoglyceride

R1

C

O

CH2

R2

C

O

CH

O

O-

CH2

O

Glycerol Fatty acid (16 –18C, saturated or unsaturated)

P

O

R3

O Phosphorylated alcohol OH

O H CH3 (CH2)12 CH CH CH CH N C R Fatty CH2 acid Sphingosine

O

Phosphoric acid O

Sphingomyelin

P

O-

+ O CH2 CH2 N(CH3)3 Choline

OH

O H CH3 (CH2)12 CH CH CH CH N C R Fatty CH2 acid Sphingosine

Cerebroside

Glucose or Galactose

O H

OH O Sphingosine H CH3 (CH2)12 CH CH CH CH N C R CH2 Ganglioside

Sialic acid

Fatty acid

O H

Fig. 5.1 Chemical structure of membrane phospholipids and glycosphingolipids.

are classified into integral proteins and peripheral proteins. Integral proteins are anchored to membranes through a direct interaction with the lipid bilayer. Some of them run the entire thickness of the membrane, often several times through. Others are

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General Physiology

+H N 3

A

NH3+

+H N 3

COO-

NH3+

COO-

COO-

-OOC

NH3+

-OOC

B Peripheral protein (ankyrin)

Integral protein (band-3)

Peripheral proteins do not interact directly with the phospholipids in the bilayer. They are weakly bound to the hydrophilic regions of integral proteins. They are located on both surfaces of the membrane. Many hormone receptor molecules are integral proteins and therefore the polypeptide hormones that bind to these receptor molecules are considered as peripheral proteins. Peripheral proteins serve as cell adhesion molecules (CAMs) that anchor cells to neighboring cells and to the basal lamina. They also contribute to the cytoskeleton when present on the cytoplasmic side of the membrane. For example, ankyrin, a peripheral protein located on the inside of the membrane, anchors spectrin (a cytoskeletal protein in the erythrocyte) to band-3 (an integral protein of erythrocyte membrane). Ankyrin plays an important role in the maintenance of the biconcave shape of the erythrocyte (Fig. 5.2B).

Fluid mosaic model and membrane fluidity

Cytoskeletal protein (spectrin)

Fig. 5.2 Integral proteins. [A] Integral proteins with their polar residues projecting out. Also shown are a molecule of G-protein spanning the membrane 7 times, and a glucose transporter molecule, spanning the membrane 12 times. [B] A peripheral protein anchoring the integral protein to the cytoskeletal protein of an erythrocyte.

located more on the outside or inside of the membrane (Fig. 5.2A). Integral proteins are amphipathic, consisting of two hydrophilic ends separated by an intervening hydrophobic region that traverses the hydrophobic core of the bilayer. The hydrophilic ends of the integral protein are found outside the membrane: Either on its external or internal surface. Integral proteins serve as: (1) Channels, which permit the passage of selected ions through the membrane; (2) carriers (or transporters), which ferry substances across the membrane by binding to them; (3) pumps, which are carriers that split adenosine triphosphate (ATP) and use the energy derived for membrane transport of substrates; (4) receptors, which bind to specific molecules and generate a chemical signal, initiating intracellular reactions; and (5) enzymes catalyzing reactions at the membrane surfaces, both outer and inner.

Sircar_Chapter05_035-043.indd 36

The fluid mosaic model of membrane structure has been likened to icebergs (membrane proteins) floating in a sea of predominantly phospholipid molecules (Fig. 5.3A). Phospholipids too float about in the plane of the membrane. This diffusion, termed translational diffusion, can be as rapid as several micrometers per second. Several membrane transport processes and enzyme activities depend on the fluidity of the cellular membrane. As membrane fluidity increases, there is a rise in membrane permeability to water and small hydrophilic solutes. The factors affecting membrane fluidity are discussed below. Role of fatty acids A lipid bilayer that is made of only one type of phospholipid changes from a liquid state to a rigid crystalline state (gel state) at a certain freezing point. This change in state is known as phase transition and the temperature at which it occurs is called the phase transition temperature (Tm). The Tm is higher (fluidity is low) when the constituent fatty acid chains are long and mostly saturated (without double bonds). Saturated fatty acids have straight tails, whereas unsaturated fatty acids have kinked tails. Membrane fluidity increases when the tails have more kinks, which makes the membrane less tightly packed (Fig. 5.3B). Also, membranes with long-chain fatty acids are stiffer due to the greater interactions among the chains. Role of cholesterol The presence of cholesterol in the membrane makes it possible for the cell membrane to maintain its fluidity across a wide range of temperatures. The number of cholesterol molecules in the membrane can be as high as the number of phospholipids. When the cholesterol:phospholipid

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Cell Membrane

37

remainder of the molecule, among the fatty acid tails of phospholipids (Fig. 5.3B). At temperatures above the Tm, cholesterol partially immobilizes those portions of the fatty acid chains that lie adjacent to it and thus makes the membrane stiffer. At temperatures below the Tm, it minimizes the mutual interaction of the hydrocarbon tails of fatty acids and thereby increases membrane fluidity.

A Carbohydrate chains

Peripheral protein

Integral protein

Cholesterol

B

Role of membrane proteins Membrane areas having a high density of integral proteins have low membrane fluidity due to protein–protein interaction. Some of the protein–protein interactions taking place within the plane of the membrane may be due to interconnecting peripheral proteins, such as cross-linking antibodies (Fig. 5.3C). These peripheral proteins may then restrict the mobility of integral proteins within the membrane.

Membrane asymmetry Membranes are asymmetric structures. This asymmetry is of two types: Regional asymmetry and inside-out asymmetry.

Saturated (straight) fatty acid chains

C

Unsaturated (kinked) fatty acid chain

Antibody molecules cross-linking peripheral proteins

Fig. 5.3 Membrane structure. [A] The cell membrane showing integral and peripheral proteins. [B] Intercalation of kinked unsaturated fatty acid chains and cholesterol molecules spaces out the phospholipid molecules and affects membrane fluidity. [C] Antibody molecules cross-linking peripheral proteins. This reduces the mobility of integral proteins and reduces membrane fluidity.

ratio is high, the transition temperature is abolished altogether, that is, the membrane always remains fluid. Role of temperature Cholesterol intercalates among

the phospholipids of the membrane with its hydroxyl group at the aqueous interface and the

Sircar_Chapter05_035-043.indd 37

Regional asymmetry refers to the specialization of the cell membrane at different sites on the cell. For example, in renal tubules and intestinal mucosal cells, only the membrane facing the lumen is thrown into folds, forming microvilli. Similarly, only the membranes that are contiguous with adjacent cells show specializations for intercellular junctions. Inside–outside (transverse) asymmetry refers to the structural differences through the thickness of the cell membrane. For example, the phospholipids are not symmetrically disposed across the membrane thickness. The choline-containing phospholipids (lecithin and sphingomyelin) are located mainly in the outer molecular layer, while the aminophospholipids (phosphatidylserine and cephalin) are preferentially located in the inner layer. Cholesterol is generally present in larger amounts on the outside than on the inside. Glycolipids lie exclusively on the outside of the membrane. Proteins too are differentially located in the outer, inner, or middle parts of the membrane. The carbohydrates are attached only to the membrane proteins on the outer surface. In addition, specific enzymes are located exclusively on the outside or inside of membranes, as in the mitochondrial and plasma membranes.

Membrane disorders Membrane function is affected, among others, by the following factors: (1) Mutation of membrane

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General Physiology proteins affects the function of membrane receptors, transporters, ion channels, enzymes, and other structural components. For example, in hereditary spherocytosis, there is mutation in the genes encoding spectrin, resulting in the tendency of the cell to become spherical rather than biconcave. (2) Autoantibodies to the acetylcholine receptors on skeletal muscle membrane cause myasthenia gravis. (3) Ischemia quickly affects the integrity of various ion channels in membranes. (4) Excess of cholesterol in the membrane affects membrane function. Thus, the integrity of the red cell membrane, and therefore red cell fragility, are critically dependent on the protein:cholesterol ratio.

Membrane transport Simple diffusion Since simple diffusion involves no expenditure of energy, it can occur only from a region of high solute concentration to low solute concentration. Simple diffusion is bidirectional, that is, it occurs in both directions across the membrane. However, the diffusion along the concentration gradient is much higher than the diffusion against the gradient. Hence, the net diffusion is always along the concentration gradient. The rate of simple diffusion is directly proportional to the concentration gradient across the membrane and the permeability of the membrane to the solute. The membrane permeability to a substance depends on its size, lipid solubility, and electrical charge. Gases such as O2, CO2, and N2, and hydrophobic molecules like steroid hormones and weak organic acids and bases, readily diffuse through the cell membrane. Small uncharged polar molecules like water and urea can diffuse across the lipid bilayer, but not in physiologically sufficient amounts. Much larger amounts of water pass through membrane channels called aquaporins which are present on all cells. Aquaporins do not allow ions to pass through them. The aquaporin molecules are stored in endosomes inside the cells. When suitably stimulated (p 414), they are rapidly translocated to the cell membrane. Similarly, urea employs specific transporters for crossing the membrane in larger amounts. Large uncharged hydrophilic molecules such as glucose cannot diffuse through the lipid bilayer. Biological membranes employ carrier-mediated transport for glucose. Charged particles, be they large (aminoacids) or small (Na+, K+, Cl–, and Ca2+), cannot diffuse across the lipid bilayer. Aminoacids employ membrane transporters to cross the membrane. Ions cross the membranes, often in large amounts, through

Sircar_Chapter05_035-043.indd 38

membrane channels. Ion channels do not allow water to pass through them.

Carrier-mediated transport Membrane transport of several substances is carrier-mediated, that is, it employs certain integral membrane proteins as specific carriers or transporters. When a carrier transports only a single substance, it is called uniport. When it transports more than one substance in the same direction, it is called cotransport or symport. When it transports two substances in opposite directions, it is called countertransport or antiport. The energy for carrier-mediated transport may be derived (1) from the concentration gradient of the substrate, in which case it is called passive carrier-mediated transport or facilitated diffusion, or (2) from ATP, directly or indirectly, and is accordingly called primary active or secondary active carrier-mediated transport. These are discussed below in detail. Passive carrier-mediated transport Also called

facilitated diffusion, it is generally much faster than simple diffusion: Glucose and other large uncharged hydrophilic molecules have extremely slow rates of simple diffusion across the lipid bilayer but they cross the membrane much faster through facilitated diffusion. Although faster than simple diffusion, the amount transported by facilitated diffusion is limited by the availability of the carrier (Fig. 5.4). Hormones regulate facilitated diffusion by increasing or decreasing the number of carriers available. For example, insulin increases glucose transport into cells by moving glucose transporters from an intracellular reservoir to the membrane surface. Like simple diffusion, facilitated diffusion is bidirectional, that is, it occurs in both directions. However, when the concentration on one side is higher than the other, the difference in the kinetics of solute–carrier interaction ensures that there is always a net solute movement from high to low concentration, just as it is in simple diffusion. Facilitated diffusion can take the form of cotransport or counter-transport. Facilitated cotransport of Na+ with monosaccharides and amino acids occurs in renal tubular cells and intestinal mucosal cells. An example of facilitated counter-transport is the Cl––HCO3– antiport found in renal tubular cells and gastric parietal cells. Primary-active carrier-mediated transport involves energy expenditure. The energy comes mostly from ATP that is hydrolyzed by the carrier protein itself, which also acts as an ATPase. Unlike passive transport, active transport can transport

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Cell Membrane

39

Fig. 5.4 The boys with roller skates (carriers) are able to roll faster (facilitated diffusion) down the slope (concentration gradient) compared to those who are sliding down (simple diffusion). However, the number of boys who can roll down is limited by the availability of the roller skates.

substrates against a concentration gradient. The best-known example of a carrier ATPase is the Na+–K+ ATPase. It has binding sites for both ATP and Na+ on the cytoplasmic side of the membrane but the K+ binding site is located on the extracellular side of the membrane (Fig. 5.5). This asymmetry of location of the binding sites explains why, unlike facilitated diffusion, primary-active transport can occur only in one direction. Ouabain or digitalis inhibits this ATPase by binding to the extracellular site on the transporter.

Low solute concentration

A Pong

Pong

Ping High solute concentration

B

Na+ K+

Extracellular fluid

Secondary-active carrier-mediated transport rep-

resents a combination of primary-active transport and facilitated diffusion. It is exemplified by glucose transport across renal tubular cells and intestinal mucosal cells (Fig. 5.6). The basolateral border of the cell lowers the intracellular Na+ concentration through primary active transport of Na+ ions to the exterior. The low intracellular Na+ concentration provides the necessary concentration gradient for Na+ to diffuse in passively at the luminal border through facilitated cotransport with glucose. Thus, the Na+–K+ ATPase indirectly powers the movement of glucose into the cell, and glucose can move in against a concentration gradient so long as Na+ diffuses in along a concentration gradient. The rate of carrier-mediated transport depends on (1) the concentration gradient across the membrane, (2) the amount of carrier available (which is the key control step), and (3) the rapidity of bonding and dissociation of the carrier with its substrate. The rate cannot exceed a certain maximum,

Sircar_Chapter05_035-043.indd 39

Pong

ATP

Pong

ADP

Ping

Intracellular fluid

Fig. 5.5 The ping-pong model of carrier-mediated transport. [A] Facilitated diffusion. Note that transport of solute occurs in both directions. However, transport is greater from higher to lower solute concentration. [B] Active transport. Receptors for Na+ are present only at the inner side while receptors for K+ are present only at the outer side of the membrane carrier. This ensures that Na+ can only move out while K+ can only move in.

called the Vmax. At Vmax all substrate-binding sites on the carrier are saturated. The substrate concentration at which the transport is 50% of the maximum

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General Physiology

Glucose

GLUT-2 (glucose transporter)

Passive uniport

K+ Active antiport Na+–K+ ATPase

Glucose Na+

SGLT-1 (Na+-dependent glucose transporter)

Glucose Secondary active symport

Fig. 5.6 Passive, active, and secondary active transport. SGLT-1 transports glucose against its concentration gradient. The energy for this uphill transport is derived from the favorable concentration gradient of Na+ with which it is cotransported. The Na+ concentration gradient is created by Na+–K+ ATPase.

is called the binding constant (Km) of the carrier (Fig. 5.7). Inhibitors of carrier-mediated transport Carrier-

mediated transport can be blocked by inhibitors that bear structural similarity to the physiological substrate and compete with it for a place on the carrier. Once they bind to the carrier these inhibitors do not dissociate easily, thereby impairing the transport mechanism. The inhibitors are often classified as competitive and noncompetitive. A noncompetitive inhibitor binds irreversibly to the carrier, leaving no chance for the physiological substrate to compete for a place on the carrier. The carrier in effect gets inactivated.

Rate of transport

Vmax 100%

rr Ca

m ie r

50% Sim

pl

e di

d ate

iffu ed

sio

n

0 Km

Solute concentration

Fig. 5.7 Chemical kinetics of simple diffusion and carriermediated membrane transport. Note that while the amount of carrier-mediated transport plateaus off at high solute concentration, there is no such limit to simple diffusion.

Sircar_Chapter05_035-043.indd 40

A competitive inhibitor, on the other hand, binds reversibly to the carrier, allowing the physiological substrate a fair chance of competing and dislodging it from the binding site. Mechanism of carrier-mediated transport It is unlikely that the carriers, which are integral membrane proteins, actually move through the thickness of the membrane, carrying their substrate with them. The inside–outside asymmetry of membrane proteins is too stable to permit such movements. Rather, a ping-pong mechanism is proposed. In this model, the carrier protein exists in two principal conformations: Ping and pong. In the pong state, it is exposed to high concentrations of solute and the molecules of the solute bind to specific sites on the carrier protein. Transport occurs when a conformational change to the ping state exposes the carrier to a lower concentration of solute. The transition between the ping and pong states is powered by the bond energy released when the substrate binds to the solute. This is true for all carrier-mediated transport. In active transport, the binding of ATP to the carrier provides additional energy (Fig. 5.5). While integral membrane proteins employ the ping-pong mechanism for transporting ions, certain microbes synthesize small organic molecules called ionophores that transport ions by traveling across the membrane. These ionophores contain hydrophilic centers that bind specific ions and a hydrophobic exterior that allows them to dissolve in the membrane and diffuse across it.

Endocytosis Endocytosis is the process by which cells take up macromolecules and large particles. The process requires ATPase, Ca2+, and microfilaments. Endocytosis occurs by invagination of the plasma membrane so as to enclose a small droplet of extracellular fluid and its contents. The invagination is pinched off at its neck to form an endocytotic vesicle. The vesicle then transports its contents to other organelles by fusing with their membranes. Alternatively, it can fuse back with the plasma membrane. Depending on what is endocytosed, endocytosis is called phagocytosis or pinocytosis. Endocytosis of cells, bacteria, viruses, or debris is called phagocytosis. Endocytic vesicles containing these fuse with primary lysosomes to form secondary lysosomes where the ingested particles are digested. Endocytosis of water, nutrient molecules, and parts of the cell membrane is called pinocytosis.

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Cell Membrane Fluid-phase pinocytosis is a nonselective process

in which the cell takes up fluid and all its solutes indiscriminately. Vigorous fluid-phase pinocytosis is associated with internalization of considerable amounts of the plasma membrane. To avoid reduction in the surface area of the membrane, the membrane is replaced simultaneously by exocytosis of vesicles. In this way, the plasma membrane is constantly recycled. Absorptive pinocytosis is also called receptor-

mediated pinocytosis. It is responsible for the uptake of selected macromolecules for which the cell membrane bears specific receptors. Such uptake minimizes the indiscriminate uptake of fluid or other soluble macromolecules. The vesicles formed during absorptive pinocytosis are derived from invaginations (pits) that are coated on the cytoplasmic side with a filamentous material called clathrin, a peripheral membrane protein. Such pits are called coated pits. An example of absorptive pinocytosis is provided by the endocytosis of low-density lipoprotein (LDL) molecules. LDL molecules bind with their receptor on the plasma membrane and the receptor–LDL complexes are internalized by means of coated pits. The endocytotic vesicles fuse with lysosomes in the cell. The LDL is metabolized. The receptor is released and deposited back to the cell membrane. Endocytosed hormone receptors can trigger intracellular events after being endocytosed. Following pinocytosis, these hormone receptors form receptosomes, vesicles that avoid lysosomes and deliver their contents to other intracellular sites such as the Golgi body. Receptor-mediated endocytosis can at times be self-defeating. Viruses causing hepatitis, poliomyelitis, and AIDS gain access into the cell through this mechanism. Iron toxicity also begins with excessive uptake through endocytosis.

41

Membrane channels Ion channels are integral membrane proteins that enclose a central pore. They traverse the entire thickness of the cell membrane, projecting a little at both the outer and inner membrane surfaces. The structural characteristics of some ionic channels are shown in Fig. 5.8 and summarized in Table 5.1. A voltage-sensitive Na+ ion channel, for example, is made of four subunits designated as α, β, γ, and δ. Each subunit in turn is made of six coiled transmembrane segments designated S1 to S6. In general, channels have variable numbers of subunits and transmembrane domains having different designations.

Ion channel specificity Ion channels are highly specific for certain ions. Ions, regardless of their size, tend to pass through A voltage-sensitive channel with 4 subunits

One subunit removed to show the central pore

A single subunit with 6 transmembrane domains Transmembrane domain COOH NH2

ACh binding sites ACh NH2 COOH

Exocytosis Exocytosis is the process for release of macromolecules to the exterior. Exocytosis is associated with an increase in the area of the plasma membrane. Working in tandem with fluid-filled endocytosis, this process is involved in remodeling of the membrane. Exocytosed molecules are of three types: (1) Some attach to the cell surface and become peripheral proteins, for example, antigens. (2) Some become part of the extracellular matrix, for example, collagen and glycosaminoglycans. (3) Some enter extracellular fluid and serve as hormones and neurotransmitters. These are exocytosed only when the cell is stimulated.

Sircar_Chapter05_035-043.indd 41

A ligand-gated channel with 5 subunits

A single subunit has only 4 transmembrane domains

Fig. 5.8 (Above) Structure of a voltage-gated channel. It is made of four subunits with each subunit made of six transmembrane domains. The subunits enclose a central pore. (Below) Structure of a ligand-gated cation channel. It is made of five subunits, each with four transmembrane domains. The subunits enclose a central pore. The binding sites for acetylcholine are present on the exterior at the junctions between two adjacent subunits. ACh, acetylcholine.

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42

General Physiology Table 5.1 Structural characteristics of ionic channels Number of subunits

Number of transmembrane domains per subunit

Voltage-gated Na+ and K+ channels

Four subunits. All are α-type and are designated I, II, III, and IV

Six (S1, S2, S3, S4, S5, and S6)

Ligand-gated cation channel

Five subunits. Two are α-type, one each are β, γ, and δ.

Four (M1, M2, M3, and M4)

their own channels. While it is understandable that a larger ion cannot pass through a smaller channel, it requires some explanation as to why smaller ions do not pass through larger channels. This is explained by the closest-fit hypothesis. The hydration of ions is an important consideration in this hypothesis. The smaller an ion, the more highly localized is its charge and stronger is its electric field. Smaller ions such as Na+ (crystal radius of 0.095 nm) have stronger effective electric fields than larger ions such as K+ (crystal radius of 0.133 nm). As a result, smaller ions attract water more strongly. Thus, the

Hydrated Na+

Na+ channel

Hydrated Na+

K+ channel

Hydrated K+

Na+ channel

Fig. 5.9 The “closest-fit theory” of ion channel specificity. (Left) A sodium ion passes through the outer and inner pores. (Middle) A hydrated sodium ion is unable to pass through the outer pore of a K+ channel. (Right) A hydrated K+ is unable to pass through the inner pore.

Sircar_Chapter05_035-043.indd 42

strong electrostatic attraction for water causes Na+ to have a larger water shell. For passing completely through a channel, an ion has to negotiate two barriers: An outer pore, and another pore called the selectivity filter located midway inside the channel (Fig. 5.9). The ion enters the outer pore with its complete water of hydration. Once it arrives at the inner selectivity filter, the ion sheds most of its water shell and forms a weak electrostatic bond with the polar (carboxyl) residues of the amino acids that line the channel wall. This electrostatic bond must release adequate energy for stripping the ion of its water shell. The energy released is maximum when the unhydrated ion fits closely in the channel. The energy released is less if the ion floats loosely within the channel. The hydrated Na+ ion is larger than the hydrated + K ion and as would be expected, a Na+ channel has a larger diameter than a K+ channel. A hydrated Na+ ion is a little too large to pass through the outer pore of a K+ channel. The hydrated K+ ion is slightly less in diameter than the Na+ channel and yet it is unable to pass through the Na+ channel because the selectivity filter of the Na+ channel is oversized for a K+ ion bereft of its water shell. Hence, the energy released due to the electrostatic attraction between the K+ ion and the wall of the Na+ selectivity filter is inadequate for stripping the K+ ion of its water shell. With its shell intact, the K+ is unable to negotiate the selectivity filter of Na+ channel.

Types of channels What makes channels unique as compared to other mechanisms of membrane transport is that they can be gated precisely. Depending on the factors that produce their opening and closing (gating), ion channels are classified into four types. Voltage-gated channels are gated by changes in membrane potential. Examples are voltage-gated Na+, K+, and Ca2+ channels. Ligand-gated channels are regulated by ligands, that is, chemicals that bind to them. The ligand affects channel permeability in different ways (Fig. 5.10). (1) It can bind to the receptor channel protein at an extracellular site, for example, in acetylcholine receptors. (2) It can bind to the channel at an intracellular site (e.g., pronase, local anesthetics). (3) It can bind to membrane receptors and activate a second messenger cascade leading to phosphorylation of channel protein. The consequent structural transformation of the protein results in the opening of the channel enclosed.

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Cell Membrane

Membrane receptor site

Extracellular receptor site

Membrane

2nd messenger

43

Mechanically gated channels have pores that respond to stretch. Resting channels are not gated at all. Resting channels make a substantial contribution to the membrane potential. Besides physiological channels, membrane pores may be created in pathological situations. Diphtheria toxin and activated serum complement components like the C5b–C6–C7–C8–C9 fragment can produce large pores in cellular membranes and thereby provide macromolecules with direct access to the cell interior.

Intracellular receptor site

Phosphorylation

Fig. 5.10 Ligand-binding sites may be located on the outer membrane surface, or they may be present on the outer or inner parts of a membrane channel.

REVISION QUESTIONS 1. What are the important integral proteins in the cell membrane? How are they different from peripheral proteins?

5. Ion-specific membrane channels do not allow other ions to pass through them even when they are smaller than the channel. How?

2. Long chain fatty acids make the cell membrane stiffer. Why?

6. What are the four main types of membrane channels?

3. How does cholesterol affect the fluidity of cell membrane?

7. Membrane channels may be created in pathological situations. Give examples.

4. Which is faster: simple diffusion or carriermediated transport? Give reasons.

Sircar_Chapter05_035-043.indd 43

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6

Cell Cycle

The sequence of events between the birth of a cell (through division of its parent cell) and its division into daughter cells is called the cell cycle. A cell roughly doubles its cytoplasm and organelles, and duplicates its DNA. Thereafter, the cell nucleus divides through a process called mitosis and its cytoplasm is apportioned into two daughter cells that have identical genomes. The apportioning of cytoplasm is called cytokinesis. Together, mitosis and cytokinesis constitute the M phase (mitotic phase) of the cell cycle. The remaining part of the cell cycle is called interphase and constitutes 90% of the cell cycle. The interphase is further subdivided into three phases (Fig. 6.1). (1) The phase that immediately follows the M phase is the G1 phase (G1 for the first gap). In this phase, there is rapid growth and metabolic activity in the cell, and its centrioles replicate. (2) The next phase is the S phase in which DNA replication occurs. (3) The S phase is followed by the G2 phase (second gap) in which there is further growth and final preparation for the impending mitosis.

G0 phase

rphase Inte hase Sp

Mitotic Phase M phase

G 1 phase

G2 phase

Mitosis (Greek mitos = thread, fiber) is the type of cell division that occurs in the somatic cells of the body during growth. In mitosis, each of the two daughter cells receives exactly the same number and the same type of chromosomes contained in the parent cell. Mitosis occurs in five stages: interphase, prophase, metaphase, anaphase, and telophase.

of DN A Am ou nt S

In interphase, the nucleus is well defined and G2

M

Fig. 6.1 The cell cycle. (Above) Phases of the cell cycle. (Below) Amount of DNA in different phases.

Sircar_Chapter06_044-048.indd 44

An understanding of the cell-cycle kinetics is essential for the proper use of anticancer (antineoplastic, cytotoxic) drugs. (1) Many of the potent anticancer agents act by damaging DNA and their toxicity is greater during the S phase. (2) Other anticancer agents block the formation of mitotic spindles in the M phase. These agents are effective only against cells that are in the process of division. Accordingly, neoplasms with a high percentage of cells undergoing division are highly susceptible to chemotherapeutic measures. For the same reason, normal tissues that proliferate rapidly (bone marrow, hair follicles, and intestinal epithelium) are susceptible to these drugs. On the other hand, slowly growing tumors are often irresponsive to cytotoxic agents. Cells of slow-growing tumors may remain in the G0 state for prolonged periods, only to reenter the cell cycle at a later time. If the p53 gene is intact and it exerts its normal checkpoint function, damaged cells that reach the restriction point undergo apoptosis (see below). If the p53 gene is mutated and the checkpoint function fails, damaged cells will not be diverted to the apoptotic pathway. These cells will proceed through S phase and some will emerge as a drug-resistant population. Cytotoxic drugs

Mitosis

Cell cycle

G1

Somewhere within the G1 phase is a stage called the restriction point where the cell is at a crossroads: from there it goes either into a nondividing state called the G0 phase or through the entire cell cycle all over again. This “checkpoint function” is under the control of the p53 gene.

bound by the nuclear membrane. It contains one or more nucleoli. Just outside the nucleus are two pairs of centrioles, formed earlier by the replication from a single pair. The two centrioles at first lie

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Cell Cycle

Early interphase Autosomal pairs

XY

22 pairs of autosomal chromosomes 1 pair sex chromosomes (X and Y) Genome = 2n (23 x 2 = 46) (Diploid)

Prophase 44 pairs of autosomal chromatids 1 pair X chromatids 1 pair Y chromatids Genome = 4n (23 x 4 = 92) (Tetraploid)

Metaphase

Anaphase

45

stranded DNA, the structure is called a tetrad and contains a tetraploid genome. In the cytoplasm, there is (1) formation of mitotic spindles. The mitotic spindles are made of microtubules extending between the two pairs of centrioles. (2) The centrioles move apart, pushed by the elongating bundles of microtubules between them. (3) Late in prophase, the nuclear membrane fragments. During metaphase, (1) the chromosomes line up in the equatorial region of the cell; (2) the two centriole pairs move to the opposite poles of the cell; (3) bundles of microtubules called polar fibers extend from each pole toward the equator of the cell; and (4) the microtubules invade the nucleus and interact with the chromosomes, which by now is even more condensed. Anaphase begins when the paired centromeres of

each chromosome move apart, liberating the sister chromatids from each other. Each chromatid now represents a fully-fledged chromosome. By the end of anaphase, the two poles of the cell have the complete (diploid) set of chromosomes. Telophase

Each daughter cell contains: 22 pairs of autosomal chromosomes 1 X chromosome 1 Y chromosome Genome = 2n (23 x 2 = 46) (Diploid)

Fig. 6.2 Stages of mitosis. Note that the cell is diploid in interphase, becomes tetraploid in prophase due to DNA replication, and finally, becomes diploid again in telophase.

side-by-side just outside the nucleus. Around each centriole pair, microtubules are formed in a radial array called an aster (star). During early interphase, the cell is diploid, that is, its nucleus contains 22 pairs of autosomal chromosomes and a pair of sex chromosomes (Fig. 6.2). By mid-interphase, the chromosomes duplicate, making the cell tetraploid. Till this stage the chromosomes cannot be distinguished individually as they are still in the form of loosely packed chromatin fibers. During prophase, changes occur in both the nucleus and the cytoplasm. In the nucleus, (1) the nucleoli disappear. (2) The chromatin become more tightly coiled and folded into discrete chromosomes. Each duplicated chromosome now appears as two identical sister chromatids joined at the centromere. Since each of the two sister chromatids contains a double-

Sircar_Chapter06_044-048.indd 45

At telophase, the daughter nuclei begin to form at the two poles of the cell where the chromosomes have gathered. The nuclear membrane forms, the nucleoli reappear and the chromosomes uncoil. Cytokinesis occurs shortly thereafter and the cytoplasm is apportioned into the two daughter cells.

Mitotic chromosomal nondisjunction Chromosomal nondisjunction (nonseparation of chromosomes) results in abnormal mitosis. It usually occurs immediately after zygote formation and results in mosaicism. In mosaicism, the number of chromosomes is not the same in all the cells of the body. For example, approximately 50% of the body cell population may have a certain number of chromosomes while the remaining 50% have a different number of chromosomes. If half the cells in the body are 45,X (i.e., 44+X) and the remaining cells are 47,XYY (i.e., 44+XYY), the mosaicism is denoted symbolically as XY/XYY. Its mechanism is depicted diagrammatically in Fig. 6.3.

Meiosis Meiosis (Greek meioum = diminish) occurs during gamete formation (spermatogenesis and oogenesis). Like mitosis, it is preceded by the duplication of the chromosomes during interphase, but this chromosomal duplication is followed by two successive cell divisions called meiosisI and meiosis-II. Meiosis-II is almost identical to

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46

General Physiology

Prophase-I 44 pair of autosomal chromatids 1 pair of X chromatids 1 pair of Y chromatids Genome = 4n (23 x 4 = 92) (Tetraploid)

Metaphase-I

Anaphase-I

22 + XYY

Telophase-I

22 + X

Autosomal

X

Y

22 pairs of autosomal chromosomes 1 X chromosome 1 Y chromosome Genome = 2n (23 x 2 = 46) (Diploid)

Fig. 6.3 Mitotic nondisjunction. The Y chromosomes fail to separate. Therefore, one of the daughter cells gets two Y chromosomes while the other gets none.

mitosis and results in the formation of four haploid daughter cells (Fig. 6.4). Meiosis-I Prophase-I takes 90% of the time required for meiosis-I. During this phase, the homologous chromosomes derived from each parent come together. Since each chromosome is made of two sister chromatids, the genome is tetraploid. The two homologous chromosomes are apposed in such a way that each gene is juxtaposed with its homologous gene on the opposite chromatid. Corresponding segments of adjacent nonsister chromatids may exchange by breaking and reattaching to the other chromatid. This event is called crossing over and it ensures that genetic traits of the homologous chromosomes get randomly mixed up. The nonsister chromatids remain attached at the sites of crossing over, which are called chiasmata (singular: chiasma). Other changes that take place during prophase-I are (1) the fragmentation of the nuclear membrane, (2) dispersion of the nucleoli, and (3) migration of the centrioles to the opposite poles.

Sircar_Chapter06_044-048.indd 46

Fig. 6.4 Stages of meiosis. During prophase-I, the cell becomes tetraploid due to DNA replication. In telophaseI, the two daughter cells become diploid, not due to separation of chromatids as in mitosis, but due to the apportioning of homologous chromosomes into two cells. Hence, one of the daughter cells gets the X chromosome, while the other gets the Y chromosome. Each chromosome still contains two chromatids. Meiosis-II results in the formation of four haploid daughter cells due to separation of chromatids to the daughter cells.

During metaphase-I, the tetrads line up in the equatorial region of the cell in such a way that the homologous chromosomes are on opposite sides of the equatorial line. Anaphase-I begins when the homologous chromosomes in each tetrad move apart. The sister chromatids in each chromosome, however, remain attached by the centromere. By the end of anaphase-I, each pole of the cell has a haploid set of chromosomes. Since each chromosome still has two chromatids, the genome is diploid. In telophase-I, cytokinesis occurs and the cytoplasm gets apportioned into the two daughter

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Cell Cycle cells. Nuclear membrane formation and reappearance of nucleoli may or may not occur depending on the duration of the interval (interkinesis) between telophase-I and prophase-II. If the interkinesis is brief, neither occurs. Meiosis-II In prophase-II, the mitotic spindles appear and the chromosomes move toward the equator. If the nuclear membrane and nucleoli appear during telophase-I, they disintegrate again during this phase. During metaphase-II, the haploid number of chromosomes line up along the equatorial line with their centromeres aligned. During anaphase-II, the paired centromeres of each chromosome move apart with the sister chromatids moving toward the opposite poles. The two poles of the cell now have a haploid genome each. In telophase-II, the nuclei begin to form at opposite poles of the cell and cytokinesis occurs and this results in the formation of four daughter cells, each with haploid chromosomes and genomes (Fig. 6.4).

Interkinesis The meiosis described above is seen in males. The primary spermatocyte of a male forms two secondary spermatocytes after meiosis-I and finally four spermatids after meiosis-II (see Fig. 89.3). Both stages of meiosis begin after puberty and are completed within 2 months. However, prophase-I takes a disproportionately long time of about 3 weeks. In females, there are long intervals called interkinesis separating the different phases of meiosis in the ovarian germ cells (Fig. 6.5). Meiosis-I of ovarian germ cells begins immediately after birth but is arrested at prophase, only to resume after puberty. Meiosis-II is arrested in metaphase, only to be completed after fertilization.

Meiotic chromosomal nondisjunction Meiotic chromosomal nondisjunction results in abnormal gametogenesis. In the classical form of Klinefelter syndrome (see Fig. 92.6), chromosomal nondisjunction during meiosis results in the formation of an abnormal ovum. When fertilized, the abnormal ovum results in a zygote with the chromosomal configuration of XXY. The mechanism through which the abnormal ovum is formed is depicted diagrammatically in Fig. 6.6.

Apoptosis Apoptosis (dropping off, like autumn leaves) is genetically programmed cell death that does not

Sircar_Chapter06_044-048.indd 47

47

Birth

Oogonia (2n) Meiosis-I (prophase-I) Primary oocyte (4n)

Interkinesis Puberty Spermatogonia (2n) Meiosis-I (prophase-I) Primary spermatocyte (4n) Meiosis-I (metaphase-I) Meiosis-I (anaphase-I) Meiosis-I (telophase-I) Secondary spermatocyte (2n) Meiosis-II (metaphase-II) Meiosis-II (anaphase-II) Meiosis-II (telophase-II) Spermatid (n)

Primary oocyte (2n) Meiosis-I (metaphase-I) Meiosis-I (anaphase-I) Meiosis-I (telophase-I) Secondary oocyte (2n) + 1st polar body Meiosis-II (metaphase-II)

Interkinesis

Fertilization Zygote Meiosis-II (anaphase-II) Meiosis-II (telophase-II) Zygote + 2nd polar body

Fig. 6.5 Male versus female meiosis. Meiosis in females shows two long intervals called the interkineses.

22 + XX

22 + O

22 + Y

22 + Y

Fig. 6.6 Meiotic nondisjunction resulting in four haploid germ cells of which two have abnormal genomes 22 + XX and 22 + 0. See also Fig. 92.5.

significantly affect neighboring cells and tissues. It is distinct from necrosis, which is an unregulated destruction of larger tissue areas. If necrosis is cell

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48

General Physiology murder, apoptosis is cell suicide. Apoptosis makes an interesting contrast with mitosis: mitosis is the manifestation of the cell’s will to divide and live on, while apoptosis represents its decision to call it quits! Apoptosis is responsible for (1) death of intestinal mucosal cells as they reach the tip of the villus to be sloughed off; (2) death of epidermal cells as they reach the surface; (3) death of a large number of neurons in the central nervous system that do not make appropriate synaptic contact with their target organs; (4) death of clones of lymphocytes that are likely to react with “self;” (5) removal of the webs between the fingers in fetal life; (6) regression of one or the other of Wolffian duct and Mullerian duct systems in the course of sexual differentiation in the fetus; (7) regression of incompletely developed Graafian follicles in ovary after ovulation; (8) cyclic breakdown of the endometrium, leading to menstruation; and (9) disintegration of apoptotic cells in the lens resulting in the yield of the crystalline lens protein. Apoptosis is completed in four phases: induction, initiation, execution, and disposal. The induction phase is the stage of gene activation. Several endogenous and exogenous stimuli activate the apoptotic genes through signal transduction. Two

well-known activating factors are Fas-antigen and tumor necrosis factor (TNF). Another antigen, the p53-antigen, which is the product of the tumor suppressor gene, exerts an anticancer activity by activation of apoptosis. Mitochondrial factors also play an important role in apoptosis. Several proapoptotic factors, such as ultraviolet light, oxidants, cytokines, neurotoxins, etc., damage the mitochondrial membranes thus causing release of apoptosisinducing factor (AIF). In the initiation phase, the activated gene initiates a proteolytic cascade involving a family of at least 10 proteases named caspases (an abbreviation for the word cysteine aspartase). The enzymes have cysteine in their active site and cleave their target proteins at aspartic acids. The execution phase completes the death program. The dying cell shrinks and loses its contact with neighboring cells. The cell DNA gets fragmented and the cytoplasm and chromatin condense. The nucleus and cytoplasm eventually break up into small cell remnants called apoptotic bodies. In the disposal phase, the apoptotic bodies are either phagocytosed or are lost from the epithelial surfaces.

REVISION QUESTIONS 1. Bone marrow, hair, and intestinal epithelium are vulnerable to anticancer chemotherapy. Why?

5. Which phase of the cell cycle is called interkinesis? In which cell is the interkinesis prominent?

2. At which stage of the cell cycle does the cell becomes tetraploid?

6. What is the difference between mitotic and meiotic dysjunction?

3. What is mosaicism?

7. What is the difference between apoptosis and necrosis?

4. What is “crossing over” of chromosomes and in which stage of the cell cycle does it occur? What would happen if crossing over doesn’t occur?

Sircar_Chapter06_044-048.indd 48

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7

Applied Genetics

Nucleic acids

There are four types of nucleotides in DNA depending on the type of their nitrogenous base: adenine, guanine, cytosine, and thymine. Similarly, the nucleotides in RNA contain adenine, guanine, cytosine or uracil. The nucleotide chain has two free ends, a 5′ (read five prime) end and a 3′ end. The sequence of nucleotides in a segment of DNA or RNA is conventionally stated from the 5′ end to the 3′ end. DNA has a double helical structure, with its two strands interconnected by hydrogen bonds. RNA usually does not assume a double helical structure but often folds upon itself to form various shapes (see tRNA, Fig. 7.3). There are three major types of RNA: (1) ribosomal RNA (rRNA), (2) transfer RNA (tRNA), and (3) messenger RNA (mRNA). The rRNA, along with several proteins, forms the ribosomes upon which protein synthesis takes place. The tRNA transports specific amino acids from the cellular amino acid pool to the ribosomes, which are the sites of protein synthesis. The mRNA acts as a template of the genetic code.

The characteristics of a cell are determined by its structural proteins and the proteinaceous enzymes that control its function. The structure and functions of proteins are determined by their amino acid sequence, which in turn is determined by the chemical composition of the nucleic acids in the cell’s nucleus. A change in the composition of the nucleic acid alters the protein synthesized, sometimes with deleterious consequences. The basic subunits of nucleic acids are the nucleotides (Fig. 7.1). A nucleotide is made of a nitrogenous base, a pentose sugar molecule, and up to three phosphate groups. The pentose sugar may be deoxyribose or ribose. Accordingly, the nucleic acid is either deoxyribonucleic acid (DNA) or ribonucleic acid (RNA). DNA is found mostly in the chromosomes but is present in the mitochondria too. RNA, though synthesized in the nucleus, is present mostly in the cytosol. In both DNA and RNA, the nucleotides are linked to each other by phosphodiester bonds, forming long chains of nucleotides. The codes for the synthesis of different types of amino acids reside in the sequence of the different nucleotides in the DNA.

Genetic code The genetic code is made of three-lettered words (triplets), each letter representing an RNA nucleotide.

O 5' End

H3C

N

O 5' H N O P O CH2 Deoxy 1' O 4' ribose 3' 2'

H O H

3' end

H N

N H O N O P O CH2 Deoxy O ribose

Phosphodiester bonds

5' end

Thymine

N Adenine H

N N H

N Cytosine O

O H N O P O CH2 Deoxy O ribose

Guanine O H

N

N

H

O 5' N O P O CH2 Deoxy 1' O 4' ribose 3' End 3' 2' OH

N

N H

H 3' end 5' end

Fig. 7.1 (Left) Nucleotides of DNA. (Right) The double helix structure of DNA.

Sircar_Chapter07_049-053.indd 49

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50

General Physiology Each triplet codon always codes for the synthesis of a specific amino acid. It is possible to arrange 4 nucleotides into 64 (43 = 64) different triplets. Of these, 61 code for amino acids and the remaining 3 (UAG, UGA, UAA) code for stop codons. Since the number of codons (61) exceed the num ber of amino acids to be coded for (20), several amino acids have more than one codon coding for them (Table 7.1). The reverse is not true, that is, one codon never represents more than one amino acid. Not all stretches of DNA in the chromosome code for proteins. For example, if the nucleotide sequence in a stretch of RNA is 5′-AUG-CCA-UUGGAU-UAA-3′, then the polypeptide coded by it is methionine–proline–leucine–aspartic acid. UAA does not code for any amino acid, but rather it signals that the chain should stop growing further. UAA is therefore called a “stop” codon. Long stretches of DNA in eukaryotic cells do not code for protein. These noncoding regions are known as introns. The intervening stretches that code for proteins are known as exons. Mutation refers to a permanent change in the genetic code. Such changes can have lethal effects on an organism as a result of alterations in the protein encoded by the mutated segment of the DNA. Table 7.1 Codons for amino acids and STOP codons Glycine

GGU, GGC, GGA, GGG

Alanine

GCU, GCC, GCA, GCG

Valine

GUU, GUC, GUA, GUG

Leucine

UUA, UUG, CUU, CUC, CUA, CUG

Isoleucine

AUU, AUC, AUA

Serine

UCU, UCC, UCA, UCG, AGU, AGC

Threonine

ACU, ACC, ACA, ACG

DNA replication During cell division, each strand of the double stranded DNA creates an identical copy of itself. This is known as DNA replication. In eukaryotes, DNA replication begins at multiple sites along the DNA helix, but in prokaryotes, the replication begins at a single site. The site(s) must contain a unique nucleotide sequence. At the site(s) of replication, the two strands of DNA unwind, forming a replication fork. Unwinding requires the enzyme DNA helicase. A complementary nucleotide sequence is assembled on each of the separated DNA strands. Since a DNA strand is read out only in the 3′ to 5′ direction, the complementary DNA strands grow in opposite directions as shown in Fig. 7.2A. Replication requires the enzyme DNA polymerase. The initiation of replication requires an RNA primer, a short RNA segment attached to the 3′ end of the DNA strands.

Transcription Transcription is the process of RNA synthesis using one of the DNA strands as the template. The part of the template bearing the nucleotide sequence TATAAT or TTGACA (read in the 5′ to 3′ A 3'

DNA polymerase

5'

DNA

3'

3' 5'

5'

DNA helicase RNA primer

B Promoter region

Transcription unit

Terminator region

Cysteine

UGU, UGC

5'

3'

Methionine

AUG

3'

5'

Aspartic acid

GAU, GAC

Aspartine

AAU, AAC

Glutamic acid

GAA, GAG

Glutamine

CAA, CAG

Arginine

CGU, CGC, CGA, CGG, AGA, AGG

Lysine

AAA, AAG

Histidine

CAU, CAC

Phenylalanine

UUU, UUC

Tyrosine

UAU, UAC

Tryptophan

UGG

Proline

CCU, CCC, CCA, CCG

STOP codons

UAA, UAG, UGA

Sircar_Chapter07_049-053.indd 50

5'

Initiation of RNA synthesis

Elongating RNA

Newly synthesized RNA

Fig. 7.2 [A] DNA replication showing the replication fork. [B] Transcription (RNA synthesis).

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Applied Genetics direction) signals the initiation of transcription. These sequences are called the promotor regions of the DNA (Fig. 7.2B). The enzyme RNA polymerase binds to the DNA at the promotor region. Transcription begins a few nucleotides downstream from the promoter site. This produces a growing chain of RNA-bearing complementary nucleotides. Transcription stops when the RNA polymerase reaches an area on the DNA known as the termination region.

1

P site

51

A site t-RNA carrying AA-1 binds to the P-site of ribosome.

1

2

t-RNA carrying AA-2 binds to the A-site of ribosome.

Translation Translation is the process of mRNA-guided protein synthesis. The mRNA is formed in the nucleus. It leaves the nucleus to enter the cytosol and reaches the ribosome. Protein synthesis takes place on the ribosomal surface. Translation requires (1) the availability of amino acids that are to be incorporated into the peptide, (2) the mRNA bearing the codons, (3) the tRNA bearing the anticodons and having a binding site for one amino acid, and (4) ribosomes on which the protein assembly can take place. Also required are (5) GTP and ATP as energy sources and (6) several protein factors that are necessary for the initiation, elongation, and termination of the peptide chain.

1 2

AA-1 gets transferred to the tRNA in the A-site and binds to AA-2.

1 2

t-RNA in the P site dissociates, leaving the P-site empty.

Initiation of translation begins with (1) the bind-

ing of the mRNA with the ribosome so that the initiation codon of the mRNA (the first codon that is to be translated) is located at the P-site (P for peptide) of the ribosome and its second codon is located at the A-site (A for amino acid) of the ribosome (Fig. 7.3). (2) Next, a tRNA carrying methionine binds to the initiation codon AUG in the mRNA. Protein molecules called initiation factors bind to the complex, lending it stability. Elongation of the peptide chain occurs when (1)

a second tRNA carrying the corresponding amino acid (say, tryptophan) binds to the next codon (UGG) on the mRNA at the A-site of the ribosome. This binding requires GTP and an elongation factor. (2) The methionine molecule binds to the tryptophan molecule to form a dipeptide. The reaction is catalyzed by the enzyme peptidyltransferase and an rRNA molecule. The tRNA left behind by methionine dissociates from the P-site. (3) The tRNA moves to the vacant P-site, carrying its dipeptide and the second codon (UGC) with it. (4) A fresh tRNA carrying a third amino acid now binds to the A-site and the cycle repeats all over again, resulting in a growing peptide chain. Termination of translation occurs when a stop codon (say, UAA) on the mRNA comes to occupy

Sircar_Chapter07_049-053.indd 51

1 2

The tRNA moves from A-site to the P-site. The mRNA moves along with the tRNA

1

2

3 4 5

The peptide chain continues to grow as the above steps are repeated.

Fig. 7.3 Steps in translation. AA, amino acid.

the A-site. There are no tRNAs for stop codons and therefore the peptide chain cannot grow further. Instead, the peptide chain is released from its tRNA through hydrolysis. The hydrolysis requires peptidyltransferase, releasing factors, and GTP.

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52

General Physiology

Molecular techniques Southern blotting The Southern blotting technique detects the presence or absence of stretches of DNA with a specific nucleotide sequence in an entire genome or in a given DNA sample. The principle of the technique is outlined as follows. The DNA isolated from eukaryotic (including human) cells is cut into multiple fragments called restriction fragments with the help of enzymes called restriction endonucleases. There are many different types of restriction endonucleases, each having a specific restriction site, that is, the site where it cuts the DNA. For example, the restriction enzyme EcoRI recognizes the sequence GAATTC and cuts the DNA wherever this nucleotide sequence occurs on the DNA. The DNA, after isolation and restriction digestion, is subjected to electrophoresis. The rate of migration of DNA fragments is inversely proportional to the size of the fragment. DNA fragments are not visible to the naked eye. To make them visible, the agarose gel containing the DNA is soaked in ethidium bromide solution. The DNA binds to ethidium bromide and becomes visible when exposed to ultraviolet light. The electrophoretically separated DNA fragments are blotted (soaked) onto an artificial membrane made of nitrocellulose or nylon, either mechanically or electrically (electroblotting), producing an exact replica of the original bands. The replica of DNA on the blotting membrane is called a blot. The transfer makes it easier for the experimenter to work with the DNA, as the artificial membrane is stronger and thus easier to handle than the fragile gel membrane. One or more of the several DNA bands that are blotted onto the artificial membrane may contain the nucleotide sequence of interest. The DNA fragment of interest is detected using a “probe,” a small piece of single-stranded radiolabelled DNA having a nucleotide sequence that is complementary to the DNA fragment of interest. The binding of the radioactive probe to the DNA fragment of interest is called hybridization. The band containing the DNA of interest is now radioactive: it can be radiographed by apposing the artificial membrane containing the DNA bands to an X-ray plate. Similar techniques (electrophoresis following hybridization with specific probes) when applied to RNA fragments is called Northern blotting and when applied to proteins, is called Western blotting. For proteins, the probes used are specific antibodies directed against the proteins.

Sircar_Chapter07_049-053.indd 52

DNA fingerprinting Most of the noncoding regions of DNA, that is, the introns, consist of multiple repeats called tandem repeats of certain similar or identical DNA sequences. These repetitive sequences of DNA are either contiguous or are dispersed randomly along the length of the DNA. An example of dispersed repetitive DNA is the Alu element. It is a 300-basepair DNA sequence that occurs randomly in the genome as many as 300,000 to 500,000 times. The location and number of these repetitive DNA is unique and is thus a molecular autograph of an individual. If the genomic DNA is digested with a restriction endonuclease, the length of the restriction fragments varies from individual to individual. This polymorphism (broad genotypic variations within a species) is known as restriction fragment length polymorphism and is made use of in DNA fingerprinting. The restriction fragments are subjected to Southern hybridization, using the probe for one of the tandem repeats of DNA nucleotides. Because of restriction fragment length polymorphism, the blot shows bands whose distribution is unique for an individual. This technique can be utilized to confirm or rule out the molecular identity

Fig. 7.4 Steps in a polymerase chain reaction. (1) A double-stranded DNA. (2) DNA strands separated and attached to RNA primers. (3) DNA replicates by elongation of the complementary strand. (4) The strands of the replicated DNA separate and get attached to primers, repeating the above cycle all over again.

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Applied Genetics of an individual. The DNA required for the purpose can be extracted from any biologic material such as blood or semen stain, or a hair.

DNA cloning Multiple copies of a DNA fragment can be produced by incorporating it into a vector and inserting the vector into an actively multiplying cell. A vector is a molecule of DNA that replicates itself when inserted into a cell. Plasmids and viruses are examples of cloning vectors.

Polymerase chain reaction The polymerase chain reaction (PCR) is an alternative to DNA cloning. It allows rapid synthesis of a large number of copies of any specific DNA segment, provided that short DNA sequences on both sides of the DNA segment, called flanking sequences, are known. PCR consists of three

53

steps: (1) denaturation (separating the DNA strands) by heating, (2) annealing (cooling the DNA and allowing the primers to get attached to the flanking DNA sequences), and (3) elongation of the primer (by allowing the assembly of base pairs, starting from the primers) (Fig. 7.4). The variations in temperature required for the process are usually achieved with the help of an instrument known as thermocycler. These three steps are repeated several times, leading to the synthesis of enormous number of copies of the given DNA. If the DNA is subjected to 30 cycles, a billion copies of the original DNA are generated. PCR has several uses: (1) it can be used to identify the presence of bacteria and viruses, even if only one organism is present. (2) It is also used in forensic medicine to detect the identity of a suspect by using any biologic material. (3) It is used in research laboratories to detect and amplify vanishingly small quantities of DNA.

REVISION QUESTIONS 1. What is the difference between Southern blotting, Northern blotting, and Western blotting? 2. Which molecular technique detects specific nucleotide sequence in a genome? 3. What is hybridization?

Sircar_Chapter07_049-053.indd 53

4. What is restriction length polymorphism? 5. DNA cloning employs a vector. What is a vector? 6. What are the three steps of a polymerase chain reaction?

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Functional Anatomy of Nerve and Muscle undergo mitosis. Smooth endoplasmic reticulum is

Neuron The neuron or nerve cell (Fig. 8.1) is unique in that it can conduct electric impulses in which are codified various types of motor and sensory information. A neuron has a cell body called the soma, and two kinds of processes, namely, the axon and the dendrites. The soma contains most of the organelles present in a typical cell except the centriole, which is necessary for mitosis. Hence, the mature neuron cannot

Nucleus

Dendritic [ Neck spine

Bulb

Golgi body Axon hillock Initial segment

Axon

present in all parts of the neuron. The cisternae of the rough endoplasmic reticulum are disposed in parallel arrays called Nissl bodies. Due to their ribosomic RNA content, Niss) bodies stain intensely with chromophilic dyes and are very conspicuous. Polyribosomes are also found free in the cytoplasm. Niss) bodies are present in the soma and dendrites but are usually absent from the axon hillock and the axon. The cytoskeleton of the neuron is made of microtubules, microfilaments, and intermediate filaments. In neurons, intermediate filaments are called neurofilaments. Under the light microscope, a network of neurofibrils (-2 µm in diameter) is seen in the perikaryon, extending into the dendrites and the axon. Neurofibrils are actually bundles of neurofilaments and microtubules. In certain degenerative diseases like Alzheimer disease, the neurofilament protein are altered, resulting in the formation of characteristic lesions called neurofibrillary tangles. The axon 1 arises as a single long process from the axon hillock, which is a conical extension of the cell body. The axon is thinner and much longer than dendrites of the same cell. In some neurons, the axon may be myelinated. The function of the axon is to conduct action potentials over long distances. However, in certain very small local-circuit neurons like the amacrine cells of the retina, there may be no

axon at all. Myelin sheath

The part of the axon between the axon hillock and the beginning of the myelin sheath is called the initial segment. In response to the various synaptic inputs on the dendrites, the axon hillock and initial segment give rise to an action potential and hence are together called the spike trigger zone. Dendrites are the multiple cell processes which

Fig. 8.1 Structure of a neuron. Note the bulb and the narrow neck of the dendritic spines.

branch extensively immediately after taking root from the soma. The dendritic tree so formed provides most of the surface for receiving signals from other neurons via their synapses with axon terminals. Dendrites often look "thorny" due to numerous minute projections called dendritic spines present on their surface. The spines are the sites of synaptic contact, connected to the main shaft

'The axon is sometimes defined as the process that carries signals away from the soma. Similarly. dendrites are sometimes defined as the processes that carry impulses toward the soma. These definitions are fallacious. In a pseudounipolar cell or a bipolar cell. the axon carries information both toward and away from the cell.

Functional Anatomy of Nerve and Muscle by a thin neck and ending in a more bulbous head. Each spine forms at least one synapse. During synaptic transmission, Ca2⫹ concentration rises in the spine. The thin neck of the spine prevents the rise in Ca2⫹ concentration in the spine from spreading to the main shaft, increasing the holding capacity of the dendrites (p 656). Spines decrease in number after deafferentation or nutritional deficiency and exhibit structural changes in the aged and in individuals with certain chromosomal abnormalities like trisomies 13 and 21. The synaptic inputs produce local potentials that add up (summate) on the surface of dendrites. Dendrites usually do not produce action potentials: They mostly conduct graded potentials. Dendrites that are very long may conduct action potentials.

Myelination of neurons Myelination of axons increases their conduction velocity but also increases their diameter. Motor neurons to muscles and sensory fibers from muscles (proprioceptive fibers) are heavily myelinated because speed is important in these fibers. Inside the brain, neurons travel short distances and hence speed is less important. Rather, there is limited intracranial space. Hence, it is advantageous to

Peripheral nervous system

55

have unmyelinated or thinly myelinated neurons that occupy less space, allowing more neurons to be accommodated inside the cranium. Myelination begins at about 4 months in utero. Motor nerve roots are largely myelinated at birth, but the optic nerve and sensory roots lag behind by 3 to 4 months. The corticospinal tracts require a year for full myelination, and commissural axons of the cerebral hemispheres require, 7 years or more. It is only after the completion of myelination that a neuron becomes fully functional. In infants, functions like vision, walking, and performance of directed movements are possible only after the completion of myelination. Peripheral myelination The myelin sheath is produced by glial cells called Schwann cells that encircle the axon forming around it a thin sleeve called the sheath of Schwann. The myelin sheath is composed of several layers of cell membrane wrapped spirally around the axon (Fig. 8.2). The myelin gets compacted by the elimination of the intervening cytoplasm. Externally, the Schwann cell is covered by a thin basal lamina and the endoneurium. The myelin sheath is interrupted at the nodes of Ranvier where the axon is covered only by the basal lamina. The

Central nervous system

Axon Oligodendrocyte

Nucleus of a Schwann cell Schwann cell with a myelinated axon Schwann cell with multiple unmyelinated axon

Axon

Fig. 8.2 (Left) Myelination of peripheral neurons by Schwann cells. (Right) Myelination of central neurons by oligodendrocytes.

Sircar_Chapter08_054-062.indd 55

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56

Nerve and Muscle basal lamina persists after nerve injury and guides the regenerating axons along the right path. The so-called unmyelinated axons are also covered by a single layer of membrane and the cytoplasm of the enveloping Schwann cell. However, the myelin is not prominent.

Pseudounipolar

Central myelination Schwann cells are found only

in peripheral nerves. Myelination of neurons in the central nervous system is made by a type of neuroglial cell called the oligodendrocyte. A single oligodendrocyte can myelinate as many as 60 axons.

Bipolar

Morphological classification of neurons Golgi type-I and type-II neurons Large cells with long axons are called Golgi type-I neurons or projection neurons. These include the neurons that form peripheral nerves and long tracts of the brain and spinal cord. The Golgi type-II neurons or local circuit neurons are small neurons with relatively short axons. These comprise the bulk of the total number of cells in the human nervous system, which is about 1 trillion. Local circuit neurons have proliferated markedly in the course of evolution. The evolutionary increase in the number of sensory neurons has been much less. The number of motor neurons has remained relatively small at about 2 million. Pseudounipolar, bipolar, and multipolar neurons

Except in early embryonic stages, true unipolar neurons are not found in vertebrates. However, the primary sensory neurons (neurons conveying impulses from the sensory receptors to the spinal cord) are pseudounipolar. During early development, these neurons are bipolar but later, the roots of the two processes shift around the perikaryon and fuse into a single stem. The stem and both its branches are myelinated axons. There may be short dendritic processes at the end of the distal branch, often in association with some kind of receptor structure. In bipolar neurons, an axon projects from each end of a fusiform cell body. Cells of this type are found in the retina, vestibulo-cochlear ganglia and in the olfactory epithelium. Most vertebrate neurons, especially in the central nervous system, are multipolar. The dendrites branch profusely to form the dendritic tree. There is usually a single axon (Fig. 8.3).

Organization of neurons The nervous system is divided into the central nervous system (CNS), constituting of the brain and the spinal cord, and the peripheral nervous system (PNS), constituting of neurons lying outside the CNS. An aggregation of neuronal cell bodies located inside

Sircar_Chapter08_054-062.indd 56

Multipolar

Fig. 8.3 Pseudounipolar, bipolar, and multipolar neurons.

the CNS is called a nucleus. An aggregation of neuronal cell bodies located outside the CNS is called a ganglion. A compact bundle of axons located inside the CNS is called a tract. A compact bundle of axons located outside the CNS is called a nerve.

Axoplasmic transport Axoplasmic transport is vital to nerve cell functions. There are two forms of axonal transport: fast and slow. Fast axoplasmic transport has a velocity of 20 to 400 mm per day and may be anterograde or retrograde in direction. (1) Fast anterograde transport occurs along microtubules. It occurs from the soma to axon terminal and is driven by the molecular motor kinesin. It transports membranebounded organelles like short segments of the endoplasmic reticulum, mitochondria, small vesicles, actin, myosin, and the clathrin used in recycling of synaptic vesicle membrane. (2) Fast retrograde transport occurs from the nerve terminals to the cell body, returning materials for degradation or reuse. These materials include proteins and small molecules picked up by the axon terminal. It employs the molecular motor dynein, and is slower than anterograde transport. Retrograde transport is responsible for carrying tetanus toxin and neurotropic viruses such as herpes simplex and rabies directly to cell bodies in the CNS. It has been employed by neuroanatomists for charting out neural pathways. axoplasmic transport Slow axoplasmic transport occurs at 0.2 to 0.4 mm/d and is always

Slow

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Functional Anatomy of Nerve and Muscle anterograde. It carries protein subunits of neurofilaments, tubulins of the microtubules, and soluble enzymes. It also moves some cytosol with it. The mechanism of slow axonal transport is not clear: Probably the entire cytoskeleton moves due to the continual polymerization at the leading end and depolymerization at the trailing end, and the axoplasmic matrix moves with it.

Neuroglia Neuroglia, meaning “nerve glue,” is the connec-

tive tissue of the brain. In the CNS, neuroglial cells are ten times more numerous than neurons. These cells provide structural and trophic support to neurons, and depending on their type, serve other important functions. Although neuroglia cells are interconnected through gap junctions, glial cells do not conduct action potentials. The major neuroglial cells are astrocytes, oligodendroglia, and microglia (Fig. 8.4). The Schwann cells of peripheral nerves and the ependymal cells of cerebral ventricles are also considered to be neuroglial cells. Astrocytes are star-shaped glial cells. (1) They form the skeleton of the CNS. In the developing nervous tissue, astrocytes provide the framework along which young neuronal cells migrate to their final positions. (2) They form an insulation around synapses so as to prevent chaotic spread of nerve impulses. These astrocytes around synapses have an important role in restoring synaptic contact following disruption of synapses. (3) Astrocytes proliferate and form scars after neuronal damage. (4) They clear the neural tissues of K+ and excess neurotransmitters that accumulate extracellularly following neural activity. (5) Through their processes

Fibrous astrocyte

Protoplasmic astrocyte

57

and footplates on the walls of blood vessels, astrocytes contribute to the formation of the blood– brain barrier. (6) Astrocytes also store glycogen. When stimulated by neurotransmitters like norepinephrine, they convert the glycogen into glucose and release it for the consumption of the neurons. Oligodendrocytes resemble astrocytes but, as their name indicates, have fewer dendrites. They myelinate central neurons. Microglial cells resemble oligodendrocytes but, as the name suggests, are much smaller in size. They are phagocytic cells that clear up myelin and cellular debris in injured areas.

Muscle fibers Muscles are contractile tissues whose cells are traditionally called “fibers.” Histologically, some muscle fibers show cross striations while others do not. Functionally, some muscles show ephaptic conduction, with the action potential spreading from cell to cell. Such muscle fibers contract spontaneously. In others, ephaptic conduction is absent. These muscle cells contract only when stimulated through nerve fibers. Accordingly, there are four types of muscle fibers based on their histological and functional characteristics (Table 8.1).

Skeletal muscle Skeletal muscle fibers are striated, cylindrical, and multinucleate (Fig. 8.5). They are 10 to 30 cm in length—long enough to justify the term “fiber.” They are formed by fusion of several smaller cells. Skeletal muscles are so named because they are attached to bones by tendons and move these bones and the loads borne by them. They are the only muscles under voluntary control. Like all other cells, the skeletal muscle fiber also has a cell membrane called the sarcolemma, smooth endoplasmic reticulum called the sarcoplasmic reticulum, cytoplasm called the sarcoplasm, and cytoskeletal proteins, which are of three types: contractile, regulatory, and anchoring proteins. The contractile proteins are myosin and actin. These two proteins interact to generate the Table 8.1 Classification of muscle fibers

Oligodendrocytes

Fig. 8.4 Neuroglial cells.

Sircar_Chapter08_054-062.indd 57

Microglia

Striated

Nonstriated

Ephaptic conduction present

Cardiac muscle

Single-unit smooth muscle

Ephaptic conduction absent

Skeletal muscle

Multiunit smooth muscle

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58

Nerve and Muscle The transverse tubules are transverse invaginations of the sarcolemma into the cell. They typically occur at the A-I junctions in mammals and at the Z-disk in amphibians (see Fig. 15.2). Being extensions of the sarcolemma, the transverse tubules conduct the action potentials from the sarcolemma into the interior of the cell along its membranes. The longitudinal tubules are disposed longitudinally along the entire length of the A and I bands. They end in dilated sacs called lateral cisterns (Fig. 8.6).

Fig. 8.5 Muscle cells. (Above) Skeletal muscle fibers. (Middle) Smooth muscle cells. (Below) Cardiac muscle cells.

contractile force in a muscle. The regulatory proteins are tropomyosin and troponin. Also called the “relaxation proteins,” these regulate the interaction between actin and myosin. The anchoring proteins are α-actinin, titin, nebulin, and dystrophin. These proteins anchor the cytoskeletal proteins to each other as well as to the sarcolemma and the extracellular matrix. Sarcoplasmic reticulum In a muscle cell, the sarcoplasmic reticulum is disposed in a highly geometrical way: some run parallel to the length of the fiber (the longitudinal or L-tubules), while others are disposed radially, coursing from the surface toward the center of the fiber (the transverse or T-tubules).

Sircar_Chapter08_054-062.indd 58

The cytoskeletal proteins are disposed in a remarkably orderly way because of which the muscle fiber shows transverse striations when viewed under the light microscope. With special techniques, the striations are seen to correspond with dark and light bands (see Fig. 15.2). A line called the Z-line extends through the middle of the light band. The part of the muscle fiber that extends between two consecutive Z-lines is called a sarcomere, which is the contractile unit of muscle. During muscle contraction, the Z-lines come closer together and the sarcomeres shorten. The five major types of cytoskeletal proteins are discussed below in details. Myosin filaments are thick and disposed longitudinally at the center of a sarcomere (Fig. 8.6). A myosin filament is made of two intertwined heavy H-chains. The heavy chain has a globular head and a long tail. The tails are helically intertwined while the heads remain separate. Each globular head contains two light L-chains. In the sarcomere, the myosin tails are grouped into a bundle from which the globular heads called myosin heads project out (Fig. 8.7A). Digestion with trypsin generates two fragments of the myosin molecule: the heavy meromyosin (HMM) and the light meromyosin (LMM). The HMM contains the globular head as well a part of its fibrous tail. It can be split further by papain into two parts: the globular HMM S1, which has all the ATPase activity and actinbinding ability, and the fibrous HMM S2, which has none of it. The LMM comes entirely from the fibrous tail of the myosin molecule. It does not have any ATPase activity or actin-binding ability (Fig. 8.7B). Actin filament is a double helical filament (F-actin) (Fig. 8.8). It is made of globular subunits called G-actin. In a sarcomere, actin filaments are attached at one end to the Z-disk. There are specific sites on the actin filament that bind to the myosin head during muscle contraction. These sites are called active sites. Tropomyosin is a filamentous molecule that consists of two chains, α and β. The tropomyosin filament lies in the groove between the two filaments of actin, and each tropomyosin filament spans

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Functional Anatomy of Nerve and Muscle

L-tubule (in A-band)

L-tubule (in I-band)

Mitochondria T-tubule

Triad

Z-disk

Terminal cistern

59

Thick filament

Thin filament

A-I junction

Fig. 8.6 The transverse and longitudinal tubules.The T-tubule and two lateral cisterns on its sides constitute a triad. Note that the L-tubules in the I-band are shorter and less regular than the L-tubules in the A-band because the width of the I-band changes during muscle contraction, subjecting the L-tubule to compression. The I-band region is crowded with mitochondria.

A

Myosin filaments

α-actinin

A

Titin

Myosin head B

B

Basal lamina matrix

HMM (Heavy meromyosin)

HMM S1

Laminin (Merosin) Dystroglycan

HMM S2

LMM (Light meromyosin)

Trypsin

α-helix Myosin head

in oph str Dy I C T

Syntrophin I C T

Fig. 8.8 Anchoring proteins in muscle. [A] Location of α-actinin and tinin filaments in a sarcomere. [B] Dystrophin-associated glycoproteins.

Myosin light chains

Fig. 8.7 Myosin filaments. [A] Organization of myosin filaments. [B] Structure of myosin filaments.

seven G-actin subunits. Tropomyosin keeps the active sites of the actin molecules covered when the muscle is not contracting. For contraction to be initiated, the tropomyosin filament must slide off and uncover the active sites (see Fig. 15.1B).

Sircar_Chapter08_054-062.indd 59

Sarcoglycan

Sarcolemma

Papain

Troponin is attached to tropomyosin (see Fig. 15.1B). It has three subunits: troponin-T, which binds to tropomyosin, troponin-C, which binds to four ions of Ca2⫹, and troponin-I, which holds the tropomyosin filament over the active sites on actin so long as troponin-C is not bound to Ca2⫹. Anchoring proteins (Fig. 8.8A) are noncontractile.They lend structural support to the sarcomere. Titin, for example, anchors the myosin filaments at

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60

Nerve and Muscle the center of the sarcomere, equidistant from the Z-disks: The sarcomere resists stretching because the titin filaments provide the series elastic component of the muscle (see p 104). Others, like desmin, maintain the spacing between myofilaments while dystrophin anchors actin to the sarcolemma. Genetic defects in dystrophin molecule produce Duchennes muscular dystrophy.

Smooth muscle Smooth muscle cells (Figs. 8.5 and 8.9) are nons-

triated, fusiform (spindle-shaped), and uninucleate. Table 8.2 Structural differences between skeletal and smooth muscle fibers Skeletal muscle fiber

Smooth muscle fiber

Is large, cylindrical, and multinucleate

Is small, spindle shaped, and uninucleate

Has well-developed T-tubules

Has caveoli that are rudimentary T-tubules

Has Z-disks

Has dense bodies that are analogous to Z-disks

Actin and myosin filaments are roughly equal in number

Actin filaments far outnumber the myosin filaments

Actin filaments are parallel

Actin filaments radiate from the dense bodies

Caveolus

Dense body

They are 0.02 to 0.5 mm in length. Smooth muscles are of two type single unit and multi-unit (see Table 8.2). Single-unit (visceral) smooth muscles are present in the walls of the gastrointestinal and genitourinary tract. All the fibers in a single-unit smooth muscle contract together, near-simultaneously or sequentially, due to the presence of ephaptic (cellto-cell) conduction of electrical excitation. Multiunit smooth muscles are found in the intrinsic ocular muscles, piloerector muscles, vas deferens, and in the walls of large elastic arteries. Fibers of multiunit smooth muscles contract in response to nerve stimulation in much the same way as skeletal muscle fibers. However, they are innervated by autonomic fibers that are not under voluntary control. Smooth muscles have functionally important structural differences with striated muscles, both skeletal and cardiac: (1) the sarcolemma shows short invaginations into the cytoplasm called caveoli, which are analogous to the T-tubules in skeletal fibers. (2) There are several fusiform densities present in the cytoplasm. These are called cytoplasmic dense bodies. They contain the protein α-actinin and are the equivalent of the Z-disks in skeletal muscle fibers. Extending between cytoplasmic dense bodies are the contractile filaments (actin and myosin), and intermediate filaments, which are made of desmin and provide a cytoskeletal framework. In vascular smooth muscle, the intermediate filament is made of vimentin. (3) Dense bodies along the inner surface of the sarcolemma are called subsarcolemmal dense plaque. They contain vinculin and talin. (4) The ratio of actin and myosin filaments is ~12:1 in smooth muscles compared to ~2:1 in skeletal muscles. The myosin filaments are different in skeletal and smooth muscles. In smooth muscles, the projecting heads of the myosin molecules form cross-bridges along their entire length with the actin filaments, whereas the thick filaments of skeletal muscle have a bare central segment that is devoid of cross-bridges. (5) The regulatory proteins tropomyosin and troponin are absent in smooth muscle. Instead, smooth muscles contain the regulatory chain of myosin, which is analogous to tropomyosin, and calmodulin, which is functionally analogous to troponin.

Cardiac muscle Fig. 8.9 Smooth muscle fiber. (Above) Structure of a smooth muscle fiber. (Middle) A smooth muscle fiber in the contracted state. (Below) Actin fibers radiate from the dense bodies, with several actin filaments surrounding a single myosin filament.

Sircar_Chapter08_054-062.indd 60

Cardiac muscle cells are striated, about 0.1-mmlong cylindrical cells, some of which are branched (Fig. 8.5). The cells are joined end-to-end, separated by the intercalated disks that provide low-resistance bridges for passage of electrical excitation

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Functional Anatomy of Nerve and Muscle

61

Myelin sheath Motor axon Motor end plate

Schwann cell Mitochondrium Synaptic vesicles

Postsynaptic folds

Nerve ending

Basal membrane

Muscle fiber

Fig. 8.10 Neuromuscular junction.

from cell to cell. Cardiac muscle is found only in the heart, and hence its name. Cardiac muscle has functional resemblances with both smooth muscle and skeletal muscle. Cardiac muscle resembles visceral smooth muscle in that (1) it has automaticity, (2) it can conduct impulses ephaptically, and (3) its contractility is affected by hormones. Cardiac muscle resembles skeletal muscle in that (1) it contains regular sarcomeres delimited by Z-disks, (2) shows similar length–tension relationship, and (3) its contraction is regulated by troponin–tropomyosin complex.

called the motor endplate that bears acetylcholine receptors. The motor endplate is thrown into folds called the junctional folds. The acetylcholine receptors are clustered at the crest of each junctional fold, which are positioned opposite the active zones of the prejunctional membrane. The 100-nm-wide space between the terminal button and the motor endplate is called the myoneural cleft. The cleft is not uniformly wide. It is less than 1 nm in width at the tips of the junctional folds. Contact junctions in multi-unit smooth muscle

Neuromuscular junction A junction between two neurons that permits the passage of an electrical impulse across it is called a synapse. The neuromuscular junction (Fig. 8.10) is essentially a synapse between an axonal ending and a muscle fiber. As the axon supplying a skeletal muscle fiber approaches its termination, it loses its myelin sheath. The axis cylinder then branches into a number of bulbshaped endings called terminal buttons, each of which innervates a muscle fiber. The terminal buttons contain many small synaptic vesicles that contain acetylcholine, which is the neurotransmitter at neuromuscular junctions. The sites of the prejunctional membrane that are specialized for vesicular release of neurotransmitter are called the active zones. The terminal buttons come in close proximity with a thickened trough on the muscle membrane

Sircar_Chapter08_054-062.indd 61

Varicosities containing neurotransmitter

Diffuse junctions in single-unit smooth muscle

Varicosities containing neurotransmitter

Fig. 8.11 Synapse en passant. (Above) Contact junctions. (Below) Diffuse junctions.

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62

Nerve and Muscle Within the cleft is a basement membrane or the basal lamina made of collagen and other matrix proteins. The enzyme acetylcholinesterase (AChE) is anchored to the collagen fibrils of the basement membrane.

branches and terminates to innervate multiple fibers. Finally, the neurotransmitters released from the varicosities (the junctional neurotransmitters) can be either acetylcholine or norepinephrine. This is unlike the axonal ending in skeletal muscle that releases only acetylcholine. Contact junctions In multiunit smooth muscles,

Neuromuscular junctions in smooth muscle Smooth muscles are innervated by autonomic nerve fibers. Unlike the skeletal muscle fiber, which has a motor endplate, the smooth muscle does not show any specialization at its site of contact with the axon. Moreover, the axon innervating smooth muscle does not end at the site of innervation. Rather, the axon shows multiple swellings or varicosities along its course (en passant) that make close contact with the muscle cells along its path. Such synapses are called synapse en passant (Fig. 8.11).The varicosites liberate neurotransmitters that act on the smooth muscle cells. This is unlike the skeletal muscle where the neuron

the varicosities come in close contact with individual cells forming contact junctions. Here, the muscle membrane is separated from the varicosity by a gap of roughly the same width as in a neuromuscular junction. Hence, the junctional delay (i.e., time taken for the impulse to travel from the neuron to the muscle membrane) is comparable to that in a neuromuscular junction of a skeletal muscle. Diffuse junction In single-unit smooth muscle, the varicosities do not come in close contact with any cell. Neurotransmitters from the varicosities diffuse away to reach all the muscle cells. This arrangement has been called a diffuse junction. The junction delay is considerably more in diffuse junctions.

REVISION QUESTIONS 1. Which morphological feature of the neuron indicates that the neuron does not undergo mitosis? 2. What are Nissl bodies? 3. Which of the following is absent in the neuronmicrotubule, microfilament or intermediate filament? 4. Which part of the neuron is called the “spike trigger zone”? 5. What is ”holding capacity” of the neuron and why is it high in the dendritic spines? When do the dendritic spines increase in number?

Sircar_Chapter08_054-062.indd 62

6. Inside the brain, neurons are mostly unmyelinated whereas outside the brain, they are mostly myelinated. What is the significance of this difference? 7. How is the myelin sheath of a neuron produced? 8. What are the differences between Golgi type I and type II neurons? 9. What is the difference between “true” unipolar neuron and”pseudo-unipolar neuron?” 10. What are the physiological roles of fast anterograde, fast retrograde and slow axoplasmic transport?

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9

Degeneration and Regeneration of Nerve and Muscle

Nerve

The epineurium is

Peripheral nerves are enclosed in three connective tissue sheaths: the epineurium, perineurium, and endoneurium (Fig. 9.1). The endoneurium is bound internally by the basal

lamina around the Schwann cells and externally by the relatively impermeable inner basal lamina of the perineurium. The interstitial fluid of the endoneurium does not exchange freely with the capillary blood flowing through it because the capillaries have tightly adherent endothelial cells. This barrier represents an extension of the blood–brain barrier. It is important for maintaining the appropriate environment for the axons and for protecting them from harmful agents. When a nerve gets infected, the sleeve of endoneurium provides a conduit through which the invading bacteria or neurotropic viruses can reach the central nervous system. The perineurium is the middle connective tissue

sheath, which is bounded by its internal and external basal lamina. The cells of the perineurium are tightly adherent and act as a barrier to passage of particulate tracers, dye molecules, or toxins into the endoneurium.

the outermost connective sheath that sends extensions into the nerve, compartmenting the nerve into fascicles. The epineurium limits the stretching of nerves during body movements or external pressure, thereby protecting the delicate axons inside the nerve.

Nerve growth The growth cone is the expanded tip of an elongating axon. It has three regions: a central core, which is rich in mitochondria, the filopodia, which are slender projections of the central core, and the lamellopodia, which are the “webs” between the filopodia (Fig. 9.2). The motility of the filopodia, is made possible by the reorganization of the cytoskeleton inside it. The actin microfilaments polymerize near the tip of the filopodia and depolymerize at the other end. The filopodial membrane also has receptors for various molecules present in its environment. When certain key molecules bind to the filopodial receptors, they activate a second messenger system that alters filopodial motility. Trophic factors affecting axonal growth Neurotrophins promote nerve growth. They are secreted by the target cells. The best known nerve growth factor

Unmyelinated neurons

Myelinated neurons

Endoneurium

Perineurium

Epineurium Blood vessels

Fig. 9.1 Structure of a peripheral nerve.

Sircar_Chapter09_063-068.indd 63

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64

Nerve and Muscle

Central core

Neurofibrils

Retrograde transneuronal degeneration

Chronic atrophic response

Acute chromatolytic response

Wallerian degeneration

Filopodia Lamellopodia

Anterograde primary transneuronal degeneration

Fig. 9.2 The growth cone of a neuron.

(NGF) is the neurotrophin, which is also the first one to be discovered. Neurotrophins are essential for the survival of neurons. In their absence, the neuron perishes through apoptosis. Neurotrophins induce the formation of certain proteins that inhibit apoptosis of neurons. Hence neurons heading toward neurotrophin-secreting target cells survive, while those straying away perish. Laminins are growthpromoting molecules present in the extracellular matrix that attract the growth cone toward them. Integrins are the complementary molecules present on the growth cone that bind to laminins and other growth-promoting molecules in the extracellular matrix. Cell-adhesion molecules (CAMs), which are known for their ability to bring about cell-to-cell adhesions, also stimulate axonal growth. They are present in the extracellular matrix. factors affecting axonal growth The word tropic means “turning toward or from a stimulus.” It is different from the word trophic, which means “nourishing or providing nutrition.” Neurons growing toward the source of a trophic factor are likely to survive while those growing away from it generally perish. Hence, “trophic” factors also function as “tropic” factors, although the reverse is not true. Netrins are chemoattractant molecules that attract the growth cone toward them. Ephrins and semaphorins provide repulsive axon guidance signals (RAGS), that is, they direct the advancing growth cone away from them. Tropic

Nerve degeneration When an axon is crushed or severed, it results in degeneration of the neuron both distal (antero-

Sircar_Chapter09_063-068.indd 64

Anterograde secondary transneuronal degeneration

Fig. 9.3 Types of neuronal degeneration.

grade) and proximal (retrograde) to the site of injury (Fig. 9.3). Anterograde degenerative changes affect not only injured neurons but also the neurons that are functionally associated with the damaged ones. Such transneuronal degeneration is common in lesions of the retina, which result not only in the primary transneuronal degeneration of the ganglion cells but also secondary transneuronal degeneration of the lateral geniculate cells. Anterograde degeneration in the injured neuron is commonly called Wallerian degeneration (Fig. 9.4). Within 24 hours, neurofilaments break up and the axon fragments into short lengths. Within 10 days, the myelin decomposes into lipid droplets and in 3 months, macrophages phagocytose the debris, leaving behind only the endoneural tube. Retrograde degenerative changes affect the part of the axon proximal to the lesion, the cell body, and the dendritic tree. However, it mostly extends only up to the first node of Ranvier proximal to the injury. Retrograde changes can be transneuronal too. For example, surgical ablation of the cerebral cortex results in retrograde degeneration of the neurons projecting from the anterior thalamic nuclei to the cortex and retrograde transneural degeneration of the neurons that project to the anterior thalamic nuclei from other thalamic nuclei.

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Degeneration and Regeneration of Nerve and Muscle

Endoneurium

65

Glial cell

Schwann cell

Nissl bodies

Peripheral displacement of nucleus

Synaptic stripping

Lipid droplets

Chromatolytic changes Fragmentation of Golgi apparatus Fragmented neurofilaments

Disappearance of neurofibrils

Fig. 9.5 Chromatolytic changes in the soma of a nerve. Macrophages

Debris

Fig. 9.4 Wallerian degenerative changes in a nerve fiber.

The degeneration in the injured neuron may be of the acute or the chronic type. The chronic retrograde atrophic response follows the acute response only occasionally. It involves the atrophy of the nerve cell body with all its processes. Acute retrograde (chromatolytic) response starts after 24 hours and is characterized by the disintegration of Nissl substance into fine dust (Fig. 9.5). Nissl substance represents inactive, aggregated RNA. Following chromatolysis, the RNA disperses in the cytoplasm, enabling the neuron to mobilize protein synthesis, which is required for regeneration. The chromatolysis begins near the nucleus and spreads to other parts of the cell body. It is therefore called central chromatolysis. Sometimes, however, the chromatolysis usually fades inward away from the cell periphery toward the nucleus. It is called peripheral chromatolysis and occurs in certain infectious or degenerative diseases of the nervous system such as poliomyelitis and progressive muscular atrophy. The chromatolysis increases with the proximity of the site of injury to the nerve cell. Following are the other acute retrograde changes that follow an axonal injury: (1) swelling of the cell. (2) Displacement of the nucleus from its normal central position to one at the periphery, away from the axon hillock. It may even be completely extruded, in which case the cell atrophies and completely disappears.

Sircar_Chapter09_063-068.indd 65

(3) Fragmentation and reduction of the Golgi apparatus. (4) Disappearance of neurofibrils. (5) Synaptic stripping, that is, withdrawal of the synapsing axon from the cell or its separation from the cell by the interposition of a glial cell. It is possible to locate the origin of a nerve or a tract by cutting it and locating its origin by looking for neurons exhibiting central chromatolysis. Such technique is now obsolete and superceded by techniques exploiting anterograde and retrograde axoplasmic transport (see p 56).

Nerve regeneration Repair begins about 20 days after nerve section and is complete in 3 months. Regenerative changes usually occur simultaneously in the cell and the axon. In the axon: (1) the Schwann cells at the site of injury multiply, forming a solid cord of elongated cells (band of Bungner) within the endoneural tube (Fig. 9.6). (2) The plasmalemma of the Schwann cells and adjacent basal lamina separate, creating an annular compartment between the Schwann cells and the endoneurium. (3) Axonal sprouts, each containing a neurofibril, grow out in all directions from the proximal axon. Some of them grow into the distal annular compartment. Eventually all but one axonal sprout degenerate. The surviving fibril enlarges to fill the distal tube. (4) The Schwann cells in the Band of Bungner form myelin sheath around the reinnervating axonal sprout. In the cell body, the Nissl substance and Golgi apparatus gradually reappear. Sometimes, they reappear in greater than the original amounts, reflecting the extra metabolic effort required to replenish large amounts of the axoplasm. The cell regains its normal size and the nucleus returns to its central position.

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Nerve and Muscle

Endoneurium

Axonal buds entering endoneural tube

Macrophage clearing debris

Schwann cells forming Band of Bungner

A single axonal bud ensheathed by Schwann cell

Axonal bud

Schwann cell

Longitudinal section

Cross section

Fig. 9.6 Regenerative changes in the axon of a neuron. Table 9.1 Sunderland classification of nerve injury Type

Axon

Basal lamina

Endoneurium Perineurium Epineurium Recovery

I (Neuropraxia)

Intact

Intact

Intact

Intact

Intact

Full recovery in Tinel sign hours absent

II (Axonotemesis) Disrupted Intact

Intact

Intact

Intact

Full recovery in Advancing Tinel 3 mo sign

III

Disrupted Disrupted

Disrupted

Intact

Intact

Incomplete Advancing Tinel recovery at 3 mo sign

IV

Disrupted Disrupted

Disrupted

Disrupted

Intact

No recovery

Tinel sign stationary

V (Neurotemesis) Disrupted Disrupted

Disrupted

Disrupted

Disrupted

No recovery

Tinel sign stationary

Classification of nerve injury Seddon classification describes three types of nerve injury, viz., neuropraxia, axonotemesis, and neurotemesis, while Sunderland classification describes five types of injury (Table 9.1). (1) Neuropraxia occurs due to minor nerve stretch or pressure causing ischemic injury to the nerve. It results in conduction block without structural damage. The common experience of a limb “going to sleep” is due to neuropraxia. (2) Axonotemesis occurs due to excessive stress injury to the nerve. It results in Wallerian degeneration. The basal lamina of Schwann cells and other sheaths are all intact. (3) Neurotemesis occurs as a result of penetrating injury to the nerve. All the sheaths are disrupted. Tinel sign The damaged nerve is tested by lightly percussing on its course with a patella hammer from

Sircar_Chapter09_063-068.indd 66

Tinel sign

the distal to the proximal end. The Tinel sign refers to the tingling sensation that is experienced when the site of regeneration is reached. As the regenerating axon grows, the site of the tingling sensation also shifts. This is called the advancing Tinel sign.

Skeletal muscle Each skeletal muscle fiber is surrounded by a thin basal lamina of connective tissue called the endomysium. Parallel fibers are grouped into fascicles that are surrounded by the perimysium. The whole muscle is enclosed in a tough connective tissue sheath called epimysium from which thin septa extend to join the perimysium. Blood vessels ramify in the epimysium and penetrate via the septa of the perimysium to form a rich capillary network in the endomysium (Fig. 9.7).

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Degeneration and Regeneration of Nerve and Muscle

Myofibril Muscle fiber (muscle cell)

10—100 µ

Endomysium

A

67

Myosatellite cell Basal lamina

Sarcolemma Basal lamina Satellite cell Cell nuclei

Secondary bundle Primary bundle

Muscle cell

Perimysium

Muscle fascia

B

Epimysium Afferent blood vessel

Normal Nerve with motor endplates

Hyperplasia

Hypertrophy Lengthening

Fig. 9.8 Muscle fibers. [A] Satellite cells in a muscle. [B] Hypertrophy and hyperplasia of muscle cells.

Tendon

Bone

Fig. 9.7 Structure of a whole muscle, shown in cross-section.

added in series, while hypertrophy if the myofibrils are added in parallel (Fig. 9.8B). Muscle hyperplasia and hypertrophy increase muscle force during contraction. Muscle lengthening allows increased muscle shortening during contraction. Effect of exercise on muscle depends on the type of

Muscle growth Skeletal muscle fibers develop from uninucleate precursors called myoblasts. These proliferate and fuse to form long multinucleate cells called myotubes, which subsequently develop in their cytoplasm myofibrils and transform into myocytes or muscle cells. Small, flattened mononucleate cells called myosatellite cells are located between the sarcolemma and the basal lamina (Fig. 9.8A). These cells are myoblasts that fail to fuse into myotubes. They are activated later during muscle hypertrophy or regeneration and provide new myocytes. Growth of skeletal muscle involves either hyperplasia, (an increase in the number of muscle fibers), hypertrophy (an increase in the diameter of the muscle fibers), or lengthening (an increase in the length of the muscle fibers). Lengthening occurs when freshly synthesized myofibrils are

Sircar_Chapter09_063-068.indd 67

exercise. Static exercise causes muscle hypertrophy and thereby increases the force-generating capacity. The hypertrophy occurs even when the load is applied on a denervated muscle. Dynamic exercise (see Fig. 42.2) leads to an increase in the rate of oxygen utilization and is associated with an increase in the number of mitochondria and muscle capillary density. There is little change in muscle fiber diameter or the ratio of slow and fast muscle fibers (see Table 116.1). Effect of aging With age, sporadic death of motor

neurons becomes frequent. The denervated muscle fibers are reinnervated by the surviving motor neurons, resulting in the formation of large motor units (p 114) and consequently, imprecise motor control. The increase in the motor unit size is apparent in the electromyogram. As more motor neurons die, more muscle fibers remain denervated causing loss of muscle power. Eventually, some muscles become completely denervated.

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Nerve and Muscle

Muscle degeneration Degeneration of muscle can occur following muscle injury. Following sarcolemmal damage, Ca2+ moves into the cell with consequent activation of Ca2+-dependent enzymes such as proteases and endogenous phospholipases. If the vascular supply to the muscle is intact, the degenerating muscle fiber is invaded by phagocytes from blood. The phagocytes cross the intact basal lamina sheaths and ingest muscle fiber debris. Within a few days, the bulk of this debris is removed by the phagocytes, which then depart from the site. Denervation supersensitivity Each motor endplate

contains about 50 million ACh receptors, which are highly concentrated near the tips of the postjunctional folds. Few AChRs are located elsewhere on the muscle membrane. Following a section of the motor nerve, the number of AChR increases more than 10-fold and are dispersed over the entire sarcolemma, as a result of which, the entire surface of the muscle cell becomes sensitive to ACh, a phenomenon known as denervation supersensitivity. Denervation also lowers the membrane potential to about –60 mV, making it prone to fibrillations. After the motor nerve regenerates and functional innervation of the muscle is reestablished, the accumulation of AChRs decreases throughout the sarcolemma and the sensitivity of the nonjunctional portion of the sarcolemma diminishes to normal levels. The normal RMP is restored and the fibrillation disappears.

Muscle regeneration Even before the degeneration of muscle is complete, satellite cells within the basal lamina sheath begin to multiply and fuse to form multinucleate myotubes within the basal lamina tube of the degenerated muscle fiber. The regenerated myotube later forms its own basal

lamina. Hence, a regenerated muscle fiber usually shows duplication of its basal lamina. If the nerve supply is intact, the myotubes are innervated within 2 days. It takes up to 3 weeks for the reinnervated muscle to grow to normal size. Cardiac muscle cannot regenerate because it does not possess satellite cells.

Synaptogenesis Synaptogenesis, that is, the formation of the junction between the axonal ending and the muscle membrane, is guided by several chemical signals emanating from both and influencing each other’s development. Prejunctional differentiation of the nerve ending is stimulated by the muscle. A major component of all basal lamina are the laminins, which are potent promoters of axonal outgrowth from the neuron. Several other factors located on the muscle, for example, cadherin and NCAM, are involved in prejunctional differentiation. Postjunctional differentiation of the motor endplate is stimulated by the nerve ending. A proteoglycan called agrin is released from nerve terminals and causes clustering of AChRs. Agrin does not bind directly to AChR. Rather, it binds to Muscle-Specific tyrosine Kinase (MuSK), a membrane-associated enzyme, triggering a second-messenger cascade that causes clustering of rapsyn, a protein associated with AChR. Neuregulin is secreted by the motor axon. It binds to specific tyrosine kinases, called erbkinases, present on the postjunctional membrane and triggers a cascade reaction that ultimately increases AChR synthesis by activating transcription of AChR genes. Also, the high sarcoplasmic Ca2+ associated with muscle contraction activates a cascade of protein kinase reactions culminating in the depression of AChR gene transcription in the in nonsynaptic areas.

REVISION QUESTIONS 1. Which connective tissue sheath of a peripheral neuron (1) acts as a barrier to the passage of particulate matter and toxin, (2) limits the stretchability of nerves, and (3) represents an extension of the blood-brain barrier? 2. “Trophic” factors also function as “tropic” factors. Why?

4. A damaged muscle fiber that has regenerated can be distinguished microscopically from an uninjured muscle fiber. How? 5. What is degeneration supersensitivity and why does it lead to fibrillation? 6. Cardiac muscle cannot regenerate. Why?

3. With age, motor control of muscle becomes less precise. Why?

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10

Resting Membrane Potential

The conduction of a nerve impulse is an electrical phenomenon. The inner surface of the neuronal membrane is charged negative with respect to its outer surface, giving the neuronal membrane a definite polarity. When this polarity, which is called the resting membrane potential, is briefly reversed, it serves as a signal that is conducted over long distances along the nerve membrane. This signal is called the action potential. However, before discussing action potential (Chapter 11), or its conduction over the nerve membrane (Chapter 13), it is necessary to appreciate the origin of the membrane polarity, which is discussed below in detail.

Diffusion potential The inner surface of a cell membrane is usually charged negative with respect to its outer surface. The potential of the inner surface of the membrane with respect to its outer surface is called the membrane potential (Fig. 10.1). The potential is called a membrane potential because it exists essentially on the membrane. The cations and anions form two layers on the outer and inner membrane surfaces, respectively. The membrane potential is pro-

+

-

Inside

+ + + + + + + + + + + + + + +

-

Outside

Fig. 10.1 A potential of about 80 mV is measurable across the cell membrane. The potential exists essentially at the membrane, with anions and cations layered on the opposite surfaces of the cell membrane.

duced by the passive diffusion of ions. Hence it is also called a diffusion potential. The membrane potential changes markedly when the membrane is stimulated. The potential recorded intracellularly when a cell is not stimulated is called the resting membrane potential (RMP) and the membrane is said to be polarized. The unmyelinated axonal membrane has an RMP of –70 mV. The membrane potential is more (–90 mV) in striated muscles and less (–50 mV) in certain smooth muscles.1 The general principles of membrane potential are the same in all excitable tissues. Most of the discussion on membrane potential in the following passages assume a membrane potential of –80 mV. When the inside of the membrane becomes more negative, it is said to be hyperpolarized. When the inside of the membrane becomes less negative, it is said to be depolarized. When following depolarization, the membrane returns to the polarized state, it is said to be repolarized.

Origin of diffusion potential The activity of the Na+–K+ pump builds up a high concentration of Na+ in the ECF and K+ in the ICF. It also indirectly contributes to the build-up of a high concentration of Cl in the ECF. The membrane potential develops when these ions leak back along their respective concentration gradients, that is, when Na+ leaks back from ECF to ICF or K+ leaks out from ICF to ECF. The streams of ions that leak back from high to low concentration are called leak currents or channel currents to differentiate them from the pump current2 produced by the Na+–K+ pump. In its resting state, the membrane is quite leaky to K+ but not so leaky to Na+. Hence, the amount of K+ that leaks out in a given time is much more than the amount of Na+ that leaks in through the membrane in the same time. As a result, an excess of K+ accumulates in the ECF, the amount of which is too small to change the ECF or ICF concentration of K+ but large enough to make the exterior of the membrane positive with respect to its interior by several millivolts.

1

The terms “low” and “high” membrane potential cause considerable confusion, and understandably so. These terms refer to the absolute values of membrane potential. Thus, whether the potential changes from -30 to -10 mV or whether it changes from +30 to +10 mV, in either case, it is decreasing.

2

The pump current is mostly ignored in discussions on membrane potential. Its role is discussed at the end of this chapter.

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Nerve and Muscle

Inside (0 mV)

Outside

K+ = 150 mEq/L

K+ = 5 mEq /L

Na+ = 10 mEq /L

Na+ = 140 mEq/L

Cl- = 5 mEq/L

Cl- = 100 mEq/L

Outward K+ current

70

60 40 20 0 5 ms

0

10

Diffusion potential of a single ion Before trying to

understand the diffusion potential of an ion, it is important to recall that whenever an ion is distributed asymmetrically across a membrane, there exists a unique potential Eion that will prevent its diffusion. This potential is called the Nernst potential of the ion (p 19) and it can be calculated using the Nernst equation. If the ions are allowed to diffuse, they produce a diffusion potential. The following passage explains why the diffusion potential produced by an ion exactly equals its Nernst potential. Take the case illustrated in Fig. 10.2. Assume that the membrane is permeable only to K+ and impermeable to Na+ and Cl–. Assume also that the membrane potential Em is 0 mV to start with. The following sequence of events will occur: (1) K+ diffuses out of the cell along its concentration gradient. The resultant decrease in intracellular K+ concentration is so small (< 10 picoEq/dL) that it hardly produces any change in the K+ concentration gradient or its rate of outward diffusion. (2) Since the membrane is impermeable to both Na+ and Cl–, the diffusion of K+ produces an intracellular negativity which is not nullified by the diffusion of Na+ in the opposite direction or by the diffusion of Cl– in the same direction. (3) The intracellular negativity reduces the rate of subsequent outward diffusion of K+. (4) As the outward diffusion of K+ continues, the membrane becomes increasingly negative inside, and the outward diffusion of K+ keeps decreasing. (5) When the membrane potential reaches about –90 mV (which is the Nernst potential for K+), the outward K+ diffusion stops. Hence, the diffusion potential produced by a single ion always equals its Nernst potential (Fig. 10.3).

3

-20 mV

Diffusion potential

0

Fig. 10.2 Distribution of ions across a semipermeable membrane that is permeable only to potassium ions. Potassium ions will diffuse out resulting in a diffusion potential that will be equal to the Nernst potential of K.

-40 -60 -80 -100 0

5 ms

10

Fig. 10.3 Consequences of the ionic distribution shown in Fig. 10.2. The outward diffusion of potassium ions declines with the build-up of a diffusion potential. The diffusion stops when the diffusion potential equals the Nernst potential of K+.

The intracellular negativity pulls back the extracellular cations to the external surface of the membrane. Similarly, the external positivity attracts the intracellular anions to the internal surface of the membrane. Hence, opposite charges line up on the opposite surfaces of the membrane.3 Hence, the membrane potential resides essentially at the membrane and can even be abolished temporarily by scraping the membrane surface. Diffusion potential of multiple ions When multi-

ple ions are diffusing across the membrane, each ion tries to drive the membrane potential its own Nernst potential. The resultant diffusion potential (Em) is called the equilibrium potential of the membrane (and not of the ion, as in case of the Nernst potential). It is given by the Goldman equation: E m = 61 log

PK [K 0 ] + PNa [Na0 ] + PCl [Cli ] PK [K i ] + PNa [Nai ] + PCl [Cl0 ]

where PK, PNa, and PCl are the conductances (permeability) of K+, Na+, and Cl–, respectively. When only one ion is permeable, the equation reduces to Nernst equation.

Together, the membrane and the opposite charges on its opposite surfaces form a parallel-plate capacitor in which the membrane is the dielectric. The capacitance of a parallel plate capacitor is known to be inversely proportional to the thickness of the dielectric. Because the membrane is very thin, the capacitance of the membrane is quite high. Membrane capacitance is an important consideration in the conduction of nerve impulses (Chapter 13).

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Resting Membrane Potential If PNa= 0 and PCl= 0, then: E m = 61 log

PK [K 0] + 0 × Na0 ] + 0 × [Cli] PK [K i ] + 0 × Nai] + 0 × [Cl0]

E m = 61 log

PK [K 0] PK [K i ]

E m = 61 log

[K 0] [K i]

In other words, when the permeability of one ion far exceeds that of the others, the equilibrium potential of the membrane will approach the Nernst potential of the highly permeable ion. The implications are as follows: (1) there is a balance of currents (Fig. 10.4), with each diffusable ion trying to drive the equilibrium potential toward its own Nernst potential. For example, Na+ tries to

A +

+60

+30

0

-30

_

71

drive the RMP toward +70 mV, K+ tries to drive the RMP toward –90 mV, and Cl– tries to drive the RMP toward +80 mV. (2) The ion that is more permeable and more distant from the equilibrium potential is more effective in driving the equilibrium potential toward its own Nernst potential. (3) The equilibrium potential or the RMP settles at –80 mV. At this RMP, both Na+ and K+ are moderately effective and balance each other. The effectiveness of the Na+ ion comes from the distance of its Nernst potential from the RMP. On the other hand, the effectiveness of the K+ ion comes from its moderate permeability. The Nernst potential of Cl– is equal to the RMP; hence Cl– is unable to influence the RMP.

Membrane currents In the case illustrated in Fig. 10.5, the outward diffusion of the positively charged K+ ions will tend to hyperpolarize the membrane. In other words, K+ carries a hyperpolarizing current.4 Since K+ is flowing out, it constitutes an outward hyperpolarizing current. Similarly, Na+ carries an inward depolarizing

-60

gNa+

gCl-

Inside (0 mV)

gK+

Membrane potential

Outside 54 μAmp

K+ = 150 mEq /L

K+ = 5 mEq /L 0.6 mΩ

B +

_

Na+ = 10 mEq /L

2.8 μA

Na+ = 140 mEq /L 0.04 mΩ

+60

+30

0

-30

-60

Cl- = 5 mEq /L

24 μA

Cl- = 100 mEq /L 0.3 mΩ

Inside (-80 mV)

Membrane potential

Fig. 10.4 [A] The balance-of-moments analogy of the balance of currents. The weights (ionic conductances) are suspended from their respective Nernst potential. A balance between the depolarizing Na+ current (anticlockwise moment) and hyperpolarizing K+ current (clockwise moment) is established when the fulcrum (RMP) is at –80 mV. Since the membrane potential is almost at the Nernst potential of Cl– (–80 mV), the chloride ion finds itself without a role in this balance of currents. [B] At the peak of action potential, the Na+ conductance increases massively and a new balance of currents is established, with the RMP at +40mV. The huge Na+ current is now balanced by the combined currents of K+ and Cl–. RMP, resting membrane potential. 4

+

K

Outside

0.6 mΩ 6 μA

= 150 mEq /L

Na+ = 10 mEq /L

6 μA

K+ = 5 mEq /L

Na+ = 140 mEq /L 0.04 mΩ Cl- = 100 mEq /L

Cl- = 5 mEq /L 0.3 mΩ

Fig. 10.5 (Above) The membrane potential is 0 mV. The total hyperpolarizing current (78 mA) carried by K+ and Cl– far exceeds the depolarizing Na+ current (2.8 mA). (Below) The membrane potential is –80 mV. The outward K+ current exactly balances the inward Na+ current.

The diffusion rate of ions can be expressed as the number of ions flowing out per second. A more convenient way is to express the ionic diffusion as a current, which is defined as the rate of flow of electric charge. One ampere current is the flow of 1 coulomb of charge per second. Since each monovalent ion carries 1.6  1019 coulombs of electric charge, 1 A of K current is the flow of 6.25  1018 K ions per second.

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72

Nerve and Muscle current and Cl– carries an inward hyperpolarizing current. The number of ions flowing out per second per square centimeter of the membrane (current density) can be calculated from Ohm Law (see p 13). Since the reciprocal of resistance is conductance, Ohm Law can be rewritten as: Current (I) = Potential (E) × Conductance (g) Outward current per unit membrane area (μA/cm-2) =

Ionic conductance Membrane Nernst potential × per unit membrane area potential of an ion (mV)

(mV)

(mΩ/cm-2)

Thus, INa = (Em – ENa ) × gNa IK = (Em – EK ) × g K ICl = (Em –ECl ) × gCl

where INa, IK, and ICI are the membrane currents, ENa, EK, and ECI are the Nernst potentials, and gNa, gK, and gCl are the membrane conductances for Na+, K+, and Cl– ions, respectively. These formulas explain why the membrane current of an ion is directly proportional to the difference between the membrane potential and the Nernst potential of the ion. This principle has already been enunciated in the balance-of-moments analogy (Fig. 10.4). The point is further illustrated through the following example. Fig. 10.5 shows the intracellular and extracellular concentrations of Na+, K+, and Cl– and their membrane conductances. Based on these data, the membrane currents of these ions at two different membrane potentials, 0 mV and –80 mV, have been calculated5 and tabulated (Table 10.1). Table 10.1 Calculation of ionic currents (Iion) at two different membrane potentials, 0 and –80 mV, using the formula: Iion = (Em – Eion)  gion

5

Membrane potential (Em mV)

Nernst potential of ion (Eion mV)

Membrane conductance of ion (gion mΩ)

Membrane current of ion (Iion mA)

0 mV

EK = -90

gK = 0.6

IK = 54

0 mV

ENa = 70

gNa = 0.04

INa = 2.8

0 mV

ECl = –80

gCl = 0.3

ICI = 24

–80 mV

EK = –90

gK = 0.6

IK = 6

80 mV

ENa = 70

gNa = 0.04

INa = 6

80 mV

ECl = –80

gCl = 0.3

ICl = 0

When membrane potential is at 0 mV, K+ will carry a strong outward hyperpolarizing current (54 mA), Na+ will carry a weak inward depolarizing current (2.8 mA), and Cl will carry a strong inward hyperpolarizing current (24 mA). Thus the total hyperpolarizing current (78 mA), carried by K+ and Cl– far exceeds the depolarizing Na+ current (2.8 mA). The intracellular potential therefore becomes negative. With increasing negativity, the depolarizing Na+ current increases and the hyperpolarizing currents of K+ and Cl– decrease. When membrane potential reaches 80 mV, K+ will carry a moderate outward hyperpolarizing current, Na+ will carry a moderate inward depolarizing current, and Cl– current stop, since –80 mV equals ECl. At this stage, the hyperpolarizing and depolarizing currents are equal and the membrane potential does not change any further. The potential at which an equilibrium is established between the depolarizing and hyperpolarizing membrane currents denotes the resting membrane potential of the membrane. Expressed mathematically, INa + IK + ICl = 0

Therefore, { (E m - E Na) × g Na } + {(Em - E K) × g K } + { (E m - E Cl) × g Cl } = 0

By expanding and rearranging, we get Em =

(EK × g K) + (E Na × g Na) + (ECl × g Cl) g K + g Na + g Cl

This is the Hodgkin-Huxley equation for calculating membrane potential. More accurate values are given by the Goldman equation, which takes into consideration the intramembrane (across the thickness of the membrane) potential gradient. Chloride current It should be clear from the

foregoing discussions that Na+ always carries an inward depolarizing current and K+ always carries an outward hyperpolarizing current. The CI– current is somewhat different. Unlike Na+ or K+ ions, there is no Cl– pump in the membrane. Hence, the Cl gradient is created almost entirely by the RMP, which pushes out Cl– ions from the cell. Hence, the Nernst potential of Cl– nearly equals the RMP. Consequently, there is no significant Cl– current across the resting membrane. Several types of nerve cells, however, do pump out Cl–through secondary active transport using K+–Cl–

In these calculations, it has been assumed that the membrane conductances of the ions do not change with changes in membrane potential. The assumption is not correct, as explained in Chapters 11 and 12.

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A

Effect of changes in ECF ionic concentrations Extracellular ionic concentrations are much more prone to perturbations as compared to intracellular concentrations. Any variation in ECF ionic concentration alters the Nernst potential of the ion. However, the change in Nernst potential is less for ions that have high concentration in the ECF (Na+, Cl–) and more for K+, which has a low ECF concentration. Table 10.2 shows that for a given amount of change in ECF concentration (e.g., 5 mEq/L), the percentage change in [Co] [Ci] is much greater for K+ (100%) than for Na+ (3.6%) or for Cl– (5%). The changes in the Nernst potentials are correspondingly larger. Hence, changes in ECF [K+] have large effects on membrane potential. As shown in the above example, a 5 mEq/L increase in the ECF concentration of Cl– will hyperpolarize the membrane slightly as its Nernst potential changes from –79.4 mV to –80.7 mV. However, a similar increase in ECF K+ depolarizes the membrane markedly as its Nernst potential changes from –90.1 mV to –71.7 mV. Hence, addition of KCl to the bathing solution of an excitable tissue depolarizes the cells (Fig. 10.6A).

Table 10.2 Effect of increasing the ECF concentration of ions (m Eq L1) on the Nernst potential (mV) Nernst potential for ions when ECF concentration are normal. Ion +

ICF conc.

ECF conc.

Nernst potential

Na

10

140

69.9

K+

150

5

–90.1

Cl

5

100

–79.4

Nernst potential for ions when ECF concentrations are increased by 5 mEq L1. Ion +

Na K

+

Cl

ICF conc.

ECF conc.

Nernst potential

10

145

70.8

150

10

–71.7

5

105

–80.7

Sircar_Chapter10_069-075.indd 73

73

0

-25

-50

-75 1

3

10

30

100

300

External [K+] (mM)

B

Na+–K+ pump activity (Na+ efflux in pM /cm2/s

cotransport. In these cells, the ECl is slightly more negative than the RMP, and Cl– carries a weak, inward hyperpolarizing current. Another situation in which the ECl and RMP are different is when the gNa increases massively, as during an action potential. In this situation, the Cl– sets up a moderately strong inward hyperpolarizing current as shown in Fig. 10.4B.

Resting membrane potential (mV)

Resting Membrane Potential

100

50

50

100 150 [Na+]i (mM)

Fig. 10.6 [A] Effect of increasing the extracellular K+ concentration of the membrane potential. [B] Dependence of Na+–K+ pump activity on the intracellular Na+ concentration.

Pump current The role of the Na+–K+ pump in the development of membrane potentials is mostly misunderstood by students. This is unfortunate, since membrane potential is one of the best understood areas of physiology. Before considering the role of the Na+–K+ pump in membrane potential, two facts that are discussed below must be understood. A strong pump that is working slowly The first thing that must be realized is that the Na+–K+ pump works very feebly in the resting cells, pumping out the small amounts of Na+ and K+ that diffuses across the cell membrane. However, during an action potential, large amounts of Na+ diffuse in and equally large amounts of K+ diffuse out. The pump works much faster to transport these ions back to the extracellular and intracellular compartments, respectively, for the maintenance of cell homeostasis. Let us imagine the original situation when the ECF and ICF concentrations were equal and the Na+–K+ pump just got into action. The pump activity must have been very high initially because the intracellular Na+ concentration was high. However, as more and more Na+ was pumped to the exterior, the pump current decreased. This is because

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74

Nerve and Muscle

Water tank

Pump house

Domestic water supply

Fig. 10.7 A water pump raises the water head in an overhead tank for domestic water supply. This provides a useful analogy for understanding the role of the Na+–K+ pump in the generation of membrane potential.

the activity of Na+–K+ pump is directly proportional to the intracellular Na+ concentration (Fig. 10.6B). At the usual intracellular Na+ concentration of 10 mEq/L, the pump current is feeble and adds only about –3 mV to the diffusion potential. The analogy of the overhead tank for domestic water supply provides a useful insight (Fig. 10.7). A water pump (analogous to the Na+–K+ pump) fills up the overhead water tank and creates a hydrostatic pressure head (analogous to the ionic concentration gradient). When the water tank is full, the pump cannot run fast. Nor is it required to, since it needs only to replenish the water that is flowing out continuously to the houses. Switching off the pump therefore will not immediately affect the water pressure at the tap (analogous to RMP), which is maintained by the pressure head in the water tank. This is analogous to the situation in neurons where inhibition of the membrane pump reduces the RMP from –70 to –67 mV, a decrease of only 3 mV. The analogy can be extended further. When the domestic water consumption is very high, the water head in the tank is low. The low water head reduces the load on the pump, which therefore pumps more water. A new equilibrium is reached in which the pump works very hard to replenish the large amount of water that is consumed by domestic users. However, the equilibrium is attained at a lower pressure head in the overhead tank. If the pump is switched off now, the pressure head in the tank will fall considerably. This is analogous to the situation in smooth muscles where the RMP is low (–50 mV) and inhibition of the pump decreases the membrane potential by as much as 20 mV. An electrogenic pump rendered electroneutral The

second important thing that must be realized is that although the Na+–K+-pump is potentially

Sircar_Chapter10_069-075.indd 74

electrogenic (because of pumping out three Na+ ions for every two K+ ions that are pumped in), the pump is too slow to increase the membrane potential significantly: As soon as the pump creates a negative potential inside the cell, chloride ions quickly restore electroneutrality by diffusing out of the cell. (Recall that at any instant, the membrane potential is nearest to the equilibrium potential of the fastest diffusing ion. In this race, the pump current does not stand a chance!) Thus in effect, the Na+–K+ pump pumps out three Na+ ions and one Cl ion for every two K+ ions it pumps in. The real role of the Na+–K+ pump is that it builds up a high K+ concentration within the cell and a high Na+ concentration outside the cell, setting the stage for the development of a diffusion potential.

Restoration of cell homeostasis During the resting state, a cell with a polarized membrane continuously loses K+ to the exterior

Inside (-80 mV)

Outside K+ 6 µA

6 µA Na+

Inside

Outside K+ 6 µA

6 µA Na+ 6 µA

4 µA

Inside (-83.2 mV)

Outside K+

6.128 µA

4.085 µA Na+ 6.128 µA

4.085 µA

Fig. 10.8 Effect of pump current on cell homeostasis and membrane potential. (Above) Membrane potential is 80 mV. Pump is not operational. The leak currents balance each other. (Middle) Pump is operational, resulting an unbalanced outward K current of 2 mA. (Below) Membrane potential is 83.2 mV. Leak currents and pump currents get readjusted accordingly.

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Resting Membrane Potential and gains Na+ through their respective channels. The membrane potential does not change because the outward K+ current equals the inward Na+ current. However, due to these continuous channel currents, the intracellular and extracellular concentrations of these ions tend to equalize which, if allowed to continue, would eventually result in the disappearance of the membrane potential. But this does not happen because of Na+–K+ pump pumps out three Na+ ions for every two K+ ions transported inside. Balancing pump current with channel current Suppose, in a resting nerve cell, the channel

currents produce Na+ influx and K+ efflux in a ratio of 1:1. Yet, the Na+–K+ pump, which produces Na+ efflux and K+ influx in a ratio of 3:2, is able to restore cell homeostasis. Before understanding how the same is possible, it is important to recall that the activity of the Na+–K+ pump (and the resultant pump current) increases when the intracellular concentration of Na+ rises. Let us take the example shown in Fig. 10.8. When the pump is inactive, the leak currents of Na+ and K+ balance each other (both are 6 mA) so that the membrane potential does not change. However, cell

75

homeostasis is threatened as the intracellular concentration of K+ and extracellular concentration of Na+ decrease continuously. To prevent these losses, the Na+–K+ pump becomes operational, generating an outward Na current of 6 mA and an inward K+ current of 4 mA. (Recall that the Na+ and K+ pump currents are in a ratio of 3:2.) The pump current of Na+ exactly balances the leak current of Na+. However, the K+ leak current is not fully balanced by the K+ pump current and there remains an unbalanced K+ leak current of 2 mA. This outward K+ current hyperpolarizes the membrane slightly, taking the membrane potential to 83.2 mV. The hyperpolarization reduces the K+ leak current to 4.085 mA and increases the Na+ leak current to 6.128 mA. The increase in Na+ leak current stimulates the pump activity so that the pump currents for K+ and Na+ become 4.085 mA and 6.128 mA, respectively. The pump currents now completely balance the leak currents and cell homeostasis is no longer threatened. In the new equilibrium, the following may be noted: (1) the Na+ current (6.128 mA) and K+ current (4.085 mA) are in a ratio of 3:2. This is true for both leak currents as well as pump currents. (2) The activity of the Na+–K+ pump has made a difference of only 3.2 mV.

REVISION QUESTIONS 1. Inactivation of the Na+-K+ pump does not immediately change the membrane potential significantly. Why? 2. The RMP of an axon is nearest to the equilibrium potential of Cl– and farthest from the equilibrium potential of Na+. Why?

Sircar_Chapter10_069-075.indd 75

3. The membrane depolarizes when KCl is added to the ECF. Why? 4. Even large changes in the ECF concentration of Na+ or Cl– does not change the RMP significantly. Why?

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11

Nerve and Muscle

Membrane Excitation and Action Potential

Action potential The action potential (nerve impulse) is the signal that is transmitted along the axon over long distances with no reduction in amplitude. Any quick and brief change in the RMP (depolarization or hyperpolarization, small or large in magnitude) constitutes a signal. However, except the action potential, all other signals fade out after traveling short distances along a membrane. The action potential is a brief reversal of membrane polarity followed by a quick restoration of the normal polarity. Each action potential lasts a few milliseconds. All-or-none law An action potential is usually fullsized with a fixed amplitude of about 110 mV (from –70 mV to +40 mV). Subthreshold stimuli cannot trigger action potentials. Once triggered, an action potential runs its entire course producing a fullyfledged spike. This is known as the all-or-none law. This law does not rule out the possibility of a small or medium-sized action potential that may be produced, depending on the prevailing conditions of membrane potential and excitability, ionic concentrations, and temperature. It only emphasizes that the height of the spike does not increase in a graded manner with the stimulus strength: it is either maximum (all) or it is not triggered at all (none) (Fig. 11.1). In vivo, a change in the strength of a physiological stimulus alters the frequency of action potentials.1 Phases of action potential The action potential, which is recorded using an intracellular electrode (Fig. 11.2), has five phases, viz. prepotential, depolarization, repolarization, after-depolarization, and hyperpolarization (Fig. 11.2). (1) The prepotential, also called the “foot” of the action potential, is a local membrane potential that drifts slowly toward –55 mV, which is called the firing level. Strictly speaking, it is not a part of the action potential. (2) During depolarization, the potential shoots up to +40 mV in less than a millisecond. (3) During repolarization, the potential drops to near resting levels, that is, to about −40 mV. This phase also lasts less than a millisecond. The depolarization and repolarization phases of the action potential together constitute the spike potential. Although the 1

Fig. 11.1 The (f)all or none law! (Above) When a vertical block is tilted slightly, it regains its vertical position. (Below) When tilted beyond a certain angle (the tipping point), it falls flat on the ground. The strength of the push determines neither the tipping point, nor the height of the fall, which are determined by the height of the block.

total duration of the action potential is about 40 ms, the spike lasts less than 2 ms. It is the spike potential rather than the entire action potential that can truly be termed as the nerve impulse. (4) During after-depolarization, the rate of repolarization slows down and gradually reaches the resting potential of −70 mV. This slow phase of repolarization lasts about 2 ms. (5) During afterhyperpolarization, the intracellular negativity overshoots the normal resting value of −70 mV to reach a more negative value of about −75 mV. It lasts for nearly 40 ms before slowly returning to the normal resting potential of −70 mV. Membrane excitability during action potential An action potential is triggered only if the stimulus raises the membrane potential above the firing level of −55 mV. The minimum strength of stimulus that can trigger an action potential is called the threshold stimulus.

In telecommunication parlance, transmission of signals by altering the frequency of the carrier waves is called frequency modulation (FM) or FM transmission. FM transmission is better than AM (amplitude modulation) transmission, which is more susceptible to external disturbances. The transmission of action potential is a form of FM transmission.

Sircar_Chapter11_076-080.indd 76

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Membrane Excitation and Action Potential

A

is about one-third complete, the membrane is absolutely refractory, that is, no stimulus howsoever strong can elicit a response. Thereafter, till the onset of after-depolarization, the membrane is relatively refractory, that is, a sufficiently high stimulus can elicit a response. During after-depolarization, the membrane is hyperexcitable. During hyperpolarization, the membrane excitability is low but slowly returns to normal. The effective refractory period (ERP) includes the absolute refractory period and the early part of the relative refractory period. In the late part of relative refractory period, the membrane is able to conduct action potentials though they are smaller and are conducted slowly.

CRO

Stimulator + -

Active electrode Impulse Axon

B

Depolarization

Millivolts

+40

Repolarization

0

-40 Foot

After-depolarization

-55

After-hyperpolarization

-70

0

2

4

6

8 10 Milliseconds

36

40

C

Millivolts

+40 Absolute refractory 0 Relative refractory

-40

Hyperexcitable -55

Subnormal excitability

-70

0

2

4

Conductance (mmho/cm2)

D

6

8 10 Milliseconds

36

40

Action potential

30

gK+

10

0 4

6 Milliseconds

8

10

Fig. 11.2 [A] Setup for the recording of an action potential. [B] Phases of an action potential. [C] Refractory periods of an action potential. Inset shows a second, smaller action potential triggered during the relative refractory period. [D] Ionic conductances during action potential.

The membrane is refractory (i.e., not responsive) to a second stimulus during most of the spike (Fig. 11.2C). From the spike onset till repolarization

Sircar_Chapter11_076-080.indd 77

Origin and spread of action potential During the

depolarization phase of action potential, ionic currents flow from the depolarized area to the adjacent polarized areas of the membrane, which then get depolarized too. When the depolarization of the adjacent area exceeds 15 mV, a fresh action potential is triggered in the adjacent area. In this way, the action potential travels along the membrane as a wave of depolarization. If every action potential is triggered by another action potential in its immediate vicinity, how is the first action potential stimulated? It stands to reason that ultimately an action potential must be triggered by other types of electrical signals. These electrical signals are of different types, for example, the excitatory postsynaptic potential, end-plate potential, receptor potential, etc. These potentials are formed by the transduction of light, sound, heat, chemical, or mechanical stimuli into electrical signals. Action potentials can also be triggered experimentally by a pair of stimulating electrodes (see below). Ionic conductances during action potential All

gNa+ 20

77

phases of the action potential except the prepotential are the direct consequence of changes in membrane permeability (conductance) to Na+ and K+. Such changes are due to channel activation and inactivation. An increase in Na+ conductance depolarizes the membrane and an increase in K+ permeability repolarizes (or hyperpolarizes) the membrane. The actual membrane potential at any instant is determined by the relative magnitudes of Na+ and K+ permeability (Fig. 11.2D). The prepotential is induced by some external source of negative potential. The source may be an external electrode (a cathode) or a depolarized area on the membrane in the immediate vicinity. Depolarization occurs due to a steep rise in Na+ conductance. Repolarization occurs due to two reasons: (1) the rapid rise of K+

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78

Nerve and Muscle conductance shortly after the surge in Na+ conductance, and (2) the spontaneous inactivation of the Na+ channels, which open during the depolarization phase (Fig. 11.3). During after-depolarization, the K+ conductance is considerably more than Na+ conductance. Yet, the potential drifts back toward the resting value very slowly. The reason for this anomaly is explained on p 83 (see Fig. 12.4). Hyperpolarization occurs because K+ conductance is still high while the Na+ conductance has returned to normal. Effect of temperature on action potential Temperature determines how fast the membrane channels open and close. With a fall in temperature, (1) the depolarization phase becomes less steep due to slower opening of Na+ channels, and (2) the overshoot goes higher due to a slower onset of Na+ channel inactivation and a delayed rise in K+ conductance (Fig. 11.4).

Membrane stimulation In clinical situations, nerves are stimulated by placing both the positive and negative electrodes on the overlying skin. When current is passed through the electrodes, nerve excitation occurs at the cathode, and the part of the nerve below the anode is hyperpolarized. In the electrodes, the current is carried by electrons, while in the tissues, the current is carried by ions, both positive and negative. The direction of the current is conventionally the direction of flow of positive ions. Cathodal stimulation When the stimulating electrodes are turned on, the anions and cations start flowing along the electric field setup between the electrodes. Initially, the ions are unable to flow across the membrane at sites where the field intersects the membrane. Hence at these sites, the ions pile up on both surfaces of the nerve membrane. These ionic currents are called capacitive currents. Immediately below the cathode, the extracellular anions flowing away from the cathode line up on the outer membrane surface while the axoplasmic cations flowing toward the cathode adhere to the

-

+

A

-

+

Fig. 11.3 The hare and tortoise story epitomizes the ionic changes during action potential. The hare (Na+ permeability) races ahead but soon goes off to sleep, allowing the tortoise (K+ permeability) to overtake it!

50

20 30

o

10

o

5

o

B

o

Square wave pulse

0

-50

Stimulus

0

1

2 ms

3

4

Fig. 11.4 Effect of temperature on action potential. As the temperature falls, both the duration and the amplitude of the action potential increase.

Sircar_Chapter11_076-080.indd 78

Saw-tooth pulse

Fig. 11.5 [A] Current flowing from anode to cathode, intersecting the axonal membrane in its path. Beneath the cathode, anions accumulate outside and cations accumulate inside the membrane. Beneath the anode, there is accumulation of cations outside and anions inside the membrane. [B] A square-pulse stimulus rises sharply to its peak level and effectively triggers an action potential, whereas a saw-tooth pulse, which rises to its peak slowly, often fails to trigger an action potential.

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Membrane Excitation and Action Potential

Propagated action potential Firing level

-55

mV

Catelectrotonic potential Local potential

-70

Anelectrotonic potential -100 0

1.0

0.5

1.5

ms

Fig. 11.6 Electrotonic and local potentials.

inner membrane surface (Fig. 11.5A). These events result in a change in membrane potential, which is called an electrotonic potential (Fig. 11.6). The potential that develops under the cathode is called catelectrotonic potential, whereas the potential that develops under the anode is called anelectrotonic potential. When the electrodes are removed, the electrotonic potentials disappear quickly. The catelectrotonic potential is the direct effect of the cathodal electric field. Another potential, called the local potential, develops simultaneously at the same site under the effect of the catelectrotonic potential (Fig. 11.6). The local potential develops due to the opening of the membrane Na+ channels and they last a little longer after the electrodes are removed. If the local potential is strong enough, it triggers the action potential.

79

However, when the membrane depolarizes slowly to the firing level, the action potential often fails to be triggered. This phenomenon is called membrane accommodation and is due to Na+ channel inactivation. When the membrane depolarizes, both Na+ and K+ channels open up. When the depolarization occurs very slowly, Na+ channels open in small batches, only to be inactivated without producing adequate prepotential for triggering an action potential. The K+ channels remain open and tend to restore the membrane potential. By the time the potential touches the firing level, most of the Na+ channels have got inactivated, while the K+ channels remain open as long as the membrane remains depolarized. Therefore, the explosive depolarization fails to occur. If, however, the membrane depolarizes rapidly to the firing level, a large number of Na+ channels open all at once. Before they get inactivated, they are able to trigger off the action potential by overcoming the effect of K+ channels. For the same reason, the square pulse is more effective than the saw-tooth pulse in stimulating the membrane (Fig. 11.5B). Strength–duration curve The excitability of a

membrane, that is, the ease with which it can be stimulated depends on two factors, viz., the strength of the stimulus and the duration for which the stimulus is applied. As the strength of stimulus increases, the time required to excite the membrane decreases and vice versa. The strength–duration curve is obtained by plotting various combinations of the stimulus strength and the time it takes to stimulate a membrane (Fig. 11.7). The indices of membrane excitability

Anode-break excitation Sometimes, the mem-

Membrane accommodation When a catelectrotonic potential depolarizes the membrane rapidly to the firing level, an action potential is triggered.

Sircar_Chapter11_076-080.indd 79

1.6 2μ

1.4 1.2 5μ 1.0 mA

brane is excited at the anode when the stimulus is switched off. This is called anode-break excitation. If the stimulus is applied for a sufficient length of time, the ions start crossing the membrane, setting up a resistive current. Thus at the anode there is a large increase in Na+ influx into the axon and a large decrease in the K+ efflux. However, these ionic fluxes are unable to change the membrane potential so long as the anodal current is passing through it and the membrane remains hyperpolarized due to the potential drop occurring along the path of the anodal current. However, the moment the anode is switched off, the combination of high Na+ influx and low K+ efflux depolarizes the membrane and triggers an action potential.

10μ

0.8 0.6

20μ 0.4 0.2 0

10

100 Pulse duration (μs)

1,000

Fig. 11.7 Strength–duration curves of nerve fibers of different diameters. The 10 μ fiber has a rheobase of 0.2 mA and a chronaxie of 100 μs (0.1 ms).

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80

Nerve and Muscle are rheobase and chronaxie. Rheobase is the minimum current of electrical stimulus, which when applied for an adequate length of time will excite the membrane. Chronaxie is the time required to stimulate the membrane using double the rheobase strength of stimulus.

Graded potentials Unlike action potentials, local potentials do not obey the all-or-none law. They are proportional to the stimulus strength and hence are also called graded potentials. Examples of graded potentials include the receptor potential and the end-plate potential. Some of the differences between graded potentials and action potentials are listed in Table 11.1.

Table 11.1 Differences between graded potential and action potential Graded potential

Action potential

Amplitude proportionate to stimulus strength and can get summated

Amplitude constant for all suprathreshold stimuli and cannot be summated

Can be a depolarization or hyperpolarization

Always a depolarization

Conduction is associated with reduction in magnitude

Conducted without reduction in magnitude

Can be generated spontaneously in response to physical or chemical stimuli

Generated only in response to membrane depolarization

REVISION QUESTIONS 1. A decrease in temperature makes the action potential taller and broader. Why? 2. When the membrane is stimulated by a pair of electrodes, the action potential is produced under the cathode and not under the anode. Why?

Sircar_Chapter11_076-080.indd 80

3. A square pulse of electrical stimulus is more effective than a saw-tooth pulse in triggering an action potential. Why? 4. Sometimes an action potential is produced at the anode when a steady current applied to an excitable tissue through a pair of electrodes is switched off. Why?

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12

Electrophysiology of Ion Channels

Channel dynamics

A

Effect of membrane potential on channel permeability

Sodium channel inactivation Both gNa+ and gK+ show similar increase with membrane depolarization but their time courses are different (Fig. 12.1A, B). The rise in gNa+ is quicker but shortlived. Almost immediately after opening, Na+ channels start closing down spontaneously. This process is called Na+ channel inactivation. As the membrane depolarizes, Na+ channels are activated in successive batches, only to be inactivated quickly. Reactivation of a channel occurs only when the membrane potential falls below its activation potential. Na+ channel inactivation has two important consequences, viz., the refractory period (p 76) and membrane accommodation (p 79). The mechanism of Na+ channel inactivation is as follows. Na+ channels are guarded by two gates: the activation and inactivation gates.1 During depolarization, the activation gate opens quickly followed by the slow closure of the inactivation gate. Hence during depolarization, the channel remains open for a brief interval (Fig. 12.1B). During repolarization, the activation gate closes first followed by the opening of the inactivation gate so that the channel remains closed throughout repolarization.

Conductance (ms/cm2)

15 10 5 0 -60

-40

-20 0 Vm mV

20

Na+ conductance

B

40

K+ conductance

20 +25 mV 0 mΩ /cm2

Both Na+ channels and K+ channels are voltage-sensitive. They open (activate) and close (deactivate) with changes in the membrane potential. Individual channels obey the all-or-none law, that is, at any instant, they remain either fully open or fully closed. When the membrane depolarizes, the probability of a channel remaining open increases. As a corollary, it may be stated that as the membrane depolarizes, more and more channels are found in the fully open state. When the membrane depolarizes, both Na+ and + K channels open, resulting in measurable increases in their conductances (i.e., membrane permeability). The increase in conductance is roughly proportional to the change in membrane potential.

gK+ gNa+

20

20 0 mV 0 10 0

-25 mV 0

2 ms

4

0

2

4 ms

6

8

C

Activation gate

Inactivation gate

Fig. 12.1 [A] Effect of membrane depolarization on peak gNa+ and gK+ over a range of –60 to +40 mV. [B] Effect of membrane depolarization on gNa+ and gK+ over a period of 4 to 8 ms. The effects of three different grades of depolarization are shown here, as the membrane is depolarized to +25 mV (above), 0 mV (middle), and –25 mV (bottom). Note that the changes in membrane permeability of Na+ are transient, while those of K+ are sustained as long as the membrane remains depolarized. [C] Activation (m) and inactivation (h) gates of a sodium channel.

1

The activation and inactivation gates are also called the m gates and h gates, respectively. The origins of the names “m” and “h” are to be found in the empirical equations developed in the 1950s by Hodgkin and Huxley to describe the time course of voltage changes during an action potential. They inferred quite correctly that the changes in Na+ conductance occurred due to two processes: a rapid process that increases channel permeability (represented by the constant m) and a slower process that reduces channel permeability (represented by the constant h). The physical evidence of the presence of activation and inactivation gates such as the identification of the protein chains came several years later as a testimony to the power of mathematical modeling.

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82

Nerve and Muscle

Effect of channel permeability on membrane potential Stabilizing effect of potassium current When the

membrane potential becomes less negative, the K+ channels open. Opening of the K+ channels increases the outward hyperpolarizing current and thereby makes the membrane more negative. Conversely, if the membrane potential becomes more negative, a large number of K+ channels close down and the membrane potential drifts to a less negative value. Thus, whenever there is a change in membrane potential, the activated K+ channels tend to restore the membrane potential to the original level. Hence, K+ channels are said to have a stabilizing effect, through negative feedback, on the membrane potential, that is, they resist changes in membrane potential (Fig. 12.2A).

Firing level It is clear from Fig. 12.1A that when

the membrane depolarizes, the rise in Na+ conductance is much quicker than the rise in K+ conductance. Hence, even a small depolarization should destabilize the membrane potential and set off the Hodgkin cycle. What actually happens is that the membrane quickly repolarizes following a small depolarization. Why is it so? The question is best answered by considering the “balance of moments” analogy (Fig. 12.3), which explains why the slightest depolarization of the membrane is immediately opposed by gK and gCl even when these conductances remain unchanged. If the K+ channels open too, the gK increases and the opposition to membrane depolarization is even greater. Thus, a fairly large increase in gNa is required before the Hodgkin cycle can be set off.

Destabilizing effect of sodium current When the

membrane depolarizes, the Na+ channels start opening. The opening of the Na+ channels increases the inward depolarizing current and thereby depolarizes the membrane further, leading to the opening of greater numbers of Na+ channels. Thus, there is a positive feedback spiral (the Hodgkin cycle) resulting in a very rapid change in membrane potential and opening of nearly all the Na+ channels. Since the opening of even a few Na+ channels can trigger off this vicious cycle resulting in large changes in membrane potential, Na+ channels are said to have a destabilizing effect on membrane potential (Fig. 12.2B).

+

+60

Increase in K+ permeability

0

-30

-60

gNa+

gCl– gK+ Membrane potential

+

+60

A

+30

_

+30

0

-30

_

-60

gNa+

increased

Opening of K+ channels

Membrane potential

Closure of K+ channels

+

Hyperpolarization of membrane

B

+

depolarizat ne els n

Openin go fN n n e a l s h + c Na g of mor nin

els Mem ann br ch re mem Mo + bra a chan eN

epolarization ed an

a

ening of mo re Op Op e ion

Fig. 12.2 Effect of channel permeability on membrane potential. [A] Stabilizing (negative feedback) effect of K+ ions on membrane potential. [B] The Hodgkin cycle, explaining the destabilizing (positive feedback) effect of Na+ ions on membrane potential.

Sircar_Chapter12_081-085.indd 82

+60

+30

0

-30

_

-60

Membrane potential

Fig. 12.3 The ionic basis of the firing level. (Above) Membrane at resting potential of –80 mV. All ionic conductances are resting conductances. (Middle) Sodium conductance (gNa) increases slightly, resulting in a depolarizing tendency. (Below) Due to the increase in gNa, the membrane depolarizes to –70 mV. Immediately, gCl and gK start exerting a strong hyperpolarizing effect. This happens even when there is no change in gCl and gK (see also Fig. 10.4).

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Electrophysiology of Ion Channels

ICF

A

ECF

K+ 150 mEq /L

5 mEq /L

ICF

B

ECF

K+ 150 mEq /L

15 mEq /L

5 mEq /L

+

C +30

0

_

-30

-90

gCl–

gNa+ gK+ Membrane potential

Fig. 12.4 The ionic basis of after-depolarization. [A] Potassium ions diffuse out slowly and is distributed uniformly in the ECF. The K+ concentration in the ECF does not increase measurably and remains 5 mEq/L. The Nernst Potential of K+ remains at –90 mV. [B] Potassium ions diffuse out very fast, forming a high-concentration zone of 15 mEq/L immediately outside the membrane. As a result, the K+ efflux slows down and the effective Nernst Potential reduces to –55 mV. [C] The balance of moments analogy shows how, consequent to the reduction of the Nernst potential of K+, the membrane remains depolarized (at about –50mV) despite a high K+ conductance and low Na+ conductance. ECF, extracellular fluid; ICF, intracellular fluid.

Sircar_Chapter12_081-085.indd 83

Agents altering channel function Several naturally occurring substances affect the permeability of Na+ or K+ channels. These compounds have been used extensively in research for studying channel properties using the voltage clamp technique. Nonspecific channel modulators An increase in extracellular Ca2+ decreases membrane excitability. Ca2+ ions bind to the negatively charged groups in the membrane phospholipids. Being a predominantly extracellular ion, Ca2+ ions bind mainly to the outer surface of the membrane. This does not affect the overall membrane potential, which is determined only by the Nernst potentials of the diffusible ions. However, it does produce a small area of hyperpolarization just where it binds to the membrane and thereby reduces the excitability of the channels located there (Fig. 12.5). Low ECF Ca2+ can cause spontaneous impulse generation, which can be reversed by the addition of Ca2+ or other bivalent ions. Spontaneous impulse generation in nerves due to low serum Ca2+ results in widespread muscle spasms. The condition is called tetany and is commonly seen in hypoparathyroidism. Specific channel blockers The activation of Na+ channels is blocked by tetrodotoxin (TTX) and saxitoxin (STX). These bind to the extracellular sites on the Na+ channel to make the membrane inexcitable. The inactivation of Na+ channels is blocked by pronase, which binds to intracellular sites on the Na+ channel. The inactivation of the K+ channel is blocked by tetraethylammonium (TEA). It prolongs the action potential. Local anesthetics are lipid-soluble substances that bind to intracellular sites on the Na+ channels. Some of them, for example, lidocaine and procainamide, tend to produce a frequency-dependent block, that

Inside

-80 -80 -80 -80 -80 -90 -90 -90 -90 -90 -80 -80 -80 -80 -80

-

After-depolarization During after-depolarization, the K+ conductance is at its peak, while the Na+ conductance is minimal (Fig. 11.2D). In such a situation, the membrane should hyperpolarize. However, it is observed that the membrane is not even repolarized completely at that instant. How does one explain the discrepancy? It is argued that at the peak of K+ conductance, the K+ ions diffuse out so fast that they accumulate just outside the membrane instead of distributing uniformly in the ECF. (Fig. 12.4B). Therefore, there is a decrease in the effective EK (Nernst potential of K+), since it is now determined by the K+ concentration just outside the membrane and not by the overall ECF concentration of K+. In accordance with

the Goldman equation, the membrane potential is less negative than expected (Fig. 12.4C).

+ + + + + ++ + + + ++ + + + + +

The membrane potential at which this occurs is called the firing level.

83

Ca2+

Ca2+

Outside

Fig. 12.5 Binding of Ca2+ to the membrane exterior produces a localized zone of hyperpolarization, which reduces channel excitability. The overall membrane potential remains unaffected.

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Nerve and Muscle is, they produce conduction block only after the membrane conducts a train of action potentials. This is probably because the local anesthetic molecule binds to an intracellular site on the channel. In its charged form, it gains access to its binding site within the pore only when the channel is in an open state. Moreover, the local anesthetic seems to bind more tightly to the inactivated Na+ channel.

Channel characterization Voltage clamp technique Measuring the electrical conductance of a membrane involves measuring membrane currents at different voltages. A major hurdle in these efforts is the explosive change in membrane potential that occurs once the voltage touches the threshold. This led to the search for a technique that would “clamp” the membrane potential at any desired value despite the surge in current. In the voltage clamp technique, the membrane potential can be stepped rapidly to a predetermined level of depolarization (called the command potential) by passing current across the cell membrane. The clamp circuit opposes any drift in membrane potential: Every time the membrane potential tends to drift from the command potential, the clamp circuit opposes the drift by injecting a precisely calculated feedback current (Fig. 12.6).

Patch clamp technique Before the advent of the patch clamp technique, the voltage clamp technique was used to determine con-

MP -70 mV

Current infused to produce 20 mV depolarization

Feedback current calculator and generator

CP -50 mV

ductance of a whole membrane with a mixed population of different types of channels. The conductance characteristics of a single type of channel were deduced by blocking other known channels present in the membrane. For example, Fig. 12.7 shows the records of membrane conductance before and after application of TTX. Does the conductance measured after applying TTX give the K+ conductance? Yes, provided the membrane has only Na+ and K+ channels. With patch clamp technique, it is possible to record the conductance of a single channel. A small fine polished glass micropipette with a tip diameter of ~1 mm is pressed against the membrane. The pipette is filled with a solution having a composition like the extracellular fluid. A metal electrode in contact with the electrolyte in the micropipette connects the pipette to a special electric circuit that measures the current flowing through channels in the membrane under the pipette tip. A small amount of suction to the patch pipette greatly increases the tightness of the seal between the pipette and the membrane. The result is a seal with extremely high resistance (the gigaohm seal) between the inside and outside of the pipette. Patch clamping offers three types of experimental possibilities (Fig. 12.8A): (1) The experimenter can apply various stimuli from within the pipette and measure the behavior of the trapped channels. (2) The experimenter can detach the membrane from the cell, thereby exposing the cytoplasmic mouth of the channels. (3) The membrane patch can be ruptured without breaking the gigaohm seal so that the experimenter can alter the constituents of the living cell’s cytoplasm. A

CP - MP 20 mV

Membrane conductance (nA)

84

20 10 0 -10 -20 0

2

4

B MP -40 mV

Current infused to produce 10 mV hyperpolarization

Feedback current calculator and generator

CP -50 mV

CP - MP -10 mV

Fig. 12.6 (Above) Membrane potential (MP = –70 mV) is made equal to the command potential (CP = –50 mV) by injecting a calculated amount of current. (Below) If membrane potential tries to change from –50 to –40 mV, it is immediately corrected by injecting a current calculated to produce 10 mV hyperpolarization.

Sircar_Chapter12_081-085.indd 84

Membrane conductance (nA)

ms 20

After applying TTX

10 0 -10 -20 0

2

4

6

8

ms

Fig. 12.7 [A] Conductance of a membrane that contains only Na and K+ channels. [B] Conductance of the same membrane after blocking the Na channels with TTX. TTX, tetrodotoxin.

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Electrophysiology of Ion Channels

85

α-subunit

A

I

II

III

IV Voltage sensor

Pore with regulator

Gigaohm seal

Cytoplasmic mouth of channel

Inactivation site Open

B

Binding site for local anesthetics

-100 mV Closed 3 pA

-90 mV -75 mV

Fig. 12.9 The ultrastructure of the α-subunit of the sodium channel showing its functionally important sites.

-50 mV

Time in open state (%)

50 ms C

100 80 60

but switch frequently between the open and closed states. The probability of a channel being open at any instant increases as the membrane depolarizes.

Channel structure

40 20 0 -120

Phosphorylation site

-80 -40 Membrane potential (mV)

Fig. 12.8 [A] Three methods of the patch clamp technique. [B] Channel current of a single channel recorded through patch clamp. The channel current obeys the all-or-none law: it is either 3 pA (maximum) or 0 pA (minimum). As the membrane is depolarized in steps (–100, –90, –75, and –50 mV), the channel remains open for longer durations. [C] Graph showing the relation between membrane potential and the time spent by the channel in the open state. Channel currents recorded by patch clamp One

striking observation made possible through patchclamp studies of single channels is that channels obey the all-or-none law: they are either fully open (conducting a maximum current of about 3 picoAmperes) or are fully closed (Fig. 12.8B, C). Also, channels are usually not continuously open

The molecular structures of several channels have been characterized and the sites responsible for specific channel characteristics have been identified. The structure of an ion channel has been described on p 41. Some of the details of a voltage-sensitive Na+ channel are shown in Fig. 12.9. The S-4 transmembrane segments in each homologous domain of the α-subunit contain the voltage sensors. The positively charged amino acid in the third position within S-4 is the voltage sensor. S-5 and S-6 transmembrane segments and the short membrane-associated P loop (segments SS1 and SS2) enclose between them the channel pore. Certain amino acids in the P loop are critical for determining conductance and ion selectivity of the Na+ channel and its ability to bind to channel blockers. The short intracellular loop connecting homologous domains III and IV serves as an inactivation gate. The loops between I and II and between III and IV are susceptible to phosphorylation. Phosphorylation at these two sites impairs channel activation and inactivation, respectively.

REVISION QUESTIONS 1. The presence of K+ channels in a membrane has a stabilizing effect on the membrane potential. Why? 2. An action potential is triggered only when the membrane potential crosses the firing level. Why?

Sircar_Chapter12_081-085.indd 85

3. Some local anesthetics, for example, lidocaine, produce conduction block only after membrane conducts a train of action potential. Why? 4. Lowering the extracellular Ca2+ concentration often leads to spontaneous generation of action potential. Why?

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13

Nerve and Muscle

Conduction of Nerve Impulses

Before considering the mechanism of nerve conduction, it will be useful to consider the analogy of a model for transfer of heat from one end of a rod to the other. Consider two rods, one wooden and the other made of steel. One end of each rod is placed over a flame with a temperature of 800°C. Which will transfer the heat more effectively from one end to the other? The answer seems too obvious: the steel rod of course. However, there is another way of looking at it. The far end of the steel rod can never get heated to 800°C because of heat losses. On the other hand, the wooden rod burns itself out and transfers the flame to its far end, which then reaches a temperature of 800°C. This novel method of heat transfer with a high fidelity may be called the traveling flame mechanism (Fig. 13.1A). However, the wooden rod can conduct the flame only once, after which a fresh wooden rod has to be provided for another flame to pass over it. Moreover, it is very slow. However, where the fidelity of the “temperature-signal” is a priority, this mechanism cannot be ignored. A hybrid model incorporating both steel and wood has the advantages of both: steel gives speed and wood gives fidelity (Fig. 13.1B). The role of steel is to transfer enough heat to its far end so that the wood catches fire. The burning wood restores the temperature to

Quick transmission

A 800oC

200oC Steel rod 800oC

800oC

High-fidelity transmission Wooden rod

Steel

B

Wood

Insulation

Fig. 13.1 The traveling flame analogy of nerve conduction. [A] A steel rod transfers the heat faster but the wood transfers the flame itself. [B] A hybrid wood-and-steel rod for speeding up flame transfer.

Sircar_Chapter13_086-092.indd 86

800°C. For achieving high speeds of heat transfer, the length of the steel rods should be long. The wooden chips should be few and far between because it is here that the heat transfer slows down. Making the steel rods too long is however fraught with the risk of heat transfer failure. If the temperature at the far end of the steel rod falls below the ignition temperature of wood, the heat transfer stops there. This imposes a limit to the length of steel rods that can be interposed between the wooden chips. This limit can be maximized by using insulated steel rods so that there is little heat loss in the intervening segments. This analogy will not be extended any farther although there can be numerous corollaries to it. For example, how does the flame temperature affect the velocity of the traveling flame?

Mechanism of nerve conduction Electrotonic conduction Local currents When an action potential is in its depolarization phase, local currents flow from the depolarized membrane to the adjacent polarized areas and depolarize them too. In the axoplasm, the current flows away from the depolarized area. The current then flows out through the axonal membrane and returns through the extracellular fluid. This passive flow of local currents to adjacent membrane areas is called electrotonic conduction. The local current circuit can be resolved into three components: (1) the internal longitudinal current or axoplasmic current, which flows through the axoplasm, (2) the radial current or membrane current, which flows out through the membrane, and (3) the external longitudinal current, which flows through the extracellular fluid. The effect of local currents becomes feebler with distance (Fig. 13.2A). In an unmyelinated neuron, a fully-fledged action potential of 110 mV can produce a depolarization of 15 mV at a distance of 1.0 mm but a depolarization of only 2.0 mV at a distance of 2.0 mm. Factors affecting electrotonic conduction Electrotonic conduction is determined by four physical factors: (1) The axoplasmic resistance (Ri) offered by the axoplasm to the flow of axoplasmic current. The thinner the axon, the higher is the axoplasmic resistance and the weaker is the electrotonic

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Conduction of Nerve Impulses

87

when the membrane is thick, as in the myelinated segment of the neuron.

A Extracellular fluid

Propagation of action potential

Axoplasm Axonal membrane

B High membrane current Low Rm Low axoplasmic current Low membrane current High Rm High axoplasmic current

Fig. 13.2 [A] In unmyelinated membrane, local currents cannot travel far because of high axoplasmic resistance (Ri), low membrane resistance (Rm), and high membrane capacitance (Cm). High Cm is shown as a dense distribution of membrane charge. [B] Membrane resistance and currents. As membrane resistance rises, membrane current decreases and axoplasmic current rises. When the axoplasmic current is low, it takes longer to depolarize the adjacent membrane to the firing level, thereby slowing down the propagation of action potential.

conduction. (2) The external longitudinal resistance (Ro) offered by the extracellular fluid to the outer longitudinal current. The greater this resistance, the weaker is the electrotonic conduction. Ro usually remains constant. (3) The membrane resistance (Rm), that is, the resistance offered by the membrane to the transmembrane current. When Rm is high, the membrane current falls resulting in higher axoplasmic current and stronger electrotonic conduction. Rm is high where the membrane is thick, as in the myelinated segment of the neuron (Fig. 13.2B). (4) The membrane capacitance (Cm). The greater the membrane capacitance, the poorer is the electrotonic conduction.1 Cm is low

Local currents from one action potential spread to the adjacent membrane area and depolarize it to the threshold level, triggering another action potential and the process continues. Thus, there are two essential components of action potential propagation: (1) The flow of local currents, which depolarize the adjacent membrane, is called the conductive component of impulse propagation. This electrotonic conduction of membrane depolarization is associated with progressive decrease in the magnitude of depolarization. (2) The triggering of a fresh action potential in the adjacent membrane is called the regenerative component of impulse propagation. The new action potential depolarizes the membrane maximally and thereby restores the depolarization to its original magnitude of 110 mV. Without the conductive component, an action potential will not be conducted at all. Without the regenerative component, an action potential will be conducted only up to a limited distance beyond which it will fade out. Before the local currents fade out completely, a fresh action potential must be generated for its continued propagation. The conductive component is very fast and depends on the cable properties (the electrical characteristics) of the membrane. The regenerative component is much slower. Frequent action potentials along the neuron tend to slow down the conduction velocity.

Nerve conduction velocity Nerve conduction velocity can be affected by factors influencing electrotonic conduction (conductive component), the action potential (regenerative component), or both. Axon diameter An axon with a larger diameter has lower axoplasmic resistance and allows easier passage to axoplasmic current.2 A stronger electrotonic conduction results in a quicker depolarization of the adjacent membrane to the firing level and thereby, quickens the propagation of action potential. In an unmyelinated fiber, the speed of propagation is directly proportional to the square root of the fiber diameter (D). The relationship can be derived mathematically, which proves the correctness of the physical model of nerve conduction.

1

An electrical impulse is conducted by inducing a potential change in its adjacent area. The greater the capacitance of a body, the more it resists any change in its potential. Hence, if the capacitance of the adjacent area is higher, it takes longer to induce a potential change in that area and therefore electrotonic conduction slows down. 2 The resistance of a conductor is inversely related to its cross-sectional area.

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88

Nerve and Muscle Conduction velocity ∝ √D

because an action potential can then trigger another action potential a longer distance away where the local currents are feeble. The threshold potential decreases when there is a low extracellular concentration of divalent ions (e.g., Ca2+).

Temperature When temperature decreases, the du-

ration of the action potential, especially the spike, increases markedly (see Fig. 11.4). This increases the conduction delay at the nodes of Ranvier and therefore, the conduction velocity decreases.

Myelination and saltatory conduction Myelination speeds up conduction by influencing both conductive and regenerative components.

Resting membrane potential Membrane hyperpolarization has two effects: (1) it “speeds up” electrotonic conduction and (2) “slows down” the generation of action potential because of the greater time required for the membrane to depolarize to threshold potential. The resultant effect on conduction velocity is variable but usually a decrease. The following example should make it clear. Suppose a membrane has an RMP of –80 mV and a part of it depolarizes to +40 mV during an action potential. The potential difference between the depolarized and repolarized areas will be 120 mV. If, however, the RMP is –100 mV and it depolarizes to +40 mV, the potential difference between depolarized and repolarized areas will be 140 mV. This higher potential difference will set up stronger local currents resulting in faster electrotonic conduction. However, hyperpolarization is usually associated with a reduction in peak depolarization. In that case, there will be no increase in electrotonic conduction. Moreover, a hyperpolarized membrane takes longer to reach the firing level and therefore slows down the regeneration component. On the other hand, when the RMP is less negative, it slows down both electrotonic conduction and the generation of action potential. The latter occurs because persistent depolarization causes inactivation of Na+ channels in large numbers. As a result, the spike generated is stunted and wider.

Effect on conductive component Myelination increases the membrane resistance and decreases the membrane capacitance. The increase in membrane resistance reduces the radial current and thereby increases the axoplasmic current. Therefore, the membrane space constant increases (see below). The decrease in membrane capacitance decreases the membrane time constant (see below). Together they ensure that the depolarization produced in one node is electrotonically conducted quickly and adequately through the myelinated segments and triggers action potentials several nodes away (Fig. 13.3). This is called saltatory conduction (Latin: saltere means to jump). In a myelinated neuron, the conduction velocity is directly proportional to the fiber diameter (D) where 6 is the proportionality constant, determined experimentally. Conduction velocity ∝ Axonal diameter Conduction velocity = 6 × Axonal diameter (in μ) (in ms−1)

Effect on regenerative component Due to poor per-

meability to K+, the resting potential in the myelinated segment is only –3 to –6 mV, and so no action potential is generated in the myelinated segment. Action potentials are generated only in the unmyelinated nodes, which are 0.2 to 1.0 mm apart. Fewer action potentials mean less delay in conduction.

Firing level (threshold potential) The conduction velocity increases if the threshold potential is low

Ro

+++ +

+++ +

----

+ +++

-- --

-- --

++++

-- --

+ +++ Rm

-- --

Ri Myelinated

Axonal

Membrane

Fig. 13.3 In the myelinated axon, local currents travel long distances. Myelinated membrane does not permit passage of current through it due to its high Rm. Also, myelination decreases membrane capacitance (Cm), which is shown here as the sparsely distributed charges on the membrane.

Sircar_Chapter13_086-092.indd 88

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5

linated Unmye

0 0

1 Fiber size (μ)

2

Fig. 13.4 Relationship of fiber diameter with conduction velocity. For the same fiber diameter, myelinated neurons conduct faster only when the fiber size is ⬎1 μm.

Neurons with diameter 40 y

Mode of onset

Abrupt

Gradual

Body weight

Nonobese

Obese

Circulating insulin levels

Low to absent

Normal or elevated

Acute metabolic complications

Ketoacidosis

Hyperosmolar coma

Treatment with Insulin

Essential and always responds

Resistant and usually not required

Response to oral hypoglycemic drugs

Unresponsive

Responsive

551

gon excess has four major metabolic consequences: (1) hyperglycemia and its consequences, (2) polyphagia despite the hyperglycemia, (3) hyperlipidemia and its consequences, and (4) ketoacidosis and its consequences. A somewhat similar metabolic picture is seen in starvation (see Fig. 80.14) except that there is no hyperglycemia. Hence, diabetes mellitus has been called starvation in the midst of plenty. Hyperglycemia and its consequences The events

that lead to hyperglycemia are shown in Fig. 87.8. Briefly, the hyperglycemia is due to (1) reduced hepatic glucose uptake and (2) stimulation of gluconeogenesis. Since lack of insulin reduces protein synthesis, large quantities of amino acids are available for gluconeogenesis. When the hyperglycemia exceeds the renal threshold of glucose, it results in glycosuria. The glucose in urine acts as an osmotic diuretic (see p 390) and results in polyuria, that is, passage of large volumes of urine. The polyuria results in dehydration and polydipsia. Severe dehydration leads to coma. The dehydration is usually not severe enough to cause peripheral circulatory failure or renal failure. Hyperglycemia increases the cellular uptake of glucose. This extra glucose that enters the cell is metabolized through the sorbitol pathway (see Fig. 79.5). The sorbitol produced accumulates in the cells of retina, lens, kidney, and nerves, leading Diabetes mellitus

either a relative deficiency of insulin or a resistance to insulin action on cells. The latter can be due to a number of causes, including (1) an abnormality in insulin structure, (2) abnormality of insulin receptors, (3) downregulation of insulin receptors, or (4) defects in glucose transporters. Obese individuals tend to have a higher-thannormal insulin level due to a decrease in insulin receptors. They develop type 2 diabetes when the compensatory rise in insulin is inadequate for overcoming the insulin resistance.

Metabolic consequences of diabetes mellitus The classic triad of polyuria, polydipsia, and polyphagia is an inadequate summary of the complex clinical picture of diabetes mellitus. The metabolic consequences of diabetes mellitus result not just from the inadequacy or ineffectiveness of insulin but equally importantly, from the unopposed action of glucagon. Quite often, diabetes mellitus is associated with higher-than-normal plasma levels of glucagon. The combination of insulin inadequacy and gluca-

Sircar_Chapter87_547-553.indd 551

Reduced hepatic uptake of glucose from blood

Reduced utilization of amino acids for protein synthesis

Stimulation of key gluconeogenetic enzymes

High level of amino acids in blood Increased uptake of amino acids by liver Increased oxidative deamination of amino acids in liver Increased availability of carbon skeletons for gluconeogenesis Increased gluconeogenesis Hyperglycemia

Fig. 87.8 Causes of hyperglycemia in diabetes mellitus.

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552

Endocrine System to osmotic swelling and contributing to the retinopathy, cataract, nephropathy, and neuropathy of diabetes mellitus. If the hyperglycemia is very high, it increases the plasma osmolarity to very high levels, causing hyperosmolar coma. despite hyperglycemia Normally, a high level of blood glucose should produce satiety. In diabetes, there is polyphagia despite the hyperglycemia. The catch in this paradox is that hunger is related to the glucose utilization by the cells of the satiety center (see Chapter 110) and not to the blood glucose level. In diabetes mellitus, the glucose utilization is reduced in the cells of the satiety center, which therefore signals a glucose deficiency to the feeding center. As a result, hunger is perceived and food intake increases.

Polyphagia

Hyperlipidemia and its consequences The events

that lead to hyperlipidemia are shown in Fig. 87.9. The increase in plasma triglyceride occurs mainly due to the reduced breakdown of VLDL and chylomicrons. The increase in plasma free fatty acid (FFA) is due to lipolysis in adipose tissues. The rise occurs despite a decrease in the hepatic synthesis of fatty acids. In the long run, the hyperlipidemia and related hypercholesterolemia result in hypertension and coronary heart disease.

Ketosis and its consequences Due to the excess FFA present in blood, there is increased uptake and oxidation of FFA by the cells. In the liver, increased oxidation of FFA results in accumulation of excess acetyl CoA. As glycolysis is inhibited in diabetes mellitus, the excess acetyl CoA forms ketoacids (see Fig. 79.12). The H+ of the ketoacids is buffered by the blood buffers. However, when the production of ketoacids exceeds the buffering capacity of the blood, it results in metabolic acidosis with all its complications (see Chapter 62). A characteristic clinical feature of the acidosis is Kussmaul breathing, a form of hyperventilation associated with increased tidal volume and a lesser increase in frequency. Vomiting is another complication of ketoacidosis. The vomiting causes dehydration and if it is followed by ingestion of plain water instead of an electrolyte solution, hyponatremia results (Fig. 87.10). The ketoacids are buffered by blood buffers, releasing organic anions. For example, buffering of acetoacetic acid produces acetoacetate. These organic anions increase the plasma anion gap. When excreted in urine, these organic anions carry with them an equal number of cations, mainly Na+ and K+. However significant hyponatremia occurs only due to vomiting, as explained above.

Diabetes mellitus Diabetes mellitus

Inhibition of lipoprotein lipase

Stimulation of hormone sensitive lipase

Inhibition of key glycolytic enzymes

Ketoacidemia

Inhibition of glycolysis

Hyperglycemia

Hyperosmolarity of blood

Reduced availability of glucose-6-phosphate Decreased breakdown of VLDL and chylomicrons

High level of FFA in blood

Reduced de novo synthesis of FFA

Increased uptake of FFA by liver Increased formation of acetyl CoA

Increased level of plasma triglyceride

Formation of ketoacids

Fig. 87.9 Pathophysiology of hyperlipidemia and ketosis in diabetes mellitus.

Sircar_Chapter87_547-553.indd 552

Polyuria Dehydration

Increased mobilization of FFA from adipose tissues +

Glycosuria

Coma Polydipsia

H+ buffered by blood buffers

Buffering capacity of blood exceeded

Increased formation of Na+ and K+ salts of ketoacids

Vomiting

Increased urinary losses of Na+ and K+ with ketoacids

Electrolyte disturbances

Metabolic acidosis

Fig. 87.10 Clinical consequences of ketoacidemia and hyperglycemia in diabetes mellitus.

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Pancreatic Hormones Hyperkalemia with intracellular depletion of potassium stores is an important feature of diabetes mellitus. Insulin causes K+ to move into the cells and therefore insulin deficiency results in movement of K+ from ICF to ECF. The hyperkalemia is associated with kaliuresis, resulting in the depletion of body K+ stores.

Diagnosis of diabetes mellitus The glucose tolerance test (GTT) is no longer considered necessary for diagnosing diabetes mellitus. In the GTT, half-hourly samples of blood and urine were tested for their glucose concentration after administering an oral glucose load of 75 g to the patient. The test however remains useful for diagnosing renal glycosuria (see Fig. 68.1). A patient having the classical signs and symptoms of diabetes mellitus is confirmed as a diabetic if the random plasma glucose is ≥ 200 mg/ dL. In the absence of the classical signs, the fasting plasma glucose must be ≥ 126 mg/dL for the diagnosis of diabetes. Those with fasting plasma glucose between 110 and 126 are diagnosed as impaired fasting glucose (IFG), and if the 2-hour postprandial plasma glucose is ≥ 200 mg/dL, the patient is diagnosed as having impaired glucose tolerance (IGT).

553

Treatment of diabetes mellitus The treatment of both type 1 and type 2 diabetes includes healthy eating habits, regular exercise, and stopping smoking. Weight reduction is important in type 2 diabetics, nearly 80% of whom are obese. The exercise can be in the form of walking daily for 30–60 minutes, or preferably more. The dietary guidelines for the diabetic patient are as follows: (1) It should be low on fat (< 30%) and high on carbohydrate (> 55%), preferably the highfiber carbohydrates. (2) Sucrose should be limited to < 50 g/d. (3) Saturated fats should be < 10% of the total energy intake. (4) Cholesterol intake should be limited to < 250 mg/d. (5) Monounsaturated fats such as olive oil and rapeseed oil should be encouraged. (6) Proteins should constitute 10 to 15% of the diet. Insulin therapy is necessary for controlling type 1 diabetes mellitus. On the other hand, up to 20% of the type 2 diabetics can be controlled by diet and exercise alone. Other cases of type 2 diabetes mellitus are treated with oral hypoglycemic drugs such as the sulfonylureas, which stimulate insulin secretion, and the biguanides, which increases insulin action and inhibit liver gluconeogenesis. Oral agents may fail to control blood glucose level after a period of apparent success due to worsening B-cell function. Most of these patients of “secondary failure” ultimately require insulin.

REVISION QUESTIONS 1. Glucose and aminoacids cause greater stimulation of insulin secretion when ingested than when administered intravenously. Why?

7. Obese individuals tend to have higher plasma insulin levels. Why?

2. How is insulin secretion affected by circulating catecholamines?

8. Diabetes mellitus and starvation have similar metabolic picture except for a salient difference. What is the difference?

3. Insulin increases glycolysis in all cells except the muscle cells and yet, it is called an ‘anabolic’ hormone. Why?

9. In hyperglycemia, some of the glucose is metabolized through the sorbital pathway. What is its clinical significance?

4. Insulin causes movement of K+ from the extracellular to the intracellular space. How?

10. In diabetes mellitus, there is polyphagia despite the hyperglycemia. Why?

5. The dietary aminoacids absorbed into blood stimulate the release of both insulin and glucagon. What is its physiological significance?

11. The hepatic synthesis of fatty acids decreases in diabetes mellitus and yet, there is a rise in the free fatty acid level in blood. Why?

6. Glucagon has a glucose-sparing effect. How?

12. What causes ketoacidosis in diabetes mellitus?

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88

Reproductive System

Testicular and Ovarian Hormones

Hormones of the testes The hormone-secreting cells in the testes are the Leydig cells and Sertoli cells. The Leydig cell secretes all the androgens, viz., dihydrotestosterone (DHT), testosterone, androstenedione, and dehydroepiandrosterone (DHEA). All of them have 19 carbon atoms, and their androgenic potencies are in a ratio of 60:20:2:1, respectively. The amount of testosterone secreted is 100 times more than the other hormones. The Leydig cell also secretes some androgenic precursors such as pregnenolone and progesterone. The Sertoli cell secretes small amounts of estradiol. Testosterone is synthesized in the Leydig cell through the same biosynthetic pathway as the adrenocortical steroids (see Fig. 85.2). Cholesterol esters, the major precursors for testosterone biosynthesis, are stored in the lipid droplets in the Leydig cells. Androgen biosynthesis in the human testes proceeds mostly from pregnenolone to DHEA and then to androstenedione, testosterone, and dihydrotestosterone, that is, the Δ4 pathway (Fig. 88.1). Only 20% of DHT is synthesized by the testes. The rest is derived from the peripheral conversion of testosterone in the skin and male reproductive tract (epididymis, prostate gland, and seminal vesicles). Two-thirds of the total plasma testosterone is bound to albumin, and one-third is bound to

testosterone-binding globulin, which is also called sex hormone-binding globulin because it binds estradiol as well. Less than 2% of the plasma testosterone is in the free form. Testosterone and androstenedione are converted to active metabolites (having hormonal activity) such as estradiol and estrone respectively through the action of aromatase, which is a microsomal enzyme found in the brain, skin, liver, mammary tissues, adipose tissue, and placenta. The active metabolites are further converted into inactive metabolites such as androsterone and etiocholanolone. The inactive metabolites are conjugated in the liver and excreted into the urine as 17-ketosteroids. Of the total urinary ketosteroids, only one-third is of testicular origin while the remainder comes from the DHEA produced by the adrenal cortex. Hence, the urinary 17-ketosteroid reflects mainly adrenocortical activity and is not a good index of testicular function.

Hormonal control of testicular function Human chorionic gonadotropin In the male fetus,

the stimulus for testosterone synthesis is human chorionic gonadotropin (HCG), which is structurally and functionally similar to luteinizing hormone (LH). Testosterone is synthesised in the Leydig cells from cholesterol. The rate-limiting step in

Cholesterol Cholesterol desmolase Pregnenolone

17-Hydroxypregnenolone 17,20-Lyase

17α-Hydroxylase

17α-Hydroxylase

DHEA 3β-Hydroxy dehydrogenase

3β-Hydroxy dehydrogenase Progesterone

Corticosteroids Progestagens Estrogens Androgens

Δ4 Pathway

17-Hydroxyprogesterone Δ5 Pathway

17,20-Lyase

Estrone AndrosteneAromatase dione

Smooth E.R. enzyme

Estriol

17β-Hydroxy dehydrogenase Testosterone

Mitochondrial enzyme

16α-Hydroxylase

Estradiol Aromatase

5α-Reductase Dihydrotestosterone

Fig. 88.1 Biosynthesis of sex steroids. Estrogens are shown in green, progestagens in blue, and androgens in red. Note that estrone and estradiol are interconvertible.

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Testicular and Ovarian Hormones testosterone synthesis is the conversion of cholesterol to pregnenolone, which is catalyzed by cholesterol desmolase. LH activates cholesterol desmolase. Follicular-stimulating hormone (FSH) increases

testosterone synthesis in two ways: (1) It stimulates the Sertoli cells to synthesize androgenbinding protein (ABP), which binds testosterone, increasing its local concentration in the testes. The high concentration of testosterone stimulates spermatogenesis. (2) FSH also indirectly increases testosterone synthesis by increasing the number of LH receptors on the Leydig cell. The secretion of FSH and LH from the anterior pituitary is stimulated by gonadotropin-releasing hormone (GnRH), which is secreted by the parvocellular neurosecretory neurons in the hypothalamus. The GnRH secretion is pulsatile and occurs at a frequency of 8 to 14 pulses per day. Feedback inhibition of LH and FSH Consistent with

the phenomenon that the secretion of the target hormone inhibits its trophic hormone, testosterone inhibits LH secretion while estradiol and inhibin inhibit FSH secretion. Inhibin is secreted by Sertoli cells and acts only at the pituitary level while testosterone and estradiol act at both pituitary and hypothalamic levels (Fig. 88.2). Physiological actions of androgens (1)

In the fetus, testosterone stimulates the differentiation of the male internal genitalia while DHT stimulates the

555

differentiation of the male external genitalia. (2) The development of the secondary sexual characteristics, libido, and potency (erectile functions) during puberty are mainly attributable to testosterone. The growth of pubic hair, increased sebum production by sebaceous glands with consequent development of acne, growth of scrotum and growth of prostate, and stimulation of prostatic secretion are largely due to DHT (Table 88.1). (3) Testosterone is essential for spermatogenesis. (4) Testosterone is a protein anabolic hormone. It stimulates cell division and maturation. Testosterone has a dual effect on skeletal growth: On the one hand, it produces linear skeletal growth and broadens the shoulders in the adolescent. On the other hand, it accelerates epiphysial fusion of the long bones and thereby limits linear growth. Testosterone also has a myotrophic effect (causes muscular development) and retention of potassium, nitrogen, and phosphorus. Treatment with testosterone reduces bone loss and osteoporosis. (5) Testosterone stimulates erythropoiesis directly as well as by stimulating erythropoietin secretion. The higher red cell count in males is due to testosterone. (6) Testosterone increases the deposition of abdominal adipose tissue. (7) Testosterone increases the plasma levels of VLDL and LDL but decreases the plasma level of HDL.

Hormones of the ovary Endocrine cells of the ovary Three types of ovarian cells (Fig. 88.3) are involved in hormone secretion, namely, the granulosa cells, luteal cells, and thecal cells (cells of theca interna).

Hypothalamus

Table 88.1 Differences between the actions of testosterone and dihydrotestosterone

GnRH

Pituitary (Ant. lobe)

m

i n if

e ro u s

T

ABP

FSH

t ub u le

Se

LH

Inhibin

Spermatogenesis

Testosterone

Dihydrotestosterone

Necessary for the differentiation of the internal genitalia

Necessary for the differentiation of the external genitalia

During puberty, promotes the growth of penis, seminal vesicles, larynx, muscles, and skeleton

During puberty, promotes the growth of facial, body, and pubic hair, scrotum, sebaceous glands with increased sebum production and development of acne, and prostate with stimulation of prostatic secretions

Promotes spermatogenesis, increases libido, promotes erythropoiesis, and brings about feedback inhibition of LH

Has none of these effects

ABP T

T Leydig cell

T

E

E

Sertoli cell

Fig. 88.2 Hormonal control of the testes. The inhibition of testosterone secretion by estradiol is a paracrine effect. E = estradiol, T = testosterone.

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556

Reproductive System

LH

Androstenedione

FSH LDL

Testosterone

Basal lamina

Thecal cell Cholesterol

Estrone Pregnenolone

Estradiol Granulosa cell

17-Hydroxy Pregnenolone 17-Hydroxy Pregnenolone

Progesterone 17α-OH Progesterone

Progesterone

Theca luteal cell Estrone

Estrone Follicular fluid Estradiol

DHEA

Androstenedione

Androstenedione

Blood Testosterone

Estradiol Granulosa luteal cell

Theca interna cell

Granulosa cell

Fig. 88.3 Hormones secreted by the granulosa cells, thecal cells, and luteal cells of the ovary. Note that the theca luteal cells and granulosa luteal cells secrete different hormones. Also note that the granulosa cells secrete estrogens into the follicular fluid but the granulosa luteal cells secrete estrogens into blood.

Fig. 88.4 Granulosa cells synthesize estrogens from the androgens provided by the thecal cells. FSH, follicularstimulating hormone;

Together they secrete estrogens (estrone, estradiol, and estriol), progestagens (17α-hydroxy progesterone and progesterone), androgens (androstenedione and testosterone), and relaxin.

17-hydroxy progesterone due to the activation of the Δ5 pathway of steroid biosynthesis. The granulosa luteal cells secrete estrone and estradiol. These estrogens are secreted directly into the blood capillaries that grow into the corpus luteum and therefore estrogen levels rise during the luteal phase (see Fig. 90.2).

Thecal cells produce androstenedione and testosterone that are converted in the granulosa cells to estrone and estradiol respectively by the enzyme aromatase (Fig. 88.4). Thecal cells do not produce appreciable amounts of progesterone or 17-hydroxy progesterone because most of the androgens are formed via the Δ4 and not the Δ5 pathway (Fig. 88.1) and therefore progestagen levels remain low in the follicular phase of the menstrual cycle (see Fig. 90.2). cells lack 17α-hydroxylase and 17,20-lyase and therefore, they cannot produce estrogens or progestagens directly from cholesterol. Estrogens are synthesized in granulosa cells from the androstenedione obtained from thecal cells. Most of the estrogen produced by granulosa cells is secreted into the follicular fluid and therefore estrogen levels remain low in the early follicular phase.

Granulosa

Luteal cells are of two types: the theca luteal cells and the granulosa luteal cells formed by the luteinization of granulosa and thecal cells respectively. Theca luteal cells produce mainly progesterone and

Sircar_Chapter88_554-559.indd 556

Estrogens Estradiol (E2) is the main estrogen secreted by the ovary and is also the most biologically active. Estrone (E1) is a weak ovarian estrogen. In postmenopausal women, estrone is the dominant plasma estrogen. It is produced in peripheral tissues, mainly in liver and adipose tissue, by the conversion of androstenedione that is produced in the adrenal cortex. Estriol (E3) is not secreted by the ovary. Large amounts are secreted only during pregnancy, when it is secreted by the placenta. It is also formed in small amounts in the liver from estradiol and estrone. Estrone and estradiol are interconvertible (Fig. 88.1). The synthesis of estriol by the placenta is described on p 587. Note that estr(one) has one hydroxyl group, estra(di)ol has two hydroxyl

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Testicular and Ovarian Hormones groups, and es(tri)ol has three hydroxyl groups (see Fig. 85.3). Over 70% of circulating estrogens are bound to sex steroid-binding globulin and 25% are bound to plasma albumin. Estradiol and estrone are hydroxylated to form estriol and catecholestrogens, which are excreted primarily as glucuronides. Estrone is excreted primarily as a sulfate. Estrogens are metabolized very quickly in the liver. Hence, the E:P ratio (estrogen : progesterone) and E:T ratio (estrogen : testosterone) rise in liver diseases. The latter is of clinical significance as it explains the appearance of feminity in male patients with chronic liver disease. The physiological actions of estrogens can be summarized as follows: (1) Metabolism: Estrogens

557

have important protein anabolic effects. They mediate the growth and development of the female reproductive organs, especially, that of the gravid uterus. They also promote cellular proliferation in the mucosal linings of these structures. (2) Endometrium: Estrogens stimulate the regeneration of the stratum functionalis during the proliferative phase of the endometrial cycle by increasing mitosis. The spiral arterioles of the stratum functionalis grow rapidly under estrogenic influence. (3) Myometrium: Estrogens cause hypertrophy of the myometrium and sensitize it to the action of oxytocin, which promotes uterine contractility. (4) Cervix: Under the influence of estrogens, the uterine cervix secretes an abundance of copious thin, watery mucus during the preovulatory phase.

Table 88.2 Differences in the physiological actions of estradiol and progesterone Site of action

Estradiol

Progesterone

Pituitary– hypothalamus

Inhibits FSH secretion by negative feedback

Inhibits LH secretion by negative feedback

Increases prolactin secretion Inhibits LH secretion by negative feedback In high concentration, stimulates midcycle surge of LH and FSH by positive feedback on pituitary Uterus

Promotes hypertrophy of myometrium

—

Promotes hyperplasia of endometrium

Arrests endometrial mitosis and induces secretory activity

Promotes uterine motility

Inhibits uterine motility Maintains the decidua and assists in the implantation of blastocyst

Cervix

Causes thinning of cervical mucus

Vagina

Causes maturation of vaginal epithelial cells and the thickening and cornification of vaginal mucosa.

Breast

Promotes ductal and lobuloalveolar growth +

Causes thickening of cervical mucus —

Promotes lobuloalveolar growth

Kidney

Promotes renal Na retention and consequently, water retention

Bone

Enhances bone growth, density, and maturation and causes early epiphyseal closure

—

Miscellaneous

Promotes development of female secondary sexual characteristics

—

Makes sebaceous secretion more fluid and thus inhibits formation of acne and comedones

Antagonizes the action of aldosterone on the kidney and thereby promotes the renal excretion of Na+ and water

— Serves as a precursor for steroid hormones Increases basal body temperature Stimulates breathing

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558

Reproductive System (5) Vagina: The vaginal epithelium cells mature under the effect of estrogen, resulting in the thickening and cornification of the vaginal epithelium. (6) Breast: Estrogens promote the development of the duct and lobuloalveolar system of the mammary gland. (7) Bone: Estrogens, such as androgens, exert a dual effect on skeletal growth: (a) On the one hand, they cause an increase in osteoblastic activity, resulting in a growth spurt at puberty. (b) On the other hand, estrogens also hasten bone maturation and promote the closure of the epiphyseal plates in the long bones more effectively than does testosterone. Therefore, the female skeleton is usually shorter. Estrogens, to a lesser degree than testosterone, promote the deposition of bone matrix by causing Ca2+ and HPO42– retention. Estrogens are responsible for the oval shape of the female pelvic inlet. (8) Liver: Estrogens stimulate the hepatic synthesis of the transport globulins, including thyroxine-binding globulin and transcortin. Estrogens increase the hepatic synthesis of coagulation factors and therefore predispose to thrombosis. Estrogens also increase the hepatic synthesis of angiotensinogen, leading to retention of Na+ and water in the body.

Progestagens

the renal excretion of Na+. This reduces the water retention caused by the elevated aldosterone levels found in pregnancy. (6) Fetus. Progesterone contributes to the growth and development of the fetus by acting as a precursor for corticosteroid synthesis by the fetal adrenal cortex. (7) Brain. Progesterone stimulates breathing through a direct effect on the brain stem respiratory center.

Hormonal control of ovarian function The development of the ovarian follicle is largely under the control of FSH. Ovulation is caused by LH which also stimulates secretion of progesterone from the corpus luteum. Consistent with the phenomenon of negative feedback in which the secretion of the target hormone inhibits its trophic hormone, progesterone inhibits LH and inhibin inhibits FSH secretion. Estradiol, whose secretion is stimulated by both LH and FSH, inhibits both LH and FSH. Progesterone and estrogen act at both hypothalamic and pituitary levels while inhibin secreted by granulosa cells acts only on the pituitary (Fig. 88.5). Under certain conditions, estrogen causes stimulation rather than inhibition of LH, resulting in a positive feedback cycle (see Ovulation, p 567).

Progestagens (progesterone and 17α-hydroxy progesterone) are secreted mainly by theca luteal cells. Progesterone is not bound to sex steroid-binding globulin. The progesterone is bound primarily to cortisol-binding globulin (transcortin) and albumin. The liver metabolizes progesterone to pregnanediol, and 17α-hydroxyprogesterone to pregnanetriol.

Hypothalamus

GnRH

The physiological effects of progestagens are attrib-

utable entirely to progesterone since 17α-hydroxy progesterone has little, if any, biological effect. The physiological actions of progesterone are as follows: (1) Endometrium. Progesterone promotes secretory changes in the stratum functionalis of the endometrium. The endometrial glands become elongated and coiled and secrete a glycogen-rich fluid. Progesterone is required for the implantation of the blastocyst and the maintenance of decidua. Antiprogesterone agents such as mifepristone are used for medical termination of pregnancy. (2) Myometrium. Progesterone inhibits uterine motility by hyperpolarizing the uterine smooth muscles. (3) Cervix. Under the influence of progesterone, the mucus secreted by the cervical glands is reduced in volume and becomes thick and viscid. (4) Breast. Progesterone promotes lobuloalveolar growth in the mammary gland. (5) Kidney. Progesterone has an anti-aldosterone effect, that is, it promotes

Sircar_Chapter88_554-559.indd 558

LH

P

C E

Pituitary (Ant. lobe)

FSH

Follicular growth Inhibin

Luteal cell

T

17-OH-P Thecal cell

E

E

Granulosa cell

Fig. 88.5 Hormonal control of the ovary. E, estradiol; GnRH, gonadotropin-releasing hormone; P, progesterone; 17-OH-P, 17α-hydroxy progesterone; T, testosterone.

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Testicular and Ovarian Hormones

559

REVISION QUESTIONS 1. Urinary 17 ketosteroid is not a good index of testicular function. Why?

6. Progestagen levels remain low during the early follicular phase of the menstrual cycle. Why?

2. The human chorionic gonadotropin (HCG) is structurally similar to which hormone of the adult?

7. Liver diseases in males tend to cause femininity. Why?

3. FSH indirectly increases spermatogenesis and testosterone synthesis. How? 4. Testosterone is necessary for spermatogenesis but systemic administration of testosterone decreases spermatogenesis. Why?

8. How do estrogens affect bone growth? 9. Estrogens predispose to thrombosis. Why? 10. How is the Na+ and water balance of the body affected by estrogens and progestagens?

5. What is the effect of testosterone on skeletal growth?

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89

Reproductive System

Puberty and Gametogenesis

Puberty Puberty or adolescence is that stage of development when the endocrine and gametogenic functions of the gonads develop for the first time to the point where reproduction is possible. Puberty generally occurs between the ages of 8 and 13 years in girls and 9 and 14 years in boys. It coincides with gametogenesis (spermatogenesis in boys and folliculogenesis in girls) and a surge of sex hormone secretion resulting in the development of the secondary sexual characteristics.

Secondary sexual characteristics Male secondary sexual characteristics At puberty, (1) the penis and scrotum increase in size and become pigmented. Rugal folds appear in the scrotal skin. (2) Facial hair develops. The scalp line undergoes temporal recession. (3) Body hair increases: Axillary hair appears and pubic hair develops as a triangle with apex up. (4) The pubertal growth spurt occurs. Shoulders broaden. (5) The prostate and seminal vesicles enlarge and start secreting seminal fluid. (6) Sebaceous gland secretion thickens and increases, predisposing to acne. (7) The pitch of the voice becomes lower due to the enlargement of the larynx and the thickening of the vocal cords. (8) The muscle bulk and strength increases and there is a positive nitrogen balance. (9) The attitude becomes more aggressive and interest in females develops.

Control of pubertal onset A plausible mechanism of the onset of puberty is that till puberty, the gonadotropin-releasing hormone (GnRH) secretion from the hypothalamus is highly sensitive to feedback inhibition by testosterone and estrogens. As a result, the levels of testosterone and estrogen are never able to rise sufficiently high to induce puberty. From birth to puberty, there is a decrease in the sensitivity of the hypothalamus to feedback inhibition by testosterone or estrogens (Fig 89.1). By puberty, there is considerable decrease in hypothalamic sensitivity to feedback inhibition by testosterone and estrogen and therefore GnRH secretion increases and becomes pulsatile. In the presence of the normal pulsatile release of GnRH, testosterone and estrogens are secreted in adequate amounts. Role of leptin Over the past couple of centuries,

the age of pubertal onset has been decreasing at the rate of 1 to 3 months per decade. Such changes are called secular changes and have been attributed to a general improvement in health and nourishment. The link between nourishment and earlier pubertal onset is provided by leptin, a satiety-producing hormone secreted by fat cells. Leptin facilitates GnRH secretion, thereby helping in pubertal onset. It is observed that young women often stop menstruating when they lose weight and resume

Hypothalamus

-

Female secondary sexual characteristics In girls,

the most striking events associated with the onset of puberty are thelarche (the development of breasts) followed by pubarche (development of axillary and pubic hair; the pubic hair develops as a triangle with apex below) and menarche (the first menstrual period). The initial periods are generally anovulatory: regular ovulation appears about a year later. A less striking event associated with puberty is adrenarche, an increase in the secretion of adrenal androgens that occurs probably because an adrenal androgen-stimulating hormone secreted from the pituitary gland stimulates the enzyme systems in the adrenal glands to channel more pregnenolone to the androgenic pathway. A growth spurt occurs with a characteristic feminine fat deposition. The external genitalia develop further. Interest in males develops.

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Gonadotropin-releasing hormone (GnRH) Increased leptin secretion from adipocytes

Increase in body fat

+

Anterior lobe of pituitary

Testosterone / Estrogen 8

9 10 11 12 13 14 Age

Fig. 89.1 Feedback control of GnRH secretion by the sex steroids. Note that the negative feedback decreases with age and is minimum at puberty.

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Puberty and Gametogenesis

561

menstruation once they regain weight. It therefore seems that a critical body weight is required for leptin release and pubertal onset.

Abnormalities of pubertal onset Precocious puberty Exposure of immature males

to androgens or females to estrogens causes early development of secondary sexual characteristics without gametogenesis. This syndrome is called precocious pseudopuberty to distinguish it from true precocious puberty that occurs due to early secretion of pituitary gonadotropins. Hypothalamic diseases are frequently associated with precocious puberty. Lesions of the ventral hypothalamus near the infundibulum cause precocious puberty, either because the neural pathways inhibiting GnRH secretion are interrupted or because the irritation caused by the lesion stimulates GnRH secretion. Sometimes luteinizing hormone (LH) secretion is high despite inadequate GnRH secretion, resulting in gonadotropin-independent precocity. Delayed puberty Puberty is considered to be pathologically delayed if menarche fails to occur by the age of 17 or testicular development fails to occur by the age of 20. Failure of maturation can occur in panhypopituitarism and Turner syndrome as well as in some otherwise normal individuals. In males, this clinical picture is called eunuchoidism. In females, it is called primary amenorrhea.

Male gametogenesis Structure of the testes Seminiferous tubules The testes are made of

convoluted loops of seminiferous tubules (see Fig. 91.2) that drain at both ends into the ducts in the epididymis. Between the coils of seminiferous tubules are the interstitial cells of Leydig which secrete testosterone. The seminiferous tubules contain the male germ cells. The tubule walls are made of Sertoli cells that rest on a basement membrane. The cell membranes of adjacent Sertoli cells are attached through tight junctions, forming a barrier (the blood—testes barrier, see below) that divides the lumen of the seminiferous tubule into two compartments: a basal compartment containing the spermatogonia and the early spermatocytes, and an adluminal compartment containing spermatocytes, spermatids, and spermatozoa (Fig. 89.2). Sertoli cell This serves numerous functions, which

are as follows: (1) It produces the bathing fluid in the seminiferous tubules and provides nourishment to the developing spermatozoa. (2) The

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Estradiol Androgen-binding protein Sertoli cells

Leydig cells Testosterone Dihydrotestosterone Androstenedione Spermatogonium Spermatocytes Spermatids Spermatozoa

Blood-testes barrier

Basal compartment Adluminal compartment

Basement membrane Epithelial cell

Fig. 89.2 A cross section of the seminiferous tubule showing Leydig and Sertoli cells.

intercellular junctions between adjacent Sertoli cells constitute the blood–testes barrier. (3) It produces inhibin which suppresses FSH secretion. (4) It secretes androgen-binding globulin (ABP) which binds testosterone with high affinity and is responsible for the high testosterone concentration in the tubular lumen. (5) It secretes transferrin for transporting iron to tubular cells, ceruloplasmin for transporting copper to the tubular cells, and plasminogen activator, which may mediate proteolytic reactions important for migration of maturing germ cells from the basal compartment to the adluminal compartment. (6) It produces Müllerian duct inhibiting substance (p 581). (7) It secretes aromatase that converts the androstenedione and testosterone produced by the Leydig cells to estrone and estradiol, respectively (see Fig. 88.1). These estrogens inhibit testosterone secretion through a paracrine effect. (8) It absorbs the residual bodies that are cast off from the spermatozoa during spermiogenesis. (9) It controls spermeation, that is, the release of sperms. Blood–testes barrier This formed by tight intracel-

lular junctions between adjacent Sertoli cells in the seminiferous tubule. The barrier separates the basal

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Reproductive System piece, the axoneme is surrounded by seven to nine outer dense fibers. The middle piece is surrounded by the spiral mitochondrial sheath made of several mitochondria tightly aligned end to end.

Spermatogenesis Spermatogenesis (male gametogenesis) is the formation of mature sperms from spermatogonia (the primitive germ cells) inside the seminiferous tubules. Spermatogenesis begins at puberty and has three phases (Fig. 89.4), viz., (1) the proliferative phase in which there is mitotic multiplication of spermatogonia (stem cells) to form primary spermatocytes, (2) the meiotic phase, which leads to the formation Spermatogonium (2n) (type A) 1 2 4 8

Sperm (spermatozoon) Each sperm (Fig. 89.3) has

a head and a long tail. The sperm head contains an elongated nucleus with highly compact chromatin. Covering the head such as a cap is the acrosome, a lysosome-like organelle rich in enzymes for sperm penetration of the ovum. The sperm tail is divided into the middle piece, principal piece, and the end piece. Through its entire length, the tail has two central microtubules surrounded by nine microtubule doublets (see Fig. 4.5B). Except in the end

Five mitotic divisions

16 32

Spermatogonia (type B) 64

Primary spermatocytes (2n) Prophase (chromatin duplication) 64

Primary spermatocytes (4n) First (reductional) meiotic division 128

Acrosomal cap

Secondary spermatocytes (2n)

Nucleus

Proliferative phase

and adluminal compartments of the seminiferous tubule. Thus, the germ cells too have to cross the barrier as they pass from the basal compartment to the adluminal compartment. The tight junctions between Sertoli cells loosen up to enable the passage of maturing germ cells through the junction, only to tighten up again after they have passed. The blood–testes barrier has the following functions: (1) It protects the spermatocytes, spermatids, and spermatozoa from blood-borne toxins and circulating antibodies. However, steroids penetrate the barrier with ease. (2) It prevents the by-products of gametogenesis from entering circulation lest they should stimulate an autoimmune reaction. Not unexpectedly, the breakdown of the barrier results in autoimmune response against the germ cells. (3) The blood–testes barrier enables the seminiferous tubule to maintain a different composition of fluid inside its lumen. The fluid in the seminiferous tubules contains very little protein and glucose but is rich in androgens, estrogens, and potassium ions.

Nuclear vacuole

Meiotic phase

562

Second (equational) meiotic division 256

Basal body

Dense fibers

Middle piece

512

Axial bundle of fibers

Spermeogenesis

Residual bodies

Mitochondria

512

Cytodifferentiative phase

Spermatids

Centriole

Spermatozoa Principal piece

Fig. 89.3 Structure of a sperm.

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Fig. 89.4 Spermatogenesis. The proliferative phase occurs in the basal compartment of the seminiferous tubule. Because of incomplete cytokinesis, all cells derived from a single spermatogonium remain connected through cytoplasmic bridges. The connections persist till the formation of the spermatozoa.

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Puberty and Gametogenesis of primary spermatids, and the (3) cytodifferentiative phase or spermiogenesis in which the spermatids differentiate into the primary spermatozoa. The spermatogonia divide and multiply in the basal compartment of the tubules. The spermatocytes formed enter the adluminal compartment where the remainder of the maturation occurs. Each spermatogonium divides seven times to form 128 primary spermatocytes. The 128 primary spermatocytes undergo the first meiotic division to form 256 secondary spermatocytes, which then complete the second meiotic division to form 512 spermatids. Finally, each spermatid develops into a mature sperm in a span of 74 days.

A

B

Countercurrent exchange of testosterone

Countercurrent exchange of heat

Low testosterone concentration in body cavity

Body cavity at 37oC

563

Artery Vein

Spermiogenesis Spermiogenesis is the transformation of the spermatids into mature spermatocytes or sperms. The spermatids mature into spermatozoa inside the membrane recesses of the Sertoli cells. Mature spermatozoa are released from the Sertoli cells and become free in the lumens of the tubules. The transformation of spermatids into spermatozoa is associated with the following changes. (1) The Golgi apparatus, containing hyaluronidase and other proteases, is transformed to the acrosome—a caplike structure covering the anterior two-thirds of the sperm head. During fertilization, the acrosome penetrates the ovum by releasing its enzymes. (2) The centrioles and mitochondria are transformed into the flagellae (sperm tails). The mitochondria provide energy for the flagellar movement. One centriole is converted into the basal body from which the dense fibers originate. (3) The nuclear protein histone is replaced by protamine, which surrounds the inactive and highly condensed chromatin in the spermatozoa. The nuclear condensation in the spermatozoa protects the genome from the deleterious effects of mutagens. (4) Unnecessary cellular organelles such as ribosomes, lipids, degenerating mitochondria, and Golgi apparatus are cast off from the spermatozoa as residual bodies. The Sertoli cells absorb these bodies. (5) The spermatozoa do not grow or divide any further.

Factors affecting spermatogenesis Testosterone The maturation of spermatids to spermatozoa requires the action of testosterone on the Sertoli cells in which the developing spermatozoa are embedded. Normal spermatogenesis therefore requires a high “local” concentration of testosterone inside the seminiferous tubule. It is to be noted that systemic administration of testosterone lowers the local testosterone concentration in the testes by inhibiting follicle-stimulating hormone (FSH)

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High testosterone concentration in the testes

Testes at 32oC

Fig. 89.5 Countercurrent exchanger mechanism for [A] conservation of local temperature and [B] testosterone concentration in the testes.

secretion. The local testosterone concentration rises only when FSH secretion increases: FSH acts on Sertoli cells to increase the synthesis of ABP, which allows a high local testosterone concentration to build up. FSH also increases the number of testosterone receptors on the Sertoli cells. A countercurrent exchanger that operates between the spermatic arteries and veins, which run parallel but in opposite direction, conserves the high local testosterone concentration in the testes (Fig. 89.5A). Temperature Spermatogenesis requires a temperature of about 32°C, which is lower than the normal body temperature. Cryptorchidism (failure of testicular descent) results in sterility due to thermal damage to the spermatogonia. Why is the scrotal temperature lower than the body temperature? The reason is 2-fold: (1) The scrotum is outside the body cavity and is kept cooler through evaporative cooling. (2) Although arterial blood flowing into the testes tends to increase the testicular temperature to 37oC, the effect is minimized by the countercurrent heatexchanger mechanism operating between the spermatic arteries and veins (Fig. 89.5B). Varicocele (dilatation of veins of the pampiniform plexus) is associated with incompetence of the venous valves, thus resulting in retrograde blood flow. This interferes with the countercurrent heat exchanger mechanism, causing impaired sperm production. There is also a seasonal effect on spermatogenesis, with sperm counts increasing in winter regardless

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564

Reproductive System

Granulosa cells

Oocyte Nucleus of oocyte

Oocyte

Zona pellucida

Theca cells

Follicular epithelial cell Primordial follicle

Follicular antrum Oocyte

Theca interna

Cumulus oophorus

Theca externa

Zone pellucida

Primary follicle

Granulosa cells

Secondary follicle (late)

Tunica albuginea

Primary follicle

Germinal epithelium (covering of ovary)

Medulla

Cortex Corpus albicans

Oocyte with corona radiata after ovulation

Ovary

Cumulus oophorus with oocyte Granulosa cells Corpus luteum

Opened follicle

Blood vessels

Theca interna Theca externa

Oocyte

Corpus luteum

Follicular antrum Ovulation

Graafian follicle

Tunica albuginea and epithelial covering of ovary

Fig. 89.6 Ovarian follicles. Note that the oocyte released from the ovary retains its coat of the granulosa cells, called the cumulus oophorus or the corona radiata.

of the temperature to which the scrotum is exposed. Sperm production continues till the age of 80 or 90 although the production rate slows down after the age of 40.

Female gametogenesis Oogenesis The female germ cell is called the oogonium, which develops into the primary oocyte and then into the secondary oocyte. At all stages of development, it is called by the general name ovum or egg (pleural: ova). At birth itself, the oogonium enters the prophase of meiosis I, forming the primary oocyte. However, immediately after it completes prophase, the meiosis I is arrested for several years.

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Metaphase I (the next phase of meiosis I) does not occur until puberty (See Fig. 6.5). When meiosis I resumes at puberty, it is completed quickly and results in the formation of two daughter cells. One of the daughter cells, the secondary oocyte, receives most of the cytoplasm, while the other, the first polar body, fragments and disappears. The secondary oocyte immediately goes into meiosis II but the division stops at metaphase. It is at this stage that ovulation occurs. Meiosis II resumes after fertilization. The second polar body is cast off and the fertilized ovum proceeds to form the embryo.

Folliculogenesis At the time of birth, there are 2 million oogonia in the ovary of which fewer than 300,000 ova are left by

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Puberty and Gametogenesis puberty. Thereafter, once every 28 days, a group of ova start maturing of which only one ovum reaches maturity while the rest degenerate. A maturing primordial follicle grows successively into the primary, secondary, tertiary, and antral follicle (Fig. 89.6). Primordial follicles are composed of an outer single layer of flat epithelial cells and a small immature oocyte arrested in the prophase of meiosis I. The epithelial cells and the oocyte are enveloped in a thin basal lamina. When the flat epithelial cells become cuboidal granulosa cells, the follicle is called a primary follicle. Secondary follicles form when the granulosa cells inside the basal lamina divide mitotically to form a multilayered stratum granulosum. The oocyte enlarges and forms a coating of mucoid substance called the zona pellucida, which separates the granulosa cells from the oocyte. Tertiary follicles are characterized by the formation of a fluid-filled cavity called the antrum. The stromal cells outside the basal lamina differentiate into two concentric layers of thecal cells called the

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theca interna and theca externa. One of the several tertiary follicles outgrows all the rest to form an antral (Graafian) follicle. It takes about 14 days for the primary follicle (about 0.4 mm) to grow into a Graafian follicle (about 30 mm). Once every 28 days, the ovary releases one follicle with the mature ovum in it, into the abdominal cavity. The process is called ovulation. The other follicles gradually regress through apoptosis and form the corpus albicans. Some of these events are discussed again in Chapter 90. A primordial follicle differentiates successively into the primary, secondary, and early tertiary follicle in the absence of FSH. It is only after reaching the early tertiary stage that its continued development depends on FSH and its own ability to secrete estrogen inside it. FSH regulates the growth and maturation of the ovarian follicle. FSH receptors are located exclusively on the granulosa cells. LH regulates the functions of the corpus luteum. LH receptors are located on the thecal cells.

REVISION QUESTIONS 1. What is the difference between precocious puberty and precocious pseudopuberty?

4. Cryptorchidism is associated with impaired sperm production. Why?

2. Where exactly in the testis is the blood-testis barrier located?

5. Varicocele is often associated with impaired sperm production. Why?

3. The maturation of spermatids to spermatozoa requires testosterone. However, testosterone administration inhibits spermatogenesis. Why?

6. What is the time interval between meiosis I and meiosis II in oogenesis?

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90

Reproductive System

Menstrual Cycle

Preovulatory period Hormonal changes The estrogen and progesterone levels are at their lowest at the beginning of the menstrual cycle (Fig. 90.2). Thereafter till ovulation, there is progressive rise in the plasma estrogens due to the secretion of estradiol by the granulosa cells of the growing ovarian follicle. The preovulatory

1

2

3

4

Ovary Uterus

5

6

7

8

9

o C 36.8

Basal body temperature

36.6 36.4 17α-Hydroxy progesterone

Progestagens

Progesterone

Hormonal concentration

The plasma levels of ovarian hormones are not constant but show cyclical fluctuations. These fluctuations occur due to cyclical changes in the ovary (ovarian cycle). The hormones bring about cyclical changes in the uterine endometrium (uterine or the menstrual cycle), the uterine cervix (cervical cycle), and in the vagina (vaginal cycle). Cyclical changes also occur in the breast and body temperature. Menstrual cycles mark the beginning of estrogen and progesterone secretion in substantial amounts. The onset of menstruation at puberty is called menarche. In early adolescence, the cycles are anovulatory and the menses are irregular. The cessation of menses is called menopause which typically occurs at about the age of 50 years, and is associated with the cessation of estrogen and progesterone secretion. The menstrual cycle is counted from the first day of menstruation (menstrual bleeding). A typical cycle has a length of 28 days with ovulation occurring at about the middle of the cycle (Fig. 90.1). All the cycles, ovarian, uterine, cervical, and vaginal, can be divided into preovulatory and postovulatory periods. The length of the postovulatory period is fairly constant at approximately 14 days. When the length of the menstrual cycle is not exactly 28 days, the time of ovulation is estimated by subtracting 14 days from the duration of the menstrual cycle. Thus in a 30-day cycle, ovulation occurs on the 16th day.

Estrogens

LH

LH and FSH

FSH

3

7

11

15

19

23

27

Day of cycle

Fig. 90.2 Basal body temperature and hormonal concentrations through the menstrual cycle. The two progestagens shown are progesterone, which comes only from the corpus luteum, and 17α-hydroxy progesterone, which comes from the thecal cells as well. Hence, progesterone concentration in the preovulatory phase is nearly zero, while 17α-hydroxy progesterone is secreted in small quantities in the preovulatory phase and shows a surge during ovulation.

changes in uterus, cervix, and vagina (described below) are largely attributable to the rising estrogen levels. The preovulatory phase of the ovarian

10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 Follicular phase O Luteal phase

Menstruation

Proliferative endometrium

Cervix

Watery mucus secretion

Vagina

High glycogen content of epithelium

Secretory endometrium Thick mucus secretion Low glycogen content of epithelium

Fig. 90.1 Phases of the menstrual cycle. Ovulation (O) occurs 14 days before the end of the cycle.

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Menstrual Cycle cycle is therefore also called the estrogenic phase. The progesterone level remains very low and nearly unchanged during this period. The early growth of the ovarian follicle occurs under the influence of FSH on granulosa cells and LH on theca cells. However, FSH secretion declines gradually in the preovulatory period due to feedback inhibition by the estrogens and inhibin secreted by the proliferating granulosa cells. The LH level rises slowly but does not stimulate enough progesterone secretion to cause its own feedback suppression. The progesterone level remains very low and nearly unchanged during this period. Ovarian changes The preovulatory period of the

ovarian cycle is called the follicular phase. It is marked by (1) follicular growth under the influence of FSH, and (2) secretion of estradiol by the developing follicles under the influence of LH from the pituitary. By the end of this phase, one follicle matures fully (see Fig. 89.5). The development of the ovarian follicle is shown in Fig. 89.5. Uterine changes During the preovulatory period, the uterus goes through two phases, viz., the menstrual phase and the proliferative phase. Although it occurs in the preovulatory period, the menstrual phase is described here in the context of postovulatory uterine changes. During the proliferative phase, estrogens stimulate endometrial proliferation, that is, mitosis of the stratum basale which regenerates the stratum functionale. The endometrium grows to about 4 mm in thickness. The blood vessels in the stratum functionale become long and coiled and are called spiral arteries. The uterine glands grow in length. The cells lining the glands accumulate glycogen but remain nonsecretory in this phase. Cervical changes During the preovulatory phase,

estrogen makes the cervical mucus watery and more alkaline. These changes promote the survival and transport of sperms. The mucus is thinnest at the time of ovulation and its elasticity, or spinnbarkeit, increases so much that by midcycle, a drop can be stretched into an 8- to 12-cm-long thin thread. In addition, it dries in an arborizing fern-like pattern when a thin layer is spread on a slide (Fig. 90.3). The characteristic ferning pattern is due to crystallization of sodium chloride. Vaginal changes The vaginal epithelium cells ma-

ture under the effect of estrogen, resulting in the thickening and cornification of the vaginal lining. By evaluating the ratio of mature to immature cells microscopically in vaginal smears, this maturation can be indicated by what is known as the karyopyknotic index (KPI). KPI peak coincides with the estrogen peak near ovulation.

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567

Ferning of cervical mucus in proliferative phase

Cervical mucus in secretory phase

Fig. 90.3 Ferning of cervical mucus. The persistence of a fern-like pattern in the secretory phase indicates anovulation.

Estrogen also increases the glycogen content of the epithelial cells, which are exfoliated throughout the menstrual cycle. The glycogen in the exfoliated cells is a rich substrate for bacterial flora which breaks down glycogen into lactic acid and lowers the vaginal pH. Breast changes During menstruation, the decrease in estradiol and progesterone is associated with a decrease in the size of the mammary duct and acini. In the preovulatory phase, there is proliferation of mammary ducts under the influence of estrogens. A gradual increase of epithelial tissue occurs with each successive cycle.

Ovulation Ovulation refers to the extrusion of the secondary oocyte from the Graafian follicle into the peritoneal cavity. Ovulation is triggered by a sharp rise in the LH level. This LH surge occurs about 24 hours before ovulation when the plasma estrogen exceeds a critical concentration and exerts a positive feedback (instead of the usual negative feedback) on the hypothalamic–hypophyseal axis. The LH surge causes a reflex release of GnRH and a concomitant surge in pituitary LH secretion. A lesser FSH surge also occurs simultaneously. The midcycle LH surge requires a plasma estradiol concentration of about 150 pg/mL for at least 36 hours, a condition which is normally achieved by day 13. The LH surge is a fairly precise indicator of ovulation. Tests for ovulation (1) The basal body tempera-

ture rises by 0.5°C immediately after ovulation and serves as an indicator of ovulation. The rise persists through most of the luteal phase. The temperature dips during the follicular phase. (2) Spinnbarkeit and ferning of cervical mucus disappear after

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Reproductive System ovulation. Hence, their persistence beyond midcycle indicates the absence of ovulation.

Postovulatory period Hormonal changes The LH surge not only trig-

gers ovulation but also initiates the luteinization of the thecal and granulosa cells. FSH and LH stimulate the corpus luteum to secrete progesterone and estradiol. The plasma concentration of both progesterone and estradiol peaks in the midluteal phase (day 21). As progesterone is secreted in greater amounts (Fig. 90.2), the postovulatory phase is also called the progestational phase. FSH and LH levels continue to decline during the luteal phase due to negative feedback of estrogens and progesterone.

(2) The glands elongate and become tortuous. Their lumen becomes wider and is filled with mucus and a glycogen-rich secretion. (3) The spiral arteries become longer, more coiled, and dilated. About 2 days before menstruation, the endometrium is infiltrated with neutrophils (Fig. 90.4). Luteolysis is associated with a sudden drop in estrogen and progesterone levels which causes arteriolar constriction, resulting in ischemia and necrosis of the stratum functionale, which is sloughed off. The stratum basale remains intact and the total endometrial thickness reduces to about 2 mm. The vasospasm seems to be mediated by PGF2. Bleeding starts when the arterioles

Ovarian changes The ruptured follicle promptly

fills up with blood, forming the corpus hemorrhagicum. Follicular rupture may be associated with mittelschmerz, the German word for “middle-pain” or the “mid-cycle pain.” This fleeting lower abdominal pain could be due to the peritoneal irritation caused by the blood released from the ruptured follicle. The pain may be unilateral, indicating which of the two ovaries has ovulated. Thereafter, the clotted blood is replaced by yellowish, lipid-rich luteal cells (derived from the granulosa and thecal cells) forming the corpus luteum. The postovulatory phase of the ovarian cycle is therefore called the luteal phase. The oocyte that is released from the ovary is picked up by the fimbriated ends of the uterine tube and is transported to the uterus. Fertilization normally occurs in the ampulla of the tube. (1) If fertilization does not occur, the corpus luteum begins to degenerate by day 24, and is eventually replaced by fibrous tissue, forming the corpus albicans. The degeneration of the corpus luteum is called luteolysis and it seems to be mediated by PGF2. (2) If fertilization occurs, the functional life span of the corpus luteum is extended under the trophic influence of placental HCG and it continues to secrete estradiol and progesterone till the third month of pregnancy when the placenta takes over its endocrine function (the luteal–placental shift, see Fig. 93.3). Uterine changes The endometrium enters its secretory phase and is prepared for a possible implantation of the fertilized ovum. (1) The endometrium thickens to about 5 mm, becomes hyperemic, and develops a scalloped Swiss cheese appearance. Progesterone halts endometrial mitosis and causes maturation of the endometrium.

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Follicular phase

Ovulation

Luteal phase

Functional layer Basal layer

28

7

14

Menstrual phase

21 Proliferative phase

Spiral arteries

28

7 Days

Secretory phase

Uterine glands

Compact layer

Endometrium (functional layer)

Spongy layer

Stroma

Endometrium (basal layer) Myometrium Basal blood vessels

Fig. 90.4 (Above) Ovarian and endometrial changes during menstrual cycle. (Below) Structure of the endometrium at the peak of the secretory phase.

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Menstrual Cycle relax. As menstrual bleeding follows a sharp fall in the plasma concentration of ovarian hormones, it is also called withdrawal bleeding. Menstrual blood clots in the uterus but liquefies in the vagina due to fibrinolysis. The average blood loss during menstruation is 40 mL (10–200 mL) over a period of 4 days. Cervical changes Progesterone makes the cervical mucus thick, tenacious, and cellular. It fails to form the fern pattern on drying and the spinnbarkeit is no longer possible. Vaginal changes The glycogen content of the epithelial cells decreases during this phase. Consequently, less lactic acid is produced in the vagina by the bacterial flora. The rise in pH makes the vagina prone to infection by Trichomonas vaginalis. The epithelium is infiltrated with leukocytes. Breast changes In the luteal phase, progesterone stimulates the proliferation of the terminal duct and alveoli, distension of the ducts, and hyperemia and edema of the interstitial tissue of the breast. All these changes, which cause a sense of breast fullness, regress during menstruation.

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Menopause Menopause is the cessation of menstruation and fertility. It occurs when the ovaries stop producing ova and is associated with low levels of estrogens and progesterone. Blood FSH level rises when a woman approaches menopause, but it is not a reliable indicator of impending menopause as its level fluctuates considerably. The fall in oestrogen levels causes vaginal dryness and osteoporosis and emotional symptoms such as hot flushes, night sweats, mood swings and vaginal dryness. Hormone therapy with estrogen is advised if the symptoms are severe. When menopause occurs following ovarectomy or chemotherapy, it is called surgical menopause. The average age of menopause is 51 to 52 years, but can occur as early as 40 or as late as 55. Menopause is preceded by the perimenopause, which begins 3 to 5 year before menopause when a woman’s estrogen levels begin to drop, and lasts a year after the menopause. During perimenopause, the periods become infrequent and can stop for a while before starting again. Periods can also stop temporarily during sickness. Therefore, menopause can be inferred only in retrospect after it has lasted a year.

REVISION QUESTIONS 1. On which day of a 30-day menstrual cycle is ovulation likely to occur?

5. What is the “safe period” and what are the methods for identifying it?

2. What are the characteristics of the cervical mucus during the premenstrual period?

6. What is the usual cause of the fleeting lower abdominal pain that commonly occurs in the postovulatory period?

3. What is karyopyknotic index and when is it the highest? 4. Which phase of the menstrual cycle is associated with a lowering of the vaginal pH, and why?

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7. The vagina is prone to infection by Trichomonas vaginalis during the postovulatory period. Why?

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91

Reproductive System

Sperm Transport and Fertilization

Sperm transport in the male tract Sperms mature as they pass through the male ducts (Figs. 91.1 and 91.2). Transport of sperms through the male ducts does not require much sperm motility. Spermatozoa show significant motility only after they are ejaculated.

Sperm passage through the rete testis Sperms are concentrated as they pass through the rete testis, which is the site of confluence of seminiferous tubules. If the concentration does not occur, the sperms entering the epididymis get diluted in a large volume of fluid and infertility results. The concentration occurs due to the reabsorption of Na+ and water under the influence of estrogen. Spermatozoa leaving the rete testis are not fully motile and are therefore incapable of fertilizing the ovum.

Ureter

Inguinal canal

Bladder

Vas deferens

Epididymis, head (caput) Efferent ductules

Testicular artery Pampiniform plexus Epididymis, body (corpus)

Septum Rete testis

Vas deferens

Epididymis, tail (cauda)

Lobule Epididymal duct in head of epidymis

Epididymal duct in body of epidymis

Efferent ductules Straight seminiferous tubules Rete testis

Seminal vesicle Ejaculatory duct Prostate Bulbourethral gland Urethra Penis Epididymis

Lobule with convoluted seminiferous tubules

Epididymal duct in tail of epididymis

Fig. 91.2 Seminiferous tubules, rete testis and epididymis. The seminiferous tubules in the testes drain into a plexus of epithelium-lined spaces called the rete testis. About a dozen efferent ducts from the rete testes drain into the epididymis. The epididymis is divided into the caput (head), the corpus (body), and the cauda (tail). It is made of over 6 m of coiled duct (the epididymal duct).

Testis

Sperm passage through epididymis

Fig. 91.1 Male reproductive tract. The epididymal duct continues into the vas deferens, which has thicker walls. Near its termination, the vas deferens joins the duct of the seminal vesicles to form the ejaculatory duct, which opens in the urethra.

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The sperms continue to mature and acquire motility during their passage through the epididymis. Sperms take 2 to 11 days to pass through the epididymis. During this transit, the epididymis serves four major functions related to sperm: its maturation, storage, decapacitation, and protection from immunological damage.

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Sperm Transport and Fertilization Sperm maturation occurs in the proximal epidi-

dymis (caput and corpus epididymis) whereby sperms gain their ability to fertilize eggs. It involves (1) development of sperm motility with a higher velocity of forward progression and a straighter path, (2) development of zona-binding capacity due to development of ZP3 receptors on the sperm, (3) development of the ability to undergo acrosome reaction, (4) development of the potential to fuse with the egg, and (5) condensation of the sperm chromatin which is later decondensed by the egg ooplasm. Sperm storage The storage capacity of the human epididymis is small and is exceeded after 2 weeks of abstinence whereafter sperms start overflowing into urine. As these aged sperms still retain their viability, a couple of weeks of abstinence is recommended for increasing the sperm output in patients with oligozoospermia. For the same reason, sperms continue to be released in semen for a few weeks after vasectomy, often causing unwanted pregnancy unless additional contraceptive measures are taken. During their storage in the epididymis, sperms come in contact with antioxidants such as superoxide dismutase and glutathione peroxidase, which protect sperms from lipid peroxidation, and with acrosin inhibitor, which protects sperms from damage by leaking acrosomal enzymes. Decapacitation of spermatozoa Spermatozoa show motility only after ejaculation. The motility of the sperm, which is acquired in the head and body of the epididymis, is suppressed (decapacitated) again in the tail of the epididymis. The decapacitation keeps the sperms quiescent till the right moment and place of fertilization. Sperm motility is inhibited when the intracellular pH is acidic and stimulated when it is alkaline. Epididymal fluid contains lactates which diffuse into the sperm, lowering the pH and with it, sperm motility. Once outside the epididymis, the sperm recovers it motility in the alkaline pH produced by the secretions of the seminal vesicles: The Na+–HCO3– cotransport into the sperm raises the intracellular pH and stimulates spermatic motility (Fig. 91.3). Na+-rich environment similar to plasma: The + Na is cotransported into the cell with HCO3–, raising the intracellular pH and stimulating spermatic motility (Fig. 91.3). This HCO3– cotransport with Na+ cannot occur inside the epididymis because the epididymal fluid has a low Na+ and high K+ concentration as compared to plasma. Immune protection of spermatozoa Immune toler-

ance to “self” develops in fetal life. As spermatozoa are formed several years after the development of

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Lactate

Inside epididymis

Na+

571

HCO3–

Outside epididymis

Fig. 91.3 Changes in pH as the sperm moves out of the epididymis.

immune tolerance, they are considered “foreign” if they are encountered by the immune system. In the epididymis, sperms are separated from circulating immune cells to prevent immunological damage. There are tight junctions in the epididymis that prevent paracellular transport. If the epididymal tubule is ruptured, as may occur after vasectomy, sperm antigens can encounter immune cells. Indeed, antisperm antibodies are present in the serum of men with epididymal occlusion.

Sperm passage through urethra During their passage through the urethra, the sperms come in contact with the secretions of seminal vesicles, prostate, and bulbourethral glands. The seminal plasma comes mostly from these accessory glands. During ejaculation, the accessory glands contract sequentially to contribute their secretions to the seminal plasma. (1) First, the bulbourethral glands secrete the preejaculatory fluid, an alkaline solution with glycoproteins, to neutralize the urinary tract acidity and lubricate the tract before ejaculation. (2) Next, the epididymis and prostate contract together, discharging spermatozoa and prostatic secretions. The latter contains the prostate-specific antigen (PSA), a serine protease that liquifies the semen. (3) Finally, the seminal vesicles contract and expel the spermatozoa to the exterior with their secretions containing semenogelin, which causes coagulation of semen.

Semen Seminal plasma The physiological role of several

constituents of seminal plasma is not known, but these constituents are estimated to assess the functioning of the accessory glands. The epididymis contributes carnitine, glycerophosphocholine, and neutral α-glucosidase to the seminal fluid. The pH of the epididymal secretion is acidic. The prostate contributes about 20% to the volume of the semen. The prostatic fluid is slightly acidic (pH 6.5) due to the presence of citric acid. It

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Reproductive System contains substances important for sperm motility, notably albumin, fibrinolysin, acid phosphatase, and an antibacterial substance. It also contributes zinc and PSA to the seminal plasma. The seminal vesicle contributes 70% to the volume of the semen and it makes the semen alkaline. It contains fructose, citrate, ascorbate, prostaglandins, hyaluronidase, and semenogelin. The fructose is a source of energy for the spermatozoa. It is broken down into lactate through anaerobic glycolysis. Prostaglandins promote sperm transport by inducing tubal contractions. Hyaluronidase breaks down the hyaluronic acid present in cervical mucus and thereby allows the sperms to pass easily through the cervix. Semenogelin causes coagulation of semen and fibrinolysin dissolves the coagulum shortly after. Semen analysis is performed on samples obtained

by masturbation after 24 to 36 hours of abstinence. Analysis is performed within an hour. Normal semen is white or opalescent in color with a specific gravity of 1.028 and a pH of 7.35 to 7.50. The normal ejaculate volume is greater than 2 mL. Immediately after ejaculation, the seminal fluid coagulates, followed within 30 minutes by liquefaction. The normal sperm count is 40 to 100 million/mL with fewer than 20% having abnormal morphology. For normal fertility, the sperm count should be at least 20 million/mL and at least 60% of the sperm should be motile with normal morphology. However, many fertile men have lower counts and many infertile men have higher counts.

Sperm transport across the sexes Coitus allows the transfer of sperms from the male to the female reproductive tract. Successful coitus is the culmination of sexual arousal, which in both sexes has four stages, viz., excitement, plateau, orgasm, and resolution. In the phase of excitement, parasympathetic activ-

ity is increased, resulting in vasocongestion in the genitalia. In the male, there is dilatation of penile arteries and accumulation of blood in the corpora cavernosum and spongiosum, resulting in erection (penile tumescence). VIP and NO are important for penile erection. Increased blood flow to the testes causes an increase in testicular size. Contraction of the longitudinal muscles of the vas deferens lifts the testes closer to the body. In the female, there is vasocongestion of the vagina. It causes transudation of fluids from the vaginal epithelium, resulting in vaginal lubrication, which facilitates insertion of the penis without discomfort. Vasocongestion also occurs in the

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external genitalia and breast. There is a general increase in muscle tone which results in nipple erection, sometimes in men too. The plateau phase is characterized by the intensification of the changes seen during the phase of excitement. In the male, blood pooling causes the glans to enlarge and become darker in color. Preejaculatory fluid from the bulbourethral glands trickles out of the penis. The preejaculatory fluid contains a few sperms and accounts for the poor safety rate of the withdrawal method of contraception. In the female, increased blood flow to the labia produces a deepening in the color of the labia minora and labia majora. The clitoris retracts. The vaginal orifice narrows due to the swelling of the vaginal walls. There is tenting of the vagina, that is, the uterus is elevated away from the vagina. There is sexual flush, with an increase in the size of the breast areola and reddening of the skin. Orgasm is the climaxing of sexual excitement dur-

ing intercourse. In the male, it culminates in ejaculation, that is, a forceful ejection of sperm from the urethra. Only sperms from the distal cauda epididymis enter the ejaculate. Ejaculation involves two processes, viz., emission and expulsion of ejaculatory fluid. Emission is the entry of the ejaculatory fluid into the urethra. It is produced by rhythmic muscular contractions of the vas deferens, seminal vesicles, and prostate. Expulsion is the ejection of ejaculatory fluid out of the urethra. It is brought about by rhythmic muscular contractions of the urethra, aided by the contraction of bulbocavernous muscles. The sphincter vesicae contracts during ejaculation and thereby prevents reflux of ejaculatory fluid into the bladder. In the female, orgasm is characterized by rhythmic muscular contractions of the uterus and vagina. Unlike males, females are multiorgasmic, that is, they are capable of experiencing more than one orgasm. In the resolution phase, all the changes associated with sexual arousal revert to the prearousal state. In the male, penile detumescence is caused by increased sympathetic nerve activity that constricts the penile arteries. Ejaculation is followed by a refractory period during which orgasm is not possible again. Females generally do not experience the refractory period.

Sperm migration in the female tract The motility of sperm is necessary for its migration out of cervical mucus, migration to the site

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Sperm Transport and Fertilization of fertilization, and penetration of the ovum’s investments. During intercourse, spermatozoa are deposited high up in the vagina. Soon after its deposition, the semen coagulates due to the presence of semenogelin in the seminal vesicle fluid. The coagulum retains the sperms in the vagina and protects them against the acidic vaginal pH. Within an hour of deposition, the coagulum dissolves due to the PSA present in the prostatic secretions and the sperms migrate out of the coagulum. During the secretory phase of the menstrual cycle, the cervical mucus is watery and favors the passage of sperms through it. The same mucus however prevents the passage of abnormal sperms with distorted head or subnormal flagellation and antibody-coated spermatozoa. This observation is put to diagnostic use in the in vitro cervical mucus contact test for the identification of abnormal sperms. Ejaculated spermatozoa reach the ampulla of the uterine tube, which is the usual site of fertilization of the ovum, within minutes (Fig. 91.4). Sperm motility cannot account for such fast transport, which occurs mainly due to the contractions of the female tract. The contractions are stimulated by the prostaglandins present in the semen.

573

Capacitation Ejaculated

sperms are ordinarily unable to fertilize the ovum in vitro. Sperms undergo capacitation, that is, gain the ability to fertilize eggs, during their passage through the female tract. For capacitation to occur, the decapacitation factors acquired in the epididymis and seminal vesicle have to be removed. These factors are present in the sperm membrane, dissolved in the membrane cholesterol. The decapacitation factors are lost with membrane cholesterol when the sterol-binding proteins present in the follicular fluid react with the sperm membrane. The follicular fluid enters the female tract during ovulation. Once a sperm cell is capacitated, (1) its tail shows hyperactivation and (2) its head acquires the capability to undergo the acrosome reaction (Fig. 91.5).

Fertilization Fertilization is the fusion of the haploid chromatin of the male and female gametes. The sperm usually meets the ovum in the ampulla of the fallopian tube. Fertilization occurs through the following steps. They are summarized in Box 91.1 on p 556.

Uterus Isthmus of fallopian tube

Uterine cavity Ampulla of fallopian tube

Ovary

Myometrium

Endometrium

Fimbriae

Internal os Cervical canal Uterine cervix Uterine cervix, vaginal part Vaginal fornix External os Vagina

Fig. 91.4 Female reproductive tract. The uterus consists of the corpus (which includes the fundus) and the cervix, separated by a narrow isthmus. The cervical cavity communicates with the uterine cavity through the internal os, and opens into the vagina through the external os. The upper part of the vaginal cavity extends around the cervix as the vaginal fornices. The Fallopian tube consists of the infundibulum, ampulla, isthmus, and uterine part. The opening of the infundibulum into the peritoneal cavity is surrounded by fimbriae.

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Reproductive System

Box 91.1 Twenty steps to fertilization

Fig. 91.5 Capacitation of spermatozoon. (Left) Sperm before capacitation. (Right) Capacitated sperm showing hyperflagellation and acrosomal reaction.

Penetration of egg investments The sperm has to pass through two layers of egg coatings before it can contact the oocyte. The outer coat is the cumulus oophorus (see Fig. 89.5), which consists of granulosa cells embedded in a matrix composed mainly of hyaluronic acid. The inner coat is the zona pellucida (Fig. 91.6), which is acellular and consists of a meshwork of glycoproteins. Penetration of the cumulus oophorus The enzyme

hyaluronidase present on the sperm surface digests and dissolves the cumulus oophorus, making way for the sperm. Penetration is also aided by the hyperactivation of the sperm which produces the required penetrative thrust by vigorous lashing of the sperm tail. Penetration of zona pellucida The initial contact of the sperm with the zona pellucida (ZP) is a loose one. The contact becomes firmer when ZP3, a zona pellucida glycoprotein, binds to ZP3 receptor on the sperm. The interaction triggers the acrosomal reaction (Fig. 91.5) in which a protease called acrosin is released. Acrosin produces a penetration slit in the zona pellucida. Through this slit, the sperm enters the perivitelline space.

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1. Sperms deposited high up in the vagina. 2. Semen first coagulates and then liquefies, allowing sperms to escape. 3. Healthy sperms pass through the cervical mucus barrier. 4. Sperms swim up to ampulla, aided by tubal contractions induced by prostaglandins in semen. 5. The tubal fluid inhibits sperm activation till ovulation. 6. Sterol-binding proteins in the follicular fluid (released with ovulation) extract cholesterol from sperms. Decapacitation factors present in sperms are lost with cholesterol. 7. Capacitation causes hyperflagellation and capacity to bind to the ovum. 8. Hyaluronidase present on sperm breaks down the matrix of cumulus oophorus. 9. Sperm penetrates cumulus oophorus through hyperflagellation. 10. Sperm comes in contact with zona pellucida of ovum. ZP3 present on zona pellucida bind to its receptors on sperm surface. 11. Acrosomal reaction is triggered and acrosin is released. 12. Acrosin produces a penetration slit in the zona pellucida. 13. Sperm enters the perivitelline space. Disintegrins present on the sperm bind to integrins present on the vitelline membrane. 14. Sperm membrane fuses with the vitelline membrane. 15. Calcium is released from the intracellular reserves of the ovum. 16. Cortical granules of the ovum are exocytosed. 17. Vitelline membrane is replaced with membrane of cortical granules, resulting in the vitelline block to polyspermy. 18. ZP3 disappears from the zona pellucida under the influence of the cortical granules, resulting in the zona block to polyspermy. 19. Sperm tail disappears and its nucleus decondenses to form the male pronucleus. 20. Mitosis results in the formation of the two-celled embryo.

Inside the perivitelline space, the sperm binds to the vitelline membrane. The binding occurs due to interaction of disintegrins (e.g., fertilin) present on the surface of acrosome-reacted sperm with integrins on the vitelline membrane. Thus the acrosome reaction is important not only for the penetration of the zona pellucida but also for the eventual fusion of the sperm cell with the egg membrane.

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Sperm Transport and Fertilization

Perivitelline space Female pronucleus in metaphase Zona pellucida

Zona block ZP3 disappears

1

575

Vitelline block Vitelline membrane replaced by granule membrane

2

Second polar body

3

8 4

7 5 6 ZP3 Cortical degranulation Vitelline membrane

Cortical degranulation

Fig. 91.6 (Left) Stages of fertilization. 1. Sperm head binding to the zona pellucida. 2. Sperm head undergoes acrosomal reaction. 3. Sperm penetrates zona pellucida. 4. Sperm head enters perivitelline space. 5. Sperm head binds to oolemma. 6. Sperm in ooplasm. 7. Sperm tail disappears and the nucleus decondenses. 8. Nucleus decondenses further to form the male pronucleus. (Right) Zona and vitelline blocks to polyspermy. The zona block occurs due to the disappearance of ZP3, shown here in faded color. Vitelline block occurs due to extensive replacement of the vitelline membrane (blue) by the membrane of the cortical granules (red).

Activation of the ovum The egg membrane depolarizes when the sperm membrane fuses with it. The depolarization stimulates the intracellular release of Ca2+ in the ovum. Certain sperm components called spermassociated oocyte-activation factors (SAOAF) are required for the Ca2+ release. Insufficient SAOAF causes infertility and can be overcome by injection of SAOAF from other sperms. Blocking of polyspermy The rise in intracellular calcium promotes the exocytosis of cortical granules that are superficially situated in the unfertilized ovum. The cortical granules inhibit polyploidy by blocking a second sperm from entering the egg. The block occurs at two levels (Fig. 91.6), the vitelline membrane and the zona pellucida. (1) When the cortical granules fuse with the vitelline membrane, large parts of the vitelline membrane are replaced by the membranes of the cortical granules for which sperms have no affinity. This constitutes the vitelline block to polyspermy. (2) The granules release glycosidases and proteases into the perivitelline space.

Sircar_Chapter91_570-579.indd 575

Glycosidases alter ZP3 so that it loses its affinity for the sperm receptors while proteases degrade ZP3 so that it is unable to bind to acrosomereacted spermatozoa. This constitutes the zona block to polyspermy.

Early embryonic development At the time of ovulation, the ovum is in the metaphase of meiosis II and spindles form for the separation of the second polar body. However, it is only after the entry of the sperm that the ovum extrudes the second polar body. The chromosomes of the ovum assume the shape of a nucleus called the female pronucleus. At the same time the nucleus of the spermatogonium transforms itself into the male pronucleus. The male and female pronuclei meet but do not fuse to form one nucleus. Their nuclear membranes disappear and their chromosomes become distinct. At this stage mitosis occurs, forming the two-cell stage embryo with each cell having a distinct nucleus containing 46 chromosomes. The embryo is still surrounded by the zona pellucida (Fig. 91.7).

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576

Reproductive System

Male pronucleus

Female pronucleus in metaphase-II

By successive cleavages, the 16-celled morula (morum = mulberry) is formed. The morula consists of an inner cell mass surrounded by an outer layer. Fluid from the uterine cavity enters the morula and partially separates the inner cell mass from the outer layer which is now called the trophoblast. As the amount of fluid increases, the morula becomes cyst-like and is called a blastocyst (Fig. 91.8).

Female pronucleus completes meiosis-II

Implantation By the time the fertilized ovum reaches the uterus, it is already a morula but is still surrounded by the zona pellucida which prevents it from sticking to the walls of the uterine tube. The trophoblast tends to invade any tissue it comes in contact with. Once the zona pellucida disappears, the trophoblast sticks to the uterine endometrium. This is called implantation. The trophoblast invades the endometrium and the blastocyst burrows deeper into the uterine mucosa till the whole of it is buried in the endometrium. This is called interstitial implantation to differentiate it from the central implantation which occurs in some mammals where the blastocyst remains in the uterine cavity (Fig. 91.9).

2nd polar body Male and female pronuclei, each with 23 chromosomes, meet but do not fuse

Nucleus with 46 chromosomes

Fig. 91.7 Formation of the two-cell stage embryo.

Extraembryonic mesoderm

Ectoderm Trophoblast

16-celled morula

Endoderm

Formation of ectoderm and endoderm

Primary yolk sac

Amniotic cavity

Formation of amniotic cavity

Formation of primary yolk sac

Chorionic villi

Formation of extraembryonic mesoderm Intraembryonic mesoderm Chorionic blood vessels

Syncytiotrophoblast Cytotrophoblast Chorion Lacunae Amnion

Formation of chorion and amnion

Formation of chorionic villi and intraembryonic mesoderm

Fig. 91.8 Development of a morula into a blastocyst.

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Sperm Transport and Fertilization

Blastocyst Morula stage (day 4-5) (day 3) Entry into the Two-cell stage uterine cavity (30 hours)

First segmentation Zygote formation 4

5

3

6 7

8

2 1

Fertilization Postovulatory ovum

9

Implantation (day 5-6)

577

any of its lesser versions, such as the rhythm method and the withdrawal method. In the rhythm method, sexual intercourse is avoided around midcycle when ovulation is most likely to occur. The rest of the cycle is called the safe period during which the chances of conception are minimal. This rhythm method works because both the sperm and the ovum have a viability of only a couple of days in the female tract, and fertilization is possible only if they enter the female tract within a couple of days of each other. Coitus interruptus is the withdrawal of penis just before ejaculation during sexual intercourse. Full sexual pleasure is often not attained by this method. It has a high failure rate, partly because of failure of timely withdrawal and partly because of the presence of sperms in the preejaculatory emissions.

Fig. 91.9 Interstitial implantation.

Female contraceptives

Assisted reproduction Assisted reproductive techniques are employed mainly for enabling couples to overcome infertilty, though there can be other reasons too. For example, ART has been used for HIV-positive men so that they do not infect their partner or the newborn. In intrauterine insemination (IUI), sperms are placed directly in the uterus in IUI and are therefore not exposed to the acidic vaginal fluid. When the sperm count is very low, the sperms are placed directly in the ampulla of uterine tube, which is the usual site of fertilization, to avoid both the cervical and uterine passages. It is called gamete intrafallopian transfer (GIFT). In vitro fertilization (IVF), the sperm avoids all contact with the female genital tract. For IVF, sperms are obtained from the epididymis (microepididymal sperm aspiration), or from the testis (testicular sperm extraction).The sperms so obtained are introduced directly into the perivitelline space, bypassing the cumulus oophorus and zona pellucida. Hence, even immotile sperm can be made to fuse with the egg. The procedure is called subzonal insemination (SUZI). Alternatively, the sperm is injected directly into the cytoplasm of the ovum, bypassing even the egg membrane. The procedure is called intracytoplasmic sperm injection (ICSI) and it allows even an immature germ cell to initiate pregnancy.

Contraception Behavioral methods The simplest method of avoiding unwanted pregnancy is abstinence or

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Barrier contraceptives such as the diaphragm (an

elastic ring with a dome of rubber) and cervical caps (Fig. 91.10A) prevent sperm from meeting the ovum. Spermicidal cream is applied to the center of the diaphragm to increase its efficacy. These methods are associated with higher failure rates than the pill or the loop. Intrauterine contraceptive devices (IUCDs) are inserted into the endometrial cavity to provide long-term contraception (up to several years). These devices are mostly made of plastic with either a serpentine shape (Lippes loop) or a T configuration of polypropylene with helically shaped arms (Fig. 91.10B). Currently available IUCDs (the copper-T, copper-7, etc.) have greater efficacy due to added progesterone or copper. IUCDs act to prevent implantation and growth of the fertilized egg by causing a sterile inflammation of the endometrium. The sperms are phagocytosed by inflammatory cells in the endometrium. Oral contraceptives contain estrogen, progestagen, or both. Estrogens induce feedback inhibition of FSH secretion and thereby inhibit follicular growth. They also make the endometrium proliferative and thereby, prevent the implantation of the blastocyst. Progestagens cause inhibition of LH secretion and ovulation. They also make the cervical secretion thick and viscid and thereby, block the passage of sperms. In practice, both are combined, with progesterone inhibiting ovulation and estrogen ensuring that the withdrawal bleeding is prompt and brief. The monophasic combined pill is the commonest type of oral contraceptive: It is taken for 21 days, from the 5th to the 28th day of the

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578

Reproductive System

A

Plain condom

Shaped condom

Diaphragm

Vimule

Cervical cap

Vault cap

B

Lippe loop

Copper-T

Multiload-Cu

Long-acting injectables and implants are preferred as contraceptives by those who do not want to take oral pills daily. Examples include progestagens such as medroxyprogesterone acetate or norethindrone enanthate that are administered intramuscularly once every 3 months. They act by inhibiting ovulation and thickening cervical mucus. Progesterone-containing intrauterine devices continuously release progesterone into the uterine cavity for 1 year. There is however an increased risk of ectopic pregnancy with such devices. Long-term hormonal contraceptives, and mainly the estrogen component, have several adverse effects such as weight gain, diabetes mellitus, impaired hepatic function, hypertension, increased incidence of thromboembolism, and increased risk of cervical, endometrial, and breast carcinoma. These adverse effects are not caused by nonsteroidal contraceptives (e.g., centchroman) which act as estrogen antagonists and interfere with implantation of the fertilized ovum. Tubectomy is a surgical method of sterilization

C

involving excision of a small segment of the uterine tube (Fig. 91.10C).

Tubectomy

Male contraception Mechanical devices such as condoms are latex

D

Vasectomy

Fig. 91.10 [A] Barrier contraceptives. [B] Intrauterine contraceptive devices. [C] Tubectomy. [D] Vasectomy.

menstrual cycle, followed by 7 days’ gap during which withdrawal bleeding takes place. The phased pill, which may be biphasic or triphasic, uses different hormonal combinations during different phases of the menstrual cycle and is associated with a lower incidence of breakthrough bleeding. The postcoital pill (“morning after” pill) contains estrogen only. It is taken within 72 hours of coitus. The minipill contains progesterone only, and is taken daily without interruption. Estrogen pills make the endometrium hyperproliferative. Progesterone pills make the endometrium hypersecretory. Therefore, both make the endometrium unfit for implantation of the blastocyst. Moreover, estrogen increases uterine motility, expelling the conceptus.

Sircar_Chapter91_570-579.indd 578

sheaths (Fig. 91.10A) that are worn over the erect penis to prevent sperms from entering the female genital tract. Applying a spermicidal cream inside the condom increases the efficacy of the method. It is an inexpensive and reasonably reliable method of male contraception. It also provides significant protection against sexually transmitted diseases. Thermal methods Bathing the scrotum in hot

(46°C) water for a few weeks reduces fertility for several months afterward. The suspensory briefs worn by men hold the testes close to the body, and because the testes are at body temperature, sperm counts gradually drop. The reliability of these methods is not established. Vas-occlusive plugs are made of polyurethane

or silicone rubber. They are injected in the liquid form into the vas deferens where they harden in situ within 20 minutes, forming a barrier against sperm. The contraception is reversible and fertility is restored after the plugs are removed. Reversible inhibition of sperm under guidance (RISUG) uses styrene malic anhydride (SMA),

a copolymer that is injected in combination with dimethyl sulfoxide into the vas deferens, where it coats the walls and partially blocks the lumen.

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Sperm Transport and Fertilization RISUG is not a vas-occlusive plug because it only partly blocks the lumen of the vas deferens. It has other contraceptive effects. (1) The basic pH of the compound interferes with the acidic pH of sperm. (2) The positive electric charge associated with SMA causes the sperm membranes to rupture. SMA can be removed by flushing the vas deferens with an injected solvent and therefore allows multiple occlusions and reversals. It is a promising male contraceptive with high efficacy and reversibility along with high levels of safety and convenience.

579

Azoospermic agents include testosterone, cyproterone, gossypol (a phenolic compound extract from the cotton plant), Trypterigium wilfordii (a vine used in traditional Chinese medicine), and nifedipine (an antihypertensive drug). Drugs causing azoospermia have not been found to be reliable for male contraception. Vasectomy is a surgical method of sterilization involving excision of a small segment of the vas deferens (Fig. 91.10D).

REVISION QUESTIONS 1. In which part of the testes are sperms concentrated? What happens if the sperms are not concentrated? 2. Unprotected sex can cause pregnancy even after vasectomy. Why? 3. In which part of the male tract do the sperms first acquire motility? 4. What is sperm decapacitation and what is its significance? Where and why does decapacitation occur? Where and how are they recapacitated? 5. Antisperm antibodies are often present in the serum of men with epididymal occlusion. Why?

7. What is the in vitro cervical mucus test? 8. What is the role of the follicular fluid in the capacitation of the sperm? 9. The acrosome reaction is important for the penetration of the zona pellucida as well as for the fusion of the sperm with the egg membrane. How? 10. What is the mechanism of the vitelline block and zona block to polyspermy? 11. What is the difference between interstitial implantation and central implantation? 12. Suspensory briefs worn by men tend to gradually decrease the sperm count. Why?

6. The semen coagulates soon after its deposition in the vagina. What is its physiological significance?

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92

Reproductive System

Sexual Differentiation of the Fetus

Normal Sexual Differentiation Sex differentiation of the embryo proceeds sequentially. The chromosomal (genotypic) sex determines the gonadal sex, that is, it causes the indifferent gonad to develop into an ovary or a testis. The gonadal sex determines phenotypic sex, that is, the internal and the external genitalia. The psychological sex is determined by both the gonadal sex (hormones) and phenotypic sex (appearance). The development of the brain is affected by androgens early in life. Early exposure of female human fetuses to androgens has masculinizing effects on behavior later during puberty.

Determination of chromosomal sex The chromosomal sex is established at fertilization. The ovum contains 22+X chromosomes. However, the spermatozoa are of two types: 50% of the spermatozoa have 22+X chromosomes while the remainder have 22+Y chromosomes. If the ovum is fertilized by an X-bearing sperm, the zygote has 44+XX chromosomes and its chromosomal sex becomes female. On the other hand, if the sperm is Y-bearing, the zygote has 44+XY chromosomes and its chromosomal sex becomes male. The human Y chromosome is smaller than the X chromosome. Hence, the sperms containing Y chromosome are lighter and swim faster up the female genital tract, reaching the ovum earlier than the X-bearing chromosomes. This probably contributes to the fact that the global male birth-rate is slightly higher than the female birth-rate.

If only one active X chromosome is necessary for normal feminine development, it is difficult to explain why Turner syndrome (44+XO) should be associated with abnormalities. Hence, it is now believed that both the X chromosomes are necessary for normal development and that the Barr body is reactivated just before oogenesis.

Differentiation of gonadal sex Till the 6th week of intrauterine life, the fetal gonads are bipotential: they have the rudiments of both male and female gonads. The bipotential gonad consists of a medulla made of mesenchymal tissue and a cortical epithelium with primordial germ cells embedded in it. In the genetic male, the medulla of the bipotential gonad begins to differentiate into testis while the cortex regresses. In the genetic female, the cortex of the bipotential gonad differentiates into the ovary while the medulla regresses (Fig. 92.2). Testicular differentiation requires testis-determining factor (TDF), which is encoded by the SRY gene (sex-determining region of the Y chromosome) located near the tip of the short arm of

Drumstick

Barr body

Barr body Soon after cell division begins in a

female embryo, one of the two X chromosomes in the female becomes functionally inactive. Even in abnormal individuals with more than two X chromosomes, only one remains active. The choice of which X chromosome remains active is random and hence roughly half of the somatic cells contain an active X chromosome of paternal origin and the rest contain an active X chromosome of maternal origin. In normal cells, the inactive X chromosome condenses and is present near the nuclear membrane as the Barr body or the sex chromatin. Thus, in an abnormal cell with three or more X chromosomes, there are two or more Barr bodies. The inactive X chromosome can also take up other forms. In up to 15% of the neutrophils, the inactive X chromosome forms a drumstick-like appendage projecting from the nucleus (Fig. 92.1).

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Fig. 92.1 Barr body and nuclear appendage. Undifferentiated gonad

Ovary

Testis

Fig. 92.2 Gonadal differentiation.

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Sexual Differentiation of the Fetus the human Y chromosome. Under the influence of TDF, the Sertoli cells appear by the seventh week and start secreting Mullerian inhibiting substance (see below). Leydig cells appear by the eighth week and start secreting testosterone. In contrast, the embryonic ovary does not secrete any hormone.

Differentiation of internal genitalia

A Testis Rete testis

Epididymis Vas deferens

Till the seventh week of intrauterine life, the internal genitalia of the fetus have the rudiments of both male and female internal genitalia, that is, the Wolffian duct and the Mullerian duct, respectively. The differentiation into male and female internal genitalia begins in the eighth week. The male internal genitalia comprises the rete testis, epididymis, vas deferens, and the seminal vesicles. By the 8th week, the testes of a genetic male fetus secretes two hormones: (1) Testosterone stimulates the development of the Wolffian ducts into male internal genitalia. (2) Mullerian inhibiting substance (MIS) causes regression of the Mullerian ducts by apoptosis (Fig. 92.3A). The action of both testosterone and MIS on internal genitalia is paracrine and unilateral, that is, if secreted from the left testes, they cause development of the left internal genitalia, and vice versa. The female internal genitalia comprises the uter-

ine tubes, uterus and the upper two-third of the vagina. The development of the female internal genitalia is independent of hormonal influence. (1) In the absence of MIS, the Mullerian ducts start proliferating in the eighth week to form the female internal genitalia. (2) In the absence of testosterone, the Wolffian ducts degenerate (Fig. 92.3B).

Differentiation of external genitalia Till the 8th week of intrauterine life, the external genitalia of the fetus are bipotential, that is, they can develop along either male or female lines. Unlike the internal genitalia which have distinct male and female rudiments, the external genitalia in both sexes develop from common rudiments, which are the urogenital sinus, the genital swellings, the genital folds, and the genital tubercle. (1) In the absence of virilizing hormones, the fetal external genitalia develop along female lines. (2) In the presence of functional testes secreting testosterone, dihydrotestosterone (formed from testosterone) transforms the fetal external genitalia along male lines (Fig. 92.4, Table 92.1).

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581

Seminal vesicle

Degenerating Mullerian duct

Gubernaculum

B Ovary

Uterine tube Uterine ligament Uterus Vagina Degenerating Wolffian duct

Fig. 92.3 Differentiation of the internal genitalia. [A] In a genetic male, the Wolffian ducts differentiate into the male internal genitalia (rete testis, epididymis, vas deferens, seminal vesicles) under the effect of testosterone while the Mullerian duct regresses under the effect of MRF. [B] In a genetic female the Mullerian ducts develop into the female internal genitalia (uterine tubes, uterus, upper two-thirds of the vagina).

Aberrant Sexual Differentiation Abnormalities of chromosomal sex Abnormalities of chromosomal sex usually arise due to chromosomal nondisjunction (p 47) during gametogenesis, that is, a pair of chromosomes fails to separate, so that both go to one of the daughter cells during meiosis. The abnormal zygotes that can result from nondisjunction of one of the X chromosomes during oogenesis are shown in Fig. 92.5. Klinefelter syndrome (Fig. 92.6) is also called seminiferous tubule dysgenesis. Its genotype is 47, XXY (i.e., 44+XXY) and it has an incidence of 1 in 500 males. It occurs in two forms: (1) The classical

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582

Reproductive System

FEMALE LINE

MALE LINE Gonad

Internal genitalia

External genitalia

Weeks

Gonad

Internal genitalia

External genitalia

Bipotential

WD

MD

Bipotential

6th

Bipotential

WD

MD

Bipotential

Male

WD

MD

Bipotential

7th

Female

WD

MD

Bipotential

Male

WD

MD

Bipotential

8th

Female

WD

MD

Bipotential

Testis

Epididymis Vas deferens

Penis Scrotum

9th

Ovary

Uterus Tubes

Vagina Labia

Fig. 92.4 Summary of sexual differentiation between the sixth and ninth week of intrauterine life. Red = male, blue = female, WD = Wolffian duct, MD = Mullerian duct. Table 92.1 Effect of DHT on the differentiation of the external genitalia

Urogenital sinus

Genital swellings Genital folds

Genital tubercle

In the presence of DHT

In the absence of DHT

Develops into the prostate and prostatic urethra

Develops into the lower one-third of the vagina

Fuse to form the scrotum

Develop into the labia majora

44 XX

22 O

ZYGOTE 44 XO

SPERM

22X

Turner Syndrome 44 XX

Abnormal meiosis

22 XX

44 XXX

22X

Superfemale

Elongate and fuse to form the shaft of the penis

Develop into labia minora

Develops into the glans penis

Develops into the clitoris

44 XX

Abnormal meiosis

22 O

44 YO

22Y

Not viable 44 XX

Abnormal meiosis

22 XX

44 XXY

22Y

Klinefelter's Syndrome

form is due to meiotic nondisjunction, that is, chromosomal nondisjunction during gametogenesis. Meiotic nondisjunction is commoner in the ovum than in the sperm. (2) The mosaic form occurs due to mitotic nondisjunction, that is, chromosomal nondisjunction after zygote formation. It occurs due to anaphase lag. Mitotic nondisjunction can occur in a normal 46,XY or an abnormal 46,XXY zygote. The latter instance is called double nondisjunction. Klinefelter syndrome is characterized by: (1) normal male internal and external genitalia and psychosexual characters; (2) underdeveloped testes, hyalinization of tubules, azoospermia, and infertility; (3) low levels of testosterone, with

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OVUM Abnormal meiosis

Fig. 92.5 Abnormalities of chromosomal sex. The XXX (superfemale) pattern is second in frequency only to the XXY pattern and is not associated with any obvious abnormalities. The YO zygote does not survive.

high levels of gonadotropins and estradiol; (4) tall build (due to increase in lower body segment) and obesity; (5) varicose vein, diabetes mellitus, thyroid abnormalities, and pulmonary diseases; and (6) mental deficiency. Turner syndrome (Fig. 92.6) has an incidence of

1 in 3,000 females. Fifty percent of them have the karyotype of 45,XO due to meiotic disjunction in either parent. Another 25% have the karyotype 46,XX/45,XO mosaicism due to mitotic disjunction.

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Sexual Differentiation of the Fetus

583

webbed neck, shield-like chest, and cubitus valgus; and (5) coarctation of aorta.

Fig. 92.6 (Left) Klinefelter’s syndrome. (Right) Turner Syndrome.

The remaining 25% have a structurally abnormal X chromosome with or without mosaicism. Turner syndrome is characterized by: (1) normal female internal and external genitalia and psychosexual characters; (2) bilateral streak gonads with infertility and primary amenorrhea and amastia; (3) characteristic facies with low posterior hairline, ptosis, epicanthus, low set ears, fish-like mouth, and micrognathia (small jaw); (4) short stature,

True hermaphrodites have both gonads—male and female. Some of them have testis on one side and ovary on the other. Others have ovotestes, that is, gonads containing both ovarian and testicular tissues. The internal genitalia correspond to the ipsilateral gonad. The external genitalia are ambiguous. Most hermaphrodites are brought up as males but at puberty, most of them become feminine, develop breasts, menstruate, and sometime even ovulate. Most of the true hermaphrodites have the genotype 46,XX. The rest have either 46,XY or mosaics. It is not clear why a normal genotype should be associated with true hermaphroditism. Probably, these XX genotypes have sufficient genetic material derived from the Y chromosome to induce growth of testicular tissue.

Abnormalities of phenotypic sex A pseudohermaphrodite is an individual with the chromosomes and gonads of one sex and the genitalia of the other (Table 92.2). A female pseudohermaphrodite is a genetic female with female gonads and internal genitalia but male external genitalia. It occurs in genetic females

Table 92.2 Phenotypic characteristics in different types of pseudohermaphroditism TST

MIS

DHT

Female internal genitalia

Male internal genitalia

External genitalia

–

+

Present, because MIS is absent.

Absent, because exposure to testosterone usually occurs late.

Male, because DHT is formed.

Female pseudohermaphroditism (Genetic XX) Exposure to TST in fetal life

+

Male pseudohermaphroditism (Genetic XY) Impaired testosterone secretion

–

+

–

Absent, because MIS secretion is unaffected.

Absent, because testosterone is absent.

Female, because DHT is absent.

Persistent Mullerian duct syndrome

+

–

+

Present, because MIS is absent.

Present, because testosterone is present.

Male, because DHT is present.

5α-reductase deficiency

+

+

–

Absent, because MIS is present.

Present, because testosterone secretion is normal.

Female, because DHT is not formed.

Receptor defect

+

+

+

Absent, because MIS is present.

Absent, because testosterone is ineffective.

Female, because DHT is ineffective.

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Reproductive System exposed to high levels of androgens during the 8th to 13th week of gestation. If the exposure occurs after the thirteenth week, the genitalia are fully formed but exposure to androgens can cause hypertrophy of the clitoris. Female pseudohermaphroditism may be due to congenital virilizing adrenal hyperplasia or it may be caused by androgens administered to the mother. A male pseudohermaphrodite is a genetic male with

male gonads but female internal or external genitalia. It occurs due to deficiency of 17α-hydroxylase (causing impaired testosterone secretion), deficiency of 5α-reductase (causing reduced peripheral formation of dihydrotestosterone), or due to nonfunctional testosterone receptors (rendering androgens ineffective). The internal genitalia, both male and female, are absent. The male internal genitalia do not develop due to the absence of testosterone. The female internal genitalia are not formed either, because the MIS

secretion is unaffected and results in the regression of the Mullerian duct. If MIS secretion is impaired but testosterone secretion is normal, it results in the persistent Mullerian duct syndrome in which both the Wolffian and Mullerian ducts develop into male and female internal genitalia respectively. In the absence of dihydrotestosterone, the internal genitalia are male and the external genitalia are female. In complete androgen resistance syndrome, earlier called testicular feminizing syndrome, there is loss of function of the testosterone receptors due to mutation. The internal genitalia are therefore neither male (as testosterone is ineffective) nor female (as MIS is present). The external genitalia are female (as DHT is not formed) but the vagina ends blindly because there are no female internal genitalia. Individuals with this syndrome develop normal breasts at puberty and usually are considered to be normal women till they are diagnosed when they seek medical advice for absence of menarche.

REVISION QUESTIONS 1. What is the Barr body? How many Barr bodies will be present in an abnormal cell with four X chromosomes? 2. What is the function of “testis-determining factor?”

4. What is the difference between a true hermaphrodite and a pseudohermaphrodite? 5. Which types of internal and external genitalia are present in “complete androgen resistance syndrome?”

3. If both male and female hormones are absent, would a bipotential fetal external genitalia develop into a male or female genitalia?

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93

Pregnancy

Placenta After the implantation of the embryo, the endometrium is called the decidua because it is shed off at the end of pregnancy. The decidua resembles the secretory endometrium of the menstrual cycle. As the blastocyst grows, the trophoblast differentiates into two layers, the outer syncytiotrophoblast and the inner cytotrophoblast (See Fig. 91.8). The syncytiotrophoblast is a layer of cytoplasm containing multiple nuclei. It is formed by the fusion of several trophoblast cells. The cytotrophoblast ultimately differentiates into the chorionic villi. Fetal blood vessels grow into the chorionic villi (Fig. 93.1). Maternal and fetal blood do not mix together (Fig. 93.2): In the fully formed placenta, maternal blood circulates through the intervillous spaces while the fetal blood flows through the core of the chorionic villi. The placental membrane that

U

te

Placental hormones The syncytiotrophoblast of the placenta serves as an endocrine organ that secretes (a) human chorionic gonadotropin, (b) human chorionic somatomammotropin, (c) human chorionic thyrotropin, (d) relaxin, (e) estrogens, and (f) progestagens. Presence of placental hormones in maternal blood or urine indicates that the placenta is functioning normally. Both estrogens and progestagens are required for the initiation and maintenance of pregnancy. In the first 60 days of pregnancy, these hormones are produced mainly by the corpus luteum. Thereafter, the

rine cav

it

y

ryonic co emb e tra

lom

Ex

Amniotic cavity

separates the maternal and fetal circulation is made of four layers, viz., (1) syncytiotrophoblast, (2) cytotrophoblast, (3) connective tissue layer, and (4) the endothelium and basement membrane of the fetal blood vessels.

Yolk sac

Uterine artery and vein Endometrium (Decidua)

Myometrium

Fig. 93.1 The blastocyst in the uterine cavity. Compare with Fig. 91.8.

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Reproductive System

Chorionic plate

Decidua basalis

Umbilical arteries

Maternal blood vessels

Umbilical cord Umbilical vein

Chorionic Decidual Intervillous space septa villi

Fig. 93.2 Structure of a placenta.

fetoplacental unit takes over the synthesis of estrogens and progestagens (Fig. 93.3). This is known as the luteal-placental shift. Hence, ovariectomy after 2 months does not interrupt pregnancy. Human chorionic gonadotropin (HCG) is a peptide hormone secreted by the syncytiotrophoblast soon after fertilization. It is detectable in maternal urine as early as 14 days after conception, which forms the basis for all pregnancy diagnostic tests. By the time a woman misses her period, her urinary HCG levels are high enough to be detected. Plasma HCG peaks between 60 and 90 days of gestation. Thereafter, the concentration falls to a low level and reduces to zero just before labor. HCG has actions similar to those of LH. Thereby, it extends the life of the corpus luteum up to

60 days after conception, that is, until the fetoplacental unit is able to synthesize its own estrogens and progesterone. (1) It stimulates the corpus luteum to secrete 17α-hydroxyprogesterone and a smaller amount of progesterone. Blood level of 17α-hydroxyprogesterone is a reliable indicator of corpus luteal function because it is not produced by the placenta which lacks 17α-hydroxylase. (2) In the male fetus, HCG stimulates testosterone secretion from the fetal testes and thereby helps in sexual differentiation. (3) HCG stimulates the secretion of DHEAS from fetal adrenal cortex. DHEAS is important for the placental synthesis of estriol. Human chorionic somatomammotropin (HCS) structurally resembles pituitary growth hormone. Its concentration in serum rises steadily from the eighth week to term. Although less active than prolactin, it is produced in such large amounts that it may exert a lactogenic effect. It is also called human placental lactogen (HPL). Human chorionic thyrotropin (HCT) is a placental

hormone that resembles TSH. Its concentration in serum follows a curve like that for HCG. The physiological role of HCT is unknown. Relaxin is discussed on p 567. Estrogens All the three types of estrogens, viz.,

estrone, estradiol, and estriol, are produced in large quantities during pregnancy and their concentration rises steadily throughout gestation, reaching their maximum at term (Fig. 93.4) and decreasing rapidly after parturition. Estriol, which is the weakest estrogen, is produced only during pregnancy. Its secretion indicates a healthy placenta and correlates well with fetal growth. Falling estriol levels indicate impending fetal death. Progesterone The placenta secretes only proges-

E HCG

P

Before 60 days

terone unlike the corpus luteum which secretes both progesterone and 17α-hydroxyprogesterone. Hence after the luteal-placental shift, the 17α-hydroxyprogesterone level falls but the progesterone level continues to rise till just before parturition (Fig. 93.4).

Fetoplacental unit E P After 90 days

Fig. 93.3 Luteal-placental shift. E, estrogens; P, progestagens.

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The fetus, placenta, and mother are interdependent and constitute a functional unit called the fetoplacentomaternal unit or simply, the fetoplacental unit. This interdependence is especially apparent in the placental synthesis of progesterone and estrogens and the fetal synthesis of cortisol, as explained below (Fig. 93.5).

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Pregnancy

587

Placental synthesis of progesterone The placenta

Estri o

Prog e

0

S

l

HCG

HC

Hormonal concentration

l dio tra s E

s t e ro

10

rone Est

ne

20 30 Weeks of gestation

40

Fig. 93.4 Changes in hormonal concentration during pregnancy. Note the slight dip in progesterone secretion at about the 10th week of gestation. The dip coincides with the luteoplacental shift and occurs due to the decrease in the progesterone secretion by the corpus luteum.

synthesizes progesterone from cholesterol. As it cannot synthesize its own cholesterol from acetate, it obtains the cholesterol from the maternal and fetal circulations. Of the total progesterone synthesized by the placenta, 90% diffuses back into the maternal circulation, resulting in the characteristic maternal changes in pregnancy, while 10% enters the fetal circulation where it is converted to cortisol. Up to the 10th week of gestation, the fetus is dependent on placental progesterone for synthesizing corticosteroids, because its own adrenal cortex is deficient in 3β-hydroxy dehydrogenase. After 10 weeks, the fetus is able to synthesize its own progesterone. It is also able to synthesize androstenedione and testosterone. These androgens diffuse into the placenta where they are converted into estrogens. Placental synthesis of estrone and estradiol In the placenta, estrone and estradiol cannot be

Mother Progesterone

Cholesterol

Estrogens

DHEAS

Placenta DHEA

DHEAS Sulfatase

Progesterone

17 αHydroxylase

17-OH Progesterone E1

3β-hydroxydehydrogenase Pregnenolone

17 αHydroxylase

Aromatase

3β-hydroxy dehydrogenase Androstene dione 17β-hydroxy dehydrogenase

17-OH Pregnenolone E2

Cholesterol desmolase

Aromatase

Testosterone

16α−hydroxylase

Cholesterol

E3

Aromatase

16 OH DHEA Sulfatase 16 OH DHEAS

Cholesterol

16 OH DHEAS

Cholesterol desmolase Pregnenolone

3β-Hydroxydehydrogenase Progesterone

17 α-Hydroxylase

17,20-Lyase 17-OH Pregnenolone

3β-hydroxydehydrogenase 17 α-Hydroxylase

DHEA

Sulfokinase

16α-hydroxylase 3β-Hydroxydehydrogenase

17,20-Lyase

17-OH Progesterone

21β-Hydroxylase 11-Deoxycortisol

DHEAS

FETAL LIVER

Androstenedione 17β-Hydroxy dehydrogenase testosterone

11β-Hydroxylase Fetal adrenal gland Cortisol

Fetus

Fig. 93.5 Hormone synthesis in the fetoplacental unit.

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Reproductive System synthesized from cholesterol because placenta lacks 17α-hydroxylase and 17, 20-lyase. In the placenta, therefore, estrone and estradiol are synthesized from DHEAS (dehydroepiandrosterone sulfate) which is obtained from maternal circulation. Of the total placental estrogens, 90% enters maternal circulation and only 10% enters the fetus.

Urine containing HCG

Placental synthesis of estriol The placenta cannot convert estrone to estriol because it lacks 16α-hydroxylase. Hence, placental estriol is synthesized from16-hydroxy DHEA sulfate (16OH DHEAS) which is obtained from fetal circulation. Since the placental synthesis of estriol is totally dependent on the 16-OH DHEAS produced by the fetal adrenal gland, the urinary excretion of estriol in the mother is an index of fetal health.

Pregnancy diagnostic tests All pregnancy diagnostic tests are based on the presence of HCG in urine, which can be detected as early as 14 days after conception, that is, within a day or two of a missed period. The accuracy of these tests is about 99%. The Gravindex test is the most commonly used pregnancy diagnostic test. It is an immunological test. Its kit consists of Gravindex antigen (latex particles coated with HCG), Gravindex antibody (serum containing HCG antibodies), dark slide, sticks, and a pipette. The procedure for the test and its interpretation are explained diagrammatically in Fig 93.6.

Urine not containing HCG

Antibodies to HCG (Gravindex antigen)

Antibodies blocked by HCG

Antibodies remain unbound

HCG-coated latex particles (Gravindex antibodies)

Latex particles not agglutinated

Latex particles agglutinated

Pregnancy positive

Pregnancy negative

Fig. 93.6 The immunological basis of the Gravindex test.

Maternal Changes in Pregnancy Most of the physiological changes associated with pregnancy are directly or indirectly related to (1) the high concentrations of hormones in maternal blood, and (2) the elevation of the diaphragm caused by the gravid uterus. These are discussed below.

Effects of hormones Amenorrhea is the first and best known change

associated with pregnancy. It occurs because the high circulating levels of progesterone and estrogens prevent withdrawal bleeding. Hyperventilation occurs due to stimulation of the

respiratory center by progesterone. The hyperventilation washes out more CO2 than is produced by the mother and fetus. Hence, it causes hypocapnia and respiratory alkalosis with bicarbonaturia.

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Circulation Estrogens dilate the uterine blood

vessels and thereby increase the uterine blood flow, helping to provide nourishment to the fetus through the placenta. Aldosterone, which is secreted in large amounts in pregnancy (see below), causes fluid and electrolyte retention, resulting in hypervolemia, increase in renal blood flow and increase in GFR. Water retention exceeds sodium retention, resulting in hypoosmolarity of the ECF. Water retention also results in hemodilutional anemia which is called the physiological anemia of pregnancy. The resulting anemic hypoxia causes vasodilatation, reducing the peripheral resistance and increasing the CVP. The CVP also increases as a direct consequence of the increase in blood volume. The raised CVP causes an increase in cardiac output. The diastolic blood pressure is low due to the large fall in peripheral resistance. For the same

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Pregnancy reason, the mean blood pressure and even the systolic blood pressure remain normal despite the increase in cardiac output. The decrease in peripheral resistance is attributable to (1) the hypoxic vasodilatation (explained above), and (2) the dilatation of uterine blood vessels. These events are summarized in Fig. 93.7.

Aldosterone

Glucose tolerance Glucose tolerance is reduced

in pregnant women due to the anti-insulin effects of progesterone, estrogen, and human chorionic somatomammotropin. The transient diabetes during pregnancy is called gestational diabetes. Gall bladder Progesterone decreases the smooth

muscle tone of the gall bladder and thereby predisposes to gall bladder stasis. Hence, gallstones

Dilatation of uterine vessels Hemodilution Anemic hypoxia

Plasma proteins (1) Estrogens stimulate liver

enzymes, causing increased synthesis of transport globulins that bind to thyroxine (TBG), corticosteroids and progestagens (transcortin), and estrogens (sex steroid binding globulin). (2) Despite the increase in transcortin, pregnant women are often in a state of mild hyperadrenocorticism. This is because the elevated placental progesterone competes with cortisol for binding sites on transcortin, thus increasing plasma free cortisol. (3) Estrogens also increase fibrinogen synthesis, resulting in hypercoagulability of blood and an increase of ESR. The hypercoagulability of blood is important in preventing excessive blood loss during placental separation. (4) Increased synthesis of thyroxine-binding globulin results in increased binding of thyroxine and compensatory increase in thyroxine secretion. The concentration of free thyroxine remains unchanged. (5) Estrogens also increase the hepatic synthesis of angiotensinogen leading to increased angiotensin II synthesis and thereby, increased aldosterone secretion.

Estrogens

Retention of fluid and electrolytes Hypervolemia

589

Vasodilatation

Increased uterine blood flow

Decreased peripheral resistance

Increased central venous pressure Increased cardiac output

Increased stroke volume

Decreased diastolic blood pressure

Increased pulse pressure

Normal mean and systolic blood pressure

Fig. 93.7 Cardiovascular changes in pregnancy.

are commoner in females who have been pregnant several times.

Effects of diaphragmatic elevation As the gravid uterus enlarges, it elevates the diaphragm and affects the lung volumes and capacities of pregnant woman (see Fig. 50.5). It also rotates the heart so that its apex shifts upward and to the left and there is a left axis deviation in the ECG.

REVISION QUESTIONS 1. Ovariectomy more than two months after conception does not abort pregnancy but does so if performed earlier. Why?

of which hormone serves as a reliable indicator of corpus luteum function? 4. What is the effect of HCG on the fetus?

2. What is the common basis for all pregnancy diagnostic tests? How early can they detect pregnancy?

5. What is the implication of falling estriol levels during pregnancy and why?

3. How long does the corpus luteum remain viable after the onset of pregnancy? The plasma level

6. The plasma level of 17α-hydroxyprogesterone falls by the end of two months. Why?

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Reproductive System 7. The urinary excretion of estriol in the mother is an index of fetal health. Why? 8. What is the “physiological anemia of pregnancy” and why does it occur? 9. Pregnancy is associated with a decrease in diastolic blood pressure and an increase in pulse pressure. Why?

12. The ESR increases during pregnancy. Why? 13. Pregnancy is associated with increase in thyroxine secretion. What is its significance? 14. Pregnancy is associated with fluid and water retention. Why? 15. What is the cause of gestational diabetes?

10. Pregnancy is often associated with mild hyperadrenocorticism. Why?

16. Gallstones are commoner in females who have been pregnant several times. Why?

11. Pregnancy is associated with hypercoaguability of blood. Why does it occur and what is its physiological significance?

17. Pregnancy is associated with left axis deviation of the heart. Why?

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94

Parturition and Lactation

Hormones of Parturition and Lactation Oxytocin Oxytocin is a nonapeptide that is synthesized in the paraventricular and supraoptic nuclei of the hypothalamus and is stored in the posterior lobe of the pituitary gland. It causes (1) galactokinesis (see below) by stimulating the myoepithelial cells of the mammary gland, and (2) stimulates uterine contractions. It plays a role in labor and is a useful therapeutic agent in the induction of labor. Along with estrogen, oxytocin is used therapeutically in arresting uterine bleeding. Oxytocin injections are given to dairy animals before milking them. Oxytocin secretion is stimulated (a) by cervical stimulation, as occurs during coitus and parturition, and (b) by suckling. Oxytocin is released in men too during genital stimulation but its role is not clear. Oxytocin secretion is inhibited by sympathetic discharge and circulating catecholamines, by pain and enkephalins, by emotional stress, especially fear, and by alcohol.

Relaxin Relaxin is a polypeptide hormone secreted by the corpus luteum and placenta in women and by the prostate in men. During pregnancy, it facilitates parturition by relaxing the pubic symphysis and other pelvic joints and softens the cervix. In men, it probably has a role in sperm motility and sperm penetration of the ovum.

in prolactin secretion during sleep, (b) vasoactive intestinal peptide (VIP) which mediates the suckling reflex, (c) estrogens and (d) thyrotropinreleasing hormone (TRH). Plasma prolactin levels start increasing by the eighth week of pregnancy and peak 2 weeks before term (see Fig. 93.4). The increase is brought about by estrogens, which directly stimulate the pituitary lactotrophs to synthesize and secrete more prolactin. After parturition, prolactin secretion falls but the fall is gradual because prolactin secretion is stimulated during each session of suckling. Prolactin secretion is also stimulated by other factors of unknown physiological significance, for example, it increases during sleep, exercise, and stress. Hyperprolactinemia is associated with galac-

torrhea in only about 30% of cases. In women, it causes infertility and amenorrhea, while in men, it causes impotence and decreased libido. Treatment for prolactin hypersecretion includes administration of a strong dopamine (D2) agonist such as bromocriptine.

Parturition Phases of parturition Parturition is the process of giving birth, which involves (1) the preparation for childbirth, (2) the process of childbirth and (3) the recovery from childbirth. During parturition, the myometrium and the cervix undergo a series of events that are divided into four phases (Fig. 94.1). Uterine phase 0 of parturition is the prelude to ini-

Prolactin Prolactin is a polypeptide hormone secreted by the pituitary acidophils. Its physiological actions are (1) mammogenesis, lactogenesis, and galactopoiesis, and (2) suppression of GnRH secretion which results in lactation amenorrhea. Normally, the control of prolactin secretion is under constant inhibition by the prolactin-inhibiting factor (PIF) secreted by the arcuate (infundibular) nucleus of the hypothalamus (see Fig. 98.2). PIF is now known to be dopamine which acts through D2 receptors. Hence, prolactin secretion is disinhibited by dopamine antagonists such as metochlorpramide. Prolactin secretion is stimulated by (a) serotonin which probably mediates the increase

Sircar_Chapter94_591_594.indd 591

tiation of parturition and extends from before implantation until late gestation. Because of the effect of progesterone, the myometrium is relaxed and the cervix is rigid and unyielding. The myometrial cells have slow conduction velocity and low contractility: The reason is the increased degradation of endogenous uterotonins such as prostaglandins, oxytocin, and histamine by prostaglandin dehydrogenase, oxytocinase, and diamine oxidase, respectively. Uterine phase 1 of parturition is the period of

uterine preparedness for labor. It is characterized by increased myometrial responsiveness to oxytocin and cervical ripening. The myometrial responsiveness to oxytocin increases due to (1) an increase in the number of oxytocin receptors in the

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592

Reproductive System

Pregnancy

Parturition Phase 0

Phase 1

Phase 2

Phase 3

Prelude to parturition

Preparation for Active labor labor

Parturient recovery

myometrium unprepared for labor

myometrium prepared for labor

Uterine involution

Breast feeding

Initiation of parturition

Onset of labor

Delivery of conceptus

Fertility restored

Fig. 94.1 Stages of parturition.

myometrium, and (2) an increase in the number and size of gap junctions between the myometrial cells, which results in faster conduction of action potentials between myometrial cells. Cervical ripening is mediated by the prostaglandins under the influence of estrogens. The cervix becomes soft and yielding due to (1) the breakdown of collagen and (2) an increase in hyaluronic acid which has high water retaining capacity. Phase 2 of parturition is under the influence of oxytocin and prostaglandins. It is the period of active labor, that is, the period of uterine contractions which bring about progressive cervical dilatation, fetal descent, and delivery of conceptus, that is, the fetus, umbilical cord, and placenta (Fig. 94.2). It has further been divided into three stages:

Uterine phase 3 of parturition is the recovery of the mother. It involves (1) uterine contraction and retraction to prevent postpartum hemorrhage, (2) initiation of lactation and milk ejection to facilitate breast feeding, (3) involution of uterus, and (4) restoration of fertility. Oxytocin and endothelin-1 are important regulators of phase 3 of parturition.

Initiation of parturition Parturition is trigerred by a sharp rise in the plasma estrogen:progesterone (E:P) ratio toward term.

Stage I is the stage of cervical effacement and dilatation.1 Stage II is the expulsion of the fetus. Stage III is the separation and expulsion of placenta.

After the expulsion of the placenta, the cord is not clamped until pulsations cease so that an additional 100 mL blood is transferred into the neonate, which is beneficial. However, clamping is not delayed for more than 1 minute, because too much blood (> 100 mL) will embarrass respiration and circulation. There is risk of blood loss to the placenta if (1) the neonate is raised above the level of the uterus or (2) if the cord is partially compressed, blocking venous return from the placenta but not the arterial flow to the placenta.

1

Fig. 94.2 Stages in the birth of the newborn (phase 2).

The external opening of the cervix is normally closed. During labor, the cervical canal dilates and shortens, and the uterus, vagina, and cervix become one continuous canal in which the cervix is almost indistinguishable as a separate part. This is known as cervical effacement.

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Parturition and Lactation Effects of high E:P ratio A high E:P ratio stimulates uterine contraction due to the following reasons. Progesterone relaxes uterine smooth muscles. On the contrary, estrogen causes (1) increased secretion of oxytocin, (2) increased synthesis of oxytocin receptors in myometrium and decidua, (3) increased synthesis of prostaglandins in the decidua, and (4) increased synthesis of myometrial contractile protein. Prostaglandins increase the formation of gap junctions in the myometrium, enabling faster conduction of impulses. Causes of high E:P ratio Although the plasma levels of both estrogen and progesterone increase in pregnancy, the E:P ratio increases toward term due to a steep rise in estrogen secretion and a slower rise in progesterone secretion2 (see Fig. 93.4). The rise in maternal plasma estrogen is triggered by an increase in fetal secretion of CRH. The increase in CRH increases fetal ACTH secretion, which in turn increases the secretion of androgens from the fetal adrenal cortex. The placenta converts these androgens to estrogens, which diffuse into maternal circulation (see Fig. 93.5). The terminal rise in maternal plasma progesterone is slower because cortisol, which is produced by the fetus in large amount, inhibits the conversion of fetal pregnenolone to progesterone. Parturition reflex Once labor starts, uterine con-

tractions push the fetal head into the cervix, which consequently dilates. Cervical dilatation stimulates the cervical afferents, which reflexly increases oxytocin secretion from the posterior pituitary. Oxytocin contracts the myometrium futher, pushing the fetal head farther into the cervix and accentuating the parturition reflex. The intensity of the labor pain increases and culminates in the expulsion of the fetus.

Lactation Phases of lactation Lactation is divided into four phases, viz., mammogenesis, lactogenesis, galactokinesis, and galactopoiesis. Mammogenesis is the preparation of the breasts. It involves both duct growth and lobuloalveolar growth. Duct growth is brought about by estrogens, growth hormone, and glucocorticoids. Lobuloalveolar growth requires, in addition to the hormones mentioned, progesterone and prolactin (Fig. 94.3).

Estrogen Growth hormone Glucocorticoids

593

Estrogen Growth hormone Glucocorticoids Progesterone Prolactin

DUCT GROWTH

LOBULOALVEOLAR GROWTH

Fig. 94.3 Effect of hormones on development of the breast.

Lactogenesis is the synthesis and secretion of

milk from breast alveoli. Around midpregnancy, the alveoli become sufficiently differentiated to secrete small amounts of casein and lactose. Lactose synthesis is catalyzed by the enzyme galactosyl transferase, the activity of which is enhanced by prolactin. Although the prolactin level is high during pregnancy, there is no milk secretion because lactogenesis is inhibited by estrogen and progesterone. After parturition, there is a sharp fall in estrogen and progesterone levels. This removes the inhibitory effect on lactogenesis. As the prolactin level is still high and mammogenesis is complete, lactogenesis occurs. Once lactation starts, it is not inhibited by administered progesterone because progesterone receptors are lost in lactating women. Limited secretion of milk, called witch’s milk, also occurs from the breast of the newborn due to the influence of maternal prolactin. Growth hormone and thyroid hormone increase milk production. These hormones are administered to dairy animals to increase the yield of milk. Galactokinesis is also called milk ejection or milk letdown. It is brought about by oxytocin which stimulates the contraction of myoepithelial cells in the mammary alveoli and ducts. Oxytocin is released on stimulation of nipple during suckling. Suckling stimulates the sensory nerve endings of the areola and the nipple. The impulses travel to the hypothalamus and cause reflex release of prolactin and oxytocin from the pituitary. Oxytocin (not prolactin) secretion can be conditioned so that the physical stimulation of the nipple no longer is required. Thus, lactating women can experience milk letdown in response to the sight, sound, and even the thought of a baby (Fig. 94.4).

2

There are considerable differences in the mechanism of parturition in different species of mammals. For example, a sharp fall in progesterone level occurs at term in rats and sheep but not in humans.

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Reproductive System

PREGNANCY

Hypothalamus (Arcuate Nucleus) Sight, sound and thought of infant

Suckling GnRH Anterior pituitary

Posterior pituitary

Prolactin

Oxytocin

Stimulation of secretion in mammary alveoli

Contraction of smooth muscles lining ducts and alveoli of the breast

POSTPARTUM

Plasma prolactin concentration

594

Suckling Suckling

No suckling 10

20

30

Weeks

40 0

5 7 Days

1

2

3

Months

Fig. 94.4 The control of milk ejection.

Fig. 94.5 Prolactin levels during pregnancy and suckling.

Galactopoiesis is the maintenance of lactation. Lactation is maintained by prolactin. After parturition, the estrogen and progesterone levels fall and with them, the prolactin level also declines. However, there are periodic surges of prolactin with each episode of suckling (Fig. 94.5). These surges maintain lactation. In fact, lactation can continue indefinitely as long as suckling is continued, as in wet nurses who offer themselves for hire for suckling another’s baby. The withdrawal

of prolactin is associated with involution of the breast. The alveolar epithelium undergoes apoptosis and remodeling, and the gland reverts to its prepregnant state. The high level of prolactin inhibits GnRH secretion, resulting in low levels of FSH and LH. Hence suckling, which stimulates prolactin secretion, is associated with anovulation and amenorrhea. Such amenorrhea is commonly called lactation amenorrhea.

REVISION QUESTIONS 1. Gallstones are more common in females who have been pregnant several times. Why? 2. The plasma prolactin level rises steadily during pregnancy and falls slowly after parturition. Why? 3. During parturition, after the expulsion of the fetus, it is preferable to clamp the cord only after its pulsations cease. Why? 4. The estrogen-to-progesterone (E:P) ratio becomes high towards term. Why? The high E:P ratio promotes uterine contraction. Why?

6. Although the prolactin level is high during pregnancy, there is no milk secretion. Why? Why does milk secretion begin only after parturition? 7. Lactating women can experience milk letdown in response to the sight, sound, and even the thought of a baby. Why? 8. How long does lactation continue in a mother suckling her baby? 9. What is lactation amenorrhea and why does it occur?

5. What is Ferguson reflex?

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95

Anatomy of the Central Nervous System

The central nervous system consists of the brain (Fig. 95.1) and the spinal cord (Fig. 95.10). The further subdivisions of the brain are shown in Fig. 95.2. The medulla oblongata, pons, and the midbrain together constitute the brain stem. The functional anatomy of the different parts of the brain is discussed in the next few chapters. However, the study of the parts does not necessarily lead to a clear understanding of the anatomy of the brain as a whole or the relationship between its different parts. An attempt has been made in this chapter to

give a holistic, three-dimensional concept of the brain through schematic diagrams. Such a concept helps in visualizing the neural connections between different parts of the brain and brain stem, many of which are of considerable physiological importance. For the most part, the brain has been schematically “dismantled” in steps so that we are able to see all the structures inside the cerebrum. The brief account given below should be combined with a more comprehensive text in a standard anatomy textbook.

Brain Cerebral hemispheres Central sulcus

Lateral sulcus

Cerebellum Brainstem

Cingulate sulcus Corpus callosum Septum pellucidum Third ventricle

Fourth ventricle

Fig. 95.1 (Above) The brain, viewed from above, behind and right. (Below) The left cerebral hemisphere

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The cerebrum is made of two cerebral hemispheres. Each hemisphere has a superolateral surface, a medial surface, and an inferior surface. The surface of the cerebrum is thrown into folds. The surface elevations created by these folds are called gyri (singular: gyrus) and the grooves separating them are called sulci (singular: sulcus). Each cerebral hemisphere is also divided into the frontal, parietal, occipital, and temporal lobes. The frontal lobe is the part of the hemisphere anterior to the central sulcus and above the lateral sulcus. The temporal lobe is inferior to the lateral sulcus. Posteriorly it is limited by an imaginary line joining the preoccipital notch to the parietooccipital sulcus. The parietal lobe is bounded anteriorly by the central sulcus and posteriorly by the line joining the preoccipital notch to the parietooccipital sulcus. The occipital lobe lies behind the line joining the preoccipital incisure to the parietooccipital sulcus (Fig. 95.3A). The two cerebral hemispheres are interconnected by the corpus callosum which must be cut to separate the two hemispheres. The medial surface of the left hemisphere (Fig. 95.3B) shows the cut surface of the corpus callosum, third ventricle, septum pellucidum, and a part of the fornix. The prominent sulci on the medial surface are the cingulate, calcarine, and parietooccipital sulci. The surface of the cerebrum has a thin layer of gray matter called the cerebral cortex. It is less than 4 mm thick and is made of cell bodies of neurons. The interior of the cerebrum contains mainly the white matter, which is made of myelinated axons. Also, present in the interior is a large aggregation

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596

Central Nervous System

Nervous System Peripheral Nervous System

Central Nervous System Spinal Cord

Encephalon (Brain) Rhombencephalon (Hindbrain) Myelencephalon (Medulla Oblongata)

Metencephalon (Pons)

Mesencephalon (Midbrain) Cerebellum (Little brain)

Prosencephalon (Forebrain) Diencephalon (Interbrain)

Thalamus Hypothalamus Subthalamus Metathalamus Epithalamus Cerebral cortex (Cerebral gray matter) Limbic Cortex

Neocortex

Centrum semiovale (Cerebral white matter) Association fibers

Commissural fibers

Telencephalon (Endbrain) (Cerebrum)

Basal ganglia

Projection fibers

Fig. 95.2 Subdivisions of the nervous system.

of cell bodies called the basal ganglia1 and large fluid-filled spaces called the cerebral ventricles. The ventricles are lined by the membranous ependyma which is shown in blue in all the diagrams. To understand the anatomy of these structures, let us imagine that the thin layer of the cerebral cortex on the medial surface has been removed and some of the white matter scooped out. The brain would then look as shown in Fig. 95.4A. Fig. 95.4 shows the corpus callosum in its entirety. The corpus callosum has a body, rostrum, splenium, forceps minor and major, and tapetum. The corpus callosum contains commissural fibers, that is, fibers that interconnect the two hemispheres. Also seen is the optic radiation, running lateral to the tapetum and coursing toward the calcarine sulcus. On removing the corpus callosum, the structures that come into view are the cerebral ventricles and the corona radiata (Fig. 95.4B). There are four cerebral ventricles, viz., the two lateral ventricles, the third ventricle, and the fourth ventricle (Fig. 95.4C). Each lateral ventricle has a body and three horns or cornu: an anterior cornu extending into the frontal lobe, a posterior cornu

extending into the occipital lobe, and an inferior cornu extending into the temporal lobe. The third ventricle is a midline structure. It communicates with the two lateral ventricles at the Y-shaped interventricular foramen (of Monro). Posteroinferiorly, the third ventricle communicates with the fourth ventricle through the aqueduct (of Sylvius) in the midbrain. The nuclear groups around the third ventricle constitute the diencephalon or interbrain which includes the dorsal thalamus (or simply, the thalamus), subthalamus, (or ventral thalamus), hypothalamus, metathalamus (lateral and medial geniculate bodies), and the epithalamus (pineal body). The thalamus lies lateral to the third ventricle and the hypothalamus lies below the third ventricle. The subthalamus has two parts, a small midline part lying behind the hypothalamus and a thin sheet extending laterally below the dorsal thalamus (Fig. 95.4D). Removal of the ventricles exposes the underlying structures which include the dorsal thalamus, fornix, stria terminalis, and the caudate nucleus (Fig. 95.5). The corona radiata is now seen lying just lateral to the caudate nucleus.

1

The term basal ganglia is a misnomer. An aggregation of cells inside the central nervous system is called a nucleus and therefore the correct name should be basal nuclei.

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Anatomy of the Central Nervous System

Central s. Precentral s. Postcentral s.

Sup. frontal s.

ule lob tal

ule l ob

Transverse temporal gyri

r erio Sup

rietoocci Pa

Inf .p a

al arc pit

t al rie

l g. tra . cen al g Pre ntr tce Pos

Sup . pa rie

Transverse occipital s.

In f. f ro nt al g.

Inf. frontal s. g. tal n ro p. f Su g. . Pre id al cen M ont tra fr l

Intraparietal s.

te

te m

Sup. occipital g.

Lateral s.

a

ora

l g.

p or

Sup. temporal s.

g. inf . te mp

Middle

Striate area

m

lg .

A

597

p o r al

Inf. occipital g.

Inf. frontal s. llum Cerebe

Lunate s.

Preoccipital notch

Lat. occipital s. B Cingulate s.

g. tal ron al f i d Me

Parietooccipital s.

us hm Ist

Cingulate s. Anterior parolfactory s. Parolfactory g. (Subcallosal area)

Third ventricle

C

Posterior parolfactory s.

Medial olfactory gyrus Paraterminal gyrus

gu a

lg .

Cuneus

Cingulate g

Precuneus

.

Cingulate g.

ule ob g. al l te ntr e c ula a r g a P Cin um cid g. te ellu a p l gu tum Cin S ep

Lin

Insula Claustrum

Calcarine s.

Lentiform Nucleus

Caudate Nucleus (body) Hippocampus

Thalamus

Fig. 95.3 [A] The “schematic” brain viewed from above, behind and right, showing the sulci and gyri on the superolateral surface of the right hemisphere. Also shown are the demarcations between the frontal, parietal, temporal, and occipital lobes. [B] The left hemisphere showing the sulci and gyri on its medial surface. [C] A coronal section through the left hemisphere.

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Central Nervous System

Forceps minor A

Body of corpus callosum Rostrum of corpus callosum Lamina terminalis of corpus callosum

C

Cerebral ventricles

Splenium

Anterior horn

Forceps major Tapetum

Body

Posterior horn

Optic radiation

Inferior horn

B

Intraventricular foramen ta dia a ra n ro Co

Pineal recess

D

Pituitary recess Aqueduct

Diencephalon Third ventricle

Crus cerebri

Hypothalamus

Subthalamus

Posterior perforated substance

Fig. 95.4 [A] Parts of the corpus callosum. Also shown is the optic radiation ending near the calcarine sulcus. [B] The corona radiata, and the cerebral ventricles. [C] Parts of the lateral and third ventricles. [D] The diencephalon, showing the relation between its parts.

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Anatomy of the Central Nervous System

Corona radiata

599

Head of caudate n. Fornix Optic nerve Optic chiasma

Crus cerebri

Globus Lentiform pallidus nucleus Putamen

Internal capsule

Caudate nucleus Fornix Hypothalamus

Pituitary Thalamus Subthalamus

Fig. 95.5 The caudate nucleus and the fornix. The head of the caudate nucleus is made slightly transparent to show the underlying striate arteries entering the cerebrum through the anterior perforated substance. Inset shows the basal ganglia, thalamus, and internal capsule.

The corona radiata is made of long projection fibers to and from the cerebral cortex. When it is transected flush with the caudate nucleus, the cut edge presents a knee-shaped tract called the internal capsule, lateral to which is the lentiform nucleus. The caudate nucleus and the lentiform nucleus together form the basal ganglia. The internal capsule is pierced from below by the striate arteries which enter the cerebrum through the anterior perforated substance. Rupture of the striate artery causes hemorrhage into the internal capsule, resulting in hemiplegia. The medial side of the temporal lobe contains the hippocampus, dentate gyrus, fimbria of fornix, amygdala, the origin of the stria terminalis, and the inferior cornu of the lateral ventricle. These structures are shown in Fig. 95.6A by removing the cerebral cortex on the medial temporal surface. The figure shows the entire fornix, that is, its origin from the hippocampus as the fimbria, its crus, body, and column of the fornix. Its termination in the mamillary body of the hypothalamus is not shown. It should also be noted that though the amygdala is closely

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related to the tail of the caudate nucleus, there is no functional relationship between the two. In Fig. 95.6B, the thalamus and basal ganglia have been removed so that all the sulci and gyri on the inferior surface of the left cerebral hemisphere are visible. The sulci are shown as elevations because they are viewed from the inside. The inset shows the posterolateral view of the anterior half of the right hemisphere. This view shows that the insula is essentially a sulcus with a greatly expanded floor. The expanded floor is triangular in shape, with its tip directed medially. The origin of the twelve cranial nerves, the cerebral arteries, and cerebral veins are shown in an anteroinferior view of the brain (Fig. 95.7). It shows that the olfactory tract occupies the olfactory sulcus. It also shows the optic chiasma anterior to the pituitary and the optic tracts as they wind round the cerebral peduncles. Fig. 95.8 shows the brain stem and the cerebellum from the same perspective as in Fig. 95.3. It shows that the fourth ventricle is bounded posteriorly by the cerebellar vermis and anteriorly by the pons

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600

Central Nervous System

A

Stria terminalis

Column of fornix Body of fornix Amygdala Hippocampus Dentate g. Fimbria of fornix

Crus of the fornix Sulcus centralis insulae

Insula

Orbital s.

B

Claustrum

Olfactory s. Anterior perforated substance Rhinal s. Uncus

Occipitotemporal s. Collateral s.

Insula

Transverse temporal g.

Fig. 95.6 [A] The hippocampus and the fimbria of the fornix, located inside the temporal lobe. Also shown are the amygdala and the stria terminalis originating from it, the tail of the caudate nucleus, and the termination of the column of fornix in the region where the mamillary body would have been. [B] The sulci and gyri on the inferior surface of the left cerebral hemisphere viewed from the inside. Inset shows the continuity of the insula with the lateral sulcus in the right hemisphere. Also shown are the transverse temporal gyri on the floor of the lateral sulcus.

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Anatomy of the Central Nervous System

Ant. cerebral a.

601

Med. olfactory stria

Ant. com. a. Olfactory bulb

Striate branches of ant. cerebral a. Mid. cerebral a. Lat. olf. stria

Post. comm. a.

III

Striate branches of post. cerebral a.

IV V (motor root)

Post. cerebral a.

V (sensory root)

Sup. cerebellar a. Basilar a.

IX X XI

Ant. inf. cerebellar a.

VI

VII VIII

XII

Post. inf. cerebellar a.

Anterior cerebral v.

Int. carotid a.

Anterior cerebral a.

Vertebral a. Anterior spinal a.

Deep middle cerebral v.

Inferior sagittal sinus Choroidal a. Great cerebral v.

Superficial middle cerebral v. Middle cerebral v.

Straight sinus

Basal v.

Fig. 95.7 (Above) The anteroinferior view of the brain showing the cerebral arteries and cranial nerves. (Below) The arteries and veins on the medial surface of left hemisphere.

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602

Central Nervous System

Substantia nigra

Crus cerebri

Aqueduct Midbrain

Pons A

Vermis Medulla

Left cerebellar hemisphere

Horizontal fissure

Superior Inferior cerebellar cerebellar peduncle Middle peduncle cerebellar peduncle

B Dentate nucleus Emboliform nucleus

Fastigial nucleus Lateral geniculate body

Globose nucleus

C

Eye

Optic n.

Optic tract

Oculomotor nucleus

Optic chiasma

Brachium of superior colliculus

Superior colliculus

Optic radiation

Lateral recess

Medial dorsal recess

Foramen of Luschii

Foramen of Magendie Flocculus

Lateral dorsal recess

D

Peduncle of flocculus Nodule

Fig. 95.8 The cerebellum and the fourth ventricle. [A] Cerebellar vermis and left cerebellar hemisphere. It shows that the cerebellum forms the roof of the fourth ventricle. [B] Left cerebellar hemisphere cut open to show the deep cerebellar nuclei. [C] Cerebellum removed to show the fourth ventricle and its recesses. Also shown is the optic pathway, showing its relation to the midbrain. [D] Left half of the brain stem and the flocculonodular lobe of the cerebellum.

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603

Oculomotor n.

Superior colliculus Inferior colliculus

Crus cerebri

Locus ceruleus

Trochlear Substantia nigra Superior cerebellar peduncle

Facial colliculus Obex

Middle cerebellar peduncle Inferior cerebellar peduncle

Trigeminal n. Locus ceruleus Facial colliculus Vestibular area Facial n.

Stria terminalis

Abducent n.

Hypoglossal triangle

Vagal triangle

Area postrema

Vagus n.

Inferior olivary nucleus

Hypoglossal n.

Olive

Lemniscal decussation

Fasciculus gracilis

Pyramidal decussation

Fasciculus cuneatus

Fig. 95.9 Posterior aspect of the brain stem that has been sectioned at various levels. (Above) Section through the midbrain at the level of superior colliculus (left) and inferior colliculus (right). (Middle) Section through the pons at the level of trigeminal nerve (left) and facial colliculus (right). (Below) Section through the medulla oblongata at the level of inferior olive (left), lemniscal decussation (middle) and pyramidal decussation (right).

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604

Central Nervous System and upper part of the medulla oblongata. It also shows the three cerebellar peduncles connecting the cerebellum to the brain stem. The four deep nuclei of the cerebellum are shown in Fig. 95.8B. The fourth ventricle is shown fully in Fig. 95.8C by removing the cerebellum. The recesses and the foramina of the fourth ventricle are also shown. The foramina are important for the circulation of cerebrospinal fluid. Also shown in the figure is the left half of the visual pathway. Removal of the fourth ventricle exposes the floor of the fourth ventricle which is shown in Fig. 95.9. The locus ceruleus and the area postrema are located on the floor of the fourth ventricle. The nuclei and tracts of the brain stem are shown by sections made at conventional sites (Fig. 95.9). Each section shows certain charac-

XII XI

I II III IV V VI VII VIII IX T1 X

Spinal Cord C1

C1

2 3 4 5 6 7 8 2 3 4 5

C3 C4 C5 C6 C7 T1 T2 T3 T5

7

T6

8

T7

9

T8

10

S1 2 3 4 5

C2

T4

6

L1

T9

11 12

T 10 T 11

2 3 4 5

T 12 L1 L2 L3 L4 L5

S3 S4 S5

S2

S1

Fig. 95.10 (Left) The brain, cranial nerves, spinal cord, and spinal nerves. (Right) Spinal nerves emerging from different segments of the spinal cord.

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teristic features. For example, the midbrain is sectioned at the levels of the upper and lower colliculi. Note the origin of the third and fourth nerves and also the characteristic shape of a midbrain section. Sections of the pons show the origin of the trigeminal and abducent nerves. The figure shows how the fibers of the facial nerve loop round the nucleus of the abducent nerve, forming an elevated ridge on the floor of the fourth ventricle, called the facial colliculus. The medulla oblongata is conventionally sectioned at the levels of the inferior olive, lemniscal decussation, and pyramidal decussation. Some of the important structures shown in the figure are the inferior olivary nucleus and the gracile and cuneate fasciculi.

The spinal cord is the caudal continuation of the medulla oblongata. It is enclosed in the vertebral canal and extends below to the border between S1 and S2 (sacral) vertebra. The caudal tip of the spinal cord is called the conus medullaris. The conus is attached to the coccygeal bone with a connective tissue cord called the filum terminale. The central canal of the medulla continues into the spinal cord. Spinal nerves originate in pairs from both sides of the spinal cord and emerge through the intervertebral foramina. Each spinal nerve consists of a ventral motor root and a dorsal sensory root. Both roots unite to form the mixed spinal nerve. The dorsal root bears a ganglion called the dorsal root ganglion. There are 31 pairs of spinal nerves: 8 pairs of cervical (C), 12 pairs of thoracic (T), 5 pairs of lumbar (L), 5 pairs of sacral (S), and 1 pair of coccygeal (Co) nerves. The segment of spinal cord giving rise to a pair of spinal nerves is called a spinal segment. The roots of all nerves below spinal segment L1 form a bunch known as the cauda equina. The spinal cord is shorter than the vertebral column and therefore a spinal segment is located higher than the corresponding vertebra (Fig. 95.10). The distance between corresponding spinal and vertebral segments increases progressively toward the lower end. This knowledge is important to the surgeon during laminectomy for relieving spinal cord compression. The spinal cord presents two fusiform enlargements, a cervical enlargement extending from C4 to T2 segments and a lumbosacral enlargement extending from L2 to S3 segments. The cervical and lumbosacral enlargements accommodate extra motor neurons to supply the muscles of the upper and lower limbs, respectively.

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605

REVISION QUESTIONS 1. What is the difference between association fibers, commisural fibers and projection fibers? 2. Which part of the brain is supplied by the striate branches of the anterior cerebral artery? What happens when the striate arteries rupture?

4. What is a spinal segment? Why is a spinal segment located higher than the correspsonding vertebra? 5. The spinal cord is thicker at the cervical and lumbar regions. Why?

3. What is the origin and termination of (1) the fornix, and (2) stria terminalis.

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Spinal Cord and Brain Stem

Spinal Cord

These laminae are useful when referring to specific areas of the spinal gray matter. At some places in the spinal gray matter, the cell bodies of neurons are closely aggregated together to form nuclei. Unlike the globular nuclei present in most parts of the central nervous system, the spinal nuclei are columns of cells extending vertically through several spinal segments.

In cross-section, the spinal cord presents gray matter (aggregation of cell bodies of neurons) in the interior and white matter (aggregation of myelinated axons) at the periphery. Each half of the spinal gray matter shows three pointed extensions named as the posterior (dorsal), lateral (intermediate), and anterior (ventral) horns. The intermediate horn is present only in the thoracic and upper lumbar segments. These horns separate the white matter into three pairs of funiculi/columns: the anterior, lateral, and posterior. A gray commissure connects the symmetrical halves of gray matter across the middle line. The anterior column is broader in cervical and lumbosacral enlargements for accommodation of the numerous motor neurons supplying the muscles of the upper and lower limbs.

The dorsal (posterior) horn contains the cells of the spinothalamic tract and other ascending tracts. The axonal endings of first order sensory neurons terminate in the dorsal horn. Together, lamina II and parts of lamina III form a gelatinous mass of nerve cells called the substantia gelatinosa. The lateral (intermediate) horn is present in the

T1 to L2 segments of the cord, and also from S2 to S4. In the T1 to L2 segments, the lateral horn contains the cells of the preganglionic sympathetic nervous system and constitutes the thoracolumbar sympathetic outflow. In the S2–S4 segments, the lateral horn contains the soma of the preganglionic parasympathetic neurons and constitutes

Spinal gray matter Cytoarchitecturally, the spinal gray matter has been divided into ten Rexed laminae (Fig. 96.1).

I

Dorsal columns II Dorsolateral tract

III

Dorsal spinocerebellar tract

Medullary reticulospinal tract

IV V VI

Lateral corticospinal tract Rubrospinal tract

VII IX

X VIII Spinocervicothalamic tract Spinoolivary tract Anterolateral spinothalamic tract

Vestibulospinal tract Tectospinal Pontine tract reticulospinal Anterior tract corticospinal tract

Fig. 96.1 Physiologically well-understood ascending and descending tracts of the spinal cord. The spinoreticular fibers are not organized into a well-defined tract and therefore, are not shown here. Also shown are the Rexed laminae.

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Spinal Cord and Brain Stem the sacral component of the craniosacral parasympathetic outflow (p 642). The ventral (anterior) horn contains the soma of the lower motor neurons, which directly innervate skeletal muscles. The soma of the lower motor neurons are organized into three groups of nuclei. The lateral group is present only in the cervical and lumbar spinal segments and supplies the limbs. The medial group is present only in the thoracic segments and supplies the trunk. The central group is present only in the C3 to C5 segments and innervates the diaphragm.

Spinal white matter The spinal white matter is composed largely of the long ascending and descending spinal tracts that are listed in Table 96.1 and illustrated in Fig. 96.1. The spinal cord also contains intersegmental tracts that run between different segments of the spinal cord. An important group of intersegmental fibers are the C3/C4 propriospinal neurons that have their cell bodies in spinal segments C3 and C4. These neurons allow selection of the correct muscle synergies that are required for visually guided reaching movements of the upper limbs, and also contribute to the associated postural readjustments. Lesions of these neurons affect the precise aiming of the hand towards the target even as the major descending inputs remain intact. Table 96.1 Physiologically well-understood long spinal tracts Ascending 1. Pathways to the thalamus and cortex a. Fasciculus gracilis and cuneatus (dorsal columns) b. Spinothalamic tracts, (anterior and lateral) 2. Pathways to the cerebellum a. Spinocerebellar tracts b. Spinoreticulocerebellar tract c. Spinoolivocerebellar tract Descending 1. Lateral pathways a. Lateral corticospinal tract b. Rubrospinal tract 2. Medial pathways a. Anterior corticospinal tract b. Vestibulospinal tract c. Reticulospinal tract d. Tectospinal tract

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607

Autonomic fibers descending from the hypothalamus do not form a compact tract but descend as scattered nerve fibers. Hence, they cannot be seen in a cross-section of the spinal cord but their presence in the spinal cord can be inferred from the effects they produce. Descending autonomic fibers carry the information from the hypothalamus and brain stem visceral nuclei (respiratory and cardiovascular) to the preganglionic autonomic neurons of intermediate horn of the spinal gray matter.

Spinal nerve As the spinal nerve approaches the spinal cord, it divides into the dorsal (sensory) and ventral (motor) roots (Fig. 96.2). All sensory fibers reach the spinal cord through dorsal nerve roots and all motor nerves exit the spinal cord through the ventral nerve root. This is known as the Bell– Magendie law. Each ventral root carries motor axons supplying a group of anatomically and functionally related skeletal muscles called the myotome. In the thoracolumbar segments, the ventral root also contains axons of the preganglionic and postganglionic sympathetic neurons. (The dorsal root is described on p 667.)

Spinal lesions Depending on its exact site, a lesion in the spinal cord can cause motor deficits (p 696), sensory deficits (p 674), or both. Lesions causing both motor and sensory deficits are discussed here. For understanding the neurological deficits, the full course of the corticospinal tracts (Fig. 96.5) and the spinothalamic tracts (see Fig. 13.9) have to be read before proceeding further. Brown–Sequard syndrome is a rare clinical condition in which there is segmental damage on one side of the spinal cord due to traumatic injury or compression by extramedullary tumors. It results in several neurological deficits below the level of the lesion. These are summarized in Table 96.2 and explained diagrammatically in Fig. 96.3. At the level of the lesion, there is flaccid paralysis (due to lower motor neuron lesion) and sensory deficits that are confined to the affected myotome and dermatome respectively. Complete transection of the cord occurs follow-

ing spinal fracture or dislocation, and results in loss of all sensations and voluntary movements below the level of the lesion. Immediately after injury, there is a period of spinal shock that may last from a few days to several weeks. During this

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608

Central Nervous System

Soma of pseudounipolar neurons

Central processes

Medial and lateral divisions of dorsal root Dorsal (sensory) root

Dorsal root ganglion

Peripheral processe Sensory fiber

Motor fiber

Ventral (motor) root

Spinal nerve

Autonomic fiber

Fig. 96.2 A transverse section of the spinal cord showing the gray and white matter. Also shown are the dorsal and ventral roots of the spinal nerves. Note that the dorsal root is further subdivided into the medial and lateral divisions.

period, all somatic and visceral reflex activities are abolished. Thereafter, the reflex activities return and the muscles become spastic with exaggerated tendon reflexes. Voluntary control over the bladder and bowel functions are lost if the lesion is above S2. Such dysfunction of the urinary bladder is called automatic bladder or cord bladder (p 434). If the transection occurs in the cervical cord, the patient becomes quadriplegic. If the site of lesion is between C1 and C4, it is called high quadriplegia and causes respiratory paralysis due to the involvement of the phrenic nerve. These patients require respiratory support. If the site of lesion is between C5 and C8, it is called low quadriplegia. If the transection occurs at T1 or below, it results in paraplegia. An isolated spinal cord favors flexor muscles and therefore a complete

transection of the spinal cord results in paraplegia in flexion. If the paraplegia is associated with predominantly extensor spasms, it is known as paraplegia in extension and it indicates an incomplete transection. Subacute combined degeneration of spinal cord is

most often seen in pernicious anemia. The dorsal columns and the lateral corticospinal tract undergo bilateral degeneration, especially involving the lumbosacral segments. The disease results in (1) loss of position and vibratory senses of the lower extremities, and (2) signs of upper motor neuron lesions.

Brain stem

Spinal lemniscus Medial lemniscus

Table 96.2 Neurological deficits in Brown–Sequard syndrome Site of lesion

Neurological signs

Dorsal columns

Ipsilateral loss of position and vibratory senses; disturbances of stereognosis and tactile discrimination

Lateral spinothalamic tract

Contralateral and segmental loss of pain and temperature—one or two segments below the level of the lesion

Corticospinal tract

Ipsilateral spastic paralysis with exaggerated tendon reflexes and positive Babinski sign

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Spinal cord

Corticospinal tract Lesion

Motor control Fine touch Pain Temperature

Motor control Fine touch Pain Temperature

Fig. 96.3 Brown–Sequard syndrome. The neurological deficits are summarized in Table 96.2.

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Spinal Cord and Brain Stem

Brainstem

609

Brainstem tracts and their nuclei

The internal structure of the brain stem is conventionally studied by making sections at levels with salient landmarks. The medulla is thus sectioned at four levels, viz., at the level of pyramidal decussation, lemniscal decussation, the midolivary level, and at the pontomedullary junction. The pons is sectioned at two levels, one above and the other below the level of the facial colliculus. The midbrain too is sectioned at two levels, one at the level of the inferior colliculus and the other at the level of the superior colliculus. The salient features seen in these sections are shown in Fig. 95.9.

Pyramidal tract (see upper motor neuron, p 688) scomprise the anterior and lateral corticospinal tracts (Fig. 96.5). These tracts descend from the cerebral cortex and after passing through the internal capsule, enter the crura cerebri of the midbrain. They continue to descend through the pons and finally through the pyramids of the medulla.

Cranial nerves nuclei All cranial nerves except the olfactory and optic nerves originate from the brain stem. The midbrain gives origin to the III and IV nerves, the pons gives origin to the V to VIII cranial nerves, and the medulla gives origin to the IX to XII cranial nerves. All cranial nerves are associated with one or more nuclei in the brain stem. These nuclei are shown in Fig. 96.4 and are listed in Table 96.3.

Oculomotor nucleus Midbrain Mesencephalic nucleus of trigeminal

Pyramidal tract in the internal capsule

Midbrain

Pyramidal tract in the crus cerebri

Pons

Trochlear nucleus

Medulla Pons Principal sensory nucleus of trigeminal Motor nucleus of trigeminal Medulla Nucleus of tractus solitarius Dorsal nucleus of vagus

Abducent nucleus Facial nucleus Superior salivatory nucleus Inferior salivatory nucleus Cochlear nuclei

Pyramidal tract in the medullary pyramid

Lateral corticospinal tract Anterior corticospinal tract

Vestibular nucleus

Pyramidal decussation

Spinal cord

Hypoglossal nucleus Spinal nucleus of trigeminal

Nucleus ambiguus

Fig. 96.4 Nuclei of cranial nerves in the brain stem.

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Fig. 96.5 The pyramidal tract.

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610

Central Nervous System Table 96.3 Cranial nerve nuclei in the brain stem

III

Cranial nerve

Associated nuclei

Function

Cells constituting the nucleus

Oculomotor nerve

Oculomotor nerve nuclear complex

Contraction of all extraocular muscles except the superior oblique and lateral rectus

Soma of lower motor neurons supplying the extraocular muscles.

Contraction of the iris and ciliary muscles

Soma of parasympathetic preganglionic neurons supplying the iris and ciliary muscles via the ciliary ganglion and short ciliary nerves.

IV

Trochlear nerve

Trochlear nucleus

Contraction of the superior oblique muscle

Soma of lower motor neurons supplying the superior oblique muscle.

V

Trigeminal nerve

Spinal nucleus of trigeminal

Sense of pain and temperature from face

Soma of the second order neurons that ascend in the trigeminal lemniscus to reach the VPM nucleus of the thalamus.

Principal sensory nucleus

Sense of fine touch from face

Soma of the second order neurons that ascend in the trigeminal lemniscus to reach the VPM nucleus of the thalamus.

Mesencephalic nucleus of trigeminal

Sense of proprioception from the muscles of mastication

Soma of the first order neurons originating in the proprioceptors of masticatory muscles. Axons of some of the neurons terminate on the motor nucleus of the trigeminal and mediate the jaw jerk.

Motor nucleus of trigeminal

Contraction of muscles of mastication

Soma of lower motor neurons supplying the muscles of mastication.

VI

Abducent nerve

Abducent nucleus

Contraction of the lateral rectus

Soma of lower motor neurons supplying the lateral rectus muscle.

VII

Facial nerve

Facial motor nucleus

Contraction of facial muscles

Soma of lower motor neurons supplying facial muscles.

Superior salivatory nucleus

Control of salivary secretion (by the submandibular and lingual glands) and lacrimal secretion

Soma of preganglionic parasympathetic secretomotor fibers that reach the submandibular, lingual, and lacrimal glands.

Nucleus of tractus solitarius

Taste sensation from anterior two-thirds of the tongue

Soma of second order sensory neurons conveying taste sensation to the thalamus. The neurons ascend through the solitariothalamic tract.

Vestibular nucleus

Sense of equilibrium and regulation of posture

Soma of neurons that descend in the vestibulospinal tract or ascend in the vestibuloreticular, vestibulocerebellar, vestibulocollicular, and vestibulothalamocortical tracts.

Cochlear nuclei

Sense of hearing

(1) Soma of the second order sensory neurons conveying auditory sensation to the medial geniculate body of the thalamus. (2) soma of first order neuron located in the spiral ganglion.

Nucleus ambiguus

Contraction of the stylopharyngeus muscle

Soma of the lower motor neurons supplying the stylopharyngeus muscle

VIII

IX

Vestibulocochlear nerve

Glossopharyngeal nerve

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Spinal Cord and Brain Stem

X

XI

XII

Vagus

Accessory

Hypoglossal

Inferior salivatory nucleus

Control of salivary secretion by the parotid gland

Soma of preganglionic parasympathetic secretomotor fibers that reach the parotid glands.

Spinal nucleus of trigeminal

Sensation of pain, temperature, and touch from the posterior one-third of tongue and the oropharynx

Soma of the second order neurons that ascend in the trigeminal lemniscus to reach the VPM nucleus of the thalamus.

Nucleus of tractus solitarius

Taste sensation from the posterior one-third of tongue, and visceral senses from carotid baroreceptors and chemoreceptors

(1) Soma of second order sensory neurons conveying taste sensation to the thalamus. The neurons ascend through the solitariothalamic tract. (2) Soma of interneurons projecting to nucleus ambiguus, dorsal nucleus of vagus, and reticular formation.

Nucleus ambiguus

Contraction of muscles of pharynx and larynx

Soma of the lower motor neurons supplying the muscles of the pharynx and larynx.

Dorsal nucleus of vagus

Parasympathetic control of, and sensations from, the heart, airways, and gastrointestinal tract

A mixed nucleus that contains (1) soma of preganglionic parasympathetic neurons to the heart, airways, and gastrointestinal tract, and (2) soma of ascending sensory neurons that convey viscerosensory information to the hypothalamus.

Nucleus of tractus solitarius

Taste sensation from the posterior pharynx

Soma of second order sensory neurons conveying taste sensation to the thalamus. The neurons ascend through the solitariothalamic tract.

Spinal nucleus of trigeminal

Sensations of pain and temperature from the tympanic membrane and the external meatus

Soma of the second order neurons that ascend in the trigeminal lemniscus to reach the VPM nucleus of the thalamus.

Nucleus ambiguus

Contraction of soft palate muscles (except tensor veli palatini), pharyngeal muscles (except stylopharyngeus), and intrinsic muscles of larynx (except cricothyroid)

Soma of the lower motor neurons supplying the respective muscles.

Spinal nucleus of accessory

Contraction of the sternocleidomastoid and trapezoid muscles

Soma of the lower motor neurons supplying the sterno-cleidomastoid and trapezoid muscles.

Hypoglossal nucleus

Contraction of the tongue

Soma of the lower motor neurons supplying the muscles of the tongue.

(1) Most of the fibers cross over at the pyramidal decussation in the lower medulla and continue their descent on the contralateral side as the lateral corticospinal tract. (2) Fibers that do not decussate continue to descend ipsilaterally as the anterior

Sircar_Chapter96_606-614.indd 611

611

corticospinal tract. The fibers of the corticospinal tracts terminate on the spinal motor neurons located in the ventral horn of spinal gray matter. Not all motor fibers from the cortex descend to the spinal cord. Those ending in the brain stem are

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612

Central Nervous System called corticobulbar fibers. These mostly terminate on cranial nerve nuclei. Some of them terminate on the scattered pontine nuclei which give rise to pontocerebellar fibers. Nuclei identical to pontine nuclei are also found in the upper medulla. These are called arcuate nuclei and give rise to the anterior external arcuate fibers which enter the cerebellum. Extrapyramidal tracts involved

in cerebellar motor control include the anterior and posterior spinocerebellar tracts, the cuneocerebellar tract (also called the posterior external arcuate fibers), the spinoolivary tract, and the rubrospinal tract. The related nuclei are the accessory cuneate nucleus, the olivary nuclear complex, and the red nucleus. These are discussed in Chapter 97. Other tracts involved in extrapyramidal motor control are the vestibulospinal tract, the tectospinal tract, and the reticulospinal tract. The brain stem nuclei of their origin are respectively, the vestibular nuclei, the tectal nuclei, and the reticular nuclei.

General sensory tracts There are two main

ascending tracts that convey general sensory information to the thalamus and thence, to the cortex. One of the tracts crosses over in the spinal cord and is known as the anterolateral sensory pathway while the other crosses over in the medulla and is called the dorsal column pathway (see Fig. 103.9). These tracts are described in detail later.

Supranuclear motor lesions The nuclei of the

III, IV, and VI cranial nerves are not controlled individually by the corticobulbar fibers. Rather, the corticobulbar fibers innervate the gaze centers that control various conjugate and disjugate movements. The gaze centers, in turn, innervate the appropriate cranial nerve nuclei. For example, close to the abducent nucleus is located the lateral gaze center (Fig. 96.6) which innervates the ipsilateral abducent nucleus and the contralateral oculomotor nucleus. When stimulated, the lateral gaze center produces conjugate gaze toward the same side. Hence, a pontine lesion affecting the lateral gaze center on one side deviates the eyes to the opposite side. However, a cortical lesion deviates the eyes toward the side of the lesion because the corticobulbar fibers control the contralateral lateral gaze center. Most of the other motor nuclei, such as the motor nuclei of the V, X, and XII receive bilateral innervation from the corticobulbar tracts. Hence, unilateral supranuclear lesions of cranial nerves associated with these nuclei do not result in motor paralysis. Similarly, the second order neurons from the termination of the cochlear afferents decussate at multiple levels. Hence, a supranuclear lesion of the VIII nerve (lesion of the corticobulbar tract innervating the nucleus of the nerve) does not impair hearing. The nucleus of the VII cranial nerve is somewhat unique in this regard. The upper part of the VII nerve nucleus supplies the ipsilateral muscles around the eye, forehead, and scalp

Special sensory tracts The tracts that convey auditory information from the cochlear nerve include the trapezoid body and the lateral lemniscus. They are related to the nucleus of the trapezoid body and the inferior colliculus, respectively (see Fig. 118.4). Ascending tracts carrying vestibular information include vestibuloreticular, vestibulocollicular, and vestibulothalamocortical fibers (see Fig. 119.4). Tracts carrying visual, olfactory, and gustatory sensations do not pass through the brain stem.

III

IV

Brainstem lesions Unlike spinal cord lesions that produce ipsilateral hemiplegia, brain stem lesions mostly produce contralateral hemiplegia As the lesion is mostly above the level of pyramidal decussation. Similarly, sensory deficits mostly occur contralaterally. Depending on the level of the brain stem lesion, one or more cranial nerve nuclei may be affected. When corticobulbar tracts innervating the cranial nerve nuclei are affected, they are called supranuclear lesions.

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VI

Corticobulbar fiber

Lateral gaze center

Fig. 96.6 Connections of the lateral gaze center with the contralateral nuclei of the III and IV nerves, and the ipsilateral nucleus of the VI nerve. Descending corticobulbar fibers innervate the contralateral gaze center.

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Spinal Cord and Brain Stem (occipitofrontalis) while the lower part of the nucleus supplies the ipsilateral muscles of the lower part of the face. The corticobulbar tract innervates the lower part of the facial nucleus contralaterally, but innervates the upper part of the nucleus bilaterally (Fig. 96.7). Hence, a supranuclear lesion of the VII nerve causes paralysis of the lower part of the face but spares the muscles around the eye and the forehead, a phenomenon that is summed up by the acronym SSS meaning supranuclear-sparessuperior.

Corticobulbar (supranuclear) fibers

Reticular Formation

Upper part VII N nuclei (supplying upper half of face)

The reticular formation is the gray matter present in the core of the brain stem. The reticular formation is so named because the neurons of this part form a network (reticulum) instead of welldefined tracts or nuclei. The reticular formation is functionally divided into the lateral and medial regions.

Lateral reticular formation The lateral reticular formation contains small localcircuit neurons that form various “reflex centers” in the brain stem. These centers are located close to the brain stem motor nuclei. For example, in the medulla, it contains centers such as the swallowing

613

Lower part VII N nuclei (supplying lower half of face)

To lower part of face To upper part of face

Fig. 96.7 The superior part of the VII cranial nerve is innervated bilaterally by the corticobulbar fibers, while the inferior part of the same nucleus receives innervation only from the contralateral corticobulbar fibers.

center, vomiting center, respiratory center, coughing center, sneezing center, vasomotor center, etc.

Reticular Formation

Lateral Reticular Formation

Medullary centers

Pontine centers

Swallowing center Vomiting center Respiratory center Coughing center Sneezing center Vasomotor center

Mastication center Facial expression center Lateral gaze center Vergence center

Medial Reticular Formation

Ascending Descending Reticular Formation Reticular Formation

Produces arousal

Modulates pain

Controls posture

Mesopontine Reticular Formation

Pontomedullary Reticular Formation

Increases antigravity muscle tone

Inhibits antigravity muscle tone

Fig. 96.8 Subdivisions of the reticular formation and their functions.

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614

Central Nervous System In the pons, there are centers that coordinate mastication and emotional facial expressions such as smiling. These centers are bilaterally innervated by the upper motor neurons and therefore, such as the upper part of the face, remain unaffected in supranuclear palsy of the VII nerve. Hence, the patient of UMNL might be able to laugh spontaneously when told a joke but is unable to do so deliberately due to paralysis of the lower face. The pons also contains the lateral gaze center located close to the abducent nucleus. The center for vergence movements of the eye is located close to the oculomotor nucleus.

Medial reticular formation Neurons of the medial reticular formation are large and have long axons. Depending upon whether these axons ascend or descend, the medial reticular formation is divided into the ascending reticular formation and the descending reticular formation. Ascending reticular formation The ascending fibers from the medial reticular formation constitute the reticular activating system. They are mostly made of monoaminergic neurons from the nucleus ceruleus and cholinergic neurons of the mesopontine cholinergic system. They are broadly organized

into two branches. One branch passes through the thalamus, relaying in specific relay nuclei and intralaminar nuclei. The other branch passes through the lateral hypothalamus and basal forebrain where they are joined by the efferents of the hypothalamus and the nucleus basalis of Meynert respectively. Both branches project massively to large areas of the cerebral cortex producing profound arousal effects. reticular formation The descending fibers from the brain stem can be functionally divided into those modulating pain and those controlling posture. There are two reticulospinal tracts, medial and lateral, that control posture. They descend from the reticular formation to the γ-motor neurons in the spinal cord. The medial reticulospinal tract originates from the facilitatory reticular formation in midbrain and pons (the mesopontine reticular formation) and controls the antigravity muscles. Stimulation of the mesopontine reticular formation produces patterned stereotype movements such as stepping movements. The lateral reticulospinal tract originates from the inhibitory reticular formation in the pons and upper medulla (pontomedullary reticular formation). It contains glycinergic neurons that inhibit the γ-motor neurons to muscle spindles and thereby, inhibit muscle tone.

Descending

REVISION QUESTIONS 1. What type of neurons originate from the (1) dorsal horn, (2) lateral horn, and (3) ventral horn of the spinal cord? 2. Where in the spinal cord are the preganglionic autonomic fibers present? 3. What are the C3/C4 propriospinal neurons and what is their physiological role? 4. What is the Bell-Magendie law? 5. What is a myotome? 6. What are the clinical features of the BrownSequard syndrome? 7. What is spinal shock and when does it occur? 8. What type of spinal injury causes (1) paraplegia in flexion, (2) paraplegia in extension? 9. Spinal cord lesions mostly produce ipsilateral hemiplegia while brainstem lesions mostly

Sircar_Chapter96_606-614.indd 614

produce contralateral hemiplegia. Also, sensory deficits mostly occur contralaterally. Why? 10. A cortical lesion deviates the eyes towards the side of the lesion while a pontine lesion deviates the gaze to the contralateral side. Why? 11. Unilateral supranuclear lesions of the V, X, and XII cranial nerves do not cause motor paralysis. Also, a supranuclear lesion of the VIII nerve does not impair hearing. Why? 12. A supranuclear lesion of the VII nerve nucleus causes paralysis of the lower part of the face but spares the muscle around the eye and the forehead. Why? 13. Where in the brain are the various “reflex centers” mostly located? 14. A patient with a brain lesion laughs spontaneously when told a joke but is unable to smile when asked to do so. What could be the site of the lesion?

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97

Cerebellum

The cerebellum consists of two hemispheres and a median vermis. A posterolateral fissure intervenes between the flocculonodular lobe and the rest of the cerebellum. The latter is further subdivided by the primary fissure into the anterior and posterior lobes. When the superior and inferior surfaces of the cerebellum are flattened out, it presents from front to back the anatomical parts as shown in Fig. 97.1.

Lingula A la e ra n g Lo lo b u l a r bu ule lu s s im Su p p. lex se mi lu n ar l obu le Inf. s e m il u n ar lobule

Qu

ad

Central lobule Culmen

Prim

s fis ar y

ur

e

Declive Folium

Horizo

nt a l

fi s s

u re

Tuber

l lobule Pyramid entra Biv

Tonsil

Uvula

Posterolateral fissure

Nodule

Anterior lobe

Posterior lobe

Flocculonodular lobe

Nucleus interpositus Emboliformis Globosus Nucleus dentatus

Nucleus fastigii

Paleocerebellum

Cerebrocerebellum

Neocerebellum

Spinocerebellum

Archicerebellum

Vestibulocerebellum

Fig. 97.1 (Above) Anatomic subdivisions of the cerebellum. (Below left) Phylogenetic lobes of the cerebellum. (Below right) Functional lobes of the cerebellum.

Sircar_Chapter97_615-621.indd 615

Phylogenetically, the cerebellum is subdivided into the archicerebellum (the flocculonodular lobe), paleocerebellum (vermis of the anterior lobe, pyramid, uvula, and paraflocculus), and neocerebellum (remaining portions). Functionally, however, the cerebellum is divided longitudinally into the vestibulocerebellum, spinocerebellum, and cerebrocerebellum that are well connected to the vestibular nuclei, spinal cord, and cerebral cortex, respectively. The vestibulocerebellum is coextensive with the flocculonodular lobe. The vermal and paravermal areas of the rest of the cerebellum constitute the spinocerebellum, while its lateral hemispheres form the cerebrocerebellum. The functions of these divisions are summarized in Fig. 97.2. The cerebellum is connected to the brain stem by pairs of inferior, middle, and superior peduncles. The superior peduncles convey cerebellar efferents to the red nucleus (interstitiorubral, dentatorubral), thalamus (dentatothalamic), and the midbrain reticular formation (fastigioreticular), while the middle peduncles convey only the afferent pontocerebellar fibers to the cerebellum. The inferior peduncles carry both afferent (spinocerebellar, olivocerebellar, and reticulocerebellar) and efferent (fastigiovestibular) fibers of the cerebellum.

Internal cerebellar structure Structurally, the cerebellum consists of an outer cortical gray matter and an inner medullary core of white matter. The cerebellar cortex consists of three layers:

(1) Outer molecular layer, containing the basket cells, (2) Intermediate Purkinje cell layer, containing the Purkinje cells, and (3) Inner granule layer containing the granule cells and Golgi cells (Fig. 97.3). The granule cell releases the excitatory neurotransmitter glutamate, while the others release the inhibitory neurotransmitter GABA. In addition to the basket cells, the outer molecular layer also contains large number of parallel fibers which are the axons of granule cells. The dendrites of the Purkinje cells synapse with the parallel fibers. The axons of the Purkinje cells are the only output from the cerebellar cortex and they inhibit the deep cerebellar nuclei (see below) and the lateral vestibular nuclei of the brain stem (see Fig. 97.7).

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616

Central Nervous System

Cerebellum

Vestibulo cerebellum

Cerebro cerebellum

Spino cerebellum

Balance

Paravermal

Vermal

Eye movements Axial muscle control

Distal muscle control

Planning and movement of complex motor actions Conscious assessment of movement errors

Gaze

Fig. 97.2 Functional lobes of the cerebellum and their role in motor control. Cerebellar medulla Embedded in the med-

ullary core are four pairs of deep cerebellar nuclei (Fig. 97.1). These nuclei are, from the medial to lateral side, the nucleus fastigii, nucleus

Cerebellar cortex Outer molecular layer

+

BC

+

Parallel fibers

+

+

Purkinje cell layer

PC

Cerebellar afferents Afferents from the inferior olivary nucleus enter the cerebellum as climbing fibers, while all other afferents reach the cerebellum as mossy fibers. Both are excitatory in nature and reach the cerebellum through the cerebellar peduncles. Each climbing fiber synapses with a Purkinje cell after sending collaterals to the deep cerebellar nuclei. The mossy fibers synapse with the granule cells. Through the granule cells and their parallel fibers, each mossy fiber is able to activate a large numberr of Purkinje cells.

+

Granule cell layer

GrC

+

BC

Climbing fiber

Cerebellar medulla

+

DCN

GoC

-

Mossy fiber

+

+ +

+

+ +

PC

GrC

-

GoC

-

+

GrC

GrC

GoC

Feed-forward inhibition of Purkinje cell

Feed-forward inhibition of granule cell

Feedback inhibition of granule cell

Fig. 97.3 (Above) Internal structure of the cerebellum. (Below) Cerebellar circuits that cause neural sharpening.

Sircar_Chapter97_615-621.indd 616

globosus, nucleus emboliformis, and nucleus dentatus (which is the largest in primates including man). In lower mammals such as the cat, the nucleus globosus and nucleus emboliformis are fused together into a single nucleus called the nucleus interpositus. The vermal area of the cerebellar cortex projects to the nucleus fastigii, the paravermal area projects to the nucleus interpositus, and the lateral area projects to the nucleus dentatus.

Cerebellar efferents originate entirely from the deep cerebellar nuclei. These efferents are discussed below with the cerebellar lobes that project to these nuclei.

Cerebellar functions The sensory inputs into the cerebellum through climbing and mossy fibers maintain the deep cerebellar nuclei in a continuously excitatory state. The

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Cerebellum deep cerebellar nuclei, in turn, maintain a tonic excitatory output which decreases when there is discharge of the inhibitory Purkinje cells of the cerebellar cortex. At least three intracerebellar circuits (Fig. 97.3) ensure what may be called neural sharpening so that the action potentials of the granule cells and Purkinje cells are accurately timed and the bursts are short-lasting, as explained below. (1) When the granule cell discharges, it excites the Purkinje cell directly. However, shortly after the excitation, the granule cell inhibits the Purkinje cell through the basket cell. This is known as feed-forward inhibition of the Purkinje cell. (2) The mossy fiber stimulates the granule cell. However, shortly after the excitation, the mossy fiber inhibits the granule cell through the Golgi cell. This is known as the feedforward inhibition of the granule cell. (3) The duration of excitation of the granule cell through the mossy fiber is further reduced because the discharge of the granule cells brings about its own inhibition through the Golgi cells. This is known as the feedback inhibition of the granule cell. The precise timing of cerebellar neurons is important for the following cerebellar functions.

617

Learning Adaptive motor learning such as the ad-

aptation of the vestibuloocular reflex (p 777) occurs due to synaptic plasticity at the parallel fiberPurkinje cell synapse.

Vestibulocerebellum The nodulus of the vestibulocerebellum is reciprocally connected to the vestibular nuclei which convey postural information from the vestibular apparatus. The flocculus of the vestibulocerebellum is reciprocally connected to the vestibuloocular relay cells in the midbrain reticular formation which convey optokinetic and visual information (Fig. 97.4). Through these connections with vestibuloocular relay cells, the flocculus is involved in long-term adaptation of compensatory eye movements (as occurs on wearing prisms, see p 735), in the generation of smooth pursuit movements of the eye, and in the suppression of the vestibuloocular reflex during smooth pursuit (see Chapter 117).

Coordination Movements at different joints are

coordinated by the long parallel fibers that interconnect the corresponding “joint areas” on the somatotopic maps of the cerebellar cortex. The relative movements at different joints are controlled by the relative strength of the synapses with Purkinje cells at different sites on the parallel fibers.

Lateral gaze center (in RF)

Vestibular apparatus

Timing and comparison The cerebellum is be-

lieved to be a timing device that times the duration of agonist muscle activity and latency of antagonist activity, so as to halt any movement at the correct point. The theory explains dysmetria (errors in the range and force of movements) as an inability to stop a movement at the correct point. According to the timing theory, the cerebral cortex initiates limb movement by stimulating the agonist muscles and the cerebellum stops the movement at the correct point by inhibiting the agonists and stimulating the antagonists. The cortex signals the desired endposition of the limb by producing a distinctive pattern of stimulation of the cerebellar cortex through the mossy fibers. The actual position of the limb at any instant is signaled through the climbing fibers to the Purkinje cells. The movement stops when the Purkinje cell receives identical signals from the mossy fibers (via the parallel fibers) and the climbing fibers.

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Convergence center (in RF)

Vestibulocerebellum Vestibular nucleus

Fig. 97.4 Connections of the vestibulocerebellum. The reticular formation (RF) relays visual and optokinetic information to the flocculus. The vestibular nuclei are the main source of mossy fiber afferents for the nodulus. The vestibular projection to the flocculus is a relatively minor one and is not shown here. See also Figs. 116.2 and 119.6.

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618

Central Nervous System

Spinocerebellum Somatotopy The spinocerebellum has two soma-

totopic maps, one in the anterior lobe and the other in the posterior lobe (Fig. 97.5). The maps are both motor and sensory in nature, that is, stimulation of the cerebellar cortex at any part of the map results in movements of the corresponding parts of the body, and stimulation of any part of the body triggers electrical activity in the corresponding part of the map. Visual and auditory information reach the areas that represent the head. Afferents Exteroceptive and proprioceptive afferents from the trunk and lower limbs reach the ipsilateral spinocerebellum after relaying in the Clarke column (nucleus dorsalis) located in the dorsal horn of the spinal gray matter (T1 to L2). Axons of the Clarks column form the dorsal spinocerebellar tract (Fig. 97.6). The same sensations from the upper limbs and upper part of the body reach the ipsilateral spinocerebellum after relaying in the accessory cuneate nucleus. Axons of the accessory cuneate nucleus form the cuneocerebellar tract (posterior external arcuate fiber). The ventral spinocerebellar tract originates in the central pattern generator in the spinal cord. The pattern generator activates the lower motor neurons for locomotion. It also sends an “efference copy” of the locomotor program to the cerebellum which compares the “actual” and the “intended” locomotion. Other spinal tracts carrying sensory information to the ipsilateral cerebellum are the spinoolivocerebellar and spinoreticulocerebellar tracts. Efferents The vermal part of the spinocerebellar

cortex projects to the fastigial nucleus (Fig. 97.7),

Pr

yf i m ar

Fig. 97.5 Somatotopy in spinocerebellum.

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iss

ur

e

Cuneocerebellar tract Dorsal spinocerebellar tract Accessory cuneate nucleus Dorsal column

Lateral reticular nucleus Accessory olivary nucleus Spinoreticulocerebellar tract Spinoolivo cerebellar tract

Sensory afferents from above T1

Sensory afferents from T1-L2

Clarke column (T1-L2)

Fig. 97.6 Spinal tracts ascending to the spinocerebellum include the spinocerebellar and cuneocerebellar tracts, the spinoolivocerebellar tract, and spinoreticuloolivary tract.

while its paravermal part projects to the interpositus nucleus (Fig. 97.8). The B zone (vermal part of the anterior lobe of the cerebellar cortex) also has a direct projection to the ipsilateral Deiters nucleus (lateral vestibular nucleus). The fastigial nucleus projects bilaterally to all the vestibular nuclei (except Dieter nucleus) and the descending facilitatory reticular formation. The fastigial projection to the facilitatory reticular formation is excitatory in nature and therefore tends to increase the γ-motor discharge to the muscles (p 678). On the contrary, the B zone projections to the fastigial nucleus as well as to Deiters nucleus, are inhibitory. Hence, the net output of the spinocerebellum to the spinal motor neurons depends on the balance between (1) the inhibitory output of the cerebellar cortex and (2) the excitatory output of the fastigial nucleus. In subprimates, the net output is inhibitory and therefore cerebellectomy causes hypertonia

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Cerebellum

Descending reticular formation (facilitatory)

619

Before In subprimates After cerebellectomy cerebellectomy

Anterior lobe (B zone) F

F

Dieter's nucleus

Spinocerebellum (vermal part) α-motor neuron

α

γ

α

Hypertonia (α rigidity)

Normal muscle tone Before cerebellectomy

γ-motor neuron

Fig. 97.7 Connections of the vermal part of the spinocerebellum. The magnocellular part and the rubrospinal tract issuing from it are prominent in cat, a commonly used animal for cerebellar research, but are poorly developed in man.

(Fig. 97.8). In primates, the inhibitory output of the cerebellar cortex is weak and the net output is excitatory and therefore cerebellectomy causes hypotonia. The same is true for humans. However, even in primates, the selective inactivation of only the B zone (by cooling) results in hypertonia. The role of cerebellum in the control of muscle tone is discussed again in Chapter 104. The interpositus nucleus of the cerebellum projects ipsilaterally to the spinal cord through the interstitiorubrospinal tract (Fig. 97.9). In humans, the rubrospinal tract contains very few fibers. They intermix with the fibers of the lateral corticospinal tract and terminate on the spinal α-motor neurons. The interpositus nucleus is essential for the conditioned eye blink reflex (p 737). This conditioned reflex is abolished by a lesion of the interpositus nucleus.

Cerebrocerebellum The cerebrocerebellum (also called pontocerebellum) has no direct connection with the spinal cord as it is concerned with motor programming and not motor execution. The principal afferents to the cerebrocerebellum are the corticopontocerebellar and olivocerebellar tracts. The cerebrocerebellum projects mostly to the dentate nucleus (Fig. 97.10), which in turn sends efferents back to the cortex via thalamus (dentatothalamocortical) and to the

Sircar_Chapter97_615-621.indd 619

In primates

After cerebellectomy

F

α

γ

α

Normal muscle tone

Hypotonia

B zone Cooling of the anterior lobe

F

α

γ

Hypertonia

Fig. 97.8 Experiments with the cerebellum. Cerebellectomy causes hypertonia in subprimates but hypotonia in primates. However, selective inactivation (by cooling) of the B zone of the anterior lobe vermis always results in hypertonia.

inferior olivary complex via the red nucleus (dentatorubroolivary). The dentatothalamocortical fibers relay in the ventrolateral nucleus (VLc) of the thalamus. The dentatorubroolivary fibers relay in the rostral parvocellular part of the red nucleus. It seems that the dentato-rubro-olivo-cerebello-dentate loop is meant for subconscious rehearsal of a

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Central Nervous System

Cerebral cortex

stitio Inter l r b u r a al ospin Rubr

I

Spinocerebellum (paravermal part)

Cort

Red nucleus magnocellular caudal part

inal i c o sp

Fig. 97.9 Connections of the paravermal part of the spinocerebellum. Note that the interstitiorubral fibers cross the midline to the magnocellular (made of large cells) caudal part of the red nucleus. Fibers from the magnocellular red nucleus cross the midline again before descending to the spinal cord.

ballistic movement (p 688) before its actual commencement.

Thalamus ventrolateral nucleus

Cerebral cortex

Corticopontocerebellar Dentatothalamocortical D

Dentatorubroolivary Olivocerebellar

Red nucleus parvocellular rostral part Pontine nuclei Central tegmental tract

Cerebrocerebellum Inferior olivary nucleus

Fig. 97.10 Connections of the cerebrocerebellum.

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An important function of the cerebrocerebellum is to enable simultaneous, well-coordinated motor actions of the limbs. Dysfunction of the cerebrocerebellum results in decomposition of movement (see below). The patient complains of inability to perform movements subconsciously and that every step of a movement has be to thought out. The cerebrocerebellum is also important for adaptive motor learning. Patients with damaged inferior olive do not show adaptive motor learning. Contrary to the general notion that the cerebellum is a purely motor organ, it is now known that the cerebrocerebellum has some purely cognitive functions. The dentate nucleus enables a judgment of time and is important for the sensory processing that is required for performing complex spatial tasks. The cerebrocerebellum has a role in speech too, being involved in verb-generation tasks (p 742).

Cerebellar dysfunctions Cerebellar dysfunctions (Fig. 97.11) usually result from trauma and ischemia. Sometimes, a selective degeneration of the anterior cerebellum (vermis and leg representation area) occurs in chronic alcoholics resulting in cerebellar symptoms only in the lower limbs. The cerebellum is also affected by a number of hereditary disorders that are collectively called hereditary cerebellar ataxias. Unilateral lesions of the cerebellum produce ipsilateral signs. This is due to double crossing of cerebellar circuits. Examples of the double crossing exist in spinocerebellum as well as cerebrocerebellum. In the spinocerebellum, efferents of the interpositus nucleus terminate on the contralateral red nucleus (magnocellular part), which in turn gives rise to descending (rubrospinal) fibers to the contralateral spinal cord (Fig. 97.9). In the cerebrocerebellum, efferents of the dentate nucleus relay in the contralateral thalamus before reaching the contralateral motor cortex. The corticospinal fibers originating from the motor cortex cross back again to the original side (Fig. 97.10). Vestibulocerebellar dysfunction disrupts the abil-

ity to use vestibular information for coordination of movements, resulting in disturbances in balance and equilibrium. It also causes nystagmus (rapid oscillating movements of the eye) due to disruption of the vestibuloocular reflex. Spinocerebellar dysfunction produces hypotonia

(decrease in muscle tone) and ataxia (lack of motor coordination). Because of the somatotopic projection of spinocerebellar afferents, vermal lesions affect axial (trunk) musculature and produce ataxia of gait (often called a drunken gait because the

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Cerebellum

621

Cerebellum

Vestibulo cerebellum

Impaired vestibular input

Cerebro cerebellum

Spino cerebellum

Hypotonia

Ataxia

Ataxia of gait

Dysarthria

Ataxia of limb

Imbalance Nystagmus

Dysmetria

Past pointing Adiadokokinesia

Intention tremor

Intensive tremor

Decomposition of movement

Decomposition

Fig. 97.11 Dysfunctions of the longitudinal lobes of the cerebellum.

patient walks like a drunkard with an unsteady balance and a wide stance), while paravermal lesions cause ataxia of limbs, leading to intention tremor and decomposition of movements (see below). As vermal lesions affect facial musculature too, they also cause dysarthria (defect in speech articulation), leading to slurring and slowing of speech. Patients tend to exhibit a speech rhythm called scanning speech in which successive syllables emerge slowly. Cerebrocerebellar dysfunction (Fig. 97.11) results in (1) defective motor programming, (2) delays in initiation and termination of movements, and (3) dysmetria, that is, errors in the range and force of movements. These basic defects result in the clinical signs discussed below. The intention tremor and decomposition of movement are also seen in spinocerebellar disorders.

Overshoot or past-pointing is a failure to stop a movement at the appropriate time. Dysdiadokokinesia is the inability to perform rhythmic, rapidly alternating movements such as pronation and supination. Intention tremor is a coarse tremor (oscillations with low frequency and high amplitude) of the hand that occurs during reaching movement and which increases as a target is approached. The tremor probably results from repeated overshoots and their corrections. The tremor does not occur at rest, which distinguishes it from the fine tremors (oscillations with high frequency and low amplitude) of Parkinson disease that occur at rest. Decomposition of movement is observed in a motor task that involves simultaneous movements at multiple joints. The movement is performed awkwardly, with the movements at the different joints performed sequentially rather than simultaneously.

REVISION QUESTIONS 1. What are climbing fibers and mossy fibers and how are they different? 2. The parallel fibers interconnect the corresponding “joint areas” on the somatotopic maps of the cerebellar cortex. What could be its physiological significance? 3. The function of which part or neural circuit of the cerebellum relates to (a) long-term adaptation of compensatory eye movements, (b) generation of smooth pursuit movements of the

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eye, (c) suppression of the vestibuloocular reflex during smooth pursuit eye movements, (d) control of muscle tone, (e) conditioning of the eye blink reflex, (f) ballistic movement, (g) adaptive motor learning, (h) judgment of time, (i) complex spatial task, and (j) verb generation tasks? 4. What are the signs and symptoms that result from a dysfunction of (a) vestibulocerebellum, (b) spinocerebellum, and (c) cerebrocerebellum.

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98

Diencephalon

nuclear masses (Fig. 98.1). Rostrally, the lamina splits in a Y-shaped manner to enclose the anterior group of nuclei. A group of midline nuclei intervenes between the ependymal lining of the third ventricle and the medial nucleus. Another thin sheet of white matter, the external medullary lamina, covers the lateral surface of the thalamus.

The diencephalon (interbrain) has five parts, viz., dorsal thalamus, epithalamus (the pineal body), metathalamus (medial and lateral geniculate bodies), hypothalamus, and subthalamus (also called ventral thalamus). Functionally, the medial geniculate body belongs to the auditory system, the lateral geniculate body belongs to the visual system, and the subthalamus belongs to the basal ganglia. The pineal body secretes melatonin (N-acetyl-5-

Dorsal thalamic nuclear groups

methoxytryptamine). Melatonin secretion peaks between 2:00 and 6:00 am, and probably serves to control the circadian rhythm of other physiological events. Melatonin secretion is controlled by sympathetic nerves originating from the superior cervical ganglion. The sympathetic fibers to the pineal gland are under the control of the suprachiasmatic nucleus of the hypothalamus which is linked to the day– night cycle through the retinohypothalamic fibers.

The dorsal thalamus contains six groups of nuclear masses, viz., the ventral, medial, lateral, intralaminar, midline, and reticular groups of nuclei. Their functions are discussed below. The ventral group of nuclei is subdivided into the

ventral anterior, ventral lateral, and ventral posterior nuclei. The ventral anterior (VA) nucleus receives input from the basal ganglia-cerebral cortex loop (p 627). The ventral lateral (VL) nucleus receives input from two major sources. Its anterior and medial parts (VLo and VLm) receive afferents from the GPi/SNpr (see Chapter 99) and project to the premotor and supplementary motor cortices (Figs. 99.2 and 100.6). Its posterior part (VLc) receives afferents from the deep cerebellar nuclei

Thalamus The term “thalamus” usually refers to the dorsal thalamus and metathalamus. A vertical sheet of white matter, the internal medullary lamina, divides the thalamus into medial and lateral

Lateral group Pulvinar Lateral Lateral posterior dorsal Reticular nucleus

Ventral group Ventrolateral

Lateral group External medullary lamina

Ventromedial Anterior group Internal medullary lamina

Ventroposterior lateral (VPL)

Medial group

Ventroposterior medial (VPM) External medullary lamina Intralaminar group

Anterior group

Nucleus medialis dorsalis Medial group

Midline nuclei

Fig. 98.1 Schematic representation of the nuclear groups in dorsal thalamus. See also Fig. 95.4D.

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Diencephalon and projects to the primary motor cortex.1 The ventral posterior (VP) nucleus acts as the specific somatosensory relay nucleus of the thalamus. Also called the ventrobasal complex, it is subdivided into the ventral posterolateral (VPL) nucleus which receives the medial and spinal lemnisci, and the ventral posteromedial (VPM) nuclei which receive the trigeminothalamic tract and solitariothalamic tracts. The anterior group of nuclei is a relay station in the

Papez circuit (see Fig. 106.3) and may have a role in attention and memory. The medial group of nuclei includes the mediodor-

sal nucleus, which is a part of the anterior cingulate circuit (p 734) that is important for procedural learning (p 627). The lateral group of nuclei consists of the lateral dorsal nucleus, lateral posterior nucleus, and the pulvinar. All of them receive afferents from the superior colliculus and establish two-way connections with the sensory association cortex. The lateral dorsal nucleus is also well connected with the limbic cortex. The physiological role of the lateral group is not well understood. The pulvinar is particularly large in man compared with other primates. It projects to area 7 of the parietal cortex (see Fig. 103.15) and is important for visual-attention and visually guided movements. The intralaminar nuclei include the centromedian nucleus which is particularly large in man. The intralaminar nuclei receive ascending fibers from the brain stem reticular formation and are relay stations for the spinoreticulothalamic pain fibers. The midline nuclei are the major thalamic target of ascending noradrenergic and serotonergic axons from the locus ceruleus and raphe nuclei, respectively, and a cholinergic input from the midbrain. Their efferents pass mainly to the hippocampus, amygdala, and nucleus accumbens. They appear to be involved in memory and arousal, and may be important in the regulation of seizure activity. The reticular thalamic nucleus forms a thin shell

of nerve cells around the thalamus and intervenes between the external medullary lamina and the posterior limb of the internal capsule. The nucleus does not, as the name might suggest, belong to the reticular activating system. The nucleus contains GABAergic neurons and receive collaterals from both thalamocortical and corticothalamic axons that pass through it (see Fig. 107.6). The reticular 1

623

nucleus has bidirectional connections with the thalamic relay nucleus which is topographically organized. They are important in EEG synchronization (p 709).

Specific and nonspecific nuclei The thalamic nuclei are categorized into the specific and nonspecific nuclei. Specific nuclei are further categorized into the relay nuclei and the association nuclei. The relay nuclei belong to the long ascending pathways to the sensory cortex and include the ventroposterior nucleus and the medial and lateral geniculate bodies. The association nuclei have reciprocal connections with the association areasofthecerebralcortexandincludethelateralgroup of nuclei and part of the medial dorsal nucleus. The nonspecific nuclei do not have direct connections with the cerebral cortex and they include the intralaminar nuclei, midline nuclei, and reticular nucleus of thalamus. Stimulation of specific nuclei produces a sharply localized ipsilateral cerebral response with a short latency, while stimulation of nonspecific nuclei produces a delayed, widespread, and bilateral cerebral response. It was assumed that the nonspecific nuclei provided the background level of cortical preparedness necessary for the processing of information from the specific nuclei. Although the terms specific and nonspecific nuclei are still in use, the distinction between them is becoming blurred as extensive interactions between the two types of nuclei have been found.

Functions of thalamus The broad functions of the thalamus are as follows: (1) The thalamus is a relay station in all sensory pathways, including gustatory and olfactory, that reach the cerebral cortex. It modulates the sensory information that is relayed through it and determines whether or not it reaches conscious awareness. (2) The thalamus is concerned with the conscious interpretation of crude touch, pain, and temperature. The final discrimination of sensory modalities however takes place in the sensory cortex after integrating the information provided by the thalamus. (3) The VA and VL nuclei of the thalamus integrate the motor information from the cerebellum and globus pallidus with the premotor cortex. (4) The pulvinar of the thalamus is important for visualattention and visually guided movements. (5) The reticular nucleus of the thalamus modulates the

The subscripts o and c in VLo and VLc refer to the terms oral (anterior) and caudal (posterior) parts.

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624

Central Nervous System synchronization and desynchronization of the brain waves and influences attention and consciousness. (6) Being a relay station in the Papez circuit, the thalamus has a role in emotions and memory.

Subthalamus

Periventricular zone Lateral zone Medial zone

Thalamic syndrome The thalamic syndrome (of Dejerine–Roussy) occurs due to a lesion of the thalamus, usually after the thalamogeniculate artery is blocked. It results in temporary contralateral hemianesthesia (loss of contralateral cutaneous sensation) with ataxia due to permanent loss of sense of position of the limbs. After a few weeks, the patients may complain of agonizing pain, called the thalamic pain (p 671), on the affected side. The threshold for pain is raised but the reaction to pain is exaggerated. The reason for the overreaction to pain is unknown. Sometimes the patient with eyes closed is unable to locate the position of a limb or may develop an illusion that the limb is lost. This is known as the thalamic phantom limb. Thalamic lesion may be associated with abnormal involuntary movements in the form of choreoathetosis or intention tremor when the projection fibers from the basal ganglia or cerebellum to the VA and VL nuclei of the thalamus are involved.

Hypothalamus The hypothalamus is the highest center of autonomic control and is therefore called the head ganglion of the autonomic nervous system. It regulates autonomic, endocrine, and visceral functions and is central to the maintenance of homeostasis. The basic drives of life, that is, hunger, thirst, and sex, originate in the hypothalamus. The hypothalamus is subdivided into the lateral and medial zones. The most lateral part of the lateral zone is sometimes called the periventricular zone. The nuclear masses of these zones are arranged rostrocaudally into four regions, viz., preoptic, supraoptic, tuberal, and mamillary (Fig. 98.2). (1) The preoptic region is important for the regulation of body temperature. (2) The supraoptic region contains the supraoptic, suprachiasmatic, and paraventricular nuclei. Together, the supraoptic and paraventricular nuclei secrete oxytocin, ADH, CRH, and somatostatin. The suprachiasmatic nucleus regulates circadian rhythms. (3) The tuberal region contains several nuclei. (a) The ventromedial and the lateral hypothalamic nuclei regulate food intake and serve as the centers for satiety and feeding respectively. (b) The arcuate (infundibular) nucleus secretes GnRH, GHRH, TRH, and PIH. (c) The dorsomedial nucleus is involved,

Sircar_Chapter98_622-625.indd 624

Pituitary Posterior perforated substance

Subthalamic nucleus

Lateral nucleus

Supraoptic nucleus

Preoptic nucleus Suprachiasmatic nucleus Paraventricular nucleus Dorsomedial nucleus

Red nucleus Substantia Posterior nigra nucleus Mamillary nucleus

Ventromedial nucleus Arcuate (Infundibular) nucleus

Fig. 98.2 Schematic representation of hypothalamic nuclei. See also Fig. 95.4D.

together with the ventromedial nucleus, in the regulation of complex integrative functions such as growth, feeding, maturation, and reproduction. (d) The posterior hypothalamic nucleus contains groups of large histaminergic neurons that are concerned with stimulating sympathetic activity, regulation of sleep-wakefulness, and activation of thermoregulatory mechanisms. (4) The mamillary region contains the mamillary nuclei which receive the terminations of the fornix and provide origin to the mamillothalamic and mamillotegmental tracts. The mamillothalamic tract is a component of the Papez circuit.

Connections of the hypothalamus The hypothalamus has bidirectional connections with the brain stem, other parts of the diencephalon, and the cerebral cortex. These connections enable the hypothalamus to receive somatosensory, visual, gustatory, and olfactory information, and to influence the autonomic and the limbic systems. Some of the connections are organized into anatomically prominent tracts, while others are not. One of the most prominent tracts associated with the hypothalamus is the medial forebrain bundle, which consists of ascending and descending fibers that run through the lateral hypothalamus to connect the cerebral cortex with the brain stem.

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Diencephalon Connections with brain stem The hypothalamus

receives somatosensory information (including gustatory information) through collaterals of the lemniscal pathways and through the dorsal longitudinal fasciculus which connects the hypothalamus to several cranial nerve nuclei. The mamillary body of the hypothalamus is also connected to the brain stem reticular formation through the mamillotegmental tract and mamillary peduncle. The hypothalamic efferents to the brain stem terminate on preganglionic autonomic neurons present in the cranial nerve nuclei in the brain stem and in the lateral horn of the spinal cord. Descending fibers also reach somatic motor neurons. Connections with other parts of diencephalon The

hypothalamus sends efferents to the anterior nucleus of the thalamus through the mammillothalamic tract which forms a part of the Papez circuit (see Fig. 106.3). It also has reciprocal connections with the medial dorsal nucleus and the midline nuclei of the thalamus. These fibers run beneath the ependymal lining of the third ventricle and form the anatomically distinct periventricular system of fibers. The suprachiasmatic nucleus receives retinohypothalamic fibers that relay in the lateral geniculate bodies of the thalamus. The hypothalamus probably receives auditory afferents too though none has been demonstrated. The hypothalamus has neurovascular links with the posterior pituitary and the infundibulum (see Figs. 82.3 and 82.4). (1) The axons of the supraoptic and paraventricular nuclei of the

625

hypothalamus reach the neurohypophysis to form the hypothalamo-hypophyseal tract. The axons end in dilated terminals called Herring bodies which contain ADH and oxytocin. (2) Axons of the arcuate nuclei of the tuberal region of the hypothalamus reach the median eminence and infundibulum to form the tuberoinfundibular tract. The axon terminals end on the capillary plexuses of the hypothalamo-hypophyseal portal system into which they secrete the hypothalamic releasing or inhibiting hormones. Connections with the limbic cortex Anatomically, the most prominent connection between the limbic system and the hypothalamus is represented by the fornix, which originates from the hippocampus and ends in the mamillary body. The fornix forms a part of the Papez circuit. Other anatomically prominent connections between the limbic system and the hypothalamus are the stria terminalis and the ventral amygdalofugal fibers that arise from different parts of the amygdala and terminate in different areas of the hypothalamus.

Functions of the hypothalamus The functions of the hypothalamus can be summarized as: (1) visceral control through autonomic nervous system and endocrine system, (2) thermoregulation, (3) control of emotions and instinctive behavior such as food intake, water and salt intake, and sexual behavior, and (4) control of sleepwakefulness and circadian rhythms.

REVISION QUESTIONS 1. Which part of the diencephalon secretes melatonin? How is melatonin secretion controlled? 2. Which nuclear group/subgroup of the thalamus acts as a relay station (a) in the Papez circuit, (b) for spinoreticular pain fibers, (c) in the anterior cingulate circuit, and (d) in the spinoreticular sensory pathway? 3. Which part of the thalamus (a) is important for visual attention and visually guided movements, (b) influences attention and consciousness, (c) has a role in emotions and memory, (d) integrates the motor information from

Sircar_Chapter98_622-625.indd 625

the cerebellum and globus pallidus with the premotor cortex, and (e) modulates sensory information and determines whether it reaches conscious awareness? 4. What is (a) thalamic pain and (b) thalamic phantom limb? 5. Which region of the hypothalamus controls (a) body temperature, (b) sleep-wakefulness and circadian rhythm, (c) feeding and satiety, (d) blood volume and osmolarity, and (e) secretion of gonadotropins, GH, TH, and prolactin?

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99

Basal Ganglia

Basal ganglia is the name given to the subcortical masses of gray matter situated in the white core of each cerebral hemisphere. It is divided by the fibers of the internal capsule into a medial part called the caudate nucleus and a lateral part called the lentiform nucleus. The heads of the caudate nucleus and lentiform nucleus are connected anteriorly by a band of gray matter. The entire nuclear mass presents a striated appearance and is called the corpus striatum (Fig. 99.1). The lentiform nucleus is further subdivided by an external medullary lamina into an outer putamen and an inner globus pallidus. The globus pallidus is further separated into an outer segment (GPe) and an inner segment (GPi) by an internal medullary lamina. Structurally as well as functionally, the caudate nucleus and putamen are similar and they are together called the neostriatum or for short, the striatum. The globus pallidus, which provides the chief efferent projection fibers of basal ganglia, is known as the paleostriatum or pallidum for short. The striatum is further subdivided into dorsal and ventral striatum. The dorsal striatum consists of the caudate nucleus and the putamen of lentiform nuclei. The tail of the caudate nucleus comes in superficial contact with the amygdaloid body without any structural and functional connections. The ventral striatum consists of the nucleus accumbens and olfactory tubercle. From the physiological viewpoint, the basal ganglia include the subthalamic nucleus and

Neurotransmitters in the basal ganglia The neurotransmitter secreted by the nigrostriatal pathway is dopamine, which exerts an excitatory effect when it acts through D1 receptors and an inhibitory effect when it acts through D2 receptors. These receptors are present on excitatory cholinergic interneurons in the striatum. In other areas of the basal ganglia, excitatory neurotransmission is through glutamate while inhibitory neurotransmission is mostly through GABA. The other inhibitory neurotransmitters involved are enkephalins and substance P.

Circuits of basal ganglia

Caudate nucleus Neostriatum Putamen Corpus callosum

VA/VL CM

Third ventricle Thalamus Subthalamus

GPe GPi Globus pallidus (Paleostriatum)

SNpr SNpc Substantia nigra

Fig. 99.1 Anatomy of the basal ganglia

Sircar_Chapter99_626-631.indd 626

substantia nigra too. The subthalamic nucleus lies lateral to the hypothalamus. The substantia nigra (SN) is a sheet of pigmented nerve cells in the midbrain located between its crura and tegmentum. It consists of the pars reticularis in front and the pars compacta behind. The pars compacta (SNpc) contains mostly dopaminergic neurons that form the mesolimbic dopamine system (p 654). About a quarter of the pars compacta neurons are cholinergic. The pars reticularis (SNpr) contains large multipolar GABAergic neurons. The globus pallidus internus (GPi) and the substantia nigra pars reticulata (SNpr) behave as the lateral and medial parts of a single functional entity (GPi/SNpr). Similarly, the globus pallidus externus (GPe) and the substantia nigra pars compacta (SNpc) together constitute another functional entity (GPe/SNpc).

The corpus striatum does not have any direct connection with the spinal cord as it is concerned with motor planning and programming and not with motor execution. Its connections are best understood in terms of neural circuits that originate and terminate in the cortex after looping through the striatum, GPi/SNpr , and the thalamus. These circuits originate from different areas of the cortex, relay in different areas of the striatum (putamen, caudate nucleus, and ventral striatum), pallidum (GPi/SNpr, GPe/SNpc), and thalamus (VA, VL, and centromedian nuclei) before returning to the same area of the cortex they originated from. These circuits are more or less independent with very little interaction between them.

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Basal Ganglia

627

Skeletomotor circuit

Cortical origin Depending on the area of corti-

cal origin, five neural circuits have been named. (1) The skeletomotor circuit originates from the precentral and postcentral areas of the cerebral cortex. It is discussed in detail below. (2) The oculomotor circuit originates in the frontal eye fields. It is important for the control of saccadic movements (p 779). Inactivation of the loop results in involuntary saccades to the contralateral side. (3) The dorsolateral prefrontal circuits originate from areas 9 and 10 of the cerebral cortex. These circuits are involved in motor planning that is required for appropriate behavioral responses to cognitive tasks. Damage to these circuits produces cognitive disorders. (4) The lateral orbitofrontal circuits play an important role in mediating socially appropriate responses. Damage to these circuits underlies obsessive-compulsive disorder (p 703). (5) The anterior cingulate circuits are important for procedural learning (p 734). Damage to this circuit underlies akinetic mutism (p 704).

The skeletomotor circuit originates from the precentral (premotor, supplementary motor, and primary motor) and postcentral (somatosensory 3a, 1, 2, and 5) areas. As already mentioned, this circuit loops through the putamen of the striatum, the GP/SN, and the VA and VL nuclei of the thalamus. There are two striatothalamic pathways from the striatum to the thalamus via GP/SN. The direct striatopallidal pathway has only one relay station, that is, in the GPi/SNpr. The indirect striatothalamic pathway has three relay stations, viz., GPe/SNpc, subthalamic nucleus, and GPi/SNpr (Fig. 99.3). The direct pathway has two inhibitory neurons; one running from striatum to the GPi/SNpr and the other, from GPi/SNpr to thalamus. Thus, the striatum disinhibits the thalamus, and the overall effect of the entire circuit is excitatory. The indirect pathway has four inhibitory neurons, three of which are inhibitory; one from the striatum to GPe/SNpc, another from GPe/SNpc to subthalamic nucleus (STN), and the third from GPi/SNpr to thalamus. Thus the striatum disinhibits the STN. The STN in its turn stimulates GPi/ SNpr which then increases its inhibitory output to the thalamus. The overall effect of the circuit is therefore inhibitory. It seems that the indirect pathway assists in braking voluntary movements while the direct pathway simultaneously facilitates the movement. Hence, in conjunction, the two pathways are able to bring about the required degree of scaling of movements. It could also result in focusing, that is, allowing only the voluntary movement to occur while preventing any change in the background posture. A third component of intricacy of the basal ganglia circuitry is introduced by the SNpc which is inhibited by the striatum through the striatonigral

Striatal and thalamic relays The

skeletomotor and oculomotor circuits loop through the putamen and are therefore called the putamen loops. The putamen loops have a role in the scaling of the intensity of movements. The other three circuits that originate from the association areas of the cortex loop through the caudate nucleus and are therefore called the caudate loops. The caudate loops help in effecting a smooth transition of one motor program to another. Both the loops pass through GPi/SNpr and thalamus (Fig. 99.2). However, they loop through different parts of GPi/SNpr (caudal vs. rostral parts) and of the thalamus (ventrolateral vs. ventroanterior nuclei).

Putamen loop

Caudate loop

Motor and sensory areas

Cortex

Frontal association area

Putamen

Striatum

Caudate

GPi Caudal Part

SNpr Caudal Part

VLo Ventrolateral Nuc. (Pars oralis)

VLm Ventrolateral Nuc. (Pars Medialis)

Pallidum and substantia nigra

Thalamus

GPi Rostral Part

SNpr Rostral Part

VApc Ventroanterior Nuc. (Parvocellular)

VAmc Ventroanterior Nuc. (Magnocellular)

Fig. 99.2 The caudate and putamen loops.

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Central Nervous System

Cerebral cortex

_ _ _

ACh

ACh

GABA

Dopamine

pathway

Indirect

D2

_ _ _

Direct

+ + +

D1 Striatum

+ pathway

+ + +

Dopamine

628

Cerebral cortex ACh D1

_ _

GPe SNpc

D2 GABA

GPe

SNpc

+ +

Indirect

Subthalamic nucleus

Subthalamic Nucleus

pathway

Direct

pathway

_ _ GABA

ACh

pathway

Indirect

Striatum

Glutamate

SNpr GPi

GPi

Thalamus

+ + + Thalamus

Fig. 99.3 The skeletomotor loop of the basal ganglia. (Red) Excitation. (Blue) Inhibition.

pathway. The SNpc in turn exerts both a facilitatory as well as an inhibitory effect on the cholinergic neurons in the striatum. Through these cholinergic neurons, a facilitatory effect is exerted on the direct pathway to the GPi/SNpr, while an inhibitory effect is exerted on the indirect pathway to the GPi/SNpr.

Disorders of basal ganglia Dysfunction of the basal ganglia result in both hyperkinetic and hypokinetic features. Hyperkinetic abnormalities occur in choreoathetosis and hemiballismus. Parkinson disease is characterized by both hyperkinetic (rigidity and tremor) and hypokinetic features.

Parkinson disease (paralysis agitans) Although dopamine and dopamine receptors decrease normally with age, in Parkinson disease

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SNpr

Damaged in Parkinsonism

Fig. 99.4 Parkinson disease. (Above left) Normal substantia nigra in a brain section. (Above right) Substantia nigra in Parkinson disease. (Below) Consequences of damage to the nigrostriatal pathway.

aging is associated with an accelerated loss of dopamine and dopamine receptors. Degenerative changes are observed in the substantia nigra with marked reduction of dopamine in the striatum and substantia nigra. In the absence of dopamine, there is a decrease in the excitatory output from the direct striatothalamic circuit while there is an increase in the net inhibitory output from the indirect striatothalamic circuit via the subthalamic nucleus (Fig. 99.4). Either way, there is an increased inhibitory output from the globus pallidus internus which explains why pallidectomy is effective in the treatment of Parkinsonism. The term Parkinsonism refers to conditions that result in symptoms similar to those in Parkinson disease. These include certain viral infections and treatment with drugs such as phenothiazines, which block dopamine D2 receptors. Experimental Parkinsonism can be produced by the drug MPTP (methylphenyltetrahydro-pyridine).

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reduced facial expression and hand gestures during speech or absence of arm swinging during walking. As a result, the patient has a masked face appearance with no emotional response.

Fig. 99.5 Typical posture of a patient with Parkinson disease while walking.

Hypokinesia Dysfunction of the putamen loop

hampers the smooth transition from one motor program to another. It results in akinesia, bradykinesia, hypokinesia, inability to execute simultaneous actions, and defective kinetic automatism. The patient has a characteristic festinating gait (festinate = hurry). He bends slightly forward and walks with short, quick steps as if to catch up with his own center of gravity to prevent himself from falling (Fig. 99.5). He experiences difficulty in taking initial steps and in stopping. (1) Akinesia is difficulty in initiating movements and a decrease in spontaneous movements. The delayed motor initiative becomes evident from the prolongation of visual or auditory response time. For example, if a subject is asked to press a button as soon as a bulb is lighted, the usual time lag is less than 0.5 seconds. This response time is prolonged in Parkinson disease. (2) Bradykinesia means slow performance of voluntary movement. (3) Hypokinesia means difficulty in reaching a target with a single continuous movement: the movement must stop and resume a few times before completing itself. (4) Inability to execute simultaneous actions is apparent when the patient, for example, can salute when seated but not when walking. (5) Inability to execute sequential actions is apparent when the patient becomes stuck in the middle of an otherwise automatic motor action, and after performing one motor act, he finds it difficult to initiate the next motor act. (6) Defective kinetic automatism is the loss of associated movements such as

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Rigidity occurs due to increased muscle tone of both agonist and antagonist muscles. During passive flexion or extension of a limb, the muscular resistance increases and decreases alternately as if it is overcoming a series of catches (cog-wheel rigidity). Sometimes, there may be a more uniform resistance to passive flexion (lead pipe rigidity). The cause of rigidity remains a subject of debate. One of the theories suggests that it results from withdrawal of facilitation of inverse-stretch (Golgi tendon) reflex. In Parkinson disease, the increased inhibitory output from the globus pallidus internus reduces the descending facilitatory influences on the inhibitory interneuron in the Golgi tendon reflex pathway (Fig. 99.6). As the Golgi tendon reflex is inhibitory to muscle tone, reduction of supraspinal facilitatory inputs to the reflex increases the muscle tone. The resulting rigidity is different from the spasticity that results from excessive facilitation of the stretch reflex. Tremor at rest is a prominent sign in Parkinson disease. The frequency of tremors ranges from 3 to 6 Hz and they are described as fine tremors to distinguish them from cerebellar tremors. The tremor activity is usually suppressed during voluntary movements and sleep and is exaggerated by stress and anxiety. The tremors often take the form of pin-rolling movement of the hand. The tremor seems to occur due to a pacemaker activity in the nucleus ventralis intermedius of the thalamus. Thalamic neurons have an intrinsic autorhythmicity and it is possible that this automaticity is unmasked by the increase in

Globus pallidus internus

Midbrain and pontine reticular rormation

Medullary reticular formation gigantocellular nuclei Ib afferent from Golgi tendon organ

Normal

Parkinson disease

Fig. 99.6 Mechanism of Parkinsonian rigidity.

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Central Nervous System the inhibitory input from the globus pallidus. The unmasked thalamic pacemaker activity induces oscillations in the long-loop reflex pathways originating from muscle spindle, resulting in tremors. Treatment Parkinsonism is treated by administration of L-dopa. Direct administration of dopamine is useless since it does not cross the blood brain barrier. Anticholinergic drugs too are effective. Surgical destruction of the globus pallidus (pallidectomy) or the subthalamus is effective in patients poorly controlled by medication. Improvement has also occurred following surgical implantation of dopaminergic cells from the patient’s own adrenal medulla or carotid body or better still, from fetal striatal tissue.

Choreoathetosis Chorea is characterized by brisk, jerky, and purposeless movements of the distal parts of the extremities, and is usually associated with twitching of the face. A slower version of chorea is athetosis which is characterized by slow, worm-like writhing movements of the extremities, affecting chiefly the fingers and the wrists. Choreoathetosis is associated with the degeneration of the indirect striatothalamic pathway via the subthalamic nucleus (Fig. 99.7). As the overall effect of this pathway is inhibitory, damage to this pathway results in hyperkinesia. Athetosis frequently occurs following damage to putamen due to birth injury while chorea is mostly due to damage to the caudate nucleus. Examples of chorea that are genetically inherited are Huntington chorea and Wilson disease.

Huntington chorea is associated with degeneration of caudate nucleus (most affected), putamen (moderately affected), and globus pallidus (least affected). It is associated with increased glutamate neurosecretion that results in glutamate excitotoxicity. Wilson disease (earlier called hepatolenticular disease) is the widespread manifestation of copper toxicity which occurs due to impaired biliary excretion of dietary copper. The toxic effects are most pronounced in the liver and the brain. In the brain, the lesions are widespread but most marked in the putamen and to a lesser degree, in the globus pallidus and caudate nucleus. Wilson disease is characteristically associated with low plasma levels of ceruloplasmin. This is because the increase in copper in liver cells inhibits the binding of copper to apoceruloplasmin; the two must be in an optimum proportion for the hepatic synthesis of ceruloplasmin. Quite a few immunological disorders are associated with chorea. Of these, the best known is Sydenham chorea which occurs following streptococcal infection: antibodies to β-hemolytic streptococci cross-react with neurons of the corpus striatum and damage them.

Hemiballismus Hemiballismus is a rare disease caused by degeneration of subthalamic nucleus. Damage to the subthalamus reduces the inhibitory output from the GPi/SNpr, resulting in the contralateral disinhibition of the thalamic output (Fig. 99.8). The condition is characterized by wild, flail-like movements of the contralateral arm.

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Fig. 99.7 Site of neuronal damage in chorea.

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Fig. 99.8 Site of neuronal damage in hemiballismus.

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REVISION QUESTIONS 1. The corpus striatum has no connections with the spinal cord and yet, it controls motor functions. How? 2. Which are the five neural circuits that originate and terminate in the cerebral cortex after looping though the striatum, pallidum, and thalamus? What are their functions? Which of these circuits loops through (1) the putamen and (2) the caudate nucleus? 3. Built into the skeletomotor circuit are two striato-thalamic pathways—one direct and another indirect. What is their functional significance? 4. Why is pallidectomy effective in the treatment of Parkinsonism? 5. What is the difference between Parkinsonism and Parkinson disease? 6. Dysfunction of the putamen loop hampers the smooth transition from one motor program to

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another, causing motor defects. What are the defects? 7. How is Parkinsonian rigidity different from spasticity? What is the probable cause of this difference? 8. What is the probable cause of Parkinsonian tremor? 9. Parkinson disease is treated by administration of L-DOPA and anticholinergic drugs. What is their mode of action? 10. A lesion in which part of the basal ganglia is associated with (1) choreoathetosis, (2) Huntington chorea, and (3) Wilson disease? 11. Wilson disease is characteristically associated with low plasma levels of ceruloplasmin. Why? 12. Which type of motor disorder is know to occur following streptococcal infection? Why does it occur?

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Cerebral Cortex

The cerebral cortex is a layer of gray matter, less than 4-mm thick, present on the surface of the cerebral hemispheres. It is thrown into folds which increase its surface area many times. The surface elevations created by these folds are called gyri and the grooves separating them are called sulci (Fig. 100.1). Cortical cells Although there are several types of cells in the cortex, most of them are either pyramidal cells or granule (stellate) cells. Pyramidal cells are so named because they have a pyramidal-shaped cell body. They are projection cells (Golgi type I) that leave the cortex. Granule cells are interneurons (Golgi type II cells) that are confined to the cortex. Pyramidal and granule cells mostly contain excitatory neurotransmitters such as glutamate and aspartate. The rest contain the inhibitory neurotransmitter GABA. Cortical areas Phylogenetically, the cortex is

subdivided into two parts; the allocortex (old cortex) which forms about 10% of the entire cortex, and the neocortex which comprises the remaining 90%. As most of the allocortex is located around the peripheral margin of the diencephalon, it is also called the limbic cortex (limbus: periphery).

Cytoarchitecturally, six laminae are discernible in the cerebral cortex. These laminae are numbered I to VI from the outside in, as shown in Fig. 100.2. Lamina I contains a dense network of dendrites of pyramidal cells and the axons of the granule cells. Lamina II contains mainly granule cells and some small pyramidal cells. Lamina III contains predominantly medium-sized pyramidal cells. Lamina IV contains predominantly granule cells. Lamina V contains predominantly large-sized pyramidal cells. Lamina VI contains all types of cells. Based on the variations in the laminar structure, the cortex is called granular or agranular. The granular cortex, which is present characteristically in the somesthetic areas, contains numerous granular cells but few pyramidal cells. The agranular cortex, which is characteristically present in the motor cortex, contains numerous and some of the largest pyramidal cells but has few granular cells. Cortical areas are also divided into several Brodmann areas (Fig. 100.3) based on a more detailed histology. The Brodmann areas do not reflect much functional difference as was previously assumed but still retain their usefulness as a convenient grid for referring to different cortical areas. Functionally, the cortex is divided into the motor and sensory areas. The sensory areas are more

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Fig. 100.1 Sulci and gyri on the medial surface of the left cerebral hemisphere (left) and the superolateral surface of the right cerebral hemisphere (right). Compare with Figs. 95.1 and 95.3.

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Cerebral Cortex extensive than the motor areas, and are further subdivided into the unimodal areas (visual, auditory, olfactory, and vestibular) and the multimodal (polysensory) association areas. There are three polysensory association areas, namely, (1) the posterior (parietooccipitotemporal) association area, (2) the anterior (prefrontal) association area, and (3) the limbic association area (Fig. 100.4). These areas are discussed below in detail.

I. Plexiform lamina II. External granular lamina III. Pyramidal lamina IV. Internal granular lamina

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Fig. 100.2 Cerebral laminae and the predominant cells present in them.

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gray matter lies the white matter which is made of fibers that originate or terminate in the cortex. Projection fibers that descend from the cerebral cortex originate in the pyramidal cells of lamina V. They include the corticostriate, corticobulbar, and corticospinal fibers. The cerebral cortex is also the terminal for the thalamocortical fibers. These long ascending and descending projection fibers squeeze through the gap between the thalamus and the basal ganglia, forming a compact band of nerve fibers called the internal capsule (see Fig. 95.5). Any damage to the internal capsule,

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Fig. 100.3 Brodmann areas on the medial surface of the left cerebral hemisphere (above) and the superolateral surface of the right cerebral hemisphere (below).

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Dorsal LPA

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Auditory area

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Fig. 100.4 Functional areas on the medial surface of the left cerebral hemisphere (above) and the superolateral surface of the right cerebral hemisphere (below).

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Central Nervous System as occurs when the striate artery (see Fig. 95.7) bleeds into it, is associated with contralateral hemiplegia and hemianesthesia. Pyramidal cells of laminae II and III give rise to association fibers (axons interconnecting different cortical areas of the same hemisphere) and commissural fibers (fibers interconnecting the two hemispheres). Prominent examples of association fibers are the neurons connecting Wernicke area with Broca area or those connecting the visual cortex with the frontal eye field. The major commissural pathway is the corpus callosum, the function of which is discussed on p 733 (see Fig. 111.3). Third-order sensory afferents from specific thalamic nuclei terminate mostly in lamina IV, while sensory afferents from nonspecific thalamic nuclei terminate mostly in lamina I. Sensory afferents from specific thalamic nuclei do not synapse directly with pyramidal cells since there are not many pyramidal cells in lamina IV.

Sex differences Anatomically, men have larger brains with more neurons than women of comparable body size. Sex differences in cerebral functions are observed in motor skill, spatial analysis, mathematical aptitude, perception, and verbal abilities. In general, (1) women are more fluent in language, whereas men tend to perform better in spatial analysis. (2) In mathematics, women are better in computations, while men are better in mathematical reasoning. (3) Women are better in perception of faces and body postures, while men are better in perception of mechanical devices and geometrical designs. (4) Women have better spatial memory, for example, of landmarks along a route, while men are better in spatial analysis as required for navigational tasks or mental rotation. (5) Women show better fine motor control in delicate tasks, while men perform better in throwing objects at targets or in intercepting flying objects.

Motor areas Interhemispheric differences In most individuals, the left hemisphere is specialized for generating complex voluntary movements. Hence, most individuals are right handed and the left hemisphere, which controls the right hand, has been called the dominant hemisphere. The term dominant hemisphere was later abandoned when it was realized that both the hemispheres showed certain specialization. It is now understood that in most right-handed individuals, the left hemisphere is specialized for visual processing of written language, auditory processing of spoken language, and languagerelated motor functions such as speech, reading, and writing. Generally, therefore, it is specialized for sequential-analytical processing and is called the categorical hemisphere. On the contrary, the right hemisphere is specialized for processing of complex geometrical patterns and of faces, auditory processing of music and the tactile recognition of complex spatial patterns, and mental rotation of complex shapes. Thus, the right hemisphere is specialized for visuospatial processing and is called the representational hemisphere. To put it pithily, the categorical hemisphere does arithmetic better, while the representational hemisphere does geometry better. The difference shows up anatomically too. Thus, the planum temporale (a part of Wernicke area, p 637), which is involved in language-related auditory processing, is larger on the left side (Fig. 100.5).

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The motor areas of the cerebrum comprise the primary motor area and the non primary motor areas that are also called Ms-I and Ms-II, respectively, indicating that although these areas are primarily motor areas, they have sensory functions too. Most of these motor areas are anterior to the central sulcus and are called precentral areas. All motor areas, whether primary or nonprimary, have an agranular cortex (i.e., the lamina IV is either deficient or absent). They give rise to the pyramidal (corticospinal) neurons which terminate in the brain stem and spinal cord.

Primary motor area The primary motor area occupies most of area 4. It includes the precentral gyrus on the superolateral surface and the anterior part of paracentral lobule on the medial surface of the hemisphere. The primary motor area receives somatotopically organized inputs directly from the primary somatosensory area (Fig. 100.6). It also receives some somatosensory neurons relayed through the VPLo nucleus of the thalamus by spinothalamic afferents. Hence each neuron in the primary motor area has a peripheral receptor field. For the same reason, a sensory stimulus can travel all the way up to the primary motor area and produce muscle contraction reflexly. Such a reflex is called a transcortical reflex, an example of which is the long-loop stretch reflex (p 679). The primary motor area also receives afferents from area 5 in the

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Anterior Secondary auditory cortex Secondary auditory cortex

Primary auditory cortex (Heschl's gyrus)

Primary auditory cortex (Heschl gyrus) Planum temporale

Planum temporale

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Fig. 100.5 The superior view of a horizontal section of the brain through the lateral sulcus, showing interhemispheric differences in the temporal lobe. Note that the planum temporale is larger on the left side. The primary auditory cortex has two gyri on the right side and only one gyrus on the left.

parietal cortex, which is the sensory association area involved in integrating multiple sensory modalities for motor planning, from the nonprimary motor areas (see below) and from the cerebellum. The cerebellar afferents are relayed to the primary motor area through the VLc nucleus of the thalamus.

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Nonprimary motor areas The nonprimary motor areas are located in areas 6 and 8 which are spread over the superolateral as well as the medial surface of the cerebrum. The part located on the superolateral surface is called the lateral premotor area (LPA) which is further

Fig. 100.6 Connections of the different areas of the cerebral cortex.

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Central Nervous System subdivided into the dorsal LPA and the ventral LPA. The part located on the medial surface includes the supplementary motor area (SMA) and presupplementary motor area (preSMA). A nonprimary motor area, in general, not only sends pyramidal neurons to the spinal cord directly but also has corticocortical connections with the region of the primary motor area that sends pyramidal neurons to the same spinal segment. The premotor area receives major input from areas 5 and 7 of the parietal cortex as well as from area 46 of the prefrontal cortex, which is important for working memory. The premotor cortex also receives afferents from the basal ganglia that are relayed through the VLo nucleus of the thalamus. The functions of the subdivisions of the nonprimary areas (see Fig. 105.3) are discussed in the context of motor programming. Electrical stimulation (see Box 100.1) of all parts of the motor area (primary or nonprimary) elicits gross movements of some part of the body. However, the primary motor area has the lowest threshold of electrical stimulation for eliciting gross movements. Centers for movements are represented somatotopically on the lateral surface of the contralateral hemisphere, with the head end below and the leg end up, which is figuratively called the motor homunculus (little man). The extent of the cortical representation of a muscle is related to its precision requirements and not on its size (Fig. 100.7). Centers for control of micturition and defecation are located on the medial surface in the anterior part of the contralateral paracentral lobule. The inverted motor homunculus is evident clinically in extradural hematoma which causes descending paralysis as the blood clot spreads upward over the motor cortex. The paralysis occurs contralaterally, first in the face, then the arm, and finally in the leg. The frontal eye field which regulates the voluntary conjugate movements of the eyes is located in area 8 and is included in the premotor area. Stimulation of this area produces conjugate deviation of the eyes to the opposite side. A supplementary eye

Box 100.1 Galvanic versus Faradic stimulation Artificial stimulation of the cortex producing simple movement does not necessarily give the correct picture of cortical motor control. The physiological stimulus for a motor fiber is a complex pattern of inputs from sensory neurons. It is impossible to replicate this pattern of stimulation through artificial electrical stimulation. This is the reason why the motor output differs with galvanic stimulation and Faradic stimulation of the cortex.

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field is present in the rostral-most area of the SMA. The writing center (of Exner) which coordinates writing movements is located in the upper part of area 6 and is included in the premotor area. The Broca area for speech is located in areas 44 and 45. It is considered an extension of the lower part of area 6 and can be considered to be a part of the premotor area.

Unimodal sensory areas General sensory areas The somesthetic areas occupy most of the parietal lobe of the cerebral cortex. The functions of the various sensory areas are discussed on p 671 in the context of sensory processing and only the functional subdivisions of the somesthetic area are discussed below. The primary somesthetic area (Sm-I) is located in the postcentral gyrus and extends onto the medial surface in the posterior part of the paracentral lobule (Brodmann areas 3, 1, and 2). It has a granular cortex densely packed with stellate cells with a few small- and medium-sized pyramidal cells. It receives afferent projections from posteromedial (VPM) and posterolateral (VPL) parts of the ventral nucleus of the thalamus, which convey exteroceptive and proprioceptive impulses from the contralateral side. The pyramidal cells of the sensory area contribute fibers to the corticospinal and corticobulbar tracts. However, areas 3, 1, and 2 are primarily sensory and secondarily motor in function. Hence, these areas are designated as SmI. Sensations from various parts of the body are somatotopically represented in Sm-I upside down with head below and leg up, and the map is called the sensory homunculus. The sensory area in the paracentral lobule receives the sense of distension from the bladder and rectum. The lower part of the postcentral gyrus acts as the taste receptive center (Fig. 100.7). The secondary (supplementary) somesthetic area (Sm-II) is situated along the upper lip of

the posterior ramus of the lateral sulcus. Most of the sensory inputs are contralateral. The area for the face is represented in front and that for the leg, behind. The most rostral part of this region produces movements when stimulated. Hence this region is designated as Sm-II. The somesthetic association area is located in the

posterior parietal cortex behind the postcentral gyrus in the superior parietal lobule. Unilateral damage to areas 5 and 7 results in contralateral sensory neglect (see Fig. 103.20). Bilateral damage

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Fig. 100.7 (Left) Motor homunculus. (Right) Sensory homunculus.

results in Balint syndrome, that is, the inability to create an internal representation of the external world (amorphosynthesis). There is neglect of everything other than a single object, which is reflected in the paucity of saccadic eye movements.

Special sensory areas Visual areas The primary visual area (visuostri-

ate area or visual area 1) is located in area 17. The visual association areas are located in areas 18 to 20. Area 20 is the inferotemporal cortex (inferior temporal gyrus) which is important for the recognition of faces and facial expressions. It sends a heavy projection to the amygdala, which has an important role in emotions. The projection therefore underlines the importance of facial expressions in emotions. Auditory areas The primary auditory area (auditory area I) is located in the anterior transverse temporal gyrus (Heschl gyrus) which is situated on the floor of the posterior ramus of the lateral sulcus (areas 41, 42, and 52). The auditory association area (auditory area II) is located in area 22 which is also known as Wernicke area and is involved in higher, language-related auditory processing. Damage to Wernicke area, where spoken words are analyzed, produces sensory aphasia.

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Vestibular areas A cortical vestibular area is

present in the primary somatosensory areas 2 and 3. There is another vestibular area in the secondary somesthetic area (Sm-II) and another in parietal association area 7. The gustatory area is located at the border

between the anterior insula and its frontal operculum. This region is rostral to the area where the somatic senses from the tongue are represented. Olfactory areas The cortical areas of olfaction in-

clude the piriform cortex, corticomedial amygdala, olfactory tubercle, and a part of the entorhinal cortex.

Multimodal sensory areas Parietooccipitotemporal association area The parietooccipitotemporal area represents the area of confluence of the parietal (sensory), occipital (visual), and superior temporal (auditory) areas of the cortex. It includes the posterior parietal cortex (area 7), the supramarginal gyrus (area 40), and the angular gyrus (area 39). The extrapersonal space, with all its somesthetic, visual, and auditory cues, is represented in area 7. Thus, a patient with a lesion in area 7 may be able to feel and see objects in his extrapersonal space but is unable to synthesize the cues to

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Central Nervous System generate a holistic and meaningful idea of his extrapersonal space. For the same reason, the patient is unable to perform any purposeful movement directed at objects in his extrapersonal space. Areas 39 and 40 are involved in the higher level of visual processing. The angular gyrus is concerned with language and receives both visual input (reading) and somatosensory input (Braille). Injury to this area produces alexia (inability to read).

Prefrontal association area Prefrontal cortex (areas 9 to 12) is the part of the frontal lobe rostral to the premotor area. It is highly developed in the human brain. It is connected reciprocally with the dorsomedial nucleus of the thalamus, hypothalamus, and limbic system. It receives long association fibers from almost all areas of the cerebral cortex. Several aspects of prefrontal functions are exemplified by the consequences of damage to the area, as in the case of Pheneas Gage (see Fig. 106.2). Broadly, the prefrontal functions may be summarized as follows: (1) The prefrontal cortex is the site of the attention allocation system of working memory and, therefore, is important for behavioral continuity. Neurons in the prefrontal cortex fire if visual attention is directed to any object placed at a particular spot in the contralateral visual hemifield. Even if the object is removed, the neurons continue to fire so long as the object’s location is remembered. Thus, these prefrontal neurons are said to possess a “memory field,” that is, a delimited area of the extrapersonal space whose memory it carries. Lesions of these neurons produce “blind spots” in visuospatial memory. (2) The prefrontal cortex is important for the central, evaluative component of emotions (see Arnold theory of emotions, p 700). Lesions in the subgenual prefrontal cortex severely compromise reasoning ability and rationality. Emotionally arousing stimuli therefore are either ineffective or produce abnormal autonomic responses. Schizophrenia, which is associated with a flat affect, is associated with prefrontal hypofunction. Conversely, irritative lesions that stimulate the prefrontal cortex are associated with anger and aggressive behavior. (3) The prefrontal cortex is the storage site for episodic memory and therefore prefrontal lesions cause source amnesia (p 732). (4) The prefrontal cortex is important for motor planning (p 685). Two important neuronal circuits connect the prefrontal cortex to the basal ganglia: One is the dorsolateral prefrontal circuit, a damage

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to which causes cognitive disorder. The other is the lateral orbitofrontal circuit which, when damaged, produces obsessive-compulsive disorder. The operation of bilateral prefrontal leucotomy (or lobotomy) is sometimes practiced in patients with symptoms of mental illness and distressing somatic pain, by severing the connections between the prefrontal area and the dorsomedial nucleus of thalamus. The resulting changes include a relief from anxiety and intractable pain. Surgical lobotomies make the individual docile and hyporesponsive to changing surroundings. It is sometimes argued, therefore, that surgical intervention does not alleviate the mental illness: rather, it demotes the patients to subhuman forms.

Limbic association area The limbic cortex includes large parts of the cortex on the medial wall of the hemisphere, principally the parolfactory gyrus (subcallosal area 25), cingulate gyrus (areas 23, 24, and 32), parahippocampal gyri (area 36), and perirhinal area (area 35). It also includes the hippocampal formation, which consists of the hippocampus, the dentate gyrus, the subiculum, and the entorhinal cortex (area 28). The limbic cortex is functionally related to certain subcortical nuclei such as the amygdala and the nucleus accumbens. Together, they constitute the limbic system. The hippocampus, also known as Ammon horn or cornu Ammonis (CA), is a trilaminar archicortex. It consists of a single pyramidal cell layer with plexiform layers above and below. It is divided into three distinct fields: CA-1, CA-2, and CA-3 (Fig. 100.8). Neurons in the multimodal association areas of the neocortex first relay in the entorhinal cortex before entering the dentate gyrus (Fig. 100.9). The dentate gyrus is the “gatekeeper” of hippocampal excitability. Neurons originating in the entorhinal cortex terminate on the dendrites of the granule cells in the dentate gyrus, forming the perforant pathway. The axons of the granule cells of the dentate gyrus constitute the mossy pathway and terminate on the dendrites of CA-3 pyramidal cells. The projections from the pyramidal cells of fields CA-3 and CA-2 to CA-1 constitute Schaffer collateral pathway. The CA-1 field projects heavily to the subiculum which projects to the entorhinal cortex. The subiculum of the hippocampal formation also projects to the mamillary body through the fornix, forming part of the Papez circuit. The hippocampus transfers newly acquired information present in the short-term memory to the

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Cerebral Cortex

Mossy pathway

M

O N I

CA-1

CA-4 s

tate g yru

pp Par o a gy cam ru p s al

C

CA-

2

CA

M

S

hi

en

D

Perforant pathway

A

-3

memory into long-term memory, without abolishing either the long-term memory, or the acquisition of new short-term memory. The hippocampus is concerned with explicit memory only (See Chapter 111). Hippocampal damage does not affect implicit memory or reflexive learning and new motor skills can still be learnt at the normal pace. For example, the patient with hippocampal damage can learn to ride a bicycle (implicit memory) and yet fail to recall subsequently that he ever rode a bicycle before (explicit memory). In explicit memory, the hippocampus is particularly important for spatial representation while the entorhinal cortex processes memory for objects. The hippocampus contains a cognitive map of the spatial environment in which we move. Our location in a particular space is encoded in the firing pattern of the hippocampal pyramidal cells. These cells are therefore called place cells that encode a particular position in space. For example, in a house which we are thoroughly familiar with, we can move about even in perfect darkness and reach a particular spot in it with considerable ease. This is possible because of our “spatial memory” of the house. Spatial learning involves long-term synaptic potentiation in the hippocampal circuits described above. The hippocampus is one of the sites where seizures are known to originate. The dentate gyrus of the hippocampus is considered to be the gateway to hippocampal excitability. When the granule cells in the dentate gyrus are excited, they produce recurrent inhibition of the afferents through the mossy cells and basket cells. The mossy cells are excitatory interneurons and the basket cells are GABAergic inhibitory interneurons (Fig. 100.10). Degeneration

Schaffer's collateral pathway

N U R

O

( C

A

)

S u b ic u l u m

E

ina nto r h

l co

r te

639

x

Fig. 100.8 The hippocampus, showing the perforant pathway, mossy fiber pathway, and Schaffer collateral pathway.

long-term memory storage system in the neocortex, ensuring that the new information does not disrupt the existing information. Hence, hippocampal damage impairs the transfer of new short-term

Start Hippocampus (CA3) Mossy fiber 2 pathway

Dentate gyrus

3 Schaffer's collateral pathway

Hippocampus (CA1)

Unimodal and Multimodal sensory cortices End

1 Perforant pathway Subiculum

Parahippocampal gyrus

Entorhinal cortex

Fig. 100.9 Schematic representation of the hippocampal circuit. Compare with Fig. 100.8.

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640

Central Nervous System

Mossy pathway

Basket cell (GABA)

Perforant pathway

DENTATE GYRUS

Mossy cell

Granule cell

Fig. 100.10 Dentate gyrus acting as the gateway to hippocampal excitability.

of the mossy cells is known to be associated with temporal lobe seizures. The amygdala has two main groups of nuclei: the corticomedial and the basolateral groups. The corticomedial group receives afferents from the olfactory bulb. It is small in humans. The large basolateral group receives afferents from the entorhinal cortex. Amygdalar efferents mainly reach the hypothalamus and limbic areas. The amygdala is an important relay station in the Papez circuit. The connections of the amygdala with the cingulate gyrus, parahippocampal gyrus, and prefrontal cortex make it important in the central evaluative component of emotions. The amygdala also has strong connections with the autonomic centers of the hypothalamus and brain stem, which makes it important in the peripheral component of emotions. The basolateral nucleus of the amygdala receives a robust input from the inferior temporal cortex (important for the explicit memory of faces). The amygdala therefore is important for “social” cognition. Amygdalar damage impairs

emotional response and social behavior and abolishes fear conditioning. The amygdala is also important in instinctive behavior and its lesion causes psychic blindness. Olfactory and gustatory fibers project to those regions of the amygdala that project to the hypothalamus. These olfactory fibers do not mediate conscious olfactory sensation but are involved in reproductive behavior. The gustatory fibers are important for discriminative appetite. The nucleus accumbens, together with the olfac-

tory tubercle, constitutes the ventral system. It receives dopaminergic innervation from the midbrain ventral tegmental area and provides the locomotor drive associated with rewarding stimuli. Psychotropic drugs such as amphetamine and cocaine accentuate the locomotor drive by stimulating the mesolimbic dopamine system. It controls the body language in emotional states, a function that is made possible by the afferents it receives from the amygdala through the stria terminalis. Bilateral ablation of the parahippocampal gyrus and hippocampus causes Korsakoff psychosis which is characterized by severe anterograde amnesia, that is, inability to establish new, longterm memories. Ablation of the piriform cortex produces hypersexuality. Cats and monkeys, after the ablation, even approach animals of other species, for example, hen. Destruction of the amygdalar cortex causes abolition of rage and induces hyperphagia with oral tendencies. Bilateral temporal lobectomy removes a sizeable part of the limbic areas and results in Kluver–Bucy syndrome characterized by docility, hyperphagia, hypersexuality, visual agnosia, increased oral tendency, loss of memory, and hypermetamorphosis (failure to ignore peripheral stimuli and therefore easily distracted).

REVISION QUESTIONS 1. What are the polysensory areas in the cerebral cortex? 2. What are the three multimodal association areas of the cerebral cortex? 3. Rupture of the striate arteries in the brain causes contralateral hemiplegia and hemianesthesia. Why? 4. What is the difference between projection, association, and commisural fibers?

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5. What are the differences between “representational hemisphere” and “categorical hemisphere?” 6. The planum temporal is better developed on the left side, whereas the Heschel gyri are better developed on the right side. What is its functional significance? 7. Each neuron in the primary motor areas has a “receptor field” in the periphery. What is the receptive field?

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Cerebral Cortex 8. What is a transcortical reflex? Give an example. 9. The motor output differs with galvanic and faradic stimulation of the motor cortex. Why? 10. Extradural hematoma sometimes causes a descending paralysis. Why? 11. What happens when the frontal eye field is stimulated? 12. What happens when the somesthetic association area is (1) unilaterally damaged and (2) bilaterally damaged? 13. Which part of the brain is important for (1) recognition of faces and facial expression, (2) emotional response to facial expression? 14. Damage to which area of the brain causes sensory aphasia? 15. Which area of the brain is concerned with language and receives both visual input and somatosensory input?

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641

16. What is prefrontal leucotomy and in which type of patients is it done? What are its consequences? 17. A patient of hippocampal damage can learn to ride a bicycle and yet, fail to recall subsequently that he ever rode a bicycle before. Why? What is the main deficit caused by hippocampal damage? 18. What is the role of “place cells” in the hippocampus? 19. Degeneration of the mossy cells in the dentate gyrus of the hippocampus is associated with temporal lobe seizures. Why? 20. What are the functions of amygdala and what are the signs of amygdalar lesions? 21. What are the consequences of (1) bilateral ablation of parahippocampal gyrus and hippocampus, (2) ablation of piriform cortex, and (3) bilateral temporal lobectomy?

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101

Autonomic Nervous System

The autonomic nervous system (ANS) is essentially an efferent visceral nervous system that controls (excites or inhibits) the contraction of cardiac and smooth muscles as well as certain secretory and metabolic processes. Visceral afferents are sometimes called autonomic afferents: however, many disagree and consider the autonomic system to be essentially an efferent system. In this chapter, the term autonomic nervous system will be considered strictly as an efferent nervous system. The hypothalamus plays an important role in the regulation of autonomic activity and has been called the head ganglion of the ANS. However, it is now known that the limbic cortex is equally important in the regulation of the ANS. Efferent fibers from the hypothalamus descend through the brain stem to terminate on the preganglionic autonomic neurons of intermediate regions of the spinal gray matter. Descending autonomic fibers do not form well-defined tracts but are intermixed with fibers of other tracts. but are intermixed with fibers of other tracts. Their presence in the brainstem can be inferred through physiological experiments. It was earlier believed that the ANS is not under voluntary control. However, persons skilled in relaxation techniques have demonstrated voluntary control over their blood pressure and heart rate, which are normally regulated by the ANS. The autonomic system has two components: the sympathetic and the parasympathetic (Fig. 101.1). The two components have both anatomic as well as functional characteristics. Anatomically, the sympathetic fibers originate from the thoracic and lumbar segments of the spinal cord (the thoracolumbar outflow), while the parasympathetic fibers originate from the brain stem and the sacral segments of spinal cord (the craniosacral outflow). Functionally, the sympathetic system is triggered during “fight-or-flight” situations and is associated with catabolic processes while the parasympathetic system is concerned with the vegetative functions of day-to-day living and supports the anabolic processes of the body. Unlike in motor nerves where a single motor neuron travels all the way from the spinal cord to the muscle, the autonomic pathway from the spinal cord to the target organ is made of two neurons that synapse in an autonomic ganglion. The neuron originating from the spinal cord is the

Sircar_Chapter101_642-647.indd 642

preganglionic neuron while the one that reaches the target organ is the postganglionic neuron. In general, sympathetic ganglia are located close to the spinal cord whereas parasympathetic ganglia are located close to the target organ. However, there are exceptions to this rule, as discussed below. It is important to stress here that no nerve is entirely made of autonomic fibers. Even the vagus nerve, which carries most of the parasympathetic fibers to the viscera, also carries sensory fibers and nerve fibers supplying skeletal muscles.

 Sympathetic nervous system The soma of the preganglionic sympathetic neurons are located in the intermediolateral horn of the thoracolumbar (T1–L3) spinal gray matter. The axons exit the spinal cord through its ventral root along with somatic nerves (Fig. 101.2). Soon thereafter, they exit the ventral root through the white rami communicantes to enter the paravertebral sympathetic ganglion and synapse with the soma of the postganglionic sympathetic neurons. The white ramus communicantes is white because the preganglionic sympathetic fibers constituting it are thinly myelinated B fibers. The postganglionic sympathetic neurons leave the ganglion through the gray rami communicantes to reenter the ventral root and run in the spinal nerve. The gray ramus communicantes is gray in color because the postganglionic sympathetic fibers are unmyelinated C fibers. Some fibers ascend or descend along the sympathetic trunk to a variable extent and make synapses with the cells of the upper or lower sympathetic ganglia. Some preganglionic sympathetic fibers pass uninterrupted through the paravertebral sympathetic ganglia. They emerge from the paravertebral ganglia as splanchnic nerves and synapse in the collateral ganglia (e.g., celiac, otic, mesenteric, etc.). Some preganglionic fibers pass uninterrupted even through the collateral ganglion to synapse in ganglia in or near the target organ (e.g., in the genital tract). The postganglionic neurons innervating these organs are very short. Finally, some preganglionic fibers synapse directly with the chromaffin cells of the adrenal medulla. The chromaffin cells secrete adrenaline when stimulated.

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Autonomic Nervous System

Sympathetic nervous system

643

Parasympathetic nervous system

Parasympathetic cranial ganglia

Oculomotor nerve

Eye Facial nerve Superior cervical ganglion

Lacrimal and salivary glands

Brain stem with parasympathetic nuclei (cranial part) Glossopharyngeal nerve

Cranial vessels

Vagus nerve Sympathetic trunk Middle cervical ganglion

Parasympathetic ganglia near organs

Stellate ganglion*

*Stellate ganglion = inferior cervical ganglion and first thoracic sympathetic ganglion

Heart T1 T2 T3

Lung Greater splanchnic nerve

T4

Stomach

T5 T6

Liver

T7 T8

Pancreas

T9

Celiac ganglion

T10

Kidney

T11 T12

Intestine

L1

Superior mesenteric ganglion

L2

Inferior mesenteric ganglion

L3 L4

Parts of the colon, rectum

L5 Bladder S2 Genitalia

S3 S4 Hypogastric plexus

Pelvic splanchnic nerves

Sacral cord with parasympathetic nuclei (sacral part)

S5

Fig. 101.1 Organization of the sympathetic and parasympathetic nervous system.

 Parasympathetic nervous system Preganglionic parasympathetic neurons are present in the craniosacral outflow from the central nervous system. In the cranial nerves, the parasympathetic fibers are present in the III, VII, IX, and X cranial nerves and originate in the nuclei of the corresponding cranial nerves (see Table 96.3). In

Sircar_Chapter101_642-647.indd 643

the sacral part of the spinal cord, the parasympathetic fibers originate in the intermediolateral gray horn of S1–S4 and emerge through the ventral spinal root of the corresponding nerves. In either case, the parasympathetic preganglionic fibers travel all the way to the target organ and synapse with the soma of the postganglionic parasympathetic

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644

Central Nervous System

2

1

Collateral ganglia

Gray rami communicantes

3

Paravertebral sympathetic ganglia White rami communicantes

4

5 Adrenal gland

Fig. 101.2 Sympathetic preganglionic and postganglionic neurons. The preganglionic fiber may relay in (1) the segmental sympathetic ganglion, (2) the sympathetic ganglion of a higher or lower spinal segment, (3) a collateral ganglion, (4) a ganglion near the target organ, or (5) adrenal gland.

neurons present in the parasympathetic ganglia located near or in the organ.

Autonomic neurotransmission neurotransmission Postganglionic parasympathetic fibers release mostly acetylcholine as their neurotransmitter. Acetylcholine has two types of receptors: muscarinic and nicotinic. Cholinergic receptors on target organs are the muscarinic type. They are blocked by atropine. The nicotinic receptors are present in ganglia (see below). Parasympathetic

neurotransmission Postganglionic sympathetic fibers release mostly noradrenaline. However, there are exceptions to this general rule: sympathetic vasodilator fibers and sympathetic fibers innervating sweat glands have acetylcholine as their neurotransmitter. The adrenergic receptors on target organs are of three types, viz., α1, β1, and β2. (See also α2 inhibitory autoreceptors, p 654.) Norepinephrine acts mainly on α receptors and to a lesser degree, on β receptors. In general, α receptors mediate Sympathetic

Sircar_Chapter101_642-647.indd 644

excitation of smooth muscles, β1 receptors mediate excitation of cardiac muscle, and β2 receptors mediate inhibition of smooth muscles. The autonomic effects on different organs are summarized in Table 101.1. Ganglionic neurotransmission At the synapse

between the preganglionic and postganglionic neurons, the neurotransmitter is mostly acetylcholine which acts on nicotinic cholinergic receptors located on the postganglionic neuron. These nicotinic receptors are blocked by ganglion blockers such as hexamethonium. Some cholinergic receptors in the ganglia are of the muscarinic type. Moreover, there are other types of ganglionic neurotransmitters too, such as dopamine and GnRH. They act through D2 receptors and GnRH receptors, respectively. Activation of the postsynaptic receptors in the ganglion leads to the generation of EPSP in the postganglionic cell, and occasionally, produces an IPSP (p 656). The neurotransmitters, the receptors they activate, and the type of postsynaptic potentials they produce are summarized in Table 101.2.

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Autonomic Nervous System

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Table 101.1 Responses of effector organs to autonomic nerve impulses and circulating catecholamines Effector organs

Cholinergic response

Adrenergic Receptor

Response

α

Contraction (mydriasis)

β

Relaxation for far vision

Eyes Radial muscle of iris Sphincter muscle of iris

Contraction (miosis)

Ciliary muscle

Contraction for near vision

Heart SA node

Decrease in heart rate, vagal arrest

β

Increase in heart rate

Atria

Decrease in contractility and increase in conduction velocity

β

Increase in contractility and conduction velocity

AV node

Decrease in conduction velocity

β

Increase in conduction velocity

His-Purkinje system

Decrease in conduction velocity

β

Increase in conduction velocity

Ventricles

Decrease in contractility

β

Increase in contractility

Constriction

α

Constriction

β

Dilation

Arterioles Coronary Skin and mucosa

Dilation

α

Constriction

Skeletal muscle

Dilation

α

Constriction

β

Dilation

Cerebral

Dilation

α

Constriction

Pulmonary

Dilation

α

Constriction

β

Dilation

α

Constriction

Abdominal viscera Salivary glands

Dilation

Renal Systemic veins

β

Dilation

α

Constriction

α

Constriction

β

Dilation

α

Constriction

β

Dilation

Lungs Bronchial muscle

Contraction

β

Relaxation

Bronchial glands

Stimulation

α

Inhibition

β

Stimulation

Stomach Motility and tone

Increase

α, β

Decrease

Sphincters

Relaxation

α

Contraction

Secretion

Stimulation

α

Inhibition

Intestine Motility and tone

Increase

α, β

Decrease

Sphincters

Relaxation

α

Contraction

Secretion

Stimulation

α

Inhibition

Gallbladder and ducts

Contraction

β

Relaxation

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646

Central Nervous System

Urinary bladder Detrusor

Contraction

β

Relaxation

Trigone and sphincter

Relaxation

α

Contraction

Ureters Motility and tone

Increase

α

Increase

Uterus

Variable

α

Contraction

β

Relaxation

Male sex organs

Erection

α

Ejaculation

α

Contraction

Generalized secretion

α

Slight, localized secretion

α

Contraction

β

Relaxation

α, β

Glycogenolysis

Skin Pilomotor muscles Sweat glands Spleen capsule Adrenal medulla

Secretion of epinephrine and norepinephrine

Liver Pancreas Acini

Increased secretion

α

Decreased secretion

Islets

Increased insulin and glucagon secretion

α

Decreased insulin and glucagon secretion

β

Increased insulin and glucagon secretion

α

Thick, viscous secretion

Salivary glands

Profuse, watery secretion

Lacrimal glands

Secretion

Nasopharyngeal glands

Secretion

Adipose tissue

β

Amylase secretion

α

Secretion

α, β

Lipolysis

Juxtaglomerular cells

Increased renin secretion

Pineal gland

Increased melatonin synthesis and secretion

Table 101.2 Major neurotransmitters of autonomic ganglia Neurotransmitter

Receptor

Postsynaptic potential

Acetylcholine

Nicotinic

Fast EPSP (30 ms)

Acetylcholine

Muscarinic

Slow EPSP (30 s)

Dopamine

D2

Slow IPSP (2 s)

GnRH

GnRH receptor

Late slow EPSP (4 s)

Valsalva maneuver (Valsalva ratio) and a change of posture from standing to lying (S/L ratio) have been used to assess parasympathetic function. The galvanic skin resistance (GSR) has been used to assess sympathetic function. The resistance offered by skin to a galvanic current is low when it is moist and therefore, GSR gives a measure of sweating. Since sweating increases during anxiety, GSR has been used in the lie detector. For the same reason, GSR has been used in anxiety patients for providing biofeedback on the amount of nervous sweating.

Autonomic function tests

 Autonomic dysfunctions

Several autonomic function tests are available for diagnosing underactivity of the autonomic nervous system. The heart rate responses to the

Sympathetic adrenergic failure causes orthostatic (postural) hypotension and ejaculatory failure, while sympathetic cholinergic failure results in

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Autonomic Nervous System anhidrosis (lack of sweating). Parasympathetic failure causes dilated pupils, a fixed heart rate, a sluggish urinary bladder, an atonic large bowel, and erectile failure. With autonomic hyperactivity, the reverse occurs. Autonomic dysfunction can also be due to localized disorders. Thus, Horner syndrome is not only an early sign of generalized autonomic failure but also occurs due to involvement of the stellate ganglion in apical lung neoplasm. Horner syndrome comprises (1) ptosis (drooping of the eyelid), (2) miosis (pupillary constriction), and

647

(3) hypohidrosis (reduced sweating of the face) on the affected side. Similarly, gustatory sweating may follow surgery to the parotid gland (Frey’s syndrome) or be the result of diabetic autonomic neuropathy. Some gustatory sweating is normal after eating hot, spicy foods. However, excessive gustatory sweating is most commonly a result of damage to the auriculotemporal nerve. One theory holds that the parasympathetic fibers in the auriculotemporal nerve that normally innervate the parotid are misdirected to the overlying sweat glands.

REVISION QUESTIONS 1. Which parts of the brain regulate the autonomic functions of the body?

cholinergic failure, and (3) parasympathetic failure?

2. What are the differences in the anatomical and functional characteristics of the sympathetic and parasympathetic system?

5. What are the common tests for diagnosing underactivity of the ANS?

3. What type of physiological actions are mediated by α1, α2, β1, and β2 adrenergic receptors? Where are these receptors located?

6. What are thoracolumbar and craniosacral outflow and how are they different? 7. What is gustatory sweating and why does it occurs?

4. What are the major consequences of: (1) sympathetic adrenergic failure, (2) sympathetic

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102

Synaptic Mechanisms and Neurotransmitters

A synapse is the site where an action potential travels across the 20 to 40-nm-wide gap (called the synaptic cleft) separating the axon terminal of one neuron (the presynaptic neuron) from the dendrites, cell body or axon terminal of another (the postsynaptic neuron). Most commonly, the dendrites form the postsynaptic element. Accordingly, the commonest type of synapse is the axodendritic synapse though axosomatic and axoaxonic synapses are also quite common. The transmission at the synapse is mediated by chemicals called neurotransmitters released from the presynaptic neuron terminal. Synaptic transmission The brief sequence of events

at a synapse (Fig. 102.1) is as follows: (1) an action potential arrives at the presynaptic nerve terminal and depolarizes the presynaptic membrane. (2) When the membrane depolarizes to –40 to –20 mV, the voltage-gated Ca2+ channels in the presynaptic terminal open, resulting in an influx of Ca2+ into the nerve terminal. (3) The rise in intracellular Ca2+ stimulates the exocytosis of synaptic vesicles from the presynaptic terminal. (4) The neurotransmitters present in the synaptic vesicles are released into the synaptic cleft. (5) The neurotransmitter binds to ionic channels present on the postsynaptic neuron. (6) The binding of neurotransmitter to the ion channels opens up the channel, allowing ions to flow across the postsynaptic membrane. (7) If the ionic current is a depolarizing current, the postsynaptic neuron depolarizes, triggering off an action potential in it and thereby completing the process of synaptic transmission. (8) The neurotransmitter released is cleared from the synaptic cleft quickly through (a) reuptake into the presynaptic terminal or nearby glial cells (the commonest mechanism),

Ca2+

Transmitter EPSP AP

Transmitter Precursor

Inactivated Transmitter

Fig. 102.1 Steps in synaptic transmission.

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(b) rapid enzymatic degradation, or (c) quick diffusion away from the synaptic cleft. The neurotransmitter glutamate has its own specific transporter for reuptake while other small-molecule transmitters (see below) share a common transporter. Synaptic delay It takes about 0.5 ms to cross the

20-nm-wide synaptic cleft. In comparison, an impulse traveling the same distance along an uninterrupted nerve membrane takes only 0.2 to 40 ns. Synaptic transmission is thus a much slower process than nerve conduction and the time taken to cross the synapse is called the “synaptic delay.” The extent to which a nerve impulse slows down gives an estimate of the number of synapses in its path. It was this type of analysis that led to the conclusion that the reflex arc for the stretch reflex (p 678) has only one synapse. Chemical versus electrical synapse The synaptic

transmission described above depends on a neurotransmitter. Hence, it is called chemically mediated transmission and the synapse is called a chemical synapse to distinguish it from an electrical synapse, which is essentially a gap junction that allows ephaptic conduction between two neurons. The differences between chemical and electrical synapses are summarized in Table 102.1. Table 102.1 Differences between chemical and electrical synapse Chemical synapse

Electrical synapse

Is mediated by the release of neurotransmitters.

Is ephaptic transmission of electrical impulses through gap junctions.

Can occur only in one direction: from the presynaptic terminal containing neurotransmitter to the postsynaptic membrane bearing receptors for the neurotransmitter.

Can occur in both directions.

Speed of synaptic transmission is much slower than the speed of nerve conduction, which results in a synaptic delay of about 0.5 ms.

Speed of synaptic transmission equals the speed of nerve conduction.

Vulnerable to synaptic fatigue on repeated stimulation.

Much less susceptible to fatigue.

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Synaptic Mechanisms and Neurotransmitters

649

Neurotransmitters Neurotransmitters

Criteria of a neurotransmitter Not every substance

that is released from the presynaptic nerve terminal during neurotransmission can be called a neurotransmitter. To qualify as a neurotransmitter, it must satisfy the following criteria: (1) it must be synthesized in the neuron. (2) It must be released on stimulation of the presynaptic terminal in amounts sufficient to exert a definite action on the postsynaptic neuron. (3) A specific mechanism must exist for removing it from the synaptic cleft. (4) When applied exogenously, it must mimic the actions of endogenously released neurotransmitter. The importance of these criteria is underlined by the examples of ATP and phenylethylamines. Gaseous compounds, such as nitric oxide (NO) and carbon monoxide (CO), can also act as neurotransmitters. NO is released without being packaged in vesicles and produces its effects on receptors within target neurons. Being membrane soluble, they can act as retrograde messengers at some synapses, carrying information from the postsynaptic to the presynaptic neuron. ATP as a neurotransmitter Although ATP is syn-

thesized by all neurons and is also released from axon terminals along with other neurotransmitters, it acts as a neurotransmitter only in selected neurons, such as the primary nociceptive group-C afferents and the autonomic fibers to the vas deferens, urinary bladder, gastrointestinal tract, and the heart. These tissues contain ionotropic receptors (see below) that are purinergic, for example, the receptors may be specific for adenosine. neurotransmitters such as phenylethylamines are taken up into adrenergic terminals where they replace norepinephrine in synaptic vesicles. They are released when the presynaptic terminal depolarizes, bind to postsynaptic adrenergic receptors and exert a weak stimulatory effect. Yet, they are called false transmitters because (1) they are not synthesized in the neuron and (2) there is no specific mechanism for their removal from the synaptic cleft. Phenylethylamines are normally produced by intestinal bacteria but are degraded in the intestine and liver by monoamine oxidase (MAO) before they can enter systemic circulation. The clinical importance of phenylethylamines is discussed again later.

False

Classification of neurotransmitters Neurotrans-

mitters can be broadly divided into two groups (Fig. 102.2): the small-molecule neurotransmitters are present in small, clear synaptic vesicles. Examples include glutamate, GABA, glycine, catecholamines, acetylcholine, and serotonin.

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Small molecule neurotransmitters

Neuropeptides Enkephalins β-endorphins Dynorphins

Aminoacids Glutamate GABA Glycine

Acetylcholine Monoaminergic neurotransmitters Dopamine Norepinephrine Epnephrine Histamine Serotonin

Fig. 102.2 Classification of neurotransmitters.

Neuropeptides are present in large dense-core vesicles. Examples include opioids, neurohormones. Small molecule neurotransmitters and neuropeptides can coexist in the same neuron. Examples of such coexistence are ACh and VIP in parasympathetic neurons to secretory glands, ACh and GRP in the vagus nerve, ACh, CGRP, and substance P in nociceptive fibers, and glutamate and dynorphin in the hippocampus.

 Small molecule neurotransmitters Small molecule neurotransmitters are synthesized in all parts of the neuron, including the nerve terminals. This is possible because except dopa β-hydroxylase, which is present inside the synaptic vesicle, the enzymes that synthesize small neurotransmitters are cytoplasmic and are found throughout the neuron. However, the neurotransmitters are packaged into vesicles only in the nerve terminal. The membranes that form synaptic vesicles are synthesized in the soma and transported by fast axon transport to the nerve terminal where they fuse with endosomes or the presynaptic membrane. They are then pinched off again to form the small clear vesicles and are filled with small molecule neurotransmitters. The membranes are repeatedly recycled before they are finally returned to the soma for degradation. Small clear vesicles are released only at selected sites called active sites on the presynaptic membrane. When the presynaptic membrane is not depolarized, the synaptic vesicles remain anchored to the cytoskeleton of the nerve terminal by a group of proteins called synapsins. This ensures that the vesicles are not released unnecessarily. When

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Central Nervous System synapsins are phosphorylated by activated kinases, the vesicles are freed from the cytoskeleton and move toward the active zone. The activation of kinases is triggered by a rise in intracellular Ca2+. The Ca2+ influx occurs near the active zone and therefore the rise in Ca2+ concentration is greater near the active zone than in other parts of the axon terminal. The high Ca2+ concentration lasts less than 1 ms before it diffuses to other parts of the axon terminal. After they are freed from the cytoskeleton, the synaptic vesicles are guided to their releasing site by a group of proteins called Rab proteins. The binding of the synaptic vesicles to the presynaptic membrane requires integral membrane proteins called the SNARE proteins. SNARE proteins that are present in the vesicular membrane are called vesicle-SNARE or v-SNARE (e.g., synaptobrevin) while those that are present on the target membrane are called target-SNARE or t-SNARE (e.g., syntaxin). For exocytosis of synaptic vesicles to occur, the v-SNARE must bind to the t-SNARE. Tetanus toxin inhibits synaptic transmission by degrading the SNARE proteins.

Glutamate is synthesized by glial cells from either glucose (via the Krebs cycle) or from glutamine. The neurotransmitter action of glutamate is terminated mainly by reuptake into the nerve terminals and neighboring glial cells through secondary active cotransport with Na+ ions (Fig. 102.3). Ischemia of these neurons and glial cells weakens the Na+-K+ pump, abolishing the glutamate cotransport with Na+ ions. The resulting high glutamate concentration in the brain interstitium is toxic to neurons and is called glutamate excitotoxicity (see below). Glutamate receptors are of two types: (1) The ionotropic receptors are present on membrane channels (hereafter called receptor-channels) and gate them directly. The action of glutamate on the ionotropic receptor is always excitatory. (2) The metabotropic receptors that gate channels indirectly through group-IIC hormonal mechanisms (see Fig. 81.6). The activation of metabotropic receptors can produce either excitation or inhibition.

 Amino acid neurotransmitters Na+ K+ Na+

Glutamate Na+ R

eu

Table 102.2 Differences between type-1 and type-2 neurons Gray Type-1

Gray Type-2

Glutaminergic

GABAergic

Mostly excitatory

Mostly inhibitory

Usually axodendritic

Usually axosomatic

Synaptic vesicles are spherical

Synaptic vesicles are flat or elongated

The synaptic cleft is wider (about 30 nm)

The synaptic cleft is narrower (about 20 nm)

Postsynaptic membrane very thick

Postsynaptic membrane is less thick and only at places

Synaptic cleft contains dense material

No dense material is present in the synaptic cleft

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e

The three main amino acid neurotransmitters are glutamate, GABA (γ-amino butyric acid), and glycine. Glutamate is an excitatory neurotransmitter. GABA and glycine are inhibitory and produce an inhibitory postsynaptic potential or IPSP. Most excitatory neurons in the central nervous system have glutamate and most inhibitory neurons have GABA as their neurotransmitter. There are several morphological differences between these two types of neurons (Table 102.2).

p tak

Inotropic glutamate receptor NMDA receptor

Glial cell

Metabotropic glutamate receptor

Non-NMDA receptors

NMDA: N-methyl AMPA receptor D-aspartate AMPA: α-amino-3-hydroxy 5-methylisoxazole Kainate receptor

Fig. 102.3 Glutamate cotransport into nerve terminals. The glutamate released binds to inotropic (NMDA and non-NMDA) and metabotropic receptors.

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Synaptic Mechanisms and Neurotransmitters Inotropic glutamate receptors are of three major subtypes: AMPA, kainate, and NMDA, each named after a synthetic agonist that stimulates it. NMDA and non-NMDA (AMPA and kainate) receptorchannels coexist on the membrane. The NMDA receptor-channel remains occluded by a Mg2+ ion that is expelled only when the membrane depolarizes slightly. Hence, it does not respond to glutamate so long as the membrane remains at resting potential. However, the membrane depolarizes when glutamate binds to the non-NMDA receptor-channels on it. The depolarization ejects the Mg2+ ion from the NMDA receptor-channel which now becomes functional. Hence, when glutamate binds to NMDA and non-NMDA receptor-channels on the membrane, it produces an EPSP that has an early and a late component: the non-NMDA receptor-channels, which open quickly, produce the large early component of the EPSP. The NMDA receptor-channels produce the small late component of the EPSP (Fig. 102.4). Since the late EPSP produced by NMDA receptorchannels is small, it requires the repeated firing of several presynaptic neurons before NMDA channels can produce their maximal effect. Hence, the long-term synaptic modification mediated by NMDA receptors is called activity-dependent synapse modification.

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Anesthetics such as ketamine and psychotomimetic and agents such as phencyclidine selectively block NMDA receptors. The hallucinations produced by phencyclidine are similar to those observed in schizophrenia, which has led to the hypothesis that schizophrenia may involve a defect in NMDA receptor function. A high ECF concentration of glutamate results in excessive inflow of Ca2+ through NMDA receptorchannels. High concentrations of intracellular Ca2+ activates Ca-dependent intracellular enzymes and produce free radicals that are toxic to the cell. This is known as glutamate excitotoxicity and it contributes to brain damage after cerebral stroke, head injury, and status epilepticus, and to degenerative diseases such as Huntington chorea. Gamma-amino butyric acid (GABA) is the main inhibitory transmitter of the central nervous system. It is abundant in the striatum and the reticular nuclei of the thalamus. Striatal GABAergic neurons project to the globus pallidus and substantia nigra. Thalamic GABAergic neurons are important in sleep and EEG synchronization and are also involved in the pathogenesis of seizures. There are two types of GABA receptors: GABAA and GABAB (Table 102.3).

NMDA receptor

Polarized neuron

Non-NMDA receptor

Depolarized neuron

Glutamate

Magnesium

1

4

Ca2+

Ca2+

2

5 3

Fig. 102.4 Early and late components of glutamate-induced EPSP. (1) Glutamate released binds to both NMDA and nonNMDA receptors; (2) non-NMDA receptors open, allowing a depolarizing current to flow through them; (3) postsynaptic membrane depolarizes; (4) magnesium ion expelled from NMDA receptor; (5) NMDA receptor opens, allowing a depolarizing current to flow through it.

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Central Nervous System Table 102.3 Differences between GABA A and GABAB receptors GABAA

GABAB

Inotropic receptor.

Metabotropic receptor.

Gates Cl- channels.

Opens K+ channels and closes Ca2+ channels through group-IIA hormonal mechanism (see Fig. 81.5).

Produces postsynaptic inhibition by increasing Cl- conductance.

Produces both presynaptic inhibition (by increasing Ca2+ permeability) and postsynaptic inhibition (by increasing K+ permeability).

Agonists include benzodiazepines (antianxiety, muscle relaxant, anti-convulsant, and sedative), barbiturates (hypnotics), and alcohol.

Agonists include baclofen, which is used for treating spasticity and flexor spasms.

is released by motor neurons at neuromuscular junctions and in the autonomic nervous system by parasympathetic postganglionic neurons and most preganglionic autonomic neurons (Fig. 102.5). In the brain, cholinergic neurons are present in the tegmentum of the pons and midbrain. The axons of these neurons project as the mesopontine cholinergic system to the brain stem reticular formation and thalamus and have an important role in the regulation of sleep-wakefulness. Another cluster of cholinergic neuron cells are found in the basal forebrain, particularly in the nucleus basalis of Meynert. The axons of these neurons project to the entire cerebral cortex where they enhance the response to incoming stimuli and thereby play an important role in selective attention. In the brain, acetylcholine acts as an excitatory neurotransmitter and its release is proportional to the level of cortical excitability. Scopolamine, a muscarinic blocker, is a sedative. Anticholinesterase drugs are used in Alzheimer disease1 to improve cognitive performances.

 Monoaminergic transmitters GABA is formed by decarboxylation of glutamate and is degraded by transamination to succinic acid. Glutamic acid decarboxylase Glutamate ⎯⎯⎯⎯⎯⎯⎯⎯ → γ aminobutyric acid(GABA)

GABA transaminase GABA ⎯ ⎯⎯⎯⎯⎯⎯→Succinic acid

Glycine It is an inhibitory transmitter that is

present mainly in the spinal cord. Glycine is released by spinal interneurons that inhibit antagonist muscles. The glycine receptor is a ligandgated chloride channel that functionally resembles the GABAA receptor. Strychnine produces convulsions by acting as a competitive antagonist of glycine at the postsynaptic inhibitory site. Tetanus toxin acts mainly by interfering with glycine release.

Monoaminergic neurotransmitters include dopamine, norepinephrine, epinephrine, serotonin, and histamine. Three of them, viz., dopamine, norepinephrine, and epinephrine comprise the

Spinal cord

ACh (Nic)

Skeletal muscle

ACh (Nic)

ACh (Mus)

Blood vessels

ACh (Nic)

ACh (Mus)

Sweat glands

ACh (Nic)

Adrenal medulla

Somatic efferent system

Ganglia

ACh (Nic)

ACh Salivary (Mus) glands etc.

Sympathetic system

Parasympathetic system

 Acetylcholine The synthesis, release, and inactivation of acetylcholine (ACh) are discussed on p 91. Acetylcholine 1

Fig. 102.5 Sites where acetylcholine is the neuro transmitter.

Alzheimer disease is a neurodegenerative disease. It is the commonest cause of dementia in the elderly. The patients show abnormalities of memory, language, cognition, and behavior. In the late stages the patients are mute, incontinent, and bedridden and usually die of unrelated medical illnesses. The basal forebrain cholinergic system is severely damaged in Alzheimer disease, resulting in attention deficits. The brain stem monoaminergic system is also damaged, resulting in behavioral and emotional disturbances. Attempts to treat Alzheimer disease with acetylcholinesterase inhibitors have met with limited success.

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Synaptic Mechanisms and Neurotransmitters catecholamines and have a common biosynthetic pathway (Fig. 102.6). After release, they are removed from the synaptic cleft partly through reuptake into the nerve terminal and partly through degradation by COMT (catechol-O-methyltransferase) present on the postsynaptic membrane. The norepinephrine inside the synaptic nerve terminal is constantly degraded by MAO (monoamine oxidase). Yet, MAO inhibitors do not increase norepinephrine release as might be expected. In the presence of MAO inhibitors, the phenylethylamines formed in the intestines by commensals are not degraded and are absorbed into systemic circulation from where they are taken up in large amounts in adrenergic terminals

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(Figs. 102.6 and 102.7). Since phenylethylamine acts as false neurotransmitter, MAO inhibitors decrease noradrenergic transmission and are used clinically as antihypertensives. Hypertensive patients on MAO inhibitor therapy, however, have to be careful not to consume food containing large amounts of phenylethylamines such as cheese, beer, and red wine. The phenylethylamine displaces norepinephrine from the nerve terminal, resulting in an abrupt release of large amounts of norepinephrine from the nerve terminal, often precipitating a hypertensive crisis. Dopamine Cells of dopaminergic neurons are con-

centrated in the substantia nigra, ventral tegmentum

Phenyl alanine

Tyrosine

DOPA

MAO

Dopamine

Normetanephrine

Phe nyl e t h

Norepinephrine O MA

yl

DHPG

a min e s

Commensal bacteria

CO M T

MAO

MAO inhibitor Cheese, beer, red wine

Phenylethylamines Norepinephrine

Phe nyl e t h

yl

Fig. 102.6 (Above) Synthesis, secretion, and inactivation of norepinephrine in a nerve terminal. (Below) Phenylethylamine as a false neurotransmitter.

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a min e s

Fig. 102.7 Effect of diet and MAO inhibitors on adrenergic transmission.

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Central Nervous System of the midbrain, and the posterior hypothalamus. (1) The dopaminergic nigrostriatal pathway is important in the regulation of posture and its degeneration causes Parkinson disease. (2) The dopaminergic cells of the ventral tegmentum of the midbrain give rise to two important projection pathways that are thought to be involved in schizophrenia. The mesolimbic pathway projects to the limbic structures of basal forebrain including the hippocampus and amygdala. It is important in emotion, thoughts, and memory. The mesocortical pathway projects to the prefrontal cortex which is involved in organization of behavior, in motivation, planning, attention, and social behavior. (3) The cells of the posterior hypothalamus give rise to descending autonomic fibers to the sympathetic preganglionic neurons in the spinal cord. The small intensely fluorescent (SIF) cells in the autonomic ganglia are dopaminergic interneurons. (4) The tubuloinfundibular tract extending from the arcuate nucleus to the infundibulum of the hypothalamus secretes dopamine (prolactin inhibiting factor). (5) Dopaminergic neurons are also found in the periglomerular cells of the olfactory bulb, in the amacrine cells of the retina, and in the medullary chemoreceptor trigger zone. There are two main classes of postsynaptic dopamine receptors, D1 and D2, though several others have been identified recently. Both act through group-IIA hormonal mechanisms. D1 stimulates cAMP. D2 inhibits cAMP and activates a receptoroperated K+ current. D2 antagonists have been used as antiemetics and prokinetics (agents that enhance gastrointestinal motility and secretions) and as antipsychotics. D2 agonists are used in galactorrhea for inhibiting prolactin secretion and have been tried in the treatment of acromegaly and Parkinsonism. Bromocriptine is a strong D2 agonist and weak D1 antagonist. Norepinephrine acts as the transmitter at the

postganglionic sympathetic nerve endings. In the central nervous system, noradrenergic neurons are organized into two main systems: (1) the locus ceruleus system originates in the pons and ascend to the cerebral cortex where it maintains arousal. It is also important for motivation and emotions and in the pathogenesis of anxiety, melancholia, and depression. It also descends to the spinal cord where it modulates pain. (2) The lateral tegmentum system originates in the medulla where it is constituted by the noradrenergic neurons in the nucleus ambiguus, nucleus of tractus solitarius, and the dorsal motor nucleus of the vagus. It projects to hypothalamic centers controlling cardiovascular and endocrine functions.

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Norepinephrine acts mainly on α receptors which have two subtypes α1 and α2. The α1 receptors are present only on the postsynaptic membrane but α2 receptors are also present presynaptically as inhibitory autoreceptors. When stimulated, these receptors reduce the amount of neurotransmitter released from the presynaptic terminal. Cocaine blocks reuptake of norepinephrine. Amphetamine is taken up by dopamine transporters. Once inside the terminal, amphetamine promotes the synaptic release of both norepinephrine (suppressing appetite) and dopamine (producing schizophrenia-like psychosis). The antihypertensive guanadrel and antiarrhythmic drug bretylium inhibit the release of norepinephrine. Reserpine, another antihypertensive drug, prevents the packaging of norepinephrine into synaptic vesicles. The norepinephrine therefore remains in the cytoplasm and is eventually degraded by MAO. Epinephrine is the neurotransmitter of the C1

group of cells, a cluster of cells in the upper medulla that descend to the sympathetic preganglionic cells in the spinal cord. Histamine is produced by the decarboxylation of

histidine. Histaminergic neuron cells are present in the tuberomamillary nucleus in the posterior lateral hypothalamus. They project to large areas of the cerebral cortex and spinal cord and are important for the arousal response and probably other visceral responses too. Serotonin (5-hydroxytryptamine, 5-HT) is produced from tryptophan as shown in Fig. 102.8. Brain tryptophan hydroxylase is not saturated with tryptophan. Hence, the availability of tryptophan is the limiting factor in the synthesis of 5-HT: if there is excess tryptophan in the brain, more 5-HT is synthesized. The level of brain tryptophan is influenced by its plasma concentration. Hence, increased dietary intake of tryptophan increases the amount of serotonin in the nerve endings. The synaptic action of serotonin is terminated entirely through reuptake. Serotonin promotes arousal, obsessive-compulsive acts, and overeating. Serotonergic neuron cells are located along the midline of the brain stem in the raphe nuclei. The caudal part of the raphe nuclei sends descending projections to the spinal dorsal horn where they modulate pain, muscle tone, and autonomic activity. The rostral part of the raphe nuclei projects to the limbic system, playing important roles in cardiovascular regulation, thermoregulation, sleep–wake

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Synaptic Mechanisms and Neurotransmitters

Tryptophan Tryptophan hydroxylase 5-Hydroxy tryptophan 5-Hydroxy tryptophan decarboxylase 5-Hydroxy indole acetic acid (5-HIAA)

5-Hydroxy tryptamine (Serotonin) MAO

5-HIAA

5-HT

Fig. 102.8 Synthesis, secretion, and reuptake of serotonin in nerve endings.

cycle, food intake, sexual behavior, and emotions. Drugs that increase the tissue-concentration of serotonin by blocking serotonin reuptake by the nerve terminals are used as antidepressants in the treatment of melancholic depression. Serotonin is a key mediator in the pathogenesis of migraine2 and serotonin agonists have been used in its treatment. There are at least 14 types of serotonin receptors. Most of them are metabotropic with groupIIA or group-IIC mechanisms. They include the 5-HT3 receptor present in the area postrema. 5-HT3 antagonists are effective antiemetics. 5-HT4 receptors are present in the enteric nervous system and 5-HT4 antagonists are used as prokinetics.

Neuropeptides Unlike small-molecule neurotransmitters, which are synthesized in all parts of the neuron, the neuropeptides are formed, processed and packaged into secretory granules in the soma. Fast axon transport carries the secretory granules to the nerve terminals where they remain as large, dense core vesicles. The large vesicles lack the 2

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proteins required for localized release at the active zones. Hence, the exocytosis occurs everywhere along the presynaptic membrane. The exocytosis of large vesicles depends on a general elevation of intracellular Ca2+ and therefore requires greater stimulation frequencies. The Ca2+ is cleared from the cytoplasm of the nerve terminal by binding to calmodulin, uptake by the endoplasmic reticulum, uptake by mitochondria or by slow pumping to the exterior. Neuropeptides are removed from the synaptic cleft by diffusion and proteolysis by extracellular peptidases. Their effect is prolonged by their slow removal. Once released, a fresh supply of neuropeptide must arrive from the cell body before release can occur again. Also, there is no mechanism for recycling the membranes of dense-core vesicles (Table 102.4). The three main endogenous opioid peptides are enkephalins, β-endorphin, and dynorphin. The three major classes of opioid receptors are μ, δ, and κ. Morphine exerts its actions through μ. Naloxone blocks it. The μ receptors are highly concentrated in the periaqueductal gray matter, Table 102.4 Differences between small molecule neurotransmitter and neuropeptide Small molecule neurotransmitter

Neuropeptide

Synthesized in all parts of the neuron and transported to the nerve terminal where it is packaged into small clear vesicles.

Synthesized and packaged into large densecore granules only in the soma and transported to the nerve terminal.

Released only at the “active sites” on the presynaptic membrane.

Released from anywhere on the presynaptic membrane.

Vesicles are released when there is Ca2+ influx near the active sites.

Vesicles are released when there is a general rise in Ca2+ concentration in the neuron.

Ca2+ diffuses away from the active sites.

Ca2+ binds to calmodulin, or pumped out of cytosol (into the endoplasmic reticulum, mitochondria, or the exterior).

Removed by enzymatic degradation. Vesicle membrane recycled.

Removed from synaptic cleft by diffusion and proteolysis. Membrane not recycled.

Migraine is a clinical condition associated with periodic vascular headache, usually temporal and unilateral, and commonly associated with vomiting and photophobia. Attacks are preceded by constriction of cranial arteries and commence with the vasodilatation that follows.

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Central Nervous System ventral medulla, and substantia gelatinosa of the dorsal horn, all of which are important in the regulation of pain. Opioid receptors are also located on peripheral terminals in skin, joints, and muscle.

10 EPSP Millivolts

656

5

0

Postsynaptic potentials Excitatory postsynaptic potential (EPSP) The binding of the neurotransmitter to receptors on the postsynaptic membrane triggers the opening of the ligand-gated Na+ channels on the postsynaptic membrane. The resultant rise in the Na+ conductance depolarizes the postsynaptic membrane. The depolarization thus produced is called the excitatory postsynaptic potential or EPSP (Fig. 102.9). The magnitude of the EPSP is 8 mV. The depolarization starts with a latency of 0.5 ms, rises to its peak in 2.0 ms, and then declines with a half-life of 4.0 ms. Inhibitory postsynaptic potential (IPSP) The soma

and dendrites of a neuron usually have synaptic connections with a large number of axon terminals. Not all of them produce an EPSP. Any number of them can produce an inhibitory postsynaptic potential (IPSP). The IPSP is produced when the neurotransmitter increases the conductance of the postsynaptic membrane to Cl- or K+ ions, producing hyperpolarization of the membrane. Its magnitude is 2 mV. The hyperpolarization has a latency of 2.0 ms, attaining its maximum at 4 ms and then returning toward the resting potential with a halflife of 3 ms (Fig. 102.9). The differences between EPSP and IPSP are summarized in Table 102.5. Synaptic integration The soma-dendritic tree acts

as an integrator that summates all the EPSPs and IPSPs. Depending on the summated postsynaptic potential, synaptic transmission may or may not occur. The summation of postsynaptic potential may be “spatial” or “temporal”. Table 102.5 A comparison of EPSP and IPSP EPSP

IPSP

Produced when excitatory neurotransmitters (like glutamate) are released.

Produced when inhibitory neurotransmitters (like GABA and glycine) are released.

Associated with the opening of ligand-gated Na+ channels.

Associated with the opening of ligand-gated Cl- or K+ channels.

Has a potential of +8 mV.

Has a potential of –2 mV.

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IPSP -5 5

10 Milliseconds

15

Fig. 102.9 Excitatory postsynaptic potential (EPSP) and inhibitory postsynaptic potential (IPSP). Case-1: Suppose there are five presynaptic neurons synapsing on one postsynaptic neuron. If two of the presynaptic neurons produce an EPSP (8 mV each) and the other three produce IPSPs (–2 mV each), the summated potential will be +10 mV and synaptic transmission will occur. On the other hand, if only one of them produces an EPSP and the other four produce IPSPs, then the summated potential will equal zero and no synaptic transmission will occur. Case-2: Suppose an inhibitory presynaptic neuron fires off thrice in quick succession, each time producing an IPSP of –2 mV at the same site. If the fresh IPSPs arrive at the synapse before the complete decay of the previous ones, then their potentials will summate “temporally” and “tend to” –6 mV.

The type of summation in case-1 presupposes that the postsynaptic potentials are produced simultaneously. It is called spatial summation because the postsynaptic potentials are “separated in space,” that is they are produced simultaneously at different sites on the soma or dendrite of the postsynaptic neuron (Fig. 102.10). Spatial summation is more complete when the membrane has a high space constant. The summation in case-2 is called temporal summation because the postsynaptic potentials are “separated in time”. Temporal summation is more complete when the membrane has a high time constant, that is, when the decay of the postsynaptic potential is slow. (Space and time constants are explained on p 88.) A less intimidating term for time constant is “holding capacity” of the membrane. The holding capacity is more in the dendritic spines: at the axodendritic synapses on the dendritic spines, the thin neck of the spine (see Fig. 8.1) prevents the high Ca2+ concentration in the spine (during synaptic transmission) from spreading to the main shaft, increasing the holding capacity of the dendrites and thereby, facilitating temporal summation.

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Synaptic Mechanisms and Neurotransmitters

EPSP (8 mV)

Postsynaptic membrane

Initial spike (30 mV)

Initial segment

Action potential (110 mV)

First node of Ranvier

Axon hillock Postsynaptic membrane

IPSP (-2 mV)

Fig. 102.10 Spatial summation of an EPSP and an IPSP, and the generation of initial spike and action potential. Initial spike and action potential If the summated

postsynaptic potential is an excitatory potential, it depolarizes the initial segment ( the axon hillock and the proximal unmyelinated part of the unmyelinated axon) by about 30 mV. This depolarization, which is called the initial spike, is more than adequate for triggering a fully fledged action potential at the first node of Ranvier. The initial segment has the lowest threshold of excitation as compared to the other parts of the soma because it has a higher density of voltage-dependent Na+ channels. The action potential triggered by the initial spike travels not only anterogradely along the axon but also retrogradely to the soma and dendrites. This retrogradely conducted potential, although identical to the action potential, is called by a different name, the soma-dendritic (SD) spike. It thus restores the soma and dendrites to the resting potential, allowing fresh summation of subsequently generated EPSPs and IPSPs. It is like making calculations on a slate and then wiping the slate clean for a fresh set of calculations!

heterosynaptic (Fig. 102.11). Homosynaptic processes occur within the neuron and result from changes in the resting membrane potential or the firing of action potentials. Heterosynaptic processes involve synaptic input from other neurons.

 Homosynaptic plasticity Long-term potentiation (LTP) is the increase in EPSP that occurs following several trains of tetanic stimulation. It persists for hours to days. Long-term potentiation has a short, early phase that does not require new protein synthesis, and a long, late phase that occurs due to growth of new presynaptic release sites and new clusters of postsynaptic receptors. There are two mechanisms of the early LTP phase, viz., posttetanic potentiation and Hebbian potentiation. Posttetanic potentiation is typically seen in the

neurons of the mossy fiber pathway of the hippocampus (see Figs. 100.9 and 100.10). Since each action potential triggers the entry of Ca2+ into the axon terminal, repeated stimulation in quick succession results in accumulation of calcium in the axon terminal. The high intracellular calcium causes the activation of Ca2+/calmodulin-dependant protein kinase. The activated kinase phosphorylates synapsin, allowing synaptic vesicles to be freed from their cytoskeletal restraints so that they can be released. Hence, after posttetanic potentiation, each action potential is associated with greater release of the neurotransmitter. Hebbian potentiation is typically seen in the hip-

pocampus at the synapse between the CA3 neurons (presynaptic) and the CA1 neurons of the Schaffer collateral pathway (postsynaptic). Unlike

Synaptic plasticity

The effectiveness of chemical synapses can be modified for both short and long periods. This modifiability is called synaptic plasticity and is controlled by two types of processes: homosynaptic and

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Heterosynaptic mechanisms

Homosynaptic mechanisms

Long term potentiation (LTP)

Early LTP

Synaptic plasticity

657

Posttetanic potentiation

Long term depression (LTD)

Late LTP

Hebbian potentiation

Presynaptic facilitation

Presynaptic inhibition

Fig. 102.11 Classification of synaptic plasticity mechanisms.

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Central Nervous System posttetanic potentiation which requires the repeated stimulation of the presynaptic neuron alone, Hebbian potentiation requires the simultaneous stimulation of both presynaptic and postsynaptic neurons. Activation of the postsynaptic NMDA and AMPA receptors results in a large Ca2+ influx into the postsynaptic terminal. The high concentration of cytoplasmic Ca2+ activates calcium-dependent protein kinases which phosphorylate the nonNMDA (AMPA) channels, increasing their sensitivity to glutamate as well as activating some inactive channels. Simultaneously, a retrograde messenger, probably nitric oxide, is released from the postsynaptic terminal and diffuses into the presynaptic terminal, resulting in greater neurotransmitter release through some yet unidentified mechanism. Late LTP (late and long-term) too is initiated by

the high concentration of cytoplasmic Ca2+. The Ca2+ activates membrane-bound adenylyl cyclase, leading to the formation of cAMP and the cascading activation of cAMP-dependent protein kinase and mitogen-activated protein kinase. These two kinases diffuse into the nucleus where they activate a transcription protein called CREB-1 (cAMP response element binding protein) and inhibit a transcription-repressing protein called CREB-2, initiating the synthesis of new proteins that lead to structural changes in the synapse. Long-term depression For behavioral flexibility,

neural circuits need to be remodelled continuously, which requires not only the potentiation of certain synapses but also a weakening of certain other synapses. The latter function is fulfilled by long-term depression (LTD) of synapses. LTD occurs on prolonged low-frequency stimulation of synapses, which produces smaller EPSPs that are less effective at relieving the Mg2+ block of NMDA receptors. Consequently, the postsynaptic rise in Ca2+ is less. This low Ca2+ concentration is inadequate for LTP but adequate for the activation of calcineurin, which denatures AMPA receptors, resulting in their endocytosis. The reduction in AMPA receptors on the postsynaptic membrane decreases the size of the EPSP.

 Heterosynaptic plasticity In heterosynaptic plasticity, the facilitatory or inhibitory neuron (neuron C in Fig. 102.12) does not make contact with the postsynaptic neuron (neuron B). Instead, it makes an axoaxonic synapse with the presynaptic axon terminal (neuron A) and increases or inhibits the release of the excitatory neurotransmitters from it. There are two

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A

B

Presynaptic inhibition

GABA

C A

B

Fig. 102.12 (a) Presynaptic facilitation (b) Presynaptic inhibition.

ways in which the presynaptic release of neurotransmitters is altered. In presynaptic facilitation, the facilitatory neuron stimulates the release of excitatory neurotransmitters. The facilitatory neuron usually releases serotonin which acts through serotonergic receptors to activate cAMP-dependent phosphokinase A (as in group-IIA hormones) and phosphokinase C (as in group-IIC hormones). Together, phosphokinase A and phosphokinase C open the L-type Ca2+ channels, thereby enhancing neurotransmitter release. Phosphokinase A also closes K+ channels, resulting in prolongation of the depolarization which keeps the Ca2+ channels open for a longer period. In presynaptic inhibition, the inhibitory neuron

releases GABA, which binds to GABAA or GABAB receptors on the presynaptic neuron terminals. Stimulation of the ionotropic GABAA receptors increases the membrane permeability to Cl– ions. Since the Nernst potential of Cl– is close to the resting membrane potential, the rise in Cl– permeability does not change the membrane potential. However, the high Cl– conductance stabilizes the membrane potential near ECl (i.e., the membrane potential does not change easily) in accordance with the general rule that the membrane potential tends to stay near the Nernst potential of the highly permeable ion. Thus, when an action potential arrives at the presynaptic axon terminal, the depolarization of the presynaptic membrane is less than usual and the presynaptic action potential is dwarfed. The smaller action potential is associated with the release of less neurotransmitter from the presynaptic axon terminal. Stimulation of the metabotropic GABAB receptors increases the membrane permeability to K+ ions and decreases the membrane permeability to

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Synaptic Mechanisms and Neurotransmitters Ca2+ ions. The rise in K+ permeability hyperpolarizes the membrane, dwarfing the presynaptic action

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potentials and reducing Ca2+ influx. The reduction in Ca2+ permeability further reduces the Ca2+ influx and with it, the neurotransmitter release too.

REVISION QUESTIONS 1. How is the number of synapses in a neural pathway estimated? 2. What criteria must be satisfied by a chemical released from the presynaptic nerve terminal to be called a neurotransmitter? 3. Name two false neurotransmitters. Why are they called so? 4. Give four examples of small-molecule neurotransmitter coexisting with neuropeptides in the same neuron. 5. Name two neurotransmitters that can act as retrograde messengers at the synapses. 6. How are neuropeptides different from small molecule neurotransmitters? 7. How are glutamate receptors classified? What is glutamate excitotoxicity? In which conditions does it occur and why? 8. What is the mechanism of “activity-dependent synapse modification” and how does it occur? 9. Name some GABA agonists that have medicinal use, giving the physiological basis of their action.

16. Increased dietary intake of tryptophan increases the amount of serotonin in the serotonergic nerve endings. Why? 17. What are the therapeutic uses of serotonin antagonists? 18. What are “space constant” and “time constant” and how do they affect spatial and temporal summation? 19. Dendritic spines have high “holding capacity”. What is holding capacity and what is its significance? 21. What is “initial spike” and in which part of the neuron is it produced? Where in the neuron is the first action potential produced? 20. What is the physiological significance of the soma-dendritic spike? 21. What is the difference between homosynaptic and heterosynaptic plasticity? 21. What is the difference between “early” and “late” long-term potentiation (LTP)? 22. What is the difference between posttetanic potentiation and Hebbian potentiation?

10. Which neurotransmitter underlies the actions of strychnine and tetanus toxin, and how?

23. What are CREB-1 and CREB-2, and what is their significance in late LTP?

11. Hypertensive patients on MAO inhibitors should not consume cheese, beer and red wine. Why?

24. What is the role of calcineurin in long-term depression? What is the physiological significance of long-term depression?

12. Name two drugs that owe their therapeutic effect to the modulation of cholinergic transmission in the central nervous system.

25. In presynaptic facilitation, serotonin released from the facilitator neuron causes the opening of L-type Ca2+ channels and the closure of K+ channels of the presynaptic neuron. How? How does it affect the neurotransmitter release?

13. The norepinephrine inside the synaptic nerve terminals is constantly degraded by MAO. However, MAO inhibitors decrease norepinephrine-release from nerve terminals. Why? 14. What is the physiological basis of the use of bromocryptine in galactorrhea, acromegaly and Parkinsonism?

26. In presynaptic inhibition, stimulation of the inotropic GABA A receptors on the presynaptic membrane stabilizes the presynaptic membrane potential. How?

15. How is noradrenergic transmission affected by (1) cocaine, (2) amphetamine, (3) guanedrel, (4) bretylium, (5) reserpine?

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Sensory Mechanisms

Sensations that can be discerned at the conscious level are called conscious sensations. They include the senses of touch, position of body parts (sensed by proprioceptors), temperature, pain, gravity and acceleration (sensed by the labyrinth), vision, hearing, taste, and smell. Senses whose receptors are present only in the head, that is, vision, audition, vestibular sense, olfaction, and gustation are called the special senses. There are other unconscious senses that never reach our conscious appraisal but nevertheless effect crucial reflex responses. These senses are mostly visceral, for example, baroreception, but may be somatic, for example, the length and tension of muscles as sensed by the muscle spindles and Golgi tendon organs. Unconscious senses also include the touch and pressure senses that reach the cerebellum through the spinocerebellar tracts and help in postural regulation.

Sensory Receptors Sensory receptors act as transducers that transform different types of stimuli (mechanical, light, sound, chemical) into electrical signals. Most often, it is the axonal ending of a neuron that is modified into a sensory receptor. In the olfactory epithelium, it is the soma of the neuron that is modified into the olfactory receptor. The sensory receptor can also be a nonneural cell. In the retina, for example, the photoreceptors are modified epithelial cells.

 Classification of sensory receptors Classification based on stimulus source Sensory

receptors are broadly classified on the basis of the stimulus source, according to which there are three types of sensory receptors (Fig 103.1): (1) exteroceptors provide information about the

Exteroceptors

General

Interoceptors

Special

Mechanoreceptors Superficial

Photoreceptors Rods and cones in retina

General Mechanoreceptors Baroreceptors

Deep

Slowlyadapting

Rapidlyadapting

Slowlyadapting

Rapidlyadapting

Merkel's disc

Meissner's corpuscle

Ruffini's end organ

Pacinian corpuscle

(Two point discrimination)

Proprioceptors

Mechanoreceptors Hair cells in cochlea

Chemoreceptors Glucoreceptors Osmoreceptors

Chemoreceptors Gustatory receptors Olfactory receptors

(Texture) (Sustained pressure, (Vibration) shape of grasped object)

Thermoreceptors Warmth receptor

Cold receptor

Nociceptors Thermal nociceptors

Mechanical nociceptors

Polymodal nociceptors

Silent nociceptors

General

Special

Mechanoreceptors Golgi tendon organ Muscle spindle Joint capsule

Mechanoreceptors Hair cells in otolith organs Hair cells in semicircular canals

Fig. 103.1 Classification of sensory receptors based both on stimulus source and stimulus energy.

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Sensory Mechanisms external environment, such as touch, pressure, temperature, light, sound, taste, smell, etc. Exteroceptors are subdivided into general exteroceptors that are present in the skin and the special exteroceptors present in the head, represented by the receptors for vision, hearing, taste, and smell. General exteroceptors are further categorized into superfical and deep receptors. (2) Proprioceptors provide information about the position and posture of the body in space. They are present in the muscles, tendons, and joints, and also in the vestibular apparatus. Proprioceptors are further subdivided into general proprioceptors present in the locomotor system (muscle spindles, Golgi tendon organ, and Pacinian corpuscles of the joints) and the special proprioceptors present in the head (receptors of the vestibular apparatus). (3) Interoceptors or visceroceptors sense the state of the viscera or the internal environment, for example, baroreceptors, osmoreceptors, chemoreceptors or proprioceptors of the urinary bladder. Classification based on stimulus energy Further classification of sensory receptors is based on the stimulus energy. According to this classification, sensory receptors are of five types: (1) photoreceptors sense light, for example, the retinal rods and cones. (2) Chemoreceptors sense chemicals. These are used for the sensations of taste and smell as well as for sensing the internal milieu, for example, the glucoreceptors in the hypothalamus. (3) Thermoreceptors sense temperature. Thermoreceptors present in the skin sense the external temperature while those present inside the body sense the core temperature. (4) Mechanoreceptors sense force and pressure. For example, the inner hair cells of the ear sense sound pressure, the otolith organs sense the direction of gravitational force, Pacinian corpuscles sense pressure applied on the skin, the muscle spindle responds to stretching forces applied to muscle, and baroreceptors sense blood pressure. (5) Nociceptors respond to high concentrations of any chemical, intense heat or cold, or intense pressures. Accordingly, they are called thermonociceptors, chemonociceptors, etc. General exteroceptors

General exteroceptors (cutaneous and subcutaneous receptors) detect cutaneous sensations that have been grouped into the epicritic and protopathic sensations. Epicritic sensations include touch, pressure, and proprioception and are mediated by encapsulated receptors. These sensations include the ability to: (1) detect a brief, light touch to the skin, as when tested with a wisp of cotton or the finger (tactile perception) and localize its position (tactile

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localization), (2) resolve by touch spatial detail, such as texture of surfaces (topognosis), and the spacing of two points touched simultaneously (two-point discrimination), (3) recognize the shape of objects grasped in the hand (stereognosis), and (4) detect vibration and determine its frequency and amplitude (pallesthesia). Fine versus crude touch A distinction is also

made between fine touch, which is the ability of two-point discrimination and topognosis, and crude touch, which is merely the ability to detect and localize touch. All types of tactile receptors contribute to the sensation of fine touch whereas crude touch sensation originates only in Meissner corpuscles and hair follicle receptors. Touch, pressure, and vibration are different forms of the same sensation. Pressure is felt when the force applied on the skin is sufficient to reach the deep tactile receptors (see below) whereas touch is felt when the force is insufficient to reach them. Vibrations are rhythmic variations in pressure. Whether a tactile receptor senses pressure or vibration depends on whether the receptor is rapidly adapting or slowly adapting. Slowly adapting deep receptors are meant for signaling sustained pressure: they are useless for signaling vibrations. Conversely, rapidly adapting deep receptors stop discharging in response to sustained pressure: they are useful only when the pressure fluctuates rapidly, that is, during vibration. The higher the adaptation rate of the receptor, the greater is the vibration frequency it can detect. Protopathic sensations involve pain and temperature senses and are mediated by receptors with bare nerve endings. Protopathic sensations are cruder than epicritic sensations and have a protective function of warning of injury. The pain that occurs due to the activation of nociceptors is called nociceptive pain to distinguish it from neuropathic pain that occurs due to direct injury to neurons. Inflammatory pain is an example of nociceptive pain. Examples of neuropathic pain are the neuralgias, phantom limb pain, and anesthesia dolorosa. Anesthesia dolorosa is the occurrence of pain in the absence of sensations. It sometimes follows therapeutic transection of sensory nerves (e.g., dorsal root nerves) performed in an attempt to block neuralgic pain. Tactile receptors, are general exteroceptors for

epicritic senses (Figs. 103.2 and 103.3). They are subdivided into superficial and deep receptors (Box 103.1). Superficial receptors are present in the epidermis or the papillary layer of the dermis. (1) In

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Central Nervous System

Glabrous skin

Hairy skin

Free nerve endings Ruffini endings Meissner corpuscle Merkel receptor Stratum corneum Epidermis

Epidermaldermal junction

Dermis

Hair follicle receptor

Pacinian corpuscle

Fig. 103.2 Location of cutaneous receptors in the skin.

Epithelial cell

Merkel disk

Merkel cell Merkel disk

Schawann cells

Meissner corpuscle Ruffini ending

Pacinian corpuscle

Fig. 103.3 Morphology of cutaneous receptors.

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Sensory Mechanisms

hairy skin, superficial receptors include the hair follicle receptors that respond to hair displacement and the field receptors that respond to skin stretch. (2) In glabrous (nonhairy) skin, the superficial receptors are crowded under the epidermal ridges, especially under the fingerprint ridges, and include Meissner corpuscles and Merkel disks. The Meissner corpuscles are rapidly adapting receptors that sense the texture of a surface, that is, detect whether a surface is rough or smooth. (If the skin is rubbed on a rough surface, the irregularities present on the surface stimulate the touch receptors in rapid succession.) On the other hand, the slowly adapting Merkel disk has the smallest receptor field (see below) and provides the sharpest spatial resolution enabling the finest twopoint discrimination.

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Pain receptors The naked nerve endings of some

of the primary sensory neurons (see below) function as nociceptors. The nociceptors are of four types. The thermal nociceptors are the naked nerve endings of Aδ fibers that respond to extreme temperatures (> 45 or < 5°C). Mechanical nociceptors are the naked nerve endings of Aδ fibers that respond to intense pressure applied to the skin. Polymodal nociceptors are the naked nerve endings of C fibers that respond to high intensity mechanical, chemical, or thermal (hot or cold) stimuli. A subpopulation of these receptors are the pruriceptors that produce the sensation of itch when stimulated. Finally, there are the silent visceral nociceptors that respond to noxious stimuli only in the presence of inflammation, which reduces the threshold of these receptors, resulting in primary hyperalgesia (see below). Temperature receptors Cold receptors are active in the temperature range of 5 to 40°C with maximum sensitivity at 25°C whereas hot receptors are active in the temperature range of 29 to 45°C with maximum sensitivity at 45°C (Fig. 103.4).

Warm fiber

9 Firing rate (per second)

Meissner corpuscles are rapidly adapting superficial receptors which are coupled mechanically to the edge of the papillary ridge, a relationship that confers to them fine mechanical sensitivity. The receptor is a pear-shaped, fluid-filled structure that encloses a stack of flattened cells which are modified Schwann cells. The axon terminal zigzags through the various layers of the corpuscle (Fig. 103.3). Merkel disk receptor is a slowly adapting superficial receptor. It is a small epithelial cell (Merkel cell) in contact with a disk-like expansion of the axon terminal. Merkel receptors are found in clusters (called Iggo touch domes) at the center of the papillary ridge. Ruffini endings are slowly adapting deep receptors. They are fusiform structures that link the subcutaneous tissue to folds in the skin at the joints and in the palm or to the fingernails. Parallel bundles of collagen fibers run through the core of the corpuscle and intermingle with the collagen bundles of the surrounding collagen tissues. The tension on the collagen bundles stimulates the axon endings running through the corpuscle. Pacinian corpuscles (Fig. 103.2) are rapidly adapting deep receptors. They are ovoid structures about 1 mm in length. The corpuscle contains the axon terminal, which is surrounded by several concentric lamellae made of very thin, flat cells separated by narrow, gel-filled spaces. The entire structure is enclosed in a thin connective tissue capsule. There are several other types of sensory receptors, many of which structurally resemble the Pacinian corpuscle and are therefore called Paciniform corpuscles. However, they are much smaller than Pacinian corpuscles and their exact function remains speculative. An example of a Paciniform corpuscle is the end bulbs of Krause.

The deep receptors are present deeper in the dermis or in the subcutaneous tissues. The deep receptors are the same in both glabrous and hairy skin and include Pacinian corpuscles, which sense vibration and Ruffini end organs, which enable the perception of the shape of grasped objects.

6

Normal skin temperature

3

Cold fiber

0 0

10

6 Firing rate (per second)

Box 103.1 Cutaneous receptors

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20 30 40 Skin temperature (oC)

50

Cold fiber Warm fiber

3

0 Skin temperature 34oC

33oC

34oC

Fig. 103.4 Static (above) and dynamic (below) responses of warmth and cold receptors.

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Central Nervous System Temperatures lower than 5°C stimulate cold nociceptors and temperatures higher than 45°C stimulate heat nociceptors. At the normal skin temperature of 34°C, thermoreceptors trigger action potentials at low rates of 2 to 5/s, with the cold receptors more active than the warm receptors. The above characteristics of thermoreceptors denote their static response because they are observed when the temperature is held constant at a particular value and the extent of stimulation depends on the magnitude of temperature change. Thermoreceptors also show a dynamic response that is observed only when the temperature changes. The response depends on the rate of change in temperature.

 Receptor field and sensory acuity Sensations are not present uniformly all over the skin but are intense only in areas overlying sensory receptors. The small intervening areas between receptors are less sensitive to stimuli. This is known as the punctate character of sensations. Receptor field A sensory neuron that has sensory

receptors connected to its dendrites is called a primary sensory neuron and the entire ensemble is called a sensory unit. While each superficial receptor detects touch in a tiny area of the skin, the primary sensory neuron, due to its connections with several superficial receptors, detects touch from a large area of the skin called the receptor field. Unlike superficial receptors, a deep receptor is connected to a single sensory neuron, but it detects pressure from a much larger area of the skin (Fig. 103.5). Hence, the receptor field of a primary sensory neuron that innervates a deep receptor is much larger. Receptor fields overlap considerably. Hence, there is hardly any area on the skin that is not sensed by a receptor field. However, receptor fields of thermoreceptors do not show any overlap, probably because precise localization of thermal stimulus is rarely important to the body. Because of the lack of overlap, it is possible to delineate distinct hot and cold spots on the skin that respond respectively to warmth and cold. Sensory acuity When a single receptor field is

stimulated at multiple spots on it, only a single sensory unit is stimulated and the multiple stimuli will be perceived as a solitary stimulus by the brain. For two stimuli to be perceived distinctly, they must impinge on two distinct receptor fields, stimu-

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Receptor field for pressure Receptor fields for touch 1 2

2

1

Fig. 103.5 Superficial receptors sense only a small area of skin directly overlying them. A primary sensory neuron innervates several of these receptors. A deep receptor such as the Pacinian corpuscle can be stimulated from a much larger area of the skin. It is connected to a single primary sensory receptor.

lating two different sensory units. It follows that the smaller the receptor field, the greater is the sensory acuity, that is, the more acute is the two-point discrimination.

Sensory transduction Adequate stimulus A sensory receptor responds

only to a specific stimulus that is called the adequate stimulus. Stimuli other than the adequate stimulus usually do not stimulate the receptor. However, a strong stimulus can stimulate several kinds of sensory receptors. For example, photoreceptors respond to a blow to the eye, producing a perceptible flash of light called a phosphene. On application of the adequate stimulus, the receptor membrane depolarizes. The magnitude of the depolarization is proportional to the strength of the stimulus and is usually about 10 mV. This potential is known as the generator potential. The generator potential is a local potential that does not propagate but triggers an action potential in the neuron that innervates it. The mechanism of transduction in various sensory receptors are as follows: a mechanoreceptor is stimulated when pressure deforms its membrane, opening stretch-sensitive cation channels on the membrane. In thermoreceptors, the Na+-K+ pump activity is highly sensitive to temperature changes. In cold receptors, a fall in temperature reduces Na+-K+ ATPase activity, thereby causing membrane depolarization. In warmth receptors, a rise in

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Sensory Mechanisms temperature activates temperature-sensitive Na+ channels, resulting in membrane depolarization. Chemoreceptors and photoreceptors are coupled to G proteins and initiate intracellular cascade reaction. Nociceptors have membrane proteins that convert thermal, mechanical, or chemical energy into a depolarizing potential. One such protein is the capsaicin or vanilloid receptor.1 The exact mechanism of pain transduction is not well understood. Primary hyperalgesia It usually occurs when

there is tissue injury and the chemicals released from the injured tissue lower the threshold for excitation of the silent visceral nociceptors, causing hyperalgesia (excessive pain). This hyperalgesia, which occurs due to the sensitization of silent nociceptors, is called primary hyperalgesia to distinguish it from the secondary hyperalgesia that occurs due to the sensitization of the spinothalamic neurons (see below). The algogenic (pain-producing) substances released from injured tissues are potassium ions (from dead cells), histamine (from mast cells), and serotonin (from platelets). Dying cells also release enzymes that lead to the formation of bradykinin (the most potent algogenic substance that is known yet) and prostaglandin E2. Aspirin reduces pain by preventing prostaglandin E2 synthesis.

Primary hyperalgesia can also occur in the absence of tissue injury if there is continuous stimulation of polymodal nociceptors. Activation of a nociceptive nerve terminal stimulates the axon reflex and releases substance P and CGRP from the other terminals of the same nociceptive nerve fiber. These chemicals sensitize the nociceptors to the stimulus, producing primary hyperalgesia (Fig. 103.6). The chemicals also bring about the inflammatory changes (see triple response to trauma, p 307) that usually accompany pain.

 Coding of stimulus intensity There are two different ways in which the intensity of the stimulus is coded, viz., frequency coding and population coding; both coexist. In frequency coding, the frequency of the action potentials generated is proportional to the magnitude of the generator potential. The perceived intensity of the stimulus increases with the increase in the firing rate of the sensory neuron. In population coding, the strength of a stimulus determines the number of sensory units stimulated. A strong stimulus stimulates multiple sensory units while a threshold stimulus excites only a single sensory unit. The number of sensory units stimulated provides to the brain cues about the stimulus strength.

Central sensitization

Mast cell

Histamine

665

CGRP Substance P

Bradykinin 5-HT PG E2 Tissue injury

K+

Receptor sensitization

WDR neuron CGRP Substance P

Nociceptive-specific neuron

Blood vessel

Fig. 103.6 Sensitization of nociceptors through axon reflex. WDR, wide dynamic range.

1

The term “receptor” has two different meanings that are not to be mixed up. A receptor can be a modification of sensory nerve endings, for example, Pacinian corpuscles, muscle spindle, etc. A receptor can also be a large molecule present on the cell membrane or inside the cell that binds to certain specific molecules to initiate cascade reactions.

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Central Nervous System

 Receptor adaptation

Sensory pathways

When a steady stimulus is applied to a receptor, the frequency of the action potentials generated declines gradually. This gradual decline in receptor response to a “sustained” stimulus is called receptor adaptation and it explains why most stimuli, when present continuously, tend to be perceived with decreasing intensity. Some receptors, notably nociceptors, vestibular receptors, and muscle spindle, do not show adaptation. Adaptation may be slow or rapid. Slow adaptation is brought about by (1) the inactivation of Na+ and Ca2+ channels or (2) the activation of Ca+-dependent K+ channels. Both restore the membrane potential to the resting level. Rapid adaptation occurs when, as in the case of the Pacinian corpuscle, the receptor structure filters out the steady component. When pressure is applied to a Pacinian corpuscle, it initially causes deformation of all its concentric layers and deforms the nerve ending in its core. However, the inner layers slowly regain their original position, relieving the pressure on the nerve ending although the outer layers remain deformed (Fig. 103.7).

The general sensations from all parts of the body (except the face) are carried to the spinal cord through the spinal nerves. As the spinal nerve approaches the spinal cord, it divides into the dorsal (sensory) and ventral (motor) roots (the Bell–Magendie law, p 607). The area of skin relaying sensations to a spinal segment is called a dermatome (Fig. 103.8). First, second, and third order neurons The dorsal

root ganglion contains the soma of sensory neurons that are the first in a chain of three neurons that convey sensory information to the cortex via the thalamus. It is called the primary (first order) sensory neuron and it carries sensory information from the sensory receptor to the spinal cord or the brain stem. The secondary (second order) sensory neuron carries the sensations from the spinal cord or brain stem to the specific relay nuclei of the thalamus (the ventroposterior nuclei). The tertiary (third order) sensory neuron carries the sensations from the specific thalamic nuclei to the sensory cortex, mostly to its fourth layer.

Undistorted Pacinian corpuscle

T2

C2

T7

T12 L1

L3

S1 S3

C3 C4 Outer lamina distorted Brief Pressure Inner lamina distorted

S5

C5

C6

T1

T1

Nerve ending distorted

Outer lamina distorted

L3

C8 Sustained Pressure

Inner lamina undistorted

L4 C7 S2 L5

Nerve ending undistorted

Fig. 103.7 Adaptation of Pacinian corpuscle.

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S1

Fig. 103.8 Dermatomes.

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Sensory Mechanisms

 First order (primary) sensory neurons

 Second order (secondary) sensory neurons

The primary sensory neuron is a T-shaped pseudounipolar neuron with peripheral and central processes. Its cell body is located in the dorsal root ganglion. Its peripheral process reaches the sensory receptor, and its central process reaches the spinal cord through the dorsal nerve root of the spinal nerve. The primary sensory neurons in the dorsal nerve root are of different types, viz., Aα, Aβ, Aδ, and C group fibers (Table 18.1) . These fibers are respectively called group I, II, III, and IV by sensory physiologists. Aγ and B fibers are not present in sensory pathways (Table 103.1). At root entry, each rootlet presents the medial and lateral divisions. The medial division contains neurons that carry fine touch, pressure, and proprioception and ascends as the dorsal column pathway while the lateral division contains neurons that carry pain, temperature, and crude touch and ascends as the anterolateral pathway. The two pathways converge on the thalamus, from where both travel to the sensory cortex by the thalamocortical pathway. The anatomic separation of the two sensory tracts has important clinical implications. (1) It permits the surgical abolition of pain by cutting the pain-carrying fibers in the anterolateral spinothalamic tract. (2) As touch travels through both pathways it is often spared in lesions of the central nervous system. (3) A lesion in the dorsal column pathway abolishes fine touch but spares crude touch (see Tabes dorsalis, p 674).

Dorsal column-medial lemniscal pathway The

Table 103.1 Classification of sensory nerve fibers Fiber type

Sensory group

Origin

Aα

Ia

Annulospiral endings on intrafusal muscle fibers

Ib

Golgi tendon organ

II

Flower-spray endings on intrafusal muscle fibers

Aβ

Touch and pressure receptors Aγ Aδ

Absent in the sensory system III

B C

2

Receptors for pain (fast), cold, and crude touch Absent in the sensory system

IV

Pain (slow) and temperature

667

medial division of the dorsal root contains the myelinated group-I (Aα) and group-II (Aβ) fibers that carry fine touch, pressure, and proprioceptive information and ascend through the spinal cord ipsilaterally. The fibers from the lower part of the body ascend as the fasciculus gracilis while the fibers from the upper part of the body ascend as the fasciculus cuneatus. The two fasciculi are together called the dorsal columns and they terminate respectively on the nucleus gracilis and the nucleus cuneatus in the medulla. The secondary sensory neurons originating in these dorsal column nuclei decussate in the medulla as the internal arcuate fibers and ascend in the brain stem as the medial lemniscus, terminating finally in the ventroposterior nucleus of the thalamus (Fig. 103.9). pathway The lateral division of the dorsal root consists of thinly myelinated group-III (Aδ) fibers and unmyelinated group-IV (C) fibers that carry pain and temperature. After entering the spinal cord, these primary sensory neurons ascend or descend one or two spinal segments before terminating in the dorsal horn of the spinal gray matter on the cell bodies of the spinothalamic (second-order) neurons. The second-order neurons are of two functional subtypes: the nociceptive-specific neurons that respond only to nociceptive stimuli, and the wide dynamic range (WDR) neurons that respond to both noxious and nonnoxious stimuli (Fig. 103.6). The axons of these cells decussate in the anterior white commissure. The pain fibers cross horizontally in the same cord segment. The temperature fibers cross obliquely, that is, they ascend slightly while crossing. Crude touch fibers cross even more obliquely.2 After crossing, the fibers for pain and temperature ascend contralaterally in the lateral spinothalamic tract which, higher up in the brain stem, is called the spinal lemniscus. The secondary sensory neurons carrying the sensation of crude touch ascend in the contralateral anterior spinothalamic tract. In the brain stem, the anterior spinothalamic tract joins the medial lemniscus. As pain is conducted by both Aδ and C fibers that differ considerably in conduction velocities, it results in two types of pain: following an injury, Anterolateral-spinothalamic

It is important to bear in mind the obliquity of the crossing fibers while diagnosing the level of a spinal lesion.

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Central Nervous System there is an immediate sharp pain (conducted by Aδ fibers) called the fast pain followed after a few seconds by a dull aching pain (conducted by C fibers) called the slow pain.

Trigeminal lemniscus The sensations from the

face travel directly to the brain stem through the trigeminal nerve. Fibers for fine touch terminate in the pons on the principal sensory nucleus of the trigeminal nerve. Fibers for proprioception end on the mesencephalic nucleus of the trigeminal. Fibers carrying pain, temperature, and crude touch end on the spinal nucleus of the trigeminal (Fig. 103.10, and see Table 96.3). Fibers from these three nuclei of the trigeminal nerve ascend to the thalamus as the trigeminal lemniscus. (The fourth nucleus of the trigeminal is its motor nucleus that sends descending fibers to the muscles of mastication.) Spinal tracts for pain only There are three other

VPM nucleus of thalamus Midbrain

Medial lemniscus

Spinal lemniscus

spinal tracts that conduct pain only. The spinoreticulothalamic tract conveys pain sensation to the intralaminar nuclei of the thalamus after relaying in the medullary and pontine reticular formation. Pain fibers to the reticular formation produce diffuse pain and bring about a general arousal. The spinomesencephalic tract conveys pain to the reticular formation and periaqueductal gray matter in the midbrain. From there, the pain fibers project to the amygdala via the parabrachial nucleus. The

Pons

Trigeminal lemniscus Midbrain

Medulla

Fine touch to the principal sensory nucleus

Anterior spinothalamic tract

Medulla

Fine touch and proprioception

Crude touch

Dorsal column

Spinal cord

Dorsolateral tract

Pain, temperature, and crude touch to spinal nucleus

Fig. 103.9 Somatosensory pathways.

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Pons

Trigeminal ganglion

Lateral spinothalamic tract Pain and temperature

Proprioceptive fibers to the mesencephalic nucleus

Motor fibers to muscles of mastication

Fig. 103.10 Trigeminal pathways.

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Sensory Mechanisms amygdala mediates the emotional component of pain. The spinohypothalamic tract conveys pain fibers to the hypothalamus, which activates neuroendocrine and cardiovascular responses to pain.

 Third order (tertiary) sensory neurons Fibers of spinal and medial lemnisci terminate in the same thalamic nuclei, that is, mainly the ventroposterior (VP) nuclei of the thalamus. Pain and temperature are primarily appreciated by the thalamus. For other forms of sensation, the thalamus is unable to analyze the details of sensations. Fibers carrying tactile and proprioceptive information ascend through the thalamocortical pathway to area 3 of the primary somatic sensory cortex. The sensory cortex receives general sensation from all parts of the body. The various parts of the body have a cortical representation proportionate to their innervation density and not to their size. When the cortical areas are charted out for their peripheral connections and depicted diagrammatically, the distorted shape of a “little man” emerges. This is called the sensory homunculus (see Fig. 100.7).

Subcortical sensory processing Sensory processing occurs as early as in the secondary sensory neurons. This is true for both the dorsal column and the anterolateral pathways. Processing in the dorsal columns occurs in the nucleus gracilis et cuneatus. Processing in the anterolateral pathway occurs mostly in the dorsal horn of the spinal cord. Further processing occurs higher up in the thalamus.

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secondary nociceptive fibers show an exaggerated response to the discharge of primary nociceptive neurons, resulting in secondary hyperalgesia. The central sensitization underlies a clinical symptom called phantom limb pain, an excruciating pain in a nonexistent limb that has been amputated. The sensitization occurs due to the excessive stimulation of the primary nociceptive afferents during amputation. Phantom limb pain occurs even if the amputation is performed under general anesthesia. It can be prevented only by applying local anesthetics to the site of amputation so as to prevent excessive stimulation of the primary nociceptive afferents. Dorsal horn gating Lamina II of the dorsal horn

of spinal cord (substantia gelatinosa, SG) contains enkephalinergic inhibitory interneurons that inhibit, presynaptically as well as postsynaptically, the nociceptive spinothalamic neurons present in lamina V. These inhibitory interneurons are stimulated by the collaterals of tactile Aβ fibers of the dorsal root, and are inhibited by the collaterals of nociceptive Aδ and C fibers (Fig. 103.11). In other words, the SG inhibitory interneurons serve as a gate in the pain pathway. The gate opens when only Aδ and C fibers are stimulated but closes when Aβ fibers are stimulated simultaneously. The gate-control theory provides the basis for using vibratory stimulation for reducing pain. In transcutaneous electrical stimulation (TENS), surface electrodes are used to stimulate Aβ fibers in the area of injury. Stimulation of dorsal columns via surface electrodes has also been used. Even the simple massage owes its pain-relieving efficacy to the gate control of pain. The SG enkephalinergic inhibitory interneurons are also stimulated by the serotonergic neurons descending from the raphe nuclei in the medulla

 Dorsal horn of spinal cord The primary nociceptive afferents release two classes of neurotransmitters: the excitatory amino acids, such as glutamate, and the neuropeptides, such as substance P, and calcium-gene-related peptide (CGRP). The neuropeptide neurotransmitters diffuse long distances from the sensory nerve terminal as they have no specific uptake mechanisms, thereby causing poorly localized pain.

Inhibitory interneuron

Touch (Aβ) fibers

Secondary hyperalgesia When the primary noci-

ceptive C fibers discharge continuously, it sensitizes the nociceptive-specific spinothalamic fibers through long-term potentiation. This sensitization is called central sensitization or winding up to distinguish it from the nociceptor sensitization that occurs in primary hyperalgesia. Sensitized

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Pain (Aδ, C) fibers Inhibitory interneuron in substantia gelatinosa

Fig. 103.11 Dorsal horn gating.

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Central Nervous System (Fig. 103.12). Enkephalinergic and dynorphinergic neurons descending from the periaqueductal gray matter in the midbrain inhibit pain by stimulating the raphe nuclei. Neurons containing β-endorphin descend from the hypothalamus to terminate on the periaqueductal gray matter. The μ opioid receptors are highly concentrated in the periaqueductal gray matter, medullary raphe, and the dorsal horn. Hence, intrathecal or epidural injection of morphine into the spinal subarachnoid space is effective in abolishing postoperative pain and cancer pain. Opioid receptors are also located in the peripheral terminals in skin, joints, and muscle. Hence, prolonged relief of pain is obtained by intraarticular morphine injection. Stress-induced analgesia Opioid substances are

produced endogenously in response to pain and a

Hypothalamic neurons containing β-endorphin

Periaqueductal gray matter Midbrain

Neuron containing enkephalin and dynorphin descending from periaqueductal gray matter

Locus ceruleus

Neuron containing norepinephrine descending from locus ceruleus

Lateral inhibition The primary sensory neu-

rons produce lateral inhibition of the secondary sensory neurons originating in the nucleus gracilis et cuneatus. Lateral inhibition is explained diagrammatically in Fig. 103.13. Because of lateral inhibition, the signal traffic at the edges of a parallel group of neurons is greater than it is at the middle of the bundle. This is because the central neurons are mutually inhibited by lateral inhibition from both sides while the neurons at the edges escape any inhibition from the periphery. Thus, lateral inhibition causes contrast enhancement, creating an outline of the stimulated area that requires much less sensory traffic. Little traffic is devoted to the signaling of the intervening areas. In this way, the brain economizes on the traffic of signals. A common experience is that when the hand is immersed in hot water,

Secondary sensory neurons

H

I

J

K

L

M

N

A

B

C

D

E

F

G

Medulla

Neuron containing serotonin descending from raphe nucleus

Primary sensory neurons

Enkephalinergic interneuron

Fig. 103.12 Supraspinal control of pain.

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 Dorsal column nuclei

Pons

Raphe nuclei

Ascending pain pathway

variety of other stresses. These reduce the neurotransmission in nociceptive neurons by binding to the opioid receptors on their axonal endings and decreasing the neurotransmitter release. It explains why soldiers injured in the battlefield can bear the pain even when grievously injured.

Spinal cord

Fig. 103.13 Lateral inhibition in a dorsal column nucleus. Stimulation of a group of primary sensory neurons (B–F) results in weak stimulation of the secondary sensory neurons that are located in the core (J–L) because these neurons are the target of lateral inhibition from all around. Secondary neurons located at the edges (I, M) are moderately stimulated because they are inhibited only by the core neurons and not by the unstimulated neurons at the periphery (A, H, G, N). Red, stimulated neuron; White, unstimulated neuron; Blue, inhibitory interneuron.

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tions of various types are gated as required. Thus, the sensory cortex preferentially facilitates the thalamic relay of certain types of sensations while inhibiting the relay of some others, forming the basis for selective attention.

Cortical sensory processing Fig. 103.14 Lateral inhibition at work. (Left) Hand immersed in hot water. (Right) The subject points to the region of maximum heat pain.

maximum warmth is felt along the edges of the immersed area and not in the entire immersed part (Fig. 103.14). The experience provides a practical example of lateral inhibition at work.

 Thalamus Pain processing The thalamus has an important role in pain processing. The thalamus receives pain fibers through two different tracts: (1) the phyllogenetically older spinoreticulothalamic tract and (2) the newer lateral spinothalamic tract. Injury to the lateral spinothalamic tract or to the ventroposterior nucleus results in a spontaneous burning pain called thalamic pain and is part of the thalamic syndrome of Dejerine-Roussy (p 624). The cause of thalamic pain remains unknown but it could be due to the disruption of the interaction of pain with tactile and thermal stimuli. The interaction between temperature and pain is proved by the Thunberg illusion of pain produced by touching closely-spaced alternating warm and cool bars. The interaction between tactile and nociceptive stimuli can be demonstrated through another simple experiment: A blood pressure cuff is applied to the arm and the pressure in it is kept raised higher than the systolic pressure for several minutes till the conduction in Aα and Aβ fibers is blocked. (These fibers are more prone to ischemic hypoxia than the Aδ and C fibers.) The pain that is now conveyed by the Aδ and C fibers is altered. A pin-prick, a pinch or contact with ice cannot be distinguished now; instead, they all produce burning pain. Selective attention The sensory cortex issues

corticofugal fibers, that is, efferent fibers to the thalamic relay nuclei where the ascending sensa-

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The parietal cortex contains at least eight complete somatotopic sensory maps of the entire body, four of which are present in the primary sensory cortex, one each in areas 3a, 3b, 1, and 2. Each map processes a different type of sensation for the whole body, with the sensory homunculus shown in Fig. 100.7 involved only in basic tactile processing.

 Primary sensory cortex (S-I) Most thalamocortical fibers terminate in areas 3a and 3b of the primary sensory cortex. Area 3a receives proprioceptive information. Area 3b receives tactile information from cutaneous mechanoreceptors, both superficial and deep, and detects which part of the skin is touched (tactile localization). In area 3b, the mechanoreceptive inputs from rapidly and slowly adaptive receptors are processed separately. Area 1 receives, through area 3b, convergent input from large areas of the skin, mostly from the rapidly-adapting mechanoreceptors. This information allows area 1 to assess the texture of a surface over which the skin is rubbed. The neurons of area 1, with their multifinger receptor fields, fire at a higher rate if several fingers are touched together. This enables area 1 to sense the object size. Area 2 receives convergent inputs from areas 3a and 3b. Thus, it receives information from slowly and rapidly-adapting cutaneous receptors as well as from proprioceptors in the underlying muscles and joints. The multiplicity of the inputs enables area 2 to recognize the size and shape of a grasped object (stereognosis) and to recognize the direction of motion of an object on the skin. These abilities are made possible by the presence of two types of neurons in area 2: the orientation-sensitive neurons sense the angle of edges contacted by the skin, and direction-sensitive neurons respond vigorously when the skin is stroked in a preferred direction but not when stroked in the opposite direction. Such neurons are found in area 1 too, but are abundant in area 2 (Fig. 103.15).

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Central Nervous System Plasticity of sensory cortex The afferent conCutaneous mechanoreceptors

Proprioceptors

Photoreceptors

S-I Area 3b

Area 3a

Tactile localization Superior colliculus Area 1

Area 2

Object size, surface texture

Object shape (stereognosis), direction sensitivity of touch Pulvinar

S-II

 Cortical pain areas

Area 5 Hippocampus (Selective memory) Area 7 Motor areas (Visually guided movements)

Fig. 103.15 Cortical sensory processing.

 Secondary sensory cortex (S-II) The secondary somatic sensory cortex (S-II) receives information from all areas of S-I and determines whether a piece of tactile information is remembered or not. This selective memory is made possible by the projection of S-II to the hippocampus via the insular cortex.

 Posterior parietal cortex The posterior parietal cortex (areas 5 and 7) receives input from S-I and S-II as well as input from the pulvinar. The posterior parietal cortices of the two hemispheres are connected through the corpus callosum and are therefore able to integrate information from both sides. Area 5 integrates tactile inputs from mechanoreceptors in the skin with proprioceptive inputs from the underlying muscles and joints. Area 7 belongs to the multimodal association cortex. It integrates the tactile and proprioceptive inputs with visual information, enabling visually guided hand movements. The posterior parietal cortex enables the perception of extrapersonal space. It projects to the motor areas of the frontal lobe and plays an important role in the sensory initiation and guidance of reaching and grasping movements.

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nections of the sensory cortex can change with extensive use or total disuse of the senses. Rigorous sensory use of a particular part of the body leads to an increase in the area of representation of that part in the sensory cortex. Similarly, if a part of the body is ablated, sensory afferents from the neighboring parts establish connections with the deafferented area of the sensory cortex. The same is true for different modalities of sensations. Thus, auditory and tactile afferents have been observed to invade the visual cortex in the blind. Such plastic changes occur not only during development but also in adults.

The cingulate gyrus processes the emotional component of pain. The anterior cingulate gyrus is critical to the perception of thermal pain. The insular cortex receives afferents from the thalamic nuclei and integrates the sensory, cognitive, and affective components of pain. Lesions of the insular cortex results in asymbolia for pain: these patients perceive noxious stimuli as painful and can distinguish sharp from dull pain but do not display appropriate emotional response to the pain. Severe pain can be dissociated from its unpleasant feeling by prefrontal lobectomy, that is, cutting the deep connections between the frontal lobes and the rest of the brain. Patients operated in this way feel the pain but are “not bothered by it” (p 701).

Sensory perception Sensory perception is constructed internally by the brain and is not an exact reflection of the real world. For example, the colors of the rainbow reside only in our brain because electromagnetic radiations, which include light, do not have any color of their own. The relationship between the physical characteristics of a stimulus and the attributes of its sensory perception forms the subject of psychophysics. Mostly however, our perception gives a reasonably accurate picture of the reality. When it does not, it is called an illusion (Fig. 103.16). When we perceive nonexistent things, it is called hallucination. For example, cocaine consumption causes tactile hallucinations that give the feeling of ants crawling under the skin although there are none! Hallucinations are common in schizophrenia. Sensory conflict In certain situations, different sensory organs can send conflicting information

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receptors will always evoke thermal sensation, whether it is stimulated naturally through its receptors or whether the nerve is stimulated directly. Even if a sensory nerve is denuded of its receptors, it will still evoke the sensation characteristic of the severed receptors. The phenomenon is called the doctrine of specific nerve energies. If a cortical touch area gets connected with a skin temperature receptor, then the temperature stimulus will either not be recognized or will be misinterpreted as touch.

 The Weber–Fechner law

Fig. 103.16 (Above) Müller-Lyer illusion. The line above appears shorter than the line below. Measurement will show them to be of equal length. (Below) Kanizsa triangle. The white triangle with apex up is visible to most observers although its contours are illusory.

to the sensory cortex. It is believed that motionsickness results at least partly from the conflicting visual and vestibular signals regarding the inclination of the horizon.

 Doctrine of specific nerve energies The type of sensation perceived depends on the area of the sensory cortex stimulated, which in turn depends upon the type of receptors stimulated. Hence, a neuron connected to thermal

It has been observed that to provide equal increments in sensory perception, the stimulus intensity has to be increased by a constant factor. This is called the Weber–Fechner law. The law helps explain why a 1-W and a 10-W bulb (or loudspeaker) will have the same difference in brightness (or loudness) as between a 10-W and a 100-W bulb (or loudspeaker). This law forms the basis of the decibel scale of loudness, as depicted comically in Fig. 103.17. Similarly, the law explains why a 2-kg weight feels distinctly heavier than a 1-kg weight but it is difficult to distinguish a 12-kg weight from a 11-kg weight although the difference in weight in both cases is 1 kg.

Sensory projection The sensation evoked by a sensory unit is projected to (i.e., appear to originate from) the area innervated by its peripheral endings. This remains true even if the peripheral end of the nerve is severed and the central stump is stimulated, or even when the area innervated by the nerve is ablated. Thus, in a person with an amputated leg, if a sensory nerve

Fig. 103.17 The Weber–Fechner law at work. Ten babies, not two, must cry together to produce twice the noise produced by a single crying baby.

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Central Nervous System originally carrying pain from the toe is stimulated in the thigh region, pain will be felt in (referred to) the nonexistent toe! The phenomenon is known as the phantom limb (nonexistent limb). Tactile localization becomes inaccurate when abnormal connections are established between the periphery and the cerebral cortex. Suppose an area X of the sensory cortex that was originally connected with the base of the thumb becomes connected to the tip of the thumb following peripheral nerve injury and regeneration. Experience has taught the brain that cortical activity at area X represents stimulation of the thumb base. Hence, after aberrant peripheral connections are established, sensory impulses from the thumb tip reach area X and are falsely localized to the thumb base. The false localization can only be overcome, if at all, by prolonged practice. Referred pain The pain originating from the viscera is not referred to the appropriate visceral area. Instead, it is referred to the dermatome corresponding to the spinal segment through which the visceral afferents relay. This is known as referred pain. There are two theories of referred pain (Fig. 103.18). (1) The convergence-projection theory holds that the visceral and somatic afferents

Somatic pain fiber

Visceral pain fiber

Spinal lemniscus

belonging to the same spinal segment converge on the same secondary sensory neuron (in lamina V of the spinal gray matter) and any sensory signal reaching the cortex through this common path is interpreted as coming from the somatic area rather than its visceral counterpart. (2) The facilitation theory holds that any visceral sensory traffic facilitates the adjacent synapses relaying somatic sensations in the same spinal segment. The subthreshold somatic sensations from the corresponding dermatome are consequently perceived with augmented intensity.

Sensory disorders Tabes dorsalis, a consequence of tertiary syphilis,

destroys the central processes of the large diameter neurons in the dorsal root ganglia, resulting in the degeneration of the dorsal columns (Fig. 103.19). It affects mostly the lumbar and lower thoracic segments of the spinal cord and is associated with loss of fine touch, pressure, and proprioception on the side of the lesion. Loss of proprioception results in sensory ataxia: the patient walks on a broad base with the legs apart, eyes fixed to the ground for correcting the steps, raising the legs excessively high and slapping the feet on the ground. Since these patients are heavily dependent on visual cues for maintaining posture, the sensory ataxia is aggravated by closing the eye. This is known as positive Romberg sign, which distinguishes it from cerebellar ataxia. Syringomyelia is a rare condition that is char-

acterized by overgrowth of neuroglial tissue and cavitation of the gray matter around the central canal of the spinal cord. Fibers that decussate in the gray commissure are destroyed (Fig. 103.19), resulting in loss of pain and temperature sensitivity. Convergence theory of referred pain

Somatic pain fiber

Visceral pain fiber

Spinal lemniscus

Damaged in tabes dorsalis

Damaged in syringomyelia

Touch and pressure

Pain Facilitation theory of referred pain

Fig. 103.18 Two theories of referred pain.

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Fig. 103.19 Site of lesion in tabes dorsalis and syringomyelia.

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Sensory Mechanisms However, fibers carrying the sensation of fine touch that ascend in the dorsal column escape damage. Hence, syringomyelia is characterized by dissociated anesthesia, that is, loss of pain and temperature sensitivity with retention of touch sensation. The deficiency is bilateral and usually occurs in the hands and arms due to the predilection of syringomyelia for the cervical enlargement of the cord. The gliosis and cavitation may spread, resulting in motor deficits. Cortical lesions Lesions in the primary somato-

sensory cortex produce astereognosis, that is, loss of the ability for stereognosis. Damage to the right parietal association area results in left-sided sensory neglect as well as left-sided motor deficits such as poor eye–hand coordination during reaching, grasping, and hand-orientation. Sensory neglect can take three forms. In personal neglect, the patient disowns the left half of his body or its parts: he is either unaware that the left half of his body exists or believes it to belong to someone else (Fig. 103.20).

Fig. 103.20 (Above) Spatial neglect. The patient was asked to draw a clockface and set it to quarter past twelve. (Below) Personal neglect. The food is eaten from one side of the plate.

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In spatial neglect, the patient is unaware of the left side of his extrapersonal space. Thus when asked to sketch out a clock placed in front of him, he will ignore the parts of the clock in the left half (including numbers 7–11) on the clock and draw out the rest. In representational neglect, the patient ignores the left half of mental images that he recalls from memory. For example, if he is asked to sketch out his office desk imagining himself to be seated in his own chair, he forgets to sketch out things to the left. On the contrary, if he is asked to sketch out the same desk imagining himself to be seated on the opposite side of the desk, the sketch once again reveals his left-sided neglect (Fig. 103.21). Thus, although the patient is evidently aware of the complete spatial organization of his desk, the representational neglect depends on the perspective from which he recalls the mental image. It indicates that spatial memory recalled from the hippocampus must be routed through the sensory association areas.

Fig. 103.21 Example of representational neglect. (Above) A view of the office desk of a patient. (Below) The patient draws the diagram of the desk imagining himself to be seated, first on his own chair (below left) and then, on the opposite side (below right).

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Central Nervous System REVISION QUESTIONS 1. What are the unconscious senses? 2. Which part of the neuron is modified into a sensory receptor? Can a sensory receptor be a non-neural cell? 3. How are sensory receptors classified based on (1) stimulus source, (2) stimulus energy? 4. What are epicritic and protopathic senses? Which type of exteroceptors detect these sensations? 5. What is the difference between the sensations of (1) crude touch and fine touch; (2) touch, pressure and vibration? 6. What is the difference between nociceptive pain and neuropathic pain? 7. What is the difference between a superficial and a deep receptor? 8. Which type of receptor (1) senses the texture of a surface, (2) enables the finest two-point discrimination, (3) senses vibration? 9. What are silent visceral nociceptors? 10. The receptor fields of which type of sensory neurons do not show any overlap? 11. How is sensory acuity related to the size of the receptor field? 12. What is the difference between “frequency coding” and “population coding” of stimulus intensity? 13. Which sensory receptor shows rapid adaptation, and why? 14. Slow adaptation of receptors is a chemical process but rapid adaptation is a physical process. Explain. 15. What are wide dynamic range (WDR) neurons? 16. What is the difference between (1) slow and fast pain; (2) primary and secondary hyperalgesia? 17. Name the three spinal tracts for pain. How are they functionally different? 18. What is the “gate control theory” of pain and how is it put to therapeutic use?

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19. What is lateral inhibition and what is its physiological significance? 20. The perception of tactile, thermal and nociception are interdependent, which can be demonstrated through some simple experiments. What are these experiments? 21. Which area(s) of the primary sensory cortex is/are specialized for (1) tactile localization, (2) assessing the texture of a surface, (3) recognizing the shape of a grasped object, (4) assessing the size of an object, (5) recognizing the direction of motion of an object on the skin? 22. One function of S-II is attributable to the projection of the secondary sensory cortex to the hippocampus via insular cortex. What is that function? 23. What are the sensory functions of the posterior parietal cortex? 24. When the insular cortex is damaged, the patient does not display appropriate emotional response to pain. What is the condition called? 25. What is the difference between illusion and hallucination? 26. What is the doctrine of specific nerve energies? 27. What will be the sensory perception if a cortical area of touch gets connected with a skin temperature receptor? 28. What is the Weber–Fechner law? 29. What is phantom limb pain and how can it be prevented? 30. What is referred pain and why does it occur? 31. What is sensory ataxia and why is it aggravated by the closing of eyes? What is Rhomberg sign? 32. What is “dissociated anesthesia” and why does it occur in syringomyelia? 33. Damage to which part of the brain causes sensory neglect? What is the difference between personal neglect, spatial neglect, and representational neglect?

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Regulation of Muscle Length and Tone

There are two reflex mechanisms through which a muscle is maintained at a constant length. One is the monosynaptic reflex which is a spinal reflex, and the other is the long-loop stretch reflex which is a cortical reflex (i.e., its reflex center is located in the cerebral cortex). The sensory receptor involved in these reflexes is a proprioceptor called the muscle spindle that is located inside the muscle. Muscles also have a reflex mechanism through which an excessive rise in muscle tension is prevented. It is a spinal reflex called the negative stretch reflex or the Golgi-tendon reflex. The proprioceptor involved in the reflex is the Golgi tendon organ which, as the name suggests, is located in the muscle tendon.

degree of precision of the muscle. Thus, the gastrocnemius muscles contain as few as 5 to 10 spindles per gram of muscle while the interossei muscles of the hand contain as many as 100 spindles per gram of muscle. The ends of the muscle spindle are fixed to an adjacent muscle fiber. Within the spindle, a few specialized muscle fibers are present. These fibers are called intrafusal fibers to distinguish them from the fibers of the muscle itself which are called extrafusal fibers (fusus: spindle). Intrafusal fibers are of two subtypes: (1) the nuclear bag fibers, which have a bulge in the equatorial region due to the presence of a bunch of nuclei, and (2) the nuclear chain fibers, which have no such bulge since the nuclei in its equatorial region are arranged in single file (Fig. 104.1).

Muscle spindle

Sensory innervation of muscle spindle Two types of sensory nerve fibers originate from the intrafusal fibers. (1) The annulospiral (primary) endings are wound around the equatorial regions of intrafusal fibers. They are present on both nuclear bag and

Muscle spindles are located within the muscle, intermingled with the muscle fibers. The number of spindles in a muscle is proportionate to the

Group-II fibers Group-Ia fibers

α motor neuron γ2 fibers γ1 fibers

Intrafusal Nuclear chain fiber muscle fibers Nuclear bag fiber

Extrafusal muscle fiber

Fig. 104.1 Muscle spindle and the monosynaptic reflex arc.

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Central Nervous System chain fibers. Annulospiral endings are Aα nerve fibers and are called type-Ia fibers by sensory physiologists. (2) The flower-spray (secondary) endings innervate the peripheral parts of the intrafusal fibers, mostly of the nuclear chain fibers. Flower spray endings are Aβ nerve fibers and are called type-II fibers by sensory physiologists.

Spindle loading

Normal Intrafusal fiber contracted at its periphery: center stretched

Motor innervation of muscle spindle The central

nuclear region of the intrafusal fiber does not contain any contractile protein. Only the peripheral parts of the intrafusal fibers contain the contractile proteins as obvious from the cross-striations present in the periphery. The peripheral parts of the intrafusal fibers are innervated by motor fibers which are of the Aγ type and are called γ-motor neurons or fusimotor neurons. These γ-motor neurons have their cell bodies in the anterior gray horn of the spinal cord where they are interspersed among the soma of the Aα neuron which are called α-motor neurons. They supply the extrafusal fibers. As with sensory innervation, motor innervation of the spindle is also of two types, the γ1 and γ2 fibers, which innervate the polar regions of the bag and chain fibers, respectively. Aγ fibers alter spindle sensitivity to stretch. γ1 fibers alter the dynamic sensitivity while γ2 fibers alter the static sensitivity of the stretch reflex.

 Spindle loading and unloading When the extrafusal fiber contracts, it pulls its ends nearer and tries to move any external load attached to it. On the contrary, when the intrafusal fiber contracts, its ends do not come nearer because they are fixed to the adjacent extrafusal fibers; instead, its own noncontractile equatorial region is stretched. The stretching of the equatorial region of the intrafusal fiber is called spindle loading. The spindle is loaded (1) when the muscle is stretched or (2) when the γ-motor neurons are stimulated by descending motor influences from the brain. The spindle unloading occurs when the α-motor neurons are stimulated and the muscle contracts (Fig. 104.2). Spindle loading through muscle stretch When

muscle is stretched, the muscle fibers as well as the spindles are stretched. In the spindle, the stretch is unequally shared by its peripheral and equatorial parts. The stretching occurs more at the center, where the compliance is high and less at the periphery, where the compliance is low. Stretching of the equatorial region stimulates the sensory afferents originating there. The reflex muscle contraction thus produced is called the stretch reflex. 1

Extrafusal fiber stretched. With it, the intrafusal fiber is stretched too; both at center and at the periphery. Spindle unloading Normal

Extrafusal fiber contracted. With it, the intrafusal fiber becomes lax and unloaded.

Fig. 104.2 Spindle loading and unloading.

Spindle loading through γ-motor discharge The

intrafusal muscle fibers are more contractile at the periphery (which contains numerous striations) than at the center (which is sparsely striated). Moreover, it is only the peripheral part that receives the motor innervation (Aγ fibers). When the Aγ fibers are stimulated, only the peripheral parts of the intrafusal fibers contract, resulting in the stretching of its central part and stimulation of the spindle afferents. Spindle unloading through α-motor discharge

α-motor neurons produce contraction of the extrafusal fibers. Since the ends of the spindle are attached to extrafusal fibers, the spindle folds up when the extrafusal fibers contract. To stimulate the spindle, it must first be stretched to its original length before it can produce afferent discharge of the spindle. Hence, α-motor discharge decreases the spindle afferent discharge.

 Static and dynamic spindle responses When the intrafusal fiber is stretched, the primary and secondary afferents respond differently. Afferents originating in the nuclear chain fibers show a static response, that is, their discharge frequency is proportional to the magnitude of stretch. Afferents originating in the nuclear bag fibers show a dynamic response, that is, their discharge frequency is proportional to the velocity of stretch.1 Since the group-Ia

The mnemonic “(B)right (D)ay, (C)lear (S)ky” should help in remembering that (B)ag fibers show (D)ynamic response while (C)hain fibers show (S)tatic response.

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Regulation of Muscle Length and Tone afferents originate from both bag and chain fibers, they show both static and dynamic responses. GroupII afferents originate only from the chain fibers and therefore show only static response. Both static and dynamic responses are necessary because static sensors cannot detect oscillations if the mean length does not change, while dynamic sensors cannot detect length changes that are very slow (see Fig. 104.2).

Monosynaptic reflex When the muscle spindle is stretched, its intrafusal fibers are stretched too. Stretching of the equatorial region of the intrafusal fiber stimulates the afferent nerve fibers (Ia and II) of the spindle. The afferents reflexly stimulate the α-motor neuron in the ventral horn of the spinal cord, causing contraction of the extrafusal muscle fibers with consequent shortening of the muscle. Contraction of the extrafusal fibers releases (i.e., reduces) the stretch on the intrafusal fibers and the reflex stops. The MSR pathway has only a single synapse that is located in the anterior horn of the spinal cord. The MSR is the only reflex of its kind in the entire body: all other reflexes are either bisynaptic or polysynaptic.

 Gain of the monosynaptic reflex The gain of the monosynaptic reflex refers to the magnitude of response evoked by a given strength of stimulus. When the gain is high, a small stimulus evokes a huge response. When gain is low, even a large stimulus evokes a small response. When gain is zero, the reflex is absent. The gain of the monosynaptic reflex depends on two factors, viz., spindle sensitivity to stimulus and motor recruitment by group-Ia afferent discharge. Spindle sensitivity to stimulus The sensitivity of the reflex depends on the extent to which a given amount of stretch is able to distort the equatorial region of the muscle spindle. When there is a high fusimotor (γ-efferent) discharge, the peripheral parts of the intrafusal fiber contract and therefore, its compliance to stretch decreases. Hence, when the muscle is stretched, the periphery of the intrafusal fibers allows very little stretching and maximum stretching occurs at the center of the intrafusal fiber. This results in greater afferent discharge in response to stretch. Thus when fusimotor (γ-efferent) discharge is high, a given amount of stretch causes greater spindle loading. Motor recruitment by group-Ia afferents When

spindle afferent discharge is low, only the smaller motor units are recruited. At higher levels of spindle

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discharge, the larger units are recruited. This is in accordance with the Henneman principle of motor recruitment. Hence, the motor response to stretch is greater when the basal spindle afferent discharge is high.

Long-loop stretch reflex The long-loop stretch reflex is polysynaptic and its reflex center is located in the cerebral cortex. This reflex is continuously active in the erect posture and brings about a continuous correction of the “sways” that occur continuously during standing. The long-loop stretch reflex works in unison with the monosynaptic reflex on the one hand, and voluntary movement on the other. The following example would make it clear. Imagine a subject stretching out his hand with the forearm semiflexed. If a load is suddenly dropped on his hand, the hand along with the forearm is displaced down. Soon thereafter however, the limb regains its original position. The restoration to the original position occurs in three steps, as explained below. When a muscle is suddenly stretched, it first elicits the monosynaptic stretch reflex which tends to restore the muscle to its original length. However, the MSR is usually not strong enough to achieve its purpose. Next, the long-loop stretch reflex, also called functional stretch reflex, is elicited which nearly restores the muscle to its original length and sometimes, even overcorrects it. The final precise restoration of the muscle length is brought about through voluntary muscle contraction.

Golgi tendon reflex The Golgi tendon reflex is a bisynaptic reflex (Fig. 104.3), initiated by the Golgi tendon organ located in muscle tendons. Like muscle spindles, Golgi tendon organs are also stretch receptors. However, unlike the muscle spindle, which is a length-detector, the Golgi tendon organ is a tension-detector that measures muscle tension. This difference in sensory function occurs because muscle spindle is disposed in parallel to the extrafusal fibers while the Golgi tendon organ is disposed in series with the extrafusal fibers (see Box 41.1). The Golgi tendon organ is innervated by Aα sensory fibers, which are called type-Ib fibers, by sensory physiologists. These afferent fibers terminate on Ia inhibitory interneurons, called Golgi bottle neurons, in the dorsal gray horn of the spinal cord. The interneurons terminate on the α-motor neurons in the ventral gray horn of the spinal cord, completing the reflex arc.

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Central Nervous System

Group Ib Golgi afferent

From Golgi tendon organ

To extrafusal muscle fibers

Ia inhibitory interneuron

Fig. 104.3 The reflex arc of the Golgi tendon reflex.

The Golgi tendon reflex is a protective reflex that prevents excessive rise in muscle tension and thereby, prevents the muscle tendon from tearing away from its bony attachment. During isometric muscle contraction, the tendon is stretched. The stretch is sensed by the Golgi tendon organ, which reflexly inhibits the α-motor neuron discharge to the muscle, which consequently relaxes. This reflex relaxation of the extrafusal muscle fibers in response to a rise in muscle tension is called the negative (inverse) stretch reflex.

Regulation of muscle length The importance of regulation of muscle length can be appreciated from the following example. Consider the case of a person holding a cup in his hand (Fig. 104.4). If tea is poured into the cup, the forearm will instantly sag in response to the increased load. If the stretch reflex is absent, it requires fresh initiative by the brain to institute a feedback correction. Thus, the brain has to bother about every small perturbation in muscle load. If however the stretch reflex is present, the spindle will be stretched in response to the increase in load and the MSR will be triggered to correct the displacement. The correction occurs without the intervention of the brain, as the MSR is a spinal reflex. The brain only has to send out the initial “length signal” through the γ-motor neurons, specifying the amount of flexor muscle shortening required to semiflex the forearm. Through the stretch reflex, the spinal cord not only contracts the muscle to the desired length but also maintains it constant against external perturbations.

 Maintenance of a constant muscle length Stretch reflex When the MSR is triggered by

stretching the muscle, it is called the stretch

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Fig. 104.4 A girl pours tea into the cup held in the outstretched hand of her father who is reading the newspaper. Will his hand sag as the cup fills up? (After RHS Carpenter)

reflex. It helps in the maintenance of a constant muscle length in face of external perturbations in load. When a muscle is stretched, its extrafusal fibers elongate and so do the muscle spindles attached to them. In the spindle, the stretch is borne mainly by the equatorial zone of the intrafusal fibers and therefore, the spindle afferents are stimulated. This initiates the MSR which brings about reflex contraction of the extrafusal muscle fibers. The stretch reflex can be elicited as a tendon jerk (e.g., the knee jerk, biceps jerk) through a sharp tap on the muscle tendon. The nature of the jerk gives clues in the clinical diagnosis of neurological disorders: the tendon jerk is exaggerated in upper motor neuron lesion and in anxiety. It is absent in lower motor neuron lesion.

 Contracting a muscle to the desired length The muscle can be contracted to the desired length by two possible mechanisms: the α-mechanism (direct) and the γ-mechanism (reflex). In alpha-led activation of skeletal muscle, the

brain evaluates the load to be moved and based on its previous experience, sends down a calculated dose of stimulation to the α-motor neurons in order to contract the muscle to the desired length. This method has the advantage that muscle contraction is quick and powerful but has the disadvantage that there is no guarantee against a miscalculation by the brain, not to mention that any unexpected change in the load upsets all calculations made by the brain (see open loop control, p 25). Moreover, when there is contraction of extrafusal muscle fibers without simultaneous contraction of intrafusal

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Regulation of Muscle Length and Tone fibers, it results in the unloading of the muscle spindle. An unloaded spindle will be unable to produce stretch reflex and therefore, unable to maintain a constant muscle length. In gamma-led activation of skeletal muscle, the

brain makes the extrafusal fibers contract reflexly through the MSR instead of stimulating the Aα directly. Contraction of intrafusal fibers is not affected by external load. Hence, to make the intrafusal fibers contract to the desired length, the brain does not have to evaluate the external load. The intrafusal fibers contract to the desired length regardless of the uncertainties of the external load. The contracted intrafusal fibers trigger the MSR and this results in contraction of the extrafusal fibers. The MSR does not stop till the extrafusal fibers contract through exactly the same distance as the intrafusal fibers, thereby unloading the spindle to its original level. The advantage of this mechanism, which is called the length-servo mechanism, is that it is unaffected by perturbations of external load. Also, at the end of contraction, the spindle sensitivity is retained. It is now known that this type of reflex contraction is too weak to move heavy loads but it is through this mechanism that all the muscles of the body are kept in a slightly contracted state called the muscle tone. The muscle tone and its control are discussed below in detail. Alpha-gamma coactivation It seems that the brain

takes advantage of both the direct as well as indirect mechanisms by sending the length-signal simultaneously to both extrafusal and intrafusal fibers through α-motor neurons and γ-motor neurons, respectively (α-γ coactivation). The α-mediated stimulation makes the muscle contract powerfully and quickly. If the extrafusal fibers fail to contract to the desired length due to unexpected increase in the external load, it results in a mismatch between

Jack! Go up the hill and fetch a pail of water.

Jill! Tell Jack to go up the hill and fetch a pail of water.

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the degree of extrafusal and intrafusal fiber shortening. This causes spindle loading and triggers off the MSR till the disparity is eliminated and the extrafusal fibers contract to the desired length. According to this hypothesis, the MSR provides only a follow-up servo mechanism to ensure that the extrafusal fibers contract to the desired length. In the follow-up servo mechanism, the spindle is not unloaded and therefore retains its sensitivity to stretch. Hence, the stretch reflex is elicited whenever external perturbations tend to change the muscle length from the desired position, and the muscle remains at the desired length (Fig. 104.5). α-γ coactivation is rarely so perfect that the shortening of the extrafusal and intrafusal fibers are exactly equal. Such exact matching is symbolically referred to as α = γ. More commonly, the two are unequal. If the shortening of the extrafusal fibers is greater than that of intrafusal fibers (α > γ), then the contractions are called α-led, as occurs in ballistic movements (see Fig. 105.4). At the end of contraction, the spindle remains unloaded. Alternatively, if the shortening of the extrafusal fibers is less than that of intrafusal fibers (α < γ), then the contractions are called γ-led, as occurs in ramp movements. The spindle sensitivity is retained even at the end of the contraction. When a task is being learnt (say typewriting), the movements are γ-led. The movements are errorprone and require constant feedback correction. The muscles are stiff and the movements are slow. As the facility with the task increases, the contraction changes to the α-led mode. The brain, which by now is thoroughly acquainted with the task, can accurately calculate the Aα discharge required and is less dependant on feedback corrections through the stretch reflex. The switchover to the α mode is attended with increased speed and the disappearance of the background muscle stiffness.

Jack! Go up the hill and fetch a pail of water, and Jill! Nudge him on if he finds the pail too heavy.

Fig. 104.5 Jack and Jill went up the hill to fetch a pail of water. The wise man suggested to them three different methods for doing so. If Jack is an α-motor neuron, Jill is a γ-motor neuron, and the wise man is brain, then each method of fetching the pail of water exemplifies a mechanism for regulation of muscle length, that is, α-led, γ-led, and α-γ coactivation, respectively.

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Regulation of muscle tone All muscles in the living body are maintained at a slightly contracted state, which is called the muscle tone. This muscle tone is normally brought about through γ-led contraction of the muscle fibers. The resistance offered by a muscle to its passive stretch gives a measure of the muscle tone. Supraspinal control Muscle tone is normally un-

α

γ

Pons Medulla

DRF(I)

V

ARF(F)

F

Spinal cord

CVT

DRF(F)

Midbrain

der elaborate supraspinal controls. The supraspinal control is effected mainly through the vestibulospinal and reticulospinal tracts. The medial reticulospinal tract descends ipsilaterally from the pontine reticular formation to the spinal cord. The lateral reticulospinal tract descends bilaterally (but mainly ipsilaterally) to the spinal cord (see Fig. 96.1). The γ-motor neurons in the ventral horn of the spinal cord are stimulated by descending fibers from the facilitatory reticular formation, which extends from the upper medulla to the midbrain. They also receive descending inhibitory fibers from the inhibitory reticular formation in the pons and medulla. However, the facilitatory effect predominates, resulting in a tonic discharge of γ-motor neurons to the muscles, which is the main cause of muscle tone (Fig. 104.6).

As already mentioned, muscle tone is normally not under tonic control of α-motor neurons. (Tonic control of α-motor neurons should not be confused with the stimulation of α-motor neurons through corticospinal fibers during voluntary contractions.) Tonic control of α-motor neurons is exerted almost entirely through vestibulospinal pathways. However, the vestibular nucleus (especially, Dieter nucleus) is itself constantly inhibited by corticospinal fibers and the fastigiovestibular fibers from the cerebellum. It is only under certain abnormal or experimental situations that the vestibular nucleus is disinhibited, resulting in an exaggerated muscle tone that is α-led rather than γ-led (see below).

Abnormalities of muscle tone Flaccidity, spasticity, and rigidity Hypotonic muscles offer little resistance to passive stretching and are called flaccid. Conversely, a hypertonic muscle offers unusually high resistance to passive stretching and are called rigid. Sometimes, when a hypertonic muscle is stretched passively, the intense initial resistance suddenly gives way, producing the feel of a clasp knife. Hypertonia of this kind is known as spasticity. The initial resistance to muscle stretch is due to an exaggerated stretch reflex. The resistance increases muscle tension, resulting in the activation of the Golgi tendon reflex which causes the sudden yielding to stretch. Spasticity is observed mostly in extensor group of muscles and occurs due to increased fusimotor discharge to extensor muscles. A hypertonic muscle is not necessarily a spastic muscle: spasticity is absent in α-rigidity and in Parkinsonian rigidity. A spastic muscle shows an exaggerated tendon jerk. Sometimes the exaggerated contraction of the stimulated muscle triggers a stretch reflex in the antagonistic muscle. This results in clonus, that is, the rhythmic oscillations of a limb due to the alternating contractions of an agonist-antagonist muscle pair. (See p 26, Oscillations in a Regulatory System.)

 Spinal shock

Fig. 104.6 Supraspinal control of muscle tone. ARF(F), ascending reticular formation (facilitatory); CVT, corticovestibular tract; DRF(I), descending reticular formation (inhibitory); DRF(F); descending reticular formation (facilitatory).

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The net supraspinal influence descending on the γ-motor neuron is excitatory. When this facilitatory supraspinal influence is suddenly removed through spinal transection, the γ-motor neurons become quiescent for a period of days to weeks. This is called spinal shock (p 607). The duration of the spinal shock is much less in lower animals, possibly because their supraspinal facilitation is normally

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Regulation of Muscle Length and Tone much less. Since the γ-motor discharge determines the gain of spinal reflex, all spinal reflexes are abolished in the absence of γ-motor discharge. After a period of weeks, the γ-motor neurons start discharging excessively, possibly due to denervation hypersensitivity and due to the sprouting of collaterals from interneurons which excite the γ-motor neurons. The excessive γ discharge is associated with muscle spasticity.

 Decerebrate rigidity Classical decerebration Decerebrate rigidity is produced experimentally, mostly in cats, by making a midcollicular section of the midbrain. This is called classical decerebration. The exaggerated muscle tone affects both flexors and extensors but the hypertonia is greater in the antigravity extensor muscles. Even under normal conditions, the antigravity muscles are endowed with a higher resting muscle tone. In decerebrate rigidity, the same pattern is exaggerated (hypertonia), resulting in what has been described as the caricature of the normal erect posture (Fig. 104.7). In classical decerebration, the muscle tone is increased due to high γ-motor discharge. Hence, it is associated with exaggerated stretch reflexes. The hypertonia is abolished by muscle deafferentation (cutting of the groups-Ia and II proprioceptive muscle afferents), which interrupts the stretch reflex. The rigidity observed following classical decerebration is actually a form of spasticity. Spasticity is not observed if the increase in muscle tone is due to α-overdrive. Ischemic decerebration As classical decerebration was frequently associated with death of the experimental animal, the ischemic decerebration was attempted in which the cerebral cortex was rendered ischemic and nonfunctional by tying off the basilar artery. Soon it was discovered that ischemic decerebration did not result in spasticity: it resulted in a different form of rigidity, called α-rigidity, that was due to exaggerated α-motor neuron discharge.

Fig. 104.7 Decerebrate posturing.

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The α-overdrive resulted in direct stimulation of extrafusal muscle fibers. As the rigidity is not reflex in nature, it is not abolished by muscle deafferentation. Mechanism of decerebrate rigidity As already mentioned, the γ-drive to muscles is maintained by descending fibers from the descending reticular formation. The descending influences are both facilitatory and inhibitory (from the facilitatory and inhibitory reticular formation, respectively). The facilitatory influence predominates. The facilitatory and inhibitory descending reticular formations have no intrinsic activity of their own: they have to be kept activated by neurons from other areas. The inhibitory reticular formation is kept activated by descending supraspinal fibers, mostly from the basal ganglia. Hence, it is totally inactivated by decerebration and its inhibitory effect on γ-motor neurons vanishes. In contrast, the facilitatory reticular formation remains continuously activated by ascending sensory stimuli that relay to it through the ascending reticular formation, which remains active after decerebration and continues to facilitate the γ-motor neurons. The balance of descending influence on γ-motor neurons therefore tilts heavily toward facilitation. Cerebellectomy in subprimates results in α-rigidity (hypertonia due to α-overdrive, see Fig. 97.8). Cerebellectomy in a decerebrate cat changes the γ-rigidity into α-rigidity and increases the muscle tone further. Although, cerebellectomy decreases the γ-motor discharge, the muscle tone increases due to the direct α-motor discharge to the muscle fibers. The α-rigidity of ischemic decerebration occurs for a similar reason. Ischemic decerebration is unavoidably associated with ischemia and consequent necrosis of a large part of the cerebellum. As already explained above, a reduction in cerebellar activity leads to a disinhibition of α-motor neurons and a reduction of γ-facilitation. This leads to α-rigidity.

 Decorticate rigidity A decorticate preparation is made by removing the whole cerebral cortex but leaving the basal ganglia intact. The decorticate animal has a relatively milder hypertonia as compared to a decerebrate preparation. This is because the basal ganglia activates the descending inhibitory reticular formation, and thereby prevent excessive hypertonia. The tonic neck reflexes are exaggerated and override the tonic labyrinthine reflexes (see Fig. 105.17). In normal subjects, the two reflexes mutually cancel each other. Clinical decerebration and decortication are somewhat different from their experimental

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Central Nervous System counterparts. Clinical decerebrate posturing is usually caused by bilateral midbrain or pontine lesions. It is associated with (1) bilateral extension of the lower extremities, (2) adduction and internal rotation of the shoulders, and (3) extension at the elbows and wrist (see Fig. 104.7).

Clinical decorticate posturing is a much poorer localizing sign as it results from lesions in several locations, usually above the brain stem. It is associated with (1) bilateral flexion at the elbows and wrists, (2) shoulder adduction, and (3) extension of the lower extremities.

REVISION QUESTIONS 1. What is the difference between the monosynaptic reflex and the long-loop stretch reflex? 2. Which are the three different ways in which the muscle spindle can be loaded or unloaded?

6. What is spasticity and when does it occur? Give two examples of muscle rigidity that is not associated with spasticity. 7. What is spinal shock and when does it occur?

3. What is the inverse stretch reflex and which receptor initiates it?

8. Classical decerebration results in γ-rigidity and ischemic decerebration results in α-rigidity. Why?

4. What is α-γ coactivation and what is its functional significance?

9. Cerebellectomy in a decerebrate animal changes the γ-rigidity to α-rigidity. Why?

5. Which type of movement is α-led and which type of movement is γ-led?

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105

Motor Planning, Programming, and Execution

The motor control of the body has a three-tier system of planning, programming, and execution. The highest level is concerned with the generation of the motor plan, that is, the framing of the right ideas for a motor act. The middle level of motor control is concerned with developing and perfecting the motor program and subprograms for bringing about a motor act. The middle level also supervises the implementation of the motor program. The lowest level of control is vested with the spinal cord which implements the motor program designed and perfected by the middle level.

Motor planning Motor planning, as already mentioned, is the framing of the right motor ideas. The electroencephalogram (EEG) activity (see Chapter 107) associated with motor planning has been studied in instructed-delay tasks (Fig. 105.1). An example of an instructed-delay task would be when a sprinter is instructed to start running (the task) on hearing the gun shot (the cue) after a while (the delay). As the sprinter waits for the cue, an EEG potential called the preparatory-set activity (or the set-related activity) is recordable from his scalp. It reflects his motor planning for getting off to a good start. The importance of a definite motor plan is best appreciated from the consequences of its absence. The absence of a motor plan results in ideomotor apraxia,1 which usually affects movements of the face or limbs. A patient of facial apraxia, when asked to blow out a burning matchstick, may be unable to do so but may instead put it out by shaking the matchstick in his hand. However, the same patient may be able to whistle through his lips when in a happy mood, indicating the absence of any muscle paralysis. This type of motor error indicates that the patient has the right motor idea but is unable to transform the motor idea into a motor plan. While ideomotor apraxia refers to the inability to develop a motor plan corresponding to a motor idea, a less common condition called ideational apraxia is the result of a faulty motor idea 1

Fig. 105.1 (Above) Sprinters waiting for the start of the race is an example of an instructed-delay task. (Below) The crowd bursting into applause is an example of a selfinitiated task.

(Fig. 105.2). A patient of ideational apraxia who is provided with a cigarette and a matchbox might try to light the cigarette by striking it on the side of the matchbox. Lesions of the lower parts of the posterior parietal areas 5 and 7 (sensory association areas) in the left hemisphere can lead to pronounced apraxia of the limbs because these are important in motor planning. The anterior part of the corpus callosum probably conveys the motor plan to the right hemisphere. Hence, lesions of the anterior part of the corpus callosum produce only a left-sided apraxia.

Motor programming The motor program is a set of simultaneous or sequential commands issued to the muscles. It

Apraxia is an inability to carry out learned, purposeful movement that cannot be accounted for either by weakness, incoordination, or sensory loss, or by incomprehension of, or inattention to, commands. Geschwind identified three types of apraxia: ideomotor, ideational, and akinetic.

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Central Nervous System area are discussed below and are summarized in Fig. 105.3. A lesion in the premotor cortex causes motor (kinetic) apraxia. The medial premotor area is important for the learning and performance of a memorized sequence of movements in the absence of visual cues. This area has two parts: The presupplementary motor area (preSMA) is involved in learning novel motor sequences and is active only as long as a subject learns the sequence. The motor learning of the preSMA involves a continuous interchange of information with the prefrontal cortex. The supplementary motor area (SMA) designs the motor program for the execution of the memorized sequence and is the site where the readiness potentials are generated. A newly learned task gradually becomes automatic as the activity in the SMA shifts to the primary motor area. Fig. 105.2 A patient tries to comb his hair with a spoon: An example of ideational apraxia.

involves (1) formulation of the program, (2) sequencing of the sub-programs, (3) scaling, and (4) correction. The motor cortex and the cerebellum are involved in motor programming. Motor programming is associated with the appearance of a characteristic negative potential in the scalp EEG, about a full second before the commencement of a self-initiated movement (Fig. 105.1). This negative potential is called the Bereitschaft (readiness) potential and its activity increases before difficult movements like a complex sequence of finger movements. The Bereitschaft potential is recordable even when the complex sequence is imagined mentally.

Role of primary motor area Single neurons in the primary motor cortex do not control individual muscles or motor units. Rather, they move a contralateral joint in a particular direction by simultaneously stimulating a set of synergistic muscles: The contributions of a population of neurons in the primary motor cortex are vectorially summed to produce a population vector, moving the contralateral joint in the desired direction with the desired force. The force of the movement is proportional to the discharge rate of the neuron.

Role of premotor area In contrast to the primary motor area, the premotor area is important for movements involving multiple joints. It is also important for motor learning. The functions of the various parts of the premotor

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The lateral premotor area (LPA) is important for

the programming of visually guided movements, imitation of a movement, and associative learning. The motor program for visually guided movements is designed through a process called sensorimotor transformation. Hence, the LPA requires continuous sensory cues from the extrapersonal space. Visuallyguided movements are either (1) reaching movements that are programmed by the dorsal-LPA, or (2) grasping movements that are processed by the ventral-LPA. The ventral-LPA probably also enables the imitation of a movement: Certain neurons in this area, called mirror neurons, are activated when one observes a grasping movement being performed by others! The dorsal-LPA is also involved in associative learning, that is, how to associate a specific sensory cue with a specific movement.

Role of basal ganglia The role of basal ganglia in the middle level motor control is attributable to the caudate nucleus through its caudate loop and to the putamen, through its putamen loop. The caudate loop plays an important role in motor sequencing. When there is dysfunction of the caudate nucleus, the transition from one motor program to another appears extremely difficult and the patient becomes stuck in the middle of an otherwise automatic motor action. This difficulty results in akinesia, an apparent inability to initiate voluntary actions. The putamen loop has a role in scaling the intensity of movements. For example, a person signing his name on a paper uses his finger and wrist muscles for the motor act. When the person is asked to sign his name on a large blackboard, he uses his shoulder, elbow, and wrist joints and associated muscles.

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Motor Planning, Programming, and Execution

687

Motor Cortex

Primary Motor Area

Premotor Area

Signalling of Control of movements direction and force at single joint of movements

Control of movements at multiple joints

Motor learning

Medial Premotor Area

Lateral Premotor Area (LPA)

Programming of motor sequences

Pre-Supplementary Motor Area Motor learning of complex sequences

Sensorimotor transformation

Supplementary Motor Area

Dorsal LPA

Ventral LPA

Performance of memorized motor sequences Reaching movements Associative learning

Grasping movements Imitative learning

Fig. 105.3 Different areas of the motor cortex and their role in motor programming. See also Fig. 100.4.

He signs on the board perfectly even if he is doing it for the first time, provided he has enough practice of signing on paper. This is because the same motor plan is used for both the motor acts—signing on the paper and on the blackboard. The putamen loop formulates for them two different motor programs differing both in strategy (the joints and muscles used) and in intensity (the magnitude of the movements). The scaling ability of the putamen is affected in Parkinsonism: The patients retain the ability to execute motor patterns but make the constituent movements too small. Hence, their writing is small and their speech is slurred and rapid, just as their stride is a shuffling sequence of short steps.

Role of cerebellum The cerebrocerebellum (p 619) is concerned with higher motor planning, a view that is reinforced by two observations: (1) It has no direct connections with the spinal cord. (2) The dentate nucleus fires well before the onset of movement and even before the activation of the motor cortex. The dentato-rubro-olivo-cerebello-dentate loop of the cerebrocerebellum is probably involved in the mental rehearsal of ballistic movements before initiating them. Lesion of the dentate nucleus delays the initiation of movements but does not abolish them. In contrast to the basal ganglia which enable a smooth transition from one motor subprogram to

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the other, the cerebrocerebellum coordinates the simultaneous performance of multiple motor subprograms. For example, reaching out to pick up an object involves two simultaneous actions: one, the forward movement of the hand, and second, a gradual opening up of the grip. Both occur simultaneously. However, in disorders of the cerebrocerebellum, the two occur sequentially instead of simultaneously: first the hand reaches the object and then the grip opens. This abnormality is known as decomposition of movement due to the breaking up of complex motor programs into sequential subroutines. The function of the spinocerebellum as a comparator enables it to continuously refine the motor programs after obtaining sensory feedback on the accuracy of the motor actions. Long-term modification of the motor program for achieving the desired result is called adaptive motor learning and is made possible by the plasticity of cerebellar neurons.

Role of sensory feedback Sensory feedback may be proprioceptive, somatosensory, visual, or vestibular. A motor program may or may not be dependent on sensory feedback from the muscles, depending on whether the movements are of the ramp or ballistic type. An example of ramp movement is the threading a needle: Every time there is an overshoot, there is an immediate correction of the motor activ-

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Central Nervous System ity. The correction is initiated through sensory feedback and is an example of closed-loop control system (p 24) that employs a follow-up servo mechanism. Ramp activity is precise but slow, and usually lacks much power. An example of ballistic movement is the throwing of a dart: once thrown, the direction of the dart cannot be altered or guided to the bull’s eye. Ballistic movement is an example of open-loop control system (p 25) and are generally α-led: It may not be precise but it allows great speed and power (Fig.105.4). Before the onset of the ballistic movement, the brain makes all possible calculations to formulate the motor subprogram, that is, decides on the direction and the force of movements. If a breeze causes the dart to drift, then the brain also tries to estimate the wind velocity and incorporates it as a corrective factor into the subprogram formula. Hence, before throwing a dart or a ball, it is a usual practice to swing the arm a few times to get a feel of the weight of the dart as well as any wind velocity. Finally, if the dart does not hit the bull’s eye, the brain makes further corrections to its subprogram formula and the second throw is usually better than the first. The importance of sensory feedback is also underlined by the various postural reflexes that help in steadying the posture. A striking example is Romberg sign (see sensory ataxia, p 674) which demonstrates the heightened dependence on sensory (visual) feedback for standing straight in the absence of proprioceptive control.

Motor execution Upper motor neurons are the neurons that descend from the cerebral cortex, cerebellum, and brain stem to terminate on the neurons that directly innervate the skeletal muscles. The earlier categorization of descending fibers into pyramidal fibers and extrapyramidal fibers (descending fibers other than the pyramidal fibers) is an ill-conceived one that still somehow lingers on in clinical parlance. Grouping descending fibers in lateral and medial pathways is more meaningful. The lateral pathways terminate either directly on motor neurons (as in the case of fingers which require very fine movements) or on interneurons in the lateral parts of the spinal gray matter to control the movements of the distal limbs as well as the supporting musculature in the proximal limbs. It includes the lateral corticospinal tract and the rubrospinal tract. The latter is largely vestigial in man. Fewer than 200 rubrospinal fibers are present in man, and their function has been completely taken over by the corticospinal tract. Also included in the lateral pathways are the corticobulbar fibers supplying the lower part of the facial nerve nucleus and the hypoglossal nucleus. The medial pathways end in the medial part of the ventral horn of spinal gray matter. They terminate on the medial group of interneurons which connect with motor neurons that control the axial musculature bilaterally and thereby contribute to balance and posture. Medial pathways include the anterior corticospinal tract, most of the corticobulbar tracts, the vestibulospinal tract, the reticulospinal tract, and the tectospinal tract. Lower motor neurons are the neurons that

directly innervate the muscle fibers. All motor commands must ultimately be routed through this final common pathway in the spinal cord. The cell body of these neurons is located in the ventral horn of the spinal cord. These neurons, which are of the Aα type, are called the α-motor neurons: They receive and integrate inputs from various parts of the brain as well as from sensory receptors. In general, two types of inputs are funneled through the final common pathway: (1) segmental inputs originating from receptors in the muscle (the muscle spindle), the tendon (Golgi tendon organ), and skin (nociceptors), and (2) supraspinal inputs descending from various parts of the brain such as the cerebral cortex, cerebellum, and the brain stem. Fig. 105.4 The throwing of a boxing punch is an example of ballistic movement. A missed punch cannot be corrected.

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Spinal interneurons Some segmental and suprasegmental inputs terminate directly on the α-motor neuron. More often, there are intervening neurons

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Motor Planning, Programming, and Execution called interneurons. Two important spinal interneurons are the Ia interneuron and the Renshaw interneuron. Whenever a muscle contracts, the Ia interneurons (Golgi bottle neurons) ensure the relaxation of their antagonistic muscle. This is known as reciprocal inhibition (Fig. 105.5) and occurs regardless of whether the muscle contracts in response to a supraspinal input or a segmental input. The Renshaw cell is present in Rexed lamina VII of the spinal gray matter (Fig. 105.6). It is an inhibitory neuron that is stimulated by the axonal branch of the α-motor neuron. The stimulated Renshaw cell inhibits the α-motor neuron and also inhibits the Ia interneuron. Inhibition of the Ia interneuron results in the disinhibition of the antagonist muscles. The functions of the Renshaw cells are debatable but they probably bring about lateral inhibition as seen in the sensory system, resulting in motor focusing so that only the intended muscles contract. By inhibiting the Ia interneuron, they prevent the reciprocal inhibition of antagonist muscles, thereby promoting the simultaneous contraction of the agonist and antagonist muscles (Fig. 105.7). They probably also influence the balance of α–γ coactivation.

Ia inhibitory interneuron

689

Renshaw cells

α-motor neuron to the antagonist -

-

+

α-motor neuron to the agonist

Fig. 105.6 Renshaw cell inhibition.

Spinal reflexes When a sensory input relays, directly or indirectly, to the α-motor neurons, it constitutes a reflex arc. Depending on the number of synapses in the reflex arc, the reflex may be monosynaptic, bisynaptic, or polysynaptic. Monosynaptic and bisynaptic reflexes are described in Chapter 104. An example

Ia inhibitory interneuron

Fig. 105.7 Whither reciprocal inhibition? Showing off the muscles involves simultaneous contraction of agonistantagonist muscle pairs, overriding reciprocal inhibition.

Supraspinal (corticospinal) fibers

of a polysynaptic reflex is the withdrawal (flexor) reflex, which is a protective reflex triggered by painful stimuli. It results in flexion (Box 105.1) of the stimulated limb. Withdrawal reflex is also associated with a crossed-extensor reflex, the physiological significance of which is discussed on p 691 in the context of postural control. + Segmental (Ia) afferents

+

--

Fig. 105.5 Reciprocal inhibition occurs during both reflex (left) and voluntary (right) muscle contraction.

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The clinical classification of reflexes is based on

how the reflex is elicited: Withdrawal reflexes are called superficial reflexes because they are elicited by stroking the skin, which is superficial. The stretch reflex and the inverse stretch reflex are called deep reflexes as they are elicited by striking the tendon, which lies deep beneath the skin.

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Box 105.1 Defining flexion The term flexion can have different meanings to the anatomist and the physiologist. The gastrocnemius muscle, for example, is a flexor when considered anatomically but physiologically, it is an extensor. Physiological flexion can be defined as the position of the fetus in utero. Flexor muscles help in withdrawing a limb from a noxious stimulus. Thus physiologically, the so-called “plantar flexion” is an extension of the foot as it takes the foot closer to a painful stimulus.

Afferent–efferent correspondence In reflexes, the sensory afferents and the α-motor neurons do not have a one-to-one correspondence. Rather, a single sensory afferent makes contact with several motor neurons. As a result, some reflexes might show the phenomenon of subliminal fringe while others might indicate the presence of occlusion. Subliminal fringe and occlusion are quite marked in the withdrawal reflex. Subliminal fringe is evident when the afferent neurons of a reflex arc are stimulated using single, threshold stimuli. Due to the subliminal fringe, the strength of the motor output obtained by stimulating all the afferent neurons together is more than the sum of outputs obtained by stimulating the afferent neurons singly. As explained diagrammatically in Fig. 105.8, it occurs due to the subliminal excitation of neurons, that is, when some of the neurons are slightly depolarized but not depolarized to the firing level. The occurrence of subliminal fringe in reflexes explains the phenomenon of reinforcement of tendon jerks through Jendrassik maneuver.2 When a muscle is stretched intensely, the resulting stretch reflex not only causes its own contraction through the monosynaptic reflex but also places a substantial number of α-motor neurons in the subliminal fringe. When the central excitatory state (the state of activity in the α-motor neuron pool) is high, other motor reflexes too are exaggerated. Occlusion is evident when the afferent neurons are stimulated by a train of suprathreshold stimuli. Due to occlusion, the strength of the motor output obtained by stimulating all the input neurons together is less than the sum of outputs obtained by stimulating the input neurons singly (Fig. 105.9).

A B

X Y Z

Fig. 105.8 Subliminal fringe. Threshold stimulation of the afferent neuron A causes excitation (shown in red) of neuron Z. Similarly, stimulation of B excites neuron X. In both cases, neuron Y, which has a low excitability, is subliminally stimulated (shown in red outline). When A and B are together, neuron Y is excited due to spatial summation. Neuron Y is therefore said to be in the subliminal fringe of neurons A and B.

The tension in a reflexly contracting muscle rises and declines slowly. The slow rise and fall in tension is prominent in the withdrawal reflex, and especially in the crossed extensor reflex. The slow rise in muscle tension is due to the phenomenon of motor recruitment. The slow decline in the muscle tension is due to the phenomenon of after discharge. The after discharge occurs due to the presence of multiple parallel connections between the sensory afferent and the motor efferent fibers, constituting what are called the reverberating circuits (Fig. 105.10).

2

It is a method of enhancing the patellar reflex. The subject hooks his hands together by the flexed fingers and pulls against them with all his strength.

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Control of posture

A B

X Y Z

Fig. 105.9 Occlusion. When neuron A is stimulated with a train of suprathreshold stimuli, neurons Y and Z are stimulated. When neuron B is stimulated with a train of suprathreshold stimuli, neurons X and Y are stimulated. Neuron Y, although of a lower excitability, is stimulated in both cases due to temporal summation. Hence, when neurons A and B are stimulated together, the total number of efferent fibers excited (three) is less than the number of fibers excited when neurons A and B are stimulated separately (four).

Posture refers to the static position of any part of the body. Movements are the transition from one posture to another. The motor system is endowed with wide-ranging postural mechanisms, which are as follows. (1) The antigravity muscle tone ensures that there is a good amount of basal contraction (i.e., muscle tone) in those extensor muscles that keep the body upright (the antigravity muscles). This ensures that the weight-bearing joints such as the knee joint do not give way under the effect of gravity. (2) The positive supporting reaction ensures that once in the standing position, the ankle joint is steadied in such a way that it can neither flex nor extend under the body weight. This is made possible by simultaneous contraction of the ankle flexors and extensors. (3) The crossed extensor reflexes ensure that the body is not thrown off balance when one limb is flexed. Sudden flexion of a limb in a quadruped, say the right forelimb, can occur if a painful stimulus is inflicted on it. This will throw the quadruped off balance unless the contralateral forelimb and ipsilateral hindlimb compensate by increasing their extensor tone. (4) The tonic labyrinthine reflexes and the tonic neck reflexes ensure that the body is not thrown off balance even when standing on an inclined plane. (5) The rescue reactions such as the long-loop stretch reflexes, and the hopping and placing reactions ensure that the body is not thrown off balance when tipped over its center of gravity. (6) The righting reflexes ensure that the body regains its upright stance even after it is thrown off balance. The centers for these reflexes are at different levels of the central nervous system (Table 105.1). Table 105.1 Postural reflexes

REVERBERATING CIRCUITS

Afferent

Fig. 105.10 Reverberating circuits.

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Efferent

Postural reflex

Integrating center

Muscle tone

Spinal cord

Positive supporting reaction

Spinal cord

Crossed extensor reflexes

Spinal cord

Tonic labyrinthine reflexes

Medulla oblongata

Tonic neck reflexes

Medulla oblongata

Righting reflexes

Midbrain

Long-loop stretch reflexes

Cerebral cortex

Hopping and placing reactions

Cerebral cortex

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Central Nervous System Antigravity muscle tone Antigravity muscles are those extensor muscles that keep the weight-bearing joints of the body extended, for example, the extensors of the neck (erector capitis), spine (erector spinae), hip (glutei), and knee (quadriceps). The antigravity muscles of the body are endowed with higher muscle tone than the other muscles of the body. This higher muscle tone is provided by elaborate supraspinal mechanisms that are strikingly apparent in decerebrate rigidity. The hypertonia in decerebrate preparations has a characteristic extensor distribution, resulting in a caricature (exaggeration) of the normal posture. Interestingly, in bats, it is the flexor muscles that act as antigravity muscles because bats hang from the tree. Accordingly in bats, the exaggerated muscle tone is present in the flexor muscles and not the extensor muscles. supporting reaction While standing, steadying the ankle joint is much more difficult than steadying other weight-bearing joints such as the knee joint. The knee joint can be steadied by simply contracting the knee extensors because the knee joint does not permit hyperextension. At the ankle joint, however, both dorsiflexion and plantar flexion are possible (Fig. 105.11). During standing, neither of them is desirable. Dorsiflexion of the foot would tip the body forward, while plantar flexion would throw the body backward. What is required therefore is that the ankle is steadied at an intermediate position. This is possible only by the simultaneous contraction of the flexors and extensors of the foot. This in turn is brought about by the positive supporting reaction, which is stimulated by pressure on the sole of the foot. Afferent impulses from the stimulated skin and the muscles (especially, the interossei) cause reflex contraction of

Positive

both the agonist and antagonist muscles acting on the ankle joint, fixing the ankle joint at a right angle. Crossed extensor reflex The importance of this reflex in postural regulation is best understood with reference to quadrupeds. If a cat inadvertently places its right front paw on a sharp object and is hurt, it reflexly flexes the limb (withdrawal reflex). The flexion of the right forelimb tends to destabilize its erect posture. The destabilization is prevented by the associated reflexes, that is, hyperextension of the left forelimb and right hindlimb, and flexion of the left hindlimb (Fig. 105.12). Tonic neck and labyrinthine reflexes In a person standing straight, the neck is neither flexed nor extended and the tonic neck reflexes are not active. However, the vestibular apparatus is tilted 30 degrees backward (see Fig. 119.1). The backward tilt of the labyrinth reflexly increases the extensor tone in the lower limbs and reduces the extensor tone in the upper limbs. If the person flexes his neck forward, the vestibular apparatus becomes horizontal and therefore the labyrinthine reflex ceases. However, flexion of the neck activates the tonic neck reflex which increases the extensor tone in the lower limbs and reduces the tone in the upper limbs. Thus regardless of the position of the head, the extensor tone is high in the lower limbs and low in the upper limbs so long as the trunk remains upright. The distribution of muscle tone in the extremities changes when the trunk is tilted. In the crawling infant (Fig. 105.13), the trunk is horizontal and therefore the neck has to be extended to hold the head up. The extension of the neck increases the extensor tone in the forelimbs and reduces the extensor tone in the hind-limbs. Similar reversal of muscle tone distribution is seen in a falling man whose trunk is inclined (Fig. 105.14). The head of the

Motoneuron Motoneuron Dorsiflexion of foot due to contraction of tibialis

Plantarflexion of foot due to contraction of gastrocnemius

Body falls forward

Body falls backward

Nociceptive afferent

Flexor reflex

Fig. 105.11 Positive supportive reaction is necessary for steadying the ankle joint.

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Crossed extensor reflex

Fig. 105.12 Crossed extensor reflex.

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Fig. 105.15 Tonic neck and labyrinthine reflexes are a common occurrence in daily activities. Here, they are seen in a game of soccer, in both the striker and the goalkeeper. Fig. 105.13 A man standing erect has greater extensor tone in the lower limbs than in the upper limbs. This distribution of extensor muscle tone is attributable to the tonic labyrinthine reflex when the head is held straight (left), and to the tonic neck reflex when the head is bent forward slightly (middle). In the crawling infant (right), the neck is extended and therefore the forelimbs have higher extensor tone than the lower limbs.

falling man is tilted slightly forward so that the tonic labyrinthine reflex would be absent. However his neck is fully extended, which increases the extensor tone in the upper limbs and reduces the extensor tone in the lower limbs. However, as with all other postural reflexes, these reflexes too can be suppressed voluntarily. Tonic neck and labyrinthine reflexes are also elicited when the head is tilted or the neck is flexed sideways (Fig. 105.15). If the head is “tilted” to the left, the tonic labyrinthine reflexes are activated and therefore the extensor tone increases in the

Fig. 105.14 While falling with head down, the tonic neck and labyrinthine reflexes come into play. However, the reflexes can be voluntarily suppressed, as during diving.

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left upper and lower limbs and decreases on the right side. If the neck is “flexed” to the left, the tonic neck reflexes are activated and therefore the extensor tone decreases in the left upper and lower limbs and increases on the right side. Hence, when both the reflexes are active, their effects are mutually cancelled. However, when the trunk inclines, only one of them is active and therefore its postural effects are apparent. It should be clear from the above examples that the tonic neck and labyrinthine reflexes work in concert, bringing about a redistribution of extensor tone in the limbs depending on the inclination of the trunk. These reflexes are important because for standing on an inclined plane, it is important to redistribute the muscle tone in the limbs for maintaining a stable posture (Fig. 105.16). They do not occur while standing erect on a level plane because the effects of the two reflexes cancel each other. The exaggerated tonic neck reflexes can be seen clinically in the decorticate posture (Fig. 105.17). Rescue reactions In the erect posture, the body behaves like an inverted pendulum, hinged at the ankle joint, that continuously sways back and forth. These “sways” are instantaneously corrected by two long-loop postural reflexes that are continuously active in the erect posture: one is proprioceptive, and the other is visual. When the body sways forward, there is stretching of the gastrocnemius muscle. This triggers not only the monosynaptic stretch reflex but also the long-loop stretch reflex which brings about reflex contraction in the gastrocnemius muscle with consequent correction of the sway. A long-loop postural reflex is also triggered by visual inputs suggesting that the body is swaying. The importance of the two long-loop postural reflexes is obvious in patients with lesions

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Head tilted to the right

Left limbs flexed, and right limbs extended

Head tilted back

Fore limbs flexed, and hind limbs extended

Neck flexed to the left

Neck flexed

Left limbs flexed, and right limbs extended

Front limbs flexed, and hind limbs extended

Fig. 105.16 Tonic labyrinthine reflexes (above) and tonic neck reflexes (below) in quadrupeds. The redistribution of muscle tone in the limbs gives postural stability on inclined planes.

of the dorsal columns, as in tabes dorsalis. Such patients suffer from sensory ataxia. The patient walks on a broad base with the legs apart, raising the legs excessively high and slapping the feet on the ground. The eyes are fixed to the ground for correcting the steps visually. Closing of the eye accentuates the ataxia. This is known as the Romberg sign, which is characteristic of sensory ataxia. The sign is absent in cerebellar ataxia. Hopping and placing reactions are programmed reflexes that are centered in the motor cortex. When the foot comes in contact with any firm surface, the foot is reflexly placed on the surface and the leg muscles are adjusted so as to support the body. This is the placing reaction. The placing reaction is also triggered during a fall under gravity, preparing the animal for landing by causing extension of the forelimbs. It is called the vestibular

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Fig. 105.17 Decorticate posture. It is not certain whether the clinically observed decorticate posture is caused by a lesion similar to the experimental lesion that produces the decorticate posture in animals.

placing reaction and occurs due to the stimulation of the otolith organs by gravity. The hopping reaction occurs when the body is pushed forward. The leg hops in the direction of the displacement, bringing the foot under the body so that the center of gravity of the body is kept between the legs. Righting reflexes When the body goes off balance and falls down, the righting reflexes help the body to regain the upright position. The receptors responsible are the (1) vestibular apparatus, (2) the neck stretch receptors, and (3) the mechanoreceptors of the body surface. When the head is not in the upright position, the vestibular apparatus is stimulated. It reflexly stimulates the appropriate muscles to bring the head back to the upright position. This is known as the head righting reflex. When the body is lying flat on the ground, one of its surfaces (the anterior or posterior, depending on whether the body is prone or supine) is in contact with the ground. This differential stimulation of body surfaces provides the necessary cues for reflexly bringing the head back to the upright position. This is known as the body-on-head righting reflex. Righting of the head (through the head righting reflex) while the body continues to be in the horizontal position results in the flexion or extension of the neck and activation of the neck-on-body righting reflex which stimulates the appropriate postural muscles to bring the whole body back to the upright position. The righting of the body is also aided by the body-on-body reflex which is activated by the differential stimulation of the anterior and posterior surfaces of the body when it is lying flat on the ground.

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Motor Planning, Programming, and Execution

Control of locomotion Phases of locomotion The normal rhythm for locomotion consists of alternating swing and stance phases of the lower limbs (Fig. 105.18). The swing phase of locomotion refers to the forward stepping movement of a leg due to flexion at the hip joint. During the stance phase, the leg (that has just swung forward) remains firmly rooted on the ground while the trunk moves forward due to the extension at the hip joint. The phases alternate in both the legs: When one leg is in the swing phase, the other is in the stance phase. The central pattern generator comprises a group

of aminergic neurons in the spinal cord which generates the basic pattern for locomotion. It contains two half-centers, one each for swing and stance, with each half-center inhibiting the other. Thus, the swing begins only at the end of the stance and the stance begins at the end of the swing phase. A spinal transection disconnecting the spinal cord from the cerebrum does not abolish walking in cats and dogs. Although the same is generally not true for humans, cases have been reported where patients with spinal transection have shown rhythmic stepping movements of the lower limbs that were triggered by the extension at the hip joint. Human infants produce stepping movements immediately at birth if held erect and moved on a horizontal surface. Such stepping movements are known to occur even in anencephalic infants. These stepping movements however are soon suppressed but reemerge at the end of the first year in a more

1 4

2 5

3

mature, well-coordinated form that has greater cerebral dependence. The basic spinal rhythm of locomotion can be modified by higher control centers in the medulla, midbrain, and the motor cortex. The speed and initiation of the stepping reflex are controlled by the mesencephalic locomotor region. The region has no direct connections with the spinal cord but exerts its influence through the medullary reticular formation, which controls the spinal center through the reticulospinal tract. Role of sensory feedback The importance of sen-

sory feedback in locomotion is demonstrated by the fact that when a spinal or decerebrate cat is placed on a motorized treadmill, the rate of its stepping matches the speed of the treadmill belt. One of the most important sensory stimuli that influences stepping movements comes from the muscle spindles of the hip flexors. Stretching of hip flexors occurs during normal locomotion at the end of the stance phase and it stimulates the onset of swing phase. The response can be obtained in a spinal preparation by stretching the hip flexors. Cutaneous exteroceptors also play an important role in locomotion. They detect external obstacles and adjust the stepping movements to avoid them. For example, when the plantar surface of the foot is stroked when the leg is in its swing phase, the leg flexes. The reflex is called the stumbling-corrective reaction, and the flexion it produces is meant for clearing any obstacle. Interestingly, when the same stimulus is applied to the plantar surface when the leg is in the stance phase, the leg extends. This is an example of phase-dependent reflex reversal. The

4

5

6

Double support

1 Double support

695

6 2

1 3

4 Double support

SWING

STANCE

SWING

STANCE

SWING

STANCE

Fig. 105.18 Rhythm of locomotion in humans. (Red) right leg events. (Blue) left leg events. (1) Heel strike, (2) foot flat, (3) midstance, (4) heel raise, (5) toe off, and (6) midswing.

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Central Nervous System physiological significance of the reflex reversal is obvious: when in the stance phase, the leg supports the entire weight of the body and its flexion during the stance phase would send the body tumbling down. Role of cerebellum The cerebellum has an important role in locomotion and cerebellar disorders result in ataxia. The cerebellum compares the actual movements of the legs with the intended movements. Information regarding the former originates from proprioceptors and reaches the cerebellum through the dorsal spinocerebellar tract. Information about the latter originates in the central pattern generator in the spinal cord and reaches the cerebellum through the ventral spinocerebellar tract. The cerebellum then computes the error and sends corrective signals to the spinal cord via the medullary reticular formation. Role of motor cortex The motor cortex enables skilled, visually guided walking. Lesions of the motor cortex do not impair walking on a smooth surface but they seriously impair the ability to walk past a series of obstacles.

reflex. Hence, the condition is called spastic paralysis. The spasticity is characteristically associated with clasp-knife rigidity and occasionally clonus. The spasticity of UMNL must be due to the interruption of the descending extrapyramidal fibers. The immediate effect of UMNL is flaccid paralysis due to spinal shock. The spasticity develops a few days or weeks later. Pure pyramidal lesions (see below) are associated with hypotonia rather than spasticity. Superficial reflexes are lost or diminished as their reflex pathways are transcortical and the efferent path is formed by the corticospinal tract. Examples of superficial reflex are the abdominal and cremasteric reflexes. The Babinski sign is positive, that is, the great toe is reflexly dorsiflexed, and the other toes fan out when the lateral aspect of the sole of the foot is scratched with a blunt point. The Babinski sign indicates the involvement of the corticospinal tract. Babinski sign is positive in normal infants prior to the myelination of the corticospinal tract. A comparison of the clinical features of upper and lower motor lesions is given in Table 105.2. Pure pyramidal lesion In the human brain, only

Motor deficits Lower motor neuron lesion (flaccid paralysis) Lower motor neuron lesion (LMNL) is typically observed in poliomyelitis, a disease largely eradicated, in which the polio virus selectively affects the lower motor neurons of the spinal cord and brain stem. It also occurs following injury to peripheral nerve. The damage to the lower motor neuron results in segmental paralysis of all voluntary movements and all reflexes, both superficial and deep. The abolition of the deep tendon reflex results in loss of muscle tone in the affected muscle (resulting in muscle flaccidity) and therefore, the condition is called flaccid paralysis. The paralyzed muscles often contract spontaneously due to denervation hypersensitivity, resulting in fibrillation and fasciculation. Prolonged absence of any strong muscle contraction, voluntary or reflex, results in atrophy (wasting) of affected muscles.

Upper motor neuron lesion (spastic paralysis) Upper motor neuron lesion (UMNL) refers to

damage to the corticospinal tracts and other descending motor pathways. It abolishes the voluntary contraction of the affected muscles (paralysis, usually in the form of contralateral hemiplegia) but increases their muscle tone (resulting in muscle spasticity) due to the exaggeration of the stretch

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3% of pyramidal neurons originate from giantsized pyramidal cells called Betz cells, which are confined to the primary motor area only. Pyramidal fibers do not originate from motor areas alone: Table 105.2 Differences between upper and lower motor paralysis Upper motor neuron paralysis

Lower motor neuron paralysis

Muscles affected in groups, never individually.

Individual muscles may be affected.

Muscle atrophy can occur but is not marked.

Muscle atrophy is marked.

Muscles are spastic and deep tendon reflexes are exaggerated. Clasp-knife effect is present.

Muscles are flaccid and deep tendon reflexes are absent. Clasp-knife effect is absent.

Babinski sign (extensor plantar reflex) is present.

Plantar reflex absent only if L5–S1 are affected.

Muscle fasciculations are not present.

Muscle fasciculations may be present.

Electromyogram (EMG) normal.

EMG shows fibrillations and evidence of reduced numbers of motor units.

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Motor Planning, Programming, and Execution A fairly large proportion of pyramidal neurons also originate from postcentral areas, viz., the primary somatosensory cortex and the sensory association (parietal) cortex. Pyramidal neurons owe their name, not to the pyramidal cells from which they originate, but to the medullary pyramids through which they all pass. A pure pyramidal lesion can be produced experimentally by sectioning the medullary pyramids: Elsewhere, the corticospinal tract is interspersed with several descending motor fibers other than the corticospinal fibers. Although it is tempting to believe that the robust corticospinal tract is

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primarily responsible for voluntary contraction of muscles, it is not true: There are surprisingly few motor deficits after a pure pyramidal lesion, which interrupts only the corticospinal neurons. The only deficit consistently observed after a pure pyramidal lesion is the inability to produce fine, independent (fractionated) finger movements.3 Lesions of the primary motor area produce the same deficits. These observations led to the conclusion that corticospinal fibers, especially those originating from the primary motor area, only superimpose speed and fractionation upon the movements produced by other descending systems.

REVISION QUESTIONS 1. A patient, when asked to blow out a burning matchstick, is unable to do so but puts it out by shaking the match stick. The same patient whistles through his lips when in a happy mood. What is the patient suffering from and why is he unable to blow out the flame?

motor program from another; (2) scaling of the intensity of movements.

2. A patient is provided with a cigarette and a match box. He tries to light the cigarette by striking it on the side of the match box. What condition is the patient suffering from?

7. Reaching out to pick up an object involves two simultaneous actions: one, the forward movement of the hand, and second, a gradual loosening of the grip. Dysfunction of which part of the brain makes the two actions sequential instead of simultaneous? Damage to which part of the brain delays the initiation of movement?

3. Lesions of the anterior part of the corpus callosum produce only a left-sided apraxia. Why?

8. Between ramp and ballistic movement, which one is an example of open-loop control system?

4. A negative potential is recordable from the scalp when a complex sequence of movements is imagined mentally. What is the potential called and what is its physiological significance?

9. Which of the two upper motor neuron pathways–the lateral or medial–controls the axial musculature and thereby contributes to balance and posture?

5. Which area of the motor cortex is concerned with (1) motor learning of complex sequences, (2) performance of memorized motor sequences, (3) reaching movements and associative learning, and (4) grasping movements and initiative learning? 6. Which neuronal circuit in the basal ganglia is responsible for (1) smooth transition of one

10. What is reciprocal inhibition and which spinal neuron mediates it? 11. Jendrassik maneuver enhances tendon jerks. Why? 12. In the withdrawal reflex, the tension in the contracting muscle rises and declines slowly. Why?

3

Fractionated movement means controlling the digits independently of each other, a difficult proposition considering that digits are not controlled by separate muscles but by muscles that supply them together. For example, the flexor digitalis longus, when contracted, would flex all the digits together. To flex only one digit, the flexion of the other digits has to be opposed through the contraction of the extensors.

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13. What would happen if the following reflexes were absent: (1) antigravity muscle tone, (2) positive supportive reaction, (3) crossed extensor reflexes, (4) tonic labyrinthine and neck reflexes, (5) rescue reactions, and (6) righting reflexes.

15. An upper motor lesion results in the abolition of plantar placing reaction and the appearance of Babinski sign. Why? 16. What motor deficit is produced by a pure pyramidal lesion, and why?

14. Closing of the eye accentuates sensory ataxia but not cerebellar ataxia. Why?

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Thought, Emotion, and Conation

Sensory perception is a product of the brain’s analysis of sensory input. The term cognition has a much broader meaning as it refers to all the processes by which the sensory input is transformed, reduced, elaborated, stored, recovered, and used. Cognition leads to thoughts, emotions, and conation (motor activity), in that order. Thus, on hearing a loud sound (cognition), one might think it to be a dangerous explosion (thought), feel afraid (emotion), and look for a shelter (conation). The terms cognitive disorder and thought disorder are often used synonymously.

Thought processes and disorders Thinking is the ability to have ideas and to infer new ideas from old ones. Thought processes have been divided into primary and secondary processes. Primary thought process, such as a dream, disregards logic, is based on visual images, and is dominated by wish and fantasies. Secondary thought process is based on both visual images and words. It is logical and goal-directed. Thoughts can be retarded in depression. Thought blocking, seen in schizophrenia, is a sudden break in the train of thought. Flight of ideas, seen in mania, is an increased flow of thought resulting in frequent switching from one train of thought to another. Crowding of thoughts occurs in schizophrenic patients who complain that a large number of thoughts have been compressed into their head. Delusions are fixed, false beliefs that are strongly held and will not change even with evidence to the contrary. Obsessional thought is a stereotyped, repetitive, persistent thinking which one knows to be irrational but cannot resist. They are usually seen in conjunction with compulsive behavior.

Emotions The term emotion must be distinguished from related terms such as mood and affect. Emotion is a complex feeling state with psychic, somatic, and behavioral components, that is related to affect and mood. Affect is the observed expression of emotion

over a short span of time, usually in response to an external event. Mood1 is a sustained emotion experienced by a person. Mood is to affect as climate is to weather. An emotional state has two components: a peripheral component and an affective component. For example, the feeling of fear is the affective component of the emotions associated with fear, while the associated bodily events of palpitation and heavy breathing, sweating of palms, dryness of mouth, and tense muscles that are the peripheral components of fear. The peripheral components of emotion have two functions: (1) They have a preparatory function, that is, they prepare the body for action. The preparatory function involves both general arousal, which prepares the organism as a whole for action, and specific arousal, which prepares the organism for a particular behavior. For example, sexual arousal involves general arousal as indicated by an increase of heart rate, a change that prepares for physical exertion. In addition, it involves features of specific arousal such as penile tumescence. Arousal usually enhances both intellectual and physical performance. (2) The peripheral components of emotion also have a communicative function, that is, they communicate the emotional states to other people. In humans, social communication of emotion is mediated primarily by the facial muscles and posture, both of which involve the skeletomotor system.

Theories of emotion James–Lange theory According to this view, the

perception of emotion results from the perception of one’s own physiological changes. The theory suggests that “we feel sorry because we cry, angry because we strike, afraid because we tremble.” In other words, we do not cry when we feel sorry, but it is because we find ourselves crying in a certain situation that we realize that we must be feeling sorry! In support of this theory, a very common situation is cited: A person sitting in pin-drop silence is startled by a sudden harsh sound. Instantly, his heart starts racing and his mouth goes dry even

1

Hippocrates believed that mood was determined by the balance of four factors or humors, viz., blood, phlegm, yellow bile, and black bile. According to him, an individual becomes sanguine (cheerful and optimistic) due to excess blood, phlegmatic (calm even in difficult situations) due to excess phlegm, choleric (ill-tempered) due to yellow bile, and melancholic (sad and depressed) due to black bile.

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Central Nervous System before he realizes the significance of the sound. However, he takes notice of his racing heart and dry mouth and realizes that he was scared! Thus, according to the James–Lange theory, emotions are only physical sensations and therefore, originate in the peripheral organs. The theory is partly borne out by the observation that (1) the different emotions tend to have distinct patterns of autonomic, endocrine, and voluntary responses, and (2) patients of spinal injury who have sensory deficits appear to experience a reduction in the intensity of their emotions. However, the theory fails to explain why one often continues to be emotionally aroused even after the physiological changes have subsided. Conversely, some feelings arise faster than the changes in bodily state normally associated with those feelings. The Schachter theory refines the James–Lange theory saying that the cerebral cortex takes into consideration the individual’s expectations while creating the affective response to peripheral information. Schachter injected volunteers with epinephrine: Some subjects were informed of the side effects (e.g., pounding heart) while others were not. All were then exposed to either annoying or amusing conditions. The subjects who had been warned about the side effects of epinephrine exhibited less anger or less pleasurable feelings: they attributed their arousal to the drug. The other group perceived their arousal as an intense anger or joy. In support of this theory, it may be recalled that the general arousal produced by exercise can result in specific arousal, such as sexual arousal. The Cannon–Bard theory points out that both fight

and flight (rage and fear) lead to similar autonomic (sympathetic) responses. It suggests that when a person encounters an emotional event, nerve impulses travel to the thalamus. From there they travel to the cerebral cortex to produce the affective component of fear and to the hypothalamus, where they produce simultaneous physiological changes. The theory therefore locates emotion centrally and not peripherally. Autonomic responses are however not as uniform as Cannon believed: Rather, different emotional states are typically accompanied by different patterns of autonomic responses, such as changes in blood flow or heart rate. The Arnold theory refines the Cannon–Bard theory by saying that the peripheral component of emotion results from the unconscious evaluation of a situation as potentially harmful or beneficial, while the affect is the conscious reflection of the unconscious appraisal. In other words, emotions have their own logic (Fig. 106.1). Thus, the sight of the New York Twin Towers crumbling to dust would have evoked feelings as varied as fear, rage,

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I hear a sound Cognition I understand that the sound originates from a firecracker Unconscious evaluation I evaluate the sound as harmful

I evaluate the sound as harmless

I could get Festivities burned or injured ! must be on ! Fear

Joy

I missed out on the show !

What a nuisance !

Grief

Rage

Fig. 106.1 An example of the Arnold theory of emotions, emphasizing the importance of the unconscious evaluation of a situation as potentially harmful or beneficial.

grief, or joy in the millions watching around the world!

Neural substrates of emotion The hypothalamus coordinates the peripheral, autonomic component of emotions. Stimulation of different hypothalamic regions evokes different patterns of autonomic reactions that are characteristic of different emotions. For example, animals with lesions in the lateral hypothalamus become placid, whereas animals with lesions of the medial hypothalamus are highly excitable and aggressive. Cats in which the whole cerebral cortex has been removed are thrown into rage by very mild stimuli such as a weak touch, or can even occur spontaneously without provocation. It is undirected, and the animals sometimes even bite themselves. It is termed sham rage because the responses lack the conscious experience that is characteristic of genuine rage (sham = false). No matter how it is elicited, sham rage subsides very quickly once the stimulus is removed. Sham rage largely disappears when the hypothalamus is ablated. The cerebral cortex is the site of the evalua-

tive, central component of emotions. It provides the means by which memory and imagination too can evoke emotional feelings. A cortical area that can evoke autonomic responses and a general arousal when stimulated is the orbitofrontal

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Thought, Emotion, and Conation

cortex. Lesions of the orbitofrontal cortex reduce the normal aggressiveness and emotional responsiveness. Cortical mechanisms also provide the means by which conscious thought can suppress reflex emotional responses. For example, as illustrated in Fig. 106.1, once we know that an explosive sound came from only a firecracker, the fear subsides. One source of this cognitive control of emotional responses is the ventromedial frontal cortex. Patients with frontal lesions have normal galvanic skin responses (sweating measured electrically, an index of sympathetic activity) to startle stimuli such as unexpected loud noises or bright lights, indicating a normal autonomic response mechanism. However, when they are shown emotionally disturbing pictures, they fail to show the expected autonomic responses to the emotionally charged stimuli. Some patients said that they knew they should have been disturbed by the pictures but found themselves unmoved! It was this area that was probably damaged in Phineas Gage (Box 106.1). Another cortical area for control of emotional responses is the anterior cingulate cortex. Lesions of this area reduce the emotional response to chronic intractable pain. Patients in whom the cingulate gyrus has been removed are not bothered by pain. They experience pain as a sensation and exhibit appropriate autonomic reactions, but the sensation is not perceived as intensely unpleasant. The fact that the cognitive and the emotional content of a picture are processed independently

Fig. 106.2 The path of the rod that accidentally pierced the skull and brain of Phineas Gage.

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Box 106.1 Phineas Gage In September 1848, Phineas Gage had a nasty accident while working on the Rutland and Burlington Railroad. While tamping down the blasting powder for a dynamite charge, Gage inadvertently sparked an explosion. The inch-thick tamping rod flew through his cheek and brain (Fig. 106.2). Gage collapsed but a mosment later, he stood up and spoke! His fellow workers took him to a local doctor who dressed his wounds. Within 2 months, Phineas Gage recovered physically but his personality changed completely. Honest and diligent Gage had become a foulmouthed liar given to extravagant schemes that he never followed through. The tamping rod had damaged the left ventromedial region of his brain, making him antisocial. His battered skull is preserved in the Warren Medical Museum at Harvard.

is brought out by the existence of two contrasting clinical syndromes, viz., prosopagnosia and Capgras syndrome. In prosopagnosia (p 773), the patients cannot consciously identify even familiar faces and yet they exhibit autonomic responses (e.g., skin conductance change) to familiar faces but not to unfamiliar faces. In Capgras syndrome, the patients can readily recognize familiar faces but do not show emotional responses to them. The amygdala plays a pivotal role in coordinating the peripheral components (autonomic responses) and central component (the affect) of emotional processing. The autonomic responses to emotion involve the hypothalamus while the affect involves the cerebral cortex, especially the cingulate, parahippocampal, and the prefrontal cortices. These connections of the amygdala form the extended Papez circuit (Fig. 106.3). It is different from the Papez circuit which was earlier thought to be important for emotions and in which the hippocampus was assigned a central role. The role of the Papez circuit in emotions is now largely discarded. Parts of the circuit may be important to the hippocampus for its role in explicit (declarative) memory for facts and personal events (p 731) that are associated with emotions. The unimportance of the hippocampus in emotion is apparent in fear-conditioning, for example, a flash of light (conditioned stimulus) followed by a loud explosion (unconditioned stimulus). Hippocampal damage will interfere with remembering the features of the conditioned stimulus such as the color of light or when it occurred, etc. However, the affective as well as the peripheral response to the loud explosion persists.

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Central Nervous System Table. 106.1 Efferent connections of the central nucleus of amygdala

Multimodal association cortices Cingulate gyrus

Anterior thalamic nuclei

Mamillothalamic tract

Hippocampal formation

Mamillary body

Fornix Stria terminalis

Hypothalamus

Amygdala

Fig. 106.3 The Papez circuit (thick arrows) is a part of the extended Papez circuit centered on the amygdala.

The main input station in the amygdala for all sensory modalities is its basolateral nucleus. The nucleus receives a major input from the inferotemporal cortex, which is important for explicit memory of facial identity. Since the amygdala also has strong connections with the autonomic nervous system, it can mediate emotional responses to facial expressions. Lesions of the amygdala therefore impair both memory of faces and the emotional response to faces. The major output station of the amygdala is its central nucleus, which gives origin to two major efferent projections: the stria terminalis and the ventral amygdalofugal pathway. (1) The stria terminalis projects to (a) hypothalamus, which mediates neuroendocrine response (like heart rate, blood pressure, and corticosteroid secretion) to stressful stimuli, and (b) the nucleus accumbens, which controls the body language in emotional states. The amygdala thereby influences the peripheral components of emotion. (2) The ventral amygdalofugal pathway projects to the brain stem, the dorsal medial nucleus of the thalamus, and the association areas of the cortex, especially, the rostral cingulate gyrus of the cortex and the orbitofrontal cortex (Table 106.1). The amygdala thereby influences the affective component of emotions.

Disorders of mood Mood disorders include depression (sorrow), mania (joy), and anxiety (fear). Each of these moods is considered perfectly normal in the presence of

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Anatomical target

Effect of amygdala stimulation

Peripheral signs of emotion

Lateral hypothalamus

Sympathetic activation

Tachycardia, GSR, pallor, pupil dilatation, BP elevation

Dorsal motor nucleus of vagus

Parasympathetic activation

Ulcers, urination, defecation, bradycardia

Parabrachial nucleus

Increased respiration

Panting, respiratory distress

Ventral tegmental area (VTA) Locus ceruleus Dorsal lateral tegmental nucleus

Activation of catecholamines

Behavioral and EEG arousal

Nucleus reticularis pontis caudalis

Increased reflexes

Increased startle

Central gray

Cessation of behavior

Social interaction

Trigeminal nucleus Facial motor nucleus

Mouth open, jaw movements

Facial expressions of fear

Paraventricular nucleus (hypothalamus)

ACTH release

Corticosteroid release (stress response)

Nucleus ambiguus

discernible causes but is considered to be a psychiatric condition if no justifiable cause can be identified. Melancholic depression (earlier called endogenous depression) is a psychopathological feeling of sadness that is associated with physiological (disturbances of feeding and sleep), psychological (slow thinking and suicidal thoughts), behavioral (paucity of movements), and social (shunning work) manifestations. Unlike the depression that follows a personal setback such as bereavement, melancholic depression persists every day, all day. Treatment of depression includes electroconvulsive therapy and antidepressants. Both cause a slow improvement in serotonergic transmission

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Thought, Emotion, and Conation that corresponds well to the gradual improvement of the mood in depressed patients. Electroconvulsive therapy acts by increasing the number and sensitivity of serotonin receptors in the hippocampus. The antidepressants mostly cause (1) a reduced reuptake of serotonin and norepinephrine along with (2) an increase in the sensitivity of serotonin receptors. (3) Some antidepressant drugs also reduce the sensitivity of serotonergic inhibitory autoreceptors. Lithium salt is useful in depression but its mechanism of action is not well understood. Mania is an extreme state of mood elevation in which one underestimates real-world difficulties and overestimates one’s ability to deal with them. The patient shows excessive energy, decreased need for sleep, excessive talking, excessive selfconfidence, and diminished judgment. Episodes of mania tend to alternate with depression, giving rise to the term manic-depressive psychosis or bipolar disorder. In PET (positron emission tomography) and fMRI (Functional Magnetic Resonance Imaging), the subgenual region of the prefrontal cortex (below the genu of the corpus callosum) shows reduced activity in depression and excess activity in mania. Serotonergic transmission seems to be important in the pathogenesis of depression: Reserpine, which depletes the brain of norepinephrine and serotonin, produces depression. Anxiety is characterized by intensely unpleasant

feeling of threat to one’s own self. Unlike fear, in which the source of threat is well defined, in anxiety disorder, the threat is either undefined or unjustifiable. The benzodiazepines (such as diazepam) that are used for treating anxiety are GABAA agonists. Anxiety can take the form of panic or phobias. Panic is a severe state of anxiety, lasting minutes to hours, characterized by a terrible feeling that one will die or go crazy. Panic attacks are associated with sympathetic crisis, that is, an intense overactivity of sympathetic nervous system. A variant of the panic attack is the posttraumatic stress disorder that occurs after an extremely traumatic stressful event. It is manifested in recurrent episodes of fear, often triggered by reminders to the initial trauma. Sympatholytic drugs greatly ameliorate the symptoms of posttraumatic stress disorders. Phobias are irrational fears of a particular phobic object (e.g., of fire, called pyrophobia) or situation (e.g., of closed spaced, called claustrophobia).

703

motivation, and cravings. They are mostly driven by bodily needs. For example, hunger and thirst drive us to seek food and water while the scorching heat of summer sends us scurrying for shade. Conation can also occur in the absence of bodily needs. Some of these behaviors are driven by circadian rhythm, as indicated by the abolition of the regularity of eating, drinking, and locomotor activity by a lesion of the suprachiasmatic nucleus. The main motivation for instinctive behavior is however the feeling of “pleasure” or “reward” that often overrides bodily needs. It explains why one eats more than one requires when the food is tasty. It also explains the instinct for sexual behavior although it has no homeostatic role to fulfill. A neural substrate of motivation is present in the dopaminergic neurons of the ventral tegmental area (VTA) that project to the nucleus accumbens, the striatum, and the frontal cortex. These neurons fire off a burst of action potentials when the animal is presented with a rewarding conditioned stimulus. They show a similar response even to a conditioned stimulus that has been paired with an unconditioned rewarding stimulus. When animals are trained to stimulate their VTA through implanted electrodes, they stimulate themselves repeatedly and endlessly, ignoring even offers of food and sex. An increase in dopamine in the nucleus accumbens causes a pleasurable sensation, similar to that produced by stimulation through electrodes. Thus it results in repeated self-administration of the drugs, which is reminiscent of drug addiction. Drugs such as cocaine, amphetamine, and nicotine increase the dopamine levels in the nucleus accumbens and other targets of the dopaminergic VTA neurons. Some opioid agonists cause addiction by inhibiting GABAergic neurons that normally suppress the dopaminergic neurons in VTA. However, not all addictive drugs act through dopaminergic neurons and other neurotransmitters are also involved.

Disorders of conation Compulsive behaviors may occur in relation to everyday activities such as gambling, sexual activity, shopping, and watching television, or in relation to addictive substances. Compulsive behaviors are driven by strong motivations and have a positive effect on emotions. Obsessive-compulsive disorder is characterized

Conation Conation refers to motor behavior driven by psychic stimuli such as impulses, instincts,

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by repetitive behaviors that are performed with the goal of reducing the anxiety associated with the obsessional thought. The anxiety however does not decrease and the repetitive behavior

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Central Nervous System continues unabated. Compulsions of washing hands clean, making certain that gas jets and electrical switches have been turned off and doors are locked, counting objects, placing objects in a particular order, and religious gestures are some of the common compulsions. Obsessive–compulsive disorder is thought to reflect a hyperactivity of the lateral orbitofrontal and anterior cingulate circuits of the basal ganglia. Addiction to drugs results in craving, a form of compulsive behavior. Withdrawal of addictive drugs results in unpleasant symptoms due to depression of the dopaminergic reinforcing system. Catatonias are motor anomalies of psychic origin,

without any organic pathology. It can take several forms, one of which is catalepsy, an immobile position that is constantly maintained. Cataplexy is a temporary loss of muscle tone and weakness precipitated by a variety of emotional states. It frequently coexists with narcolepsy (see p 719). Mutism is voicelessness without any structural abnormality. Akinetic mutism is associated with profound impairment of initiation of movements.

Schizophrenia Schizophrenia shows features related to disordered perception (hallucinations), thoughts (delusions), emotions (flat affect), and behavior (catatonia) and therefore cannot be considered to be a disease of any one process. Schizophrenia is characterized by psychotic episodes separated by long periods of nonpsychotic state. Psychotic episodes comprise delusions, hallucina-

tions, and memory disturbances. These are called the positive symptoms of schizophrenia. It has been suggested that the positive symptoms result from hyperactivity of the mesolimbic dopamine pathways to the amygdala, hippocampus, and neocortex.

Nonpsychotic state is characterized by negative

symptoms such as poor emotional arousal (flat affect), poor speech, poor attention, and poor motivation. Similar symptoms are seen following surgical disconnection of the prefrontal lobe. Negative symptoms probably result from hypoactivity of the mesocortical dopaminergic pathways to the prefrontal cortex. This may be the primary defect in schizophrenia which results in a loss of inhibitory feedback and consequent hyperactivity of the mesolimbic pathway. Brain abnormalities Schizophrenia is associated

with anatomical and functional abnormalities in the brain: (1) The medial temporal lobe is thinner and the anterior portion of the hippocampus is smaller, especially on the left side. (2) The ventricles are enlarged and there is a widening of the sulci, reflecting a reduction in the volume of the frontal lobe and temporal lobes. (3) The blood flow to the left globus pallidus is reduced and the blood flow to the frontal lobe does not increase (as it normally should) during tests of frontal lobe function involving working memory. Antipsychotic drugs are mostly dopamine (D2) antagonists such as butyrophenones (e.g., haloperidol) and thioxanthines (e.g., chlorprothixene). The therapeutic actions of these drugs are attributable to the blockade of D2 receptors in amygdala, hippocampus, and neocortex. However, these drugs also block D2 receptors in the caudate nucleus and putamen, causing motor disturbances. These side effects are known as the extrapyramidal symptoms in clinical parlance. Psychomimetic drugs produce psychotic symptoms. An example is phencyclidine, which has two actions: (1) In the mesocortical pathway, it reduces dopamine release by blocking the NMDA glutamate receptors on the dopaminergic terminals in the prefrontal cortex. (2) In the mesolimbic pathway, it increases dopamine release and inhibits its reuptake.

REVISION QUESTIONS 1. The amygdala receives a major input from the inferotemporal cortex and sends a major output through the stria terminalis to the hypothalamus. Which important function of the amygdala is enabled by these input and output?

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2. The amygdala mediates emotional responses (both peripheral and affective components) to facial expressions. Which are the neural connections of amygdala that enable these functions?

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Thought, Emotion, and Conation 3. ECT and antidepressants alleviate melancholic depression. What is their mode of action? 4. What is bipolar disorder and why is it called so? 5. Anxiety can take the form of panic or phobias. What is the difference between the two? 6. Antipsychotic drugs are mostly dopamine (D2) antagonists. Where do these D2 antagonists act to produce (1) their therapeutic effect and (2) their side effect, that is, the expyramidal symptoms.

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705

7. When an animal is trained to stimulate a certain area of its brain through implanted electrodes, they stimulate themselves repeatedly and endlessly. Why do they do so and which area of the brain is stimulated? 8. Addictive drugs like cocaine, amphetamine, and nicotine increase the concentration of a neurotransmitter in the brain. Which is the neurotransmitter and in which areas of the brain does it increase?

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Electroencephalogram and Epilepsies

Electroencephalography Electroencephalography (EEG) is to the brain what electrocardiography (ECG) is to the heart. Both are surface recordings of electric potentials (over the precordium or the scalp) that originate from the numerous dipoles that develop in excitable tissues (cardiac muscle cell or the cerebral neurons). Electroencephalography helps in diagnosis of several clinical conditions. Before the advent of the computerized axial tomography (CAT) scan, EEG was used even for the diagnosis of brain tumors and subdural hematomas. Even today, the EEG remains indispensable for the diagnosis of epilepsies, just as the ECG remains indispensable for diagnosing cardiac arrhythmias. The epilepsies are briefly discussed at the end of this chapter. EEG recording is also one of the essential components of polysomnography (see Fig. 108.2).

EEG recording technique In electroencephalography, a large number of electrodes are placed all over the scalp in order to obtain a complete map of the scalp potentials. The pairs of electrodes are connected to separate channels of an amplifying and recording device called the electroencephalograph or the EEG machine. Most EEG machines have 8 to 16 channels, although the number of channels provided may be much higher in machines allowing highdensity scalp recording. Electrode placement The majority of laboratories use the 10 to 20 system of electrode placement recommended by the International Federation of Societies for Electroencephalography and Clinical Neurophysiology. The system is based upon measurement from four standard points on the head: (1) the nasion, (2) the inion, and (3) the left and right preauricular points. The system is termed the 10 to 20 system because adjacent electrodes are spaced either at 10% or at 20% of the total distance between a given pair of skull landmarks, for example, the distance between nasion and inion in the saggital plane or the distance between the two mastoids in the coronal plane (Fig. 107.1). An important advantage of this system is that there is an anatomic correlate for each electrode, which is consistent from patient to patient.

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Electrode derivations There are three tradition-

al methods of deriving electrical signals from an electrode array: the bipolar, common reference, and average reference methods. In the bipolar method, each channel is connected to two electrodes both of which are likely to pick up appreciable EEG potentials. The common reference method is essentially a bipolar derivation in which one electrode is common to all the channels. The common electrode is also called neutral or inactive because it is usually placed on a site such as the ear lobule or mastoid where the brain potentials recordable are minimum. In average reference derivation, all the electrodes on the scalp are connected through equal resistors to a single point, which is then used as the common reference. Thus the average reference of EEG is similar to the indifferent electrode of the ECG. Each method has its advantages and disadvantages and the choice varies with the ailment and the physician’s preference. Montage With so many electrodes placed on the

scalp and with each EEG channel recording the potential difference of a single pair of electrodes, several different patterns of connection between electrodes and amplifiers become possible. Each such pattern is called a montage. While designing a montage, it is important to bear in mind (1) the number of channels available in the EEG machine (most machines have eight channels) and (2) the scalp location of interest to the clinician. Two montages are illustrated in Fig. 107.2.

Electroencephalogram The EEG signal is a continuous wave with a mixed and variable frequency. However, short segments of the EEG wave show fairly uniform frequency. According to its frequency, the EEG waves are categorized into four types: α, β, θ, and δ waves (Fig. 107.3). The appearance of the tall, rhythmic α waves or other high-amplitude, low-frequency waves is called EEG synchronization. Alpha waves are the most prominent component

of the EEG. They have a fairly regular frequency of 8 to 13 Hz and an amplitude of 50 to 100 μV. They are prominent in the parietooccipital area of the scalp and are most marked when the person is awake and relaxed with eyes closed. The α

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Electroencephalogram and Epilepsies

A

C

B

D

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Fig. 107.1 The 10–20 international system of electrode placement. [A] Lateral view. The electrodes are placed at fixed percentage intervals between the nasion and the inion. [B] Frontal view. The preauricular points serve as reference points for the placement of the central transverse row of electrodes. Cz is the intersection of the central transverse and longitudinal rows. [C] Superior view. [D] Names of the electrodes in the 10–20 system.

rhythm disappears on opening the eyes and being attentive. This transformation is known as EEG desynchronization (Fig. 107.4) and it occurs when attention is paid to a stimulus. Mere perception does not cause desynchronization as even trying to see in the dark brings about EEG desynchronization. The α rhythm disappears during deep sleep. The mean peak alpha frequency is 10.2 Hz. The frequency decreases in hypoglycemia, hypothermia, hypercapnia, and hypocortisolemia. Beta waves have frequency more than 13 Hz and

may be as high as 25 Hz. They have lower voltage than alpha waves. They are frequently recorded from the

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parietal and frontal region. Barbiturates induce beta activity. Theta waves have a frequency between 4 and 8 Hz

and have larger amplitude than alpha waves. They are seen in the parietal and temporal region in children. They are seen in emotional stress in adults, and also occur in many brain disorders. The incidence of transient theta rhythm is about 30% in normal adult subjects in the alert state. It is recordable directly from the hippocampus in experimental animals. Delta waves have a frequency of less than 3 Hz.

They are seen in deep sleep and in infancy. Delta

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Central Nervous System

Designation

Fp1

F3

Regularly waxing and waning waves at 14–30 Hz

3 α rhythm

Regular sequence of waves at 8–13.3 Hz

4 ϑ rhythm

Regular sequence of waves at 4–7 Hz

5 δ rhythm

Regular sequence of waves at 1–3.5 Hz

6 δ activity

Irregular sequence of polymorphic wa ves at 1–3.5 Hz

7 Subdelta wave

Wave with duration >1s

8 Steep waves (ste ep potential)

Conspicuous, blun t, steep individual waves

9 Sharp waves (sharp potential)

Sharp and steep waves of 80–250 ms dur ation, ascending phase usually steeper than descending phase

6 C4

3

7 P3

A2

P4

8

4 O1

F3

O2

F4

1

A1

2 Spindles F4

C3

3

1 β rhythm

5

2

2 C3

C4

4

5

6

7

8

P3

O1

P4

A2

10 Spike

Sharp and steep wave of duration < 80 ms

11 Polyspikes

Compac t series of spikes

12 Spike–wave complex

Comple x consisting of a spike and slow wave

13 Rhythmic spikes and waves

Sequence of regular spike–wave complexes at about 3 Hz

14 Sharp and slow waves

Sequence of complexes of sharp waves and slow waves of 500–1,000 ms dur ation, often rhythmic

O2

Fig. 107.2 EEG montages. (Above) Longitudinal bipolar montage. (Below) Common referential montage referred to the ipsilateral ear lobule.

activity in an awake adult signifies serious organic brain disease. Delta waves also occur in the cortex of animals that have had subcortical transections separating the cerebral cortex from the thalamus, indicating that delta rhythm occurs in the cortex independent of activities in the lower regions of the brain.

2s

Fig. 107.3 Some important EEG waves.

Epileptiform EEG discharges While there are several types of abnormal EEG waves, the epileptiform waves are of particular importance because a major use of EEG lies in the diagnosis of epilepsy. In general, the epileptiform wave may be: (1) a spike (duration of 20–70 ms), (2) a sharp wave (duration of 70–200 ms), or (3) a spike and wave complex, in which a spike or a sharp wave is followed by a slower wave. In grand mal

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Definition Regular sequence of waves at 14–30 Hz

Fp2

1

A1

Morphology

α waves

Desynchronized

α waves

50 μV 1 second Eyes closed

Eyes open

Eyes closed

Fig. 107.4 Alpha block. Alpha waves appear when the eyes are closed and the mind is relaxed. They disappear as soon as the eyes are opened.

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Electroencephalogram and Epilepsies epilepsy, there are polyspikes. In petit mal, there are spikes and waves at a rate of 3 Hz.

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+

Origin of EEG waves The scalp potentials recorded in the EEG are produced by the currents set up by the dipoles formed in the cerebral cortex. Lamina 5 of the cerebral cortex contains the pyramidal cells. At its apex, the pyramidal cell gives off a long dendrite (the apical dendrite) that is directed perpendicular to the cortical surface. The dipoles that produce the EEG are formed on these apical dendrites of pyramidal cells. As explained in the context of the ECG, a dipole is formed when different parts of an excitable tissue are in different states of polarization. In case of the cortical dendrites, the polarity of the dipole depends on (1) whether the postsynaptic potential is excitatory (EPSP) or inhibitory (IPSP) and (2) whether the postsynaptic potential develops in layers 2 and 3 (i.e., near the cortical surface) or in layer 4 (i.e., a deeper layer). Axons from the contralateral cortex terminate in layers 2 and 3 whereas thalamocortical neurons terminate in layer 4. Fig. 107.5 shows how these factors influence the polarity of the EEG wave. EEG synchronization The thalamic relay nuclei

have two different physiological states: the transmission mode and the burst mode. When the relay nucleus is in the transmission mode, its resting potential remains close to its threshold potential so that it fires off a single action potential each time it is stimulated by the spinothalamic neurons. Thus each impulse

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2. External granular lamina

3. Pyramidal lamina

5. Ganglionic lamina 6. Multiform lamina

Spinothalamocortical

4. Internal granular lamina

Commissural

1. Plexiform lamina

- - - - - - -+ + + + + + + + + +++

epilepsy, an EEG record showing epileptiform waves will confirm the diagnosis. The epileptiform waves, however, usually appear during an epileptic attack. In between attacks, that is, in the interictal period, epileptiform waves may or may not occur. As EEG records are mostly obtained during interictal periods, attempts are made to trigger the appearance of epileptiform waves and thereby clinch the diagnosis of epilepsy. The procedures for artificially triggering epileptiform waves in the EEG are called activation procedures. The most widely used activation procedure is hyperventilation for 3 to 5 minutes. However, the most effective activation procedure is intermittent photic stimulation in which flashes of bright light (frequency of 1 to 30 per second) are delivered for a period of 10 seconds. Epileptiform abnormalities seem to occur the least during REM sleep in comparison to NREM sleep or the awake state.

-- --+++ +++++++ ++ +++

-

Activation procedures In a suspected case of

Fig. 107.5 Dipoles formed on the apical dendrite of a pyramidal cell (see also Fig. 100.2). Commissural fibers produce an EPSP on the dendrite in laminae 2 and 3. The dipole is therefore negative near the surface and the EEG wave is negative. Spinothalamocortical fibers produce an EPSP on the dendrite in lamina 4. The dipole is therefore positive near the surface and the EEG wave is positive. The polarity of the EEG waves reverses if an IPSP is produced instead of an EPSP.

traveling up the spinothalamic neuron is faithfully transmitted by the relay cell to the sensory cortex. When the relay nucleus is in the burst mode, it is in a hyperpolarized state and when depolarized to the threshold potential, it fires off a burst of action potentials. These bursts are conducted to the sensory cortex and are associated with high-amplitude EEG waves. The transition of the thalamic relay nuclei from the transmission mode to the burst mode is brought about by the GABAergic inhibitory neurons of the reticular nucleus of the thalamus (Fig 107.6). These neurons hyperpolarize the thalamic relay cells through GABAB receptors, switching the cells to the burst mode. As the thalamic relay cells and the reticular cells are reciprocally connected, bursts of action potentials in the relay cells produce similar bursts in the reticular nucleus too, so that the reticular nucleus remains stimulated and the thalamic relay cells remain hyperpolarized. The burst cycles end when the reticular nucleus is inhibited by the neurons of the mesopontine and basal forebrain cholinergic systems. Similar bursts of the thalamic relay cells and reticular nucleus cells may underlie seizure discharges too.

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Central Nervous System membrane depolarization, the Ca2+ channels close but not before enough Ca2+ has entered the cell to activate a population of calcium-activated K+ channels. The opening of these K+ channels hyperpolarizes the cell and the burst of action potentials stops. However, hyperpolarization also restores the activity of the Ca2+ channel, so that the burst cycles repeat over and over again (Fig. 107.7).

Third-order sensory (thalamic relay) neuron Reticular nucleus

EEG analysis Visual analysis

Neuron of the basal forebrain cholinergic system GABAergic inhibitory neuron of reticular nucleus

Ventroposterior nucleus Second-order sensory neuron

Neuron of the mesopontine cholinergic system

Fig. 107.6 Role of the reticular nucleus in EEG synchronization. The ionic mechanism of the alternations between the transmission and burst modes is as follows. The thalamic relay cell has a population of voltagegated Ca2+ channels that remain inactivated when the membrane potential is near the firing level, and are activated when the membrane hyperpolarizes. In the hyperpolarized relay cell, therefore, an inward Ca2+ current flows through these Ca2+ channels, depolarizing the cell to the threshold potential and triggering a burst of action potentials. Following

Transmission mode

Certain features of the EEG that are of diagnostic importance can be appreciated merely by looking at the record carefully. These changes include (1) the epilepsy-seizure potentials, (2) the irregular slowing associated with cerebral trauma or metabolic coma, (3) the local changes associated with tumors, and (4) the changes associated with psychotropic drugs. Brain death results in an isoelectric or flat EEG. It is important that artifacts of EEG recording are not interpreted as clinical abnormalities of the EEG. Some common EEG artifacts are sweat artifact, blink artifact, EMG artifact, and ECG artifact (Fig. 107.8). An experienced electroencephalographer will readily identify these and other artifacts.

Quantitative analysis Data reduction Looking at the EEG, it may be pos-

sible to comment whether the voltage is somewhat high or low, or whether it shows a predominance of a particular frequency of waves. However, it is

Burst mode

Opening of GABAB -activated K+ channels

Opening of Ca2+ activated K+ channels and inactivation of Ca2+ channels

Stimulation by spinothalamic neuron Stimulation by GABAergic thalamic neurons

Activation of voltage-gated Ca2+ channels

Activation of voltage-gated Ca2+ channels

Fig. 107.7 Mechanism of transition of thalamic relay neurons from the transmission to the burst mode.

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Electroencephalogram and Epilepsies

711

-128 µV EOG -

Fz -

Cz -

Pz A2

00:00:02

00:00:04

00:00:06

00:00:08

Fig. 107.8 Blink artifact (green arrows) and ECG artifact (blue arrows) in the EEG. Note that the blink artifact is most prominent in the frontal (Fz) EEG lead and coincides with the blink recorded in the electrooculogram (EOG).

not possible to quantify these characteristics just by looking at the EEG, if only because of the sheer bulk of the record. A 16-channel EEG recorded for 5 minutes at a chart-speed of 30 mm/s will produce 9 × 16 meters of EEG record! However, a computer makes it possible to summarize the key features of such large volumes of EEG record (data reduction) in terms of voltage and frequency. A common method of data reduction is frequency analysis with spatial mapping. Frequency analysis of an EEG record gives the relative powers of EEG waves in a particular frequency band, generally corresponding to the α, β, θ, and δ waves. The graphic depiction of the same information separately for multiple electrode sites on the scalp is called spatial mapping. A more general name for the spatial mapping of various EEG characteristics (e.g., amplitude) is brain electrical activity mapping (BEAM). Evoked potentials If a stimulus is delivered to a

subject while his EEG is being recorded, it results in the appearance of several electrical waves in the EEG after a brief latency. These small but consistent EEG waves produced in response to a stimulus are called the evoked potentials. However, the evoked potentials (the signal) that are recorded are barely discernible against the dense backdrop of the spontaneous EEG waves (the noise). In order to identify the evoked potential, the signal-to-noise ratio is enhanced using the technique of averaging (Fig. 107.9). The evoked potential is called the signal because it is produced consistently and

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interests us, while the background EEG is called noise because it is produced randomly and does not interest us contextually.

A

B

C

D Stimulus Evoked potential Superimposition

Stimulus Averaging

Stimulus

Fig. 107.9 The principle of averaging. Strips A to D show the EEG record for a certain duration after delivering a stimulus (auditory or visual). The stimulus results in a consistent EEG wave (called evoked potential) after a fixed time interval. It is difficult to identify the wave in strips A to D but when all the strips are superimposed or averaged, the evoked potential stands out prominently.

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Central Nervous System Evoked potentials are classified in two waves: (1) Depending on the stimulus modality, evoked potentials are called auditory, visual, or somatosensory evoked potential. (2) Depending on their latencies, these waves are called short-latency (< 10 ms), midlatency (10–50 ms) or long-latency (> 50 ms) evoked potentials (see Fig. 118.14). Evoked potentials with latencies less than 250 ms are called stimulus-related potentials because they are strongly related to the intensity of the stimulus and are recordable even in comatose patients. They are of interest to the neurologists as they give considerable information about the conduction speed of auditory, visual, and somatosensory impulses through the brain.

The commonest type of stimulus-related evoked potential in clinical use is the short-latency auditory evoked potential, popularly known as the brain stem auditory evoked potential as it originates in the brain stem. The mid-latency (10–50 ms) response is thought to reflect activity arising in the thalamocortical radiations and the cerebral cortex. The neural generators of the longlatency (> 50 ms) response are debatable. Event-related potentials Evoked potentials with

latencies greater than 250 ms are of more interest to the psychiatrists and psychologists who have hailed it as a brain wave that reflects cognitive processes in the brain. These waves, which are called event related potentials (ERP), may or may

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Fig. 107.10 (Above) Interictal EEG in a patient with grand mal seizures, showing a synchronous paroxysm of generalized, partly atypical spikes and waves. (Below) EEG in a patient with absence seizures, showing generalized spikes and waves at 3 to 4 Hz, induced by hyperventilation.

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Electroencephalogram and Epilepsies not appear prominently in response to a stimulus depending on the attention devoted to it. When they do appear, they are independent of the stimulus intensity. The most easily recordable event-related potential is the P300 (or P3 for short), which is a large, positive potential recorded about 300 ms after the stimulus, provided the subject pays special attention to it. It is generally agreed that the amplitude of P3 is related to the amount of working memory allocation demanded by the task. The P3 wave has a longer latency and smaller amplitude in dementia.1 P3 has also been used in the evaluation of attention-deficit disorders.

Epilepsies An epileptic fit or seizure is a brief disorder of cerebral function, associated with disturbance of consciousness and accompanied by a sudden, excessive discharge of cerebral neurons. They are triggered by a population of abnormally hyperexcitable neuron cells. Seizures are of two types: generalized and focal. In generalized seizures, the excitation originates

in the midline, diencephalic areas and spreads to large areas of the brain. Clinically, there are two common subtypes of generalized seizures, the

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grand mal and the petit mal (Fig. 107.10). In grand mal epilepsy, there are tonic–clonic seizures lasting about a minute. In the first 30 seconds, there is loss of consciousness and a sustained, “tonic” spasm of all the muscles. Spasm of respiratory muscles results in inadequate ventilation, leading to cyanosis. In the next 30 seconds, there is jerky, “clonic” contraction of muscles. Contraction of the jaw and tongue results in frothing at the mouth and biting of the tongue. In petit mal epilepsy, there are “absence” seizures, lasting about 15 seconds. During these absences, there is a transient loss of consciousness and the patient may stare blankly ahead. In focal seizures, the clinical features depend on

the areas of the brain that are affected. However, the focal discharge may spread to become generalized. The temporal lobe is the commonest site of focal epilepsy. Temporal lobe epilepsy results in hallucination and disturbances of memory, including déjà vu phenomenon, that is, a sensation of reliving an experience or a feeling of great familiarity with the surroundings. A less common type of focal epilepsy is Jacksonian epilepsy. It originates in a small part of the body as muscle twitches or jerky movements, and slowly spreads to the other parts.

REVISION QUESTIONS 1. What is the 10–20 system of electrode placement, and why is it called so?

(b) when barbiturates are consumed, (c) in deep sleep, (d) in infancy?

2. What is “electrode derivation?” What are the three traditional methods of electrode derivation?

7. What are the common types of epileptiform waves?

3. What is an EEG montage? 4. What are the four main EEG waves? What are their frequency ranges? In which part of the scalp are α, β, θ, and δ waves most prominent? 5. What is EEG synchronization? What causes EEG desynchronization? 6. Which EEG wave is prominent: (a) when the subject is awake and relaxed with eyes closed,

8. What are “activation procedures?” Which are the two commonly used activation procedures? 9. The scalp potentials recorded in the EEG are produced by the current set up by the dipoles formed in the cerebral cortex. Where in the cortex are the dipoles formed? 10. The thalamic relay nuclei function in two alternating “modes.” What are these modes

1 Dementia is an abnormal deterioration of intellect affecting several areas of cognitive function, such as abstraction, orientation, judgment, and memory.

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called? Which mode is associated with highamplitude EEG waves? Which are the two types of ion channels that cause alternations between the two modes? 11. Name four common EEG artifacts.

Which is the most easily recordable eventrelated potential? 13. Which are the two common types of generalized seizures? Give two examples of focal seizures.

12. What is the difference between stimulusrelated potential and event-related potential?

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108

Sleep

Sleep is a reversible behavioral state of unresponsiveness and perceptual dissociation from the environment. Sleep is usually, but not necessarily, accompanied by postural recumbency, quiescence, and closed eyes. Most young adults report sleeping approximately 8 hours a night. Sleep length depends upon genetic factors, volitional factors (staying up late, waking by alarm, etc.), and circadian rhythms (the time of the day when one sleeps). Within sleep, there are two separate states, viz., the rapid eye movement (REM) sleep and the nonrapid eye movement (NREM).

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REM sleep REM sleep is associated with the following characteristics: (1) The EEG shows the desynchronized or wakefulness pattern. Hence, REM sleep is also called desynchronized sleep. Yet, a person is usually more difficult to awake in REM than in NREM sleep. Hence, REM sleep is also called paradoxical sleep. (2) REM sleep is associated with longer episodes of dreaming than NREM sleep. The earlier belief that dreaming occurs only in REM sleep is incorrect. (3) Inhibition of spinal motor neurons via brain stem mechanisms causes atonia of antigravity muscles in REM sleep. (4) During REM sleep, there are (a) bursts of rapid, saccadic eye movements, (b) twitches in other phasic muscles, and (c) changes in the breathing pattern. (5) During NREM sleep, there is sweating or shivering due to impaired thermoregulation. These cease during REM sleep. (6) In cats, rapid eye movements are associated with bursts of pontogeniculooccipital (PGO) waves. In humans, PGO waves are not seen in scalp EEG but are recordable by depth EEG recordings.

NREM sleep NREM sleep is subdivided into four stages based on the EEG (Fig. 108.1). Sleep is lightest in stage 1 and deepest in stage 4. A series of body movements usually signals a drift to the lighter NREM sleep stages. NREM sleep is usually associated with a lack of mental activity. The EEG pattern in NREM sleep is synchronous, and is associated with characteristic waveforms such as sleep spindles, K complexes, and high-voltage slow waves.

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Fig. 108.1 Electroencephalographic characteristics of different stages of NREM sleep. In stage 1 NREM sleep, the EEG changes from a rhythmic alpha (8—13 Hz) activity, particularly in the occipital region, to a relatively low-voltage, mixed-frequency pattern. Bursts of high-voltage, theta (3—7 Hz) activity are common during the onset of stage 1 sleep in children and young adolescents. There is considerable sensitivity to sensory stimuli during stage 1 sleep. However, mild or moderate stimuli are often unable to produce a full arousal; instead, they produce a sharp electronegative wave at the vertex called the vertex sharp wave or V wave. They can be regarded as the rudimentary form of the K complexes that appear in stage 2. They look similar too, except that the V waves are sharper and have shorter duration. Slow eye movements commonly precede the EEG transition from wakefulness to stage 1 sleep. Stage 2 NREM sleep is signaled by the appear-

ance of sleep spindles in the EEG. These are up to 100 mV in amplitude and have a frequency of about 14 Hz. Each burst lasts about 0.5 to 1.5 seconds. Auditory stimuli during this phase readily evoke the K complexes in the EEG. They also occur spontaneously during this stage. The K complex consists of one or two high-voltage waves followed by a brief 14-Hz activity. As stage 2 sleep progresses, there is a gradual appearance of high-voltage slow-wave activity in the EEG till the onset of stage 3 sleep.

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Central Nervous System Stage 3 NREM sleep is characterized by high-voltage and slow frequency waves called the delta waves, which account for 20 to 50% of the EEG activity. Stage 4 NREM sleep is characterized by delta activ-

ity accounting for more than 50% of the EEG activity. The stage 3 and stage 4 sleep together are variously called slow wave sleep, delta sleep, or deep sleep.

Sleep onset Attempts have been made to define the exact point of sleep onset in terms of polysomnographic features, behavioral responses, and intellectual functions. Polysomnography refers to the record of electroencephalogram (EEG), electromyogram (EMG), electrooculogram (EOG), and other physiological parameters that indicate the onset and depth of sleep (Fig. 108.2).

complex or sleep spindle (i.e., stage 2 sleep) has been taken as the time of sleep onset. Behavioral responses In stages 1 and 2, the subject

responds to visual stimuli infrequently. Auditory reaction time becomes longer as stage 1 sleep approaches. Auditory response is absent at sleep onset. There is some response to meaningful stimuli even in sleep, which indicates that sensory processing continues even after the onset of sleep. This is apparent from the discriminant responses during sleep to meaningful versus nonmeaningful stimuli (Box 108.1). The response to a meaningful stimulus may be indicated by the evoked K complexes instead of a full arousal. The likelihood of a response to a neutral stimulus during sleep can be increased through instrumental conditioning, for example,

Electrophysiological responses (1) In the EMG, the

Box 108.1 Examples of discriminant responses

motor unit potential (MUP) amplitudes show a gradual diminution as stage 1 sleep approaches. (2) The EOG indicates the presence of slow rolling movements of the eye called the slow eye movements (SEMs) as sleep approaches. However, the onset of stage 1 does not necessarily coincide with the perceived onset of sleep. Hence, the presence of the K

• A person tends to have a lower arousal threshold for his/ her own name versus someone else’s name. • A sleeping mother is more likely to hear her own baby’s cry than the cry of an unrelated infant. • A captain wakes up to the cry of “iceberg” in the midst of the din and bustle of a ship.

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Body position ECG Left Biceps brachii EMG Right

Left Tibialis anterior EMG Right

Fig. 108.2 Recording scheme for polysomnography.

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Sleep

Box 108.2 Examples of retrograde amnesia • • • •

Inability to grasp the instant of sleep onset in memory. Not remembering the ringing of the alarm clock. Morning amnesia for sleep talking. Poor recall of midnight dreams.

by linking the absence of response to punishment (a loud siren or an electric shock). Intellectual functions Toward the onset of sleep, thoughts become illogical and incoherent. The transition from wakefulness to sleep tends to produce a retrograde amnesia (Box 108.2). This is because sleep inactivates the consolidation of shortterm into long-term memory. At least 10 minutes of sleep is required for retrograde amnesia to occur. Patients suffering from excessive sleepiness may experience similar memory problems in the daytime if there are frequent catnaps.

Sleep cycles In normal adults, sleep mostly begins with NREM sleep. Thereafter, NREM sleep and REM sleep alternate cyclically through the night. REM-onset sleep, that is, entry into sleep occurs through REM sleep, occurs in infants. In adults, REM-onset sleep occurs in jet lag, chronic sleep deprivation, narcolepsy, acute withdrawal of REM-suppressing drugs and endogenous depression. A night’s sleep usually progresses through four or five sleep cycles (Fig. 108.3). The average duration of a sleep cycle is 90 minutes, with the first cycle a little shorter. A typical sleep cycle progresses

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Awake

Fig. 108.3 Sleep cycles during a typical night’s sleep. The fourth cycle was interrupted prematurely by wakefulness.

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through stages 1 to 4 and then back through stages 3 to 1. The cycle ends with the REM sleep. Toward the end of the night, the cycles are often separated by brief intervals of awakening. The interruptions in sleep are not remembered in the morning due to retrograde amnesia. The transition from wakefulness to sleep is always through stage 1. The transition from sleep to wakefulness occurs either at the end of REM sleep or at the end of stage 2.

Sleep stage distribution The duration of sleep stages are different in the first cycle and in the later cycles. In the first cycle, stages 2, 3, and 4 constitute 20, 30, and 40% of the duration, respectively, with stage 1 and REM sleep accounting for 5% each. In the later cycles, the duration of stage 2 increases greatly to occupy most of the NREM portion. The later cycles also show an increase in REM sleep. Stages 3 and 4 (slow-wave sleep) occupy less time in the second cycle and may disappear altogether from later cycles. Effect of age Sleep cycles are present from birth.

Neonates have REM-entry sleep cycles of 60 minutes with equal durations of REM and NREM sleep in each cycle. Slow-wave sleep is maximal in young children and it is nearly impossible to wake them in the slow-wave sleep of the night’s first sleep cycle. After adolescence, the slow-wave sleep keeps decreasing and by the age of 60, slow-wave sleep may no longer be present, particularly in men. The age-related decline in slow-wave sleep seems to parallel the reduction in cortical synaptic density. REM sleep duration does not decrease much while arousals during sleep increase markedly with age. Sleep history When an individual is selectively deprived of REM or slow-wave sleep, a rebound increase in the same type of sleep occurs when natural sleep resumes. It is called recovery sleep. Following total sleep deprivation, slow-wave sleep tends to be recovered first. REM sleep tends to recover only after the recovery of slow-wave sleep, for example, on the second or subsequent recovery nights. Chronic deprivation of nocturnal sleep can result in REM-onset sleep. Recovery sleep, whether following REM, NREM or total sleep loss, is usually deeper, that is, it has a higher arousal threshold throughout NREM and REM sleep. Drugs Slow-wave sleep is suppressed by benzodiazepines (e.g., diazepam). REM sleep is suppressed by tricyclic antidepressants and monoamine oxidase inhibitors (MAOI). Withdrawal from drugs that selectively suppress a particular stage of sleep tends to be associated with a rebound increase in

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Thalamus

the same sleep stage. Thus, acute withdrawal from benzodiazepine produces an increase of slow-wave sleep while acute withdrawal from a tricyclic antidepressant or MAOI produces an increase of REM sleep. Alcohol intake immediately before sleep produces REM suppression early in the night and a rebound increase in REM sleep later in the night as the alcohol is metabolized.

The sleep spindles of NREM sleep originate in the same thalamic circuit that produces EEG synchronization. The rhythmic discharge of this circuit (between thalamic relay nuclei and the thalamic reticular nuclei) is terminated by the neuronal discharge originating in the cells of the mesopontine cholinergic system. These cholinergic neurons also promote REM sleep and arousal by stimulating cells of the nucleus reticularis pontis oralis, which is present in the lower midbrain and upper pons.

NREM-on (GABA)

Hypothalamus The posterior hypothalamus contains histaminergic cells that stimulate the ascending reticular activating system. These cells are, however, inhibited by a group of GABAergic cells in the anterior hypothalamus called the NREM-on cells. These cells also suppress REM sleep by inhibiting the nucleus reticularis pontis oralis. The above theories explain some of the early observations in sleep research. For example, following a transection separating the brain from the

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(Histamine)

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The nucleus reticularis pontis oralis is made of

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REM-on (Glu)

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Atonia

Locus ceruleus (NE) Nucleus reticularis pontis oralis

Pons

four types of cells that are responsible for different aspects of REM sleep (Fig. 108.4). (1) The cholinergic PGO-on cells project to the lateral geniculate body and onward to the occipital cortex. They are responsible for the generation of the PGO spikes that characterize the REM sleep. The firing of these cells is blocked by the noradrenergic neurons originating in the locus ceruleus and serotonergic neurons of the REM-off cells. (2) The locus ceruleus and REM-off cells are kept inhibited by the GABAergic REM-on cells, which in turn are kept activated by the mesopontine cholinergic system. (3) The mesopontine cholinergic system also keeps the glutamatergic REM-on cells activated. Descending axons from these REM-on cells terminate on glycinergic neurons in the medulla that inhibit stretch reflex and thereby result in the atonia that is characteristic of REM sleep. (4) The REM-waking-on cells descend to the spinal cord to stimulate muscles, especially the extraocular muscles, causing muscle twitches and the rapid eye movements that are characteristic of REM sleep.

Hypothalamus

Neuronal systems of sleep–wakefulness

REM-off (serotonin)

Rapid eye movements Muscle twitches

Fig. 108.4 Neural centers involved in sleep–wake mechanisms.

spinal cord, the isolated brain (encéphale isolé) continued to show EEG characteristics of wakefulness. However, when transected just cranial to the midbrain, the isolated forebrain (cerveau isolé) showed EEG characteristics of sleep because the thalamic circuits for EEG synchronization are not inhibited by ascending brain stem influences.

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Sleep

Chemicals mediating sleep–wakefulness The chemical theories of sleep–wakefulness assumed that certain endogenous chemicals that accumulate during wakefulness are metabolized during sleep, thereby restoring the internal milieu of the brain. However, none of the several endogenous substances that have been suggested in these theories, which includes melatonin, have been found to be consistently hypnogenic.

Disorders of sleep Several abnormal behaviors can occur during sleep, for example, somnambulism (sleepwalking), sleep talking, bruxism (tooth grinding), nocturnal enuresis (bedwetting), sleep apnea, and snoring. Snoring occurs due to the hypotonia associated with sleep which results in the soft palate falling back to partially occlude the nasopharynx. Nocturnal enuresis occurs during deep sleep and

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is treated by drugs such as imipramine (primarily, an antidepressant), which reduces the duration of deep sleep and increases the duration of stage 2 sleep. In adults with irregular sleep schedules, two common conditions are narcolepsy and hypnic myoclonia. Both the conditions are characterized by REM-onset sleep. Narcolepsy is an irresistible urge to sleep during daytime. It is characterized by several brief bouts of REM-onset sleep in a day. Narcolepsy is considered abnormal if it occurs in the absence of sleep deprivation. Hypnic myoclonia is a general or localized muscle contraction often associated with vivid visual imagery. It is a fairly common experience during sleep onset and tends to occur more frequently in stress or irregular sleep schedules. It has been suggested that hypnic myoclonia occurs if REM sleep is not associated with the usual inhibition of muscle tone and therefore allows motor responses to dream events.

REVISION QUESTIONS 1. REM sleep is also called desynchronized sleep or paradoxical sleep. Why? 2. During which phase(s) of sleep are the following observed: (1) atonia, (2) sweating and shivering, (3) dreaming, (4) theta waves, (5) sleep spindles, (6) K complexes, and (7) delta waves?

7. Which type of sleep is suppressed by (1) benzodiazapines, (2) tricyclic antidepressants, and (3) alcohol?

3. Give an example of a discriminant response to sleep.

8. When the brain is separated from the spinal cord by transection, it continues to show the EEG characteristics of wakefulness. However, when transected just cranial to the midbrain, the isolated forebrain shows EEG characteristics of sleep. Why?

4. What is retrograde amnesia and why does it occur during the onset of sleep?

9. Nocturnal enuresis is treated with imipramine. What is the action of imipramine?

5. Which type of sleep—REM or NREM—is maximal in young children and decreases with age?

10. What is hypnic myoclonia?

6. Which type of sleep shows a rebound increase following deprivation: REM, NREM, or both?

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Regulation of Body Temperature

Box 109.1 The body must lose heat all the time Maintenance of a constant body temperature is possible only if the net heat lost by the body exactly matches the amount of heat generated in the body. The body surely loses heat to the exterior in winter, but is there a net heat loss to the exterior in summer too? Yes. As the body constantly produces metabolic heat, the body must also constantly lose heat to the environment if it is to maintain a constant body temperature. If the body temperature is 37°C and it makes a net gain of heat from the environment, the body temperature will rise and culminate in death. Even when we gain heat standing out in the sun or in front of a fire, heat is also lost to the environment simultaneously. The result must necessarily be a net loss of heat. If there is a net heat gain, it is unbearable and we instinctively move away from the heat source. A continuous net heat gain from the environment spells certain death. How can a net heat loss be possible if the ambient temperature is 45°C? The answer lies in the evaporative cooling of the body through sweating. Evaporative cooling is practically the sole method that prevents the body temperature from rising when the ambient temperature is high. That is why one feels hotter on a humid day when there is decreased evaporation of sweat. That is also why the simple fan is so effective in cooling the body. Obviously, the maintenance of body temperature in a cold environment is far easier than in a hot environment and the adaptive mechanisms to cold far outnumber adaptive mechanisms to warm temperature. It is common experience that ambient temperatures several degrees lower than the body temperature—even subzero temperatures—can be comfortably borne using simple behavioral methods while temperatures a few degrees higher than the body temperature kill!

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Normal body temperature The temperature of the body surface (shell temperature) is not the same as the temperature inside the body (core temperature) or inside the cranium (the intracranial temperature). The shell temperature is represented by the skin temperature. The practical way of measuring the skin temperature is to measure the armpit temperature. The skin temperature is less in the extremities. The core temperature is best represented by the aortic blood temperature. The practical way of measuring the core temperature is to note the rectal temperature. The oral temperature (37°C) is lower than the rectal temperature (37.5°C) and it is affected by many factors, including ingestion of hot or cold fluids, gum-chewing, smoking, and mouth breathing. The intracranial temperature is best represented by the tympanic membrane temperature. The central thermoreceptors located in the hypothalamus sense the intracranial temperature rather than the general core temperature. Physiological variations in body temperature

(1) The normal human core temperature undergoes a diurnal fluctuation of 0.5 to 0.7°C, being lowest at about 6:00 am and highest in the evening (Fig. 109.1). A change in the sleep–wake cycle (i.e., working on night shifts) reverses the temperature curve. Physical activity may be contributory to the temperature curve but cannot be the sole factor

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o

Humans, as indeed all mammals and birds, are temperature regulators, that is, they have the capability to maintain a constant body temperature and are therefore called homeothermic. All lower animals are temperature conformers, that is, their body temperature conforms to (i.e., equals) the environmental temperature and are called poikilothermic. As enzymes regulating metabolism have a narrow range of optimum temperature that coincides with the normal body temperature, any change in body temperature adversely affects metabolism. For the same reason, poikilothermic animals tide over winter by hibernating while their metabolism drops to the bare minimum that is compatible with life.

Mouth temperature C

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Fig. 109.1 Diurnal variation in core temperature in a normal human.

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Regulation of Body Temperature since it is present even during continuous bed rest. (2) In women, there is a monthly cycle of temperature variation, with a rise in basal temperature at the time of ovulation (see Fig. 90.2). (3) Age affects temperature regulation: It is less precise in young children and their body temperature is 0.5°C higher than that of adults. The aged have subnormal temperature and are intolerant to extremes of ambient temperature. (4) Body temperature rises with physical activity, sometimes as high as 40°C. This rise is partly due to the resetting of the hypothalamic thermostat to a higher temperature during exercise. Body temperature also rises slightly during emotional excitement, probably due to unconscious tensing of the muscles. (5) When the body temperature is chronically elevated in normal adults, it is called constitutional hyperthermia.

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exchangers. These exchangers minimize the convective heat transfer from the core to the shell. (2) The transfer of heat from the shell to the exterior occurs through conduction, convection, and radiation. (a) The conductive heat loss is partly regulated by the layer of hair on the skin. Heat is conducted from the skin to the air trapped between hairs and from the trapped air to the exterior. (b) Convective (evaporative) heat loss is regulated by the amount of sweating. (c) Radiative (nonevaporative) heat loss is proportional to the temperature difference with the exterior. The scalp has high vascularity and therefore a large amount of heat is lost from it. At subzero temperatures, up to 50% of the body heat is lost from the scalp of bald persons. It explains why old people, who have a relatively less efficient thermoregulation, should wear a cap in winter, especially if bald.

Body heat exchange with exterior The heat exchange between the body and its environment can be viewed as a two-step process: The first step is the transfer of heat between the core of the body and its shell (the skin). The second step is the heat transfer between the body shell and the exterior (Fig. 109.2). (1) The transfer of heat from the core to the shell occurs almost entirely through convection and is regulated by the cutaneous blood flow. When the cutaneous vessels are dilated, blood flows into the skin carrying the heat from the core to the shell. When the cutaneous vessels are constricted, blood does not flow into the skin and the heat remains trapped in the core of the body. The arteries supplying the limbs have accompanying veins called venae comites that serve as countercurrent heat

Thermoregulatory mechanisms The temperature of the body is determined by a “thermostat” located in the hypothalamus. The set point of the hypothalamic thermostat is 37°C but it can be reset. When the body temperature rises above or falls below the set point, the thermostat activates appropriate effector mechanisms for restoration of the body temperature. The various effector mechanisms activated by the hypothalamus (Table 109.1) broadly fall into three categories: (1) the sympathetic Table 109.1 Thermoregulatory effector mechanisms Mechanisms activated by cold Increase heat production Shivering Hyperphagia Hyperactivity Increased secretion of Norepinephrine and epinephrine Decrease heat loss Cutaneous vasoconstriction

o

37 C Core temperature

o

37 C Core temperature o

29 C

20oC Ambient temperature

Fig. 109.2 Core and shell temperatures. Regardless of the ambient temperature, the core temperature is maintained at 37°C.

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Horripilation Mechanisms activated by heat Increase heat loss

o

36 C 35oC Ambient temperature

Curling up

Cutaneous vasodilatation Sweating Increased respiration Decrease heat production Anorexia Lethargy

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Central Nervous System mechanisms (vasoconstriction or vasodilatation, sweating, chemical thermogenesis), (2) the somatic mechanism (shivering), and (3) behavioral mechanisms (hyperactivity or lethargy, hyperphagia or hypophagia). Following a transverse spinal injury above the thoracolumbar sympathetic outflow, the sympathetic and somatic thermoregulatory mechanisms do not remain under hypothalamic control. Some local vasodilatation and sweating are still possible through spinal reflexes but these are too weak for effective control of body temperature. Such patients have to depend largely on conscious behavioral thermoregulatory mechanisms.

Body heating mechanisms vasoconstriction is sympathetically mediated and occurs reflexly in response to cold. It reduces the cutaneous blood flow. Thus, the heat transfer from the body core to the body shell is minimized. Cutaneous vasoconstriction occurs through a direct effect on smooth muscles and local reflexes, as well as in response to descending hypothalamic command. When cutaneous blood vessels are cooled, they become more sensitive to catecholamines and the arterioles and venules constrict. This local effect of cold directs blood away from the skin.

Cutaneous

Shivering is a cortical reflex in which stimulation

of cold receptors in the skin causes a reflex increase in the muscle tone of the body. When the muscle tone increases above a certain threshold, it results in muscle clonus, which is commonly known as shivering. Shivering, or even the increase of muscle tone, is associated with greater metabolic activity and greater heat generation. A motor center for shivering is located in the posterior hypothalamus. Horripilation is the fluffing of the feathers or erec-

tion of the hairs seen in animals in response to cold: It traps air in its layers, reducing heat loss from the skin. Horripilation is not seen in man: What is seen instead is piloerection, that is, the cold-induced contraction of the piloerector muscles attached to the hairs on the skin, resulting in “goose pimples.” Behavioral mechanisms Cold environmental tem-

perature also stimulates several behavioral mechanisms such as hyperactivity and hyperphagia. Hyperphagia helps because the thermic effect of food increases the body metabolism. Hyperactivity generates excess body heat. A particular type of hyperactivity is the rubbing of palms: It generates frictional heat in the palms and keeps them warm. A behavioral mechanism for minimizing heat losses

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is curling up while sleeping. Curling up reduces the body surface area in contact with the environment. Behavioral responses in winter also include seeking out heat sources and putting on warm clothes. Heatseeking behavior includes standing out in the sun or by a fire and consumption of hot food and drinks. Chemical (nonshivering) thermogenesis is the major thermogenic mechanism in infants while in adults, it contributes less than 15% to the total heat production. The amount of chemical thermogenesis is proportional to the amount of brown fat in the body: Infants have considerable brown fat in the interscapular region while adults have only a small amount of it. Infants need brown fat because (1) their body is poorly insulated by adipose tissue, (2) the surface-to-volume ratio of their body is high, and (3) their ability to shiver is poor. Brown fat cells produce excess heat through the uncoupling of oxidative phosphorylation whereby oxidation of foodstuffs release heat rather than generate ATP. In keeping with this function, brown fat has two characteristics that are crucial to chemical thermogenesis: (1) It has sympathetic innervation, and (2) It has a large number of mitochondria. The cytochrome present in the mitochondria lends brown fat its color. Cold stress causes (1) hypothalamic release of TRH, which ultimately increases the secretion of thyroxine (T4) from the thyroid gland, and (2) increased sympathetic discharge, which stimulates the release of epinephrine from the adrenal gland. Epinephrine increases the conversion of T4 to T3, which upregulates (increases) the synthesis of proton (H+) channels in the inner mitochondrial membrane and thereby initiates the uncoupling of oxidative phosphorylation, as explained in Fig. 109.3.

Body cooling mechanisms Nonevaporative heat loss is radiative heat loss. It is

proportional to the difference between body temperature and the ambient temperature. As the ambient temperature decreases, there is a linear rise in heat loss. Insensible perspiration About 50 mL of water evaporates every hour from the skin at all times. This is called insensible perspiration and results in an obligatory evaporative heat loss. Cutaneous vasodilatation and sweating occur in

response to a rise in the ambient temperature. The sweating causes evaporative cooling of the skin. Vasodilatation increases the cutaneous blood flow and promotes heat transfer from the core to the cooler surface. Like vasoconstriction, vasodilatation and sweat-

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Regulation of Body Temperature

H+

+

H

Mitochondrion

H + (proton) channel

H+

H+ pump

+

H+

723

ATP synthetase

ADP + Pi +

H

H

ATP

Inner membrane

Outer membrane

Cold stress H+

+

Increased secretion of TSH

Upregulation of proton channels

Increased secretion of epinephrine

H

H+ Increased secretion of T4

H+

H+ ADP + Pi H+ ATP

T3

Fig. 109.3 Uncoupling of oxidative dephosphorylation in a mitochondrium of brown fat. (Above) Most of the protons extruded by the H+ pump reenter the mitochondrial matrix through the channel in ATP synthase, leading to ATP synthesis. (Below) Cold stress increases T3 production in the body. T3 upregulates proton channels. Most of the protons extruded by the proton pump now reenter the mitochondrial matrix through the proton channels, which offer much less resistance than the ATP synthase. Hence, ATP synthesis decreases.

ing too are produced by a local response, a spinal reflex, and a hypothalamic reflex. Acclimatization to hot climates allows profuse sweating without much sodium depletion because the sweat of an acclimatized person has low Na+ concentration due to increased aldosterone secretion. Behavioral mechanisms A rise in ambient temperature also activates behavioral responses such as lethargy and hypophagia. There is also a search for shade and a preference for cold drinks. Some mammals lose heat by panting. This rapid, shallow breathing greatly increases the amount of water that evaporates in the mouth and respiratory passages and therefore the amount of heat lost also increases. Because the breathing is shallow, there is not much change in the alveolar air composition.

Thermoneutrality and thermal comfort Thermoneutral zone (TNZ) Also called the zone

of least thermoregulatory effort, it is defined as the range of ambient temperature (normally 25–27°C)

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within which the heat produced in the body is balanced by the nonevaporative and obligatory evaporative heat losses, without stimulating any reflex heating or cooling mechanisms of the body. The lower limit of the TNZ is called the critical temperature below which the metabolic heat production increases to maintain thermal balance. The zone of thermoneutrality is not the same as the preferred ambient temperature which is the range of ambient temperature associated with thermal comfort. Thermal comfort is maximum at a skin temperature of approximately 33°C. When the humidity is high, the preferred temperature is lower than the TNZ, while if there is brisk air movement, the preferred ambient temperature is higher than the TNZ. Thermal comfort also depends on the level of physical activity and the amount of clothing. Fig. 109.4 shows the thermal balance at increasing environmental temperature. Several points are to be appreciated in the graph. (1) The deep body temperature is maintained remarkably constant through a large range of environmental temperatures. It changes only at extremes of environmental

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Temperature receptors Temperature regulation is dependent on information originating in both central and peripheral receptors. Central thermoreceptors are present in the hypothalamus and spinal cord. They sense the temperature of blood flowing through them. Peripheral thermoreceptors are of two types: (1) The cutaneous thermoreceptors sense the ambient temperature. (2) The visceral thermoreceptors present in the abdominal viscera and in or around the great veins. Both cutaneous as well as visceral thermoreceptors detect cold rather than warmth. The central and peripheral thermoreceptors rarely provide identical information about body temperature. In dealing with body temperature, therefore, the posterior hypothalamus calculates an integrated temperature from the information obtained from both the central and peripheral thermoreceptors.

Fig. 109.4 Changes in the intensity of thermoregulatory mechanisms with increase in environmental temperature.

temperature, resulting in hypothermia or hyperthermia. (2) Any fall in the environmental temperature below the critical temperature is associated with progressive increase in metabolic heat production. Above the critical temperature, the metabolic heat production remains constant at a minimum level necessitated by the basal metabolic rate. The heat production increases again at high environmental temperature if there is hyperthermia, leading to an unregulated increase in the metabolic rate of the body. (3) The nonevaporative heat loss is zero at 37°C. It rises linearly as the environmental temperature decreases. The rise is less in the thermoneutral zone due to cutaneous vasoconstriction, which minimizes the heat flow from the body core to body surface. (4) At environmental temperatures below the thermoneutral zone, the evaporative heat loss is minimal and attributable to the evaporation of insensible perspiration. Above the thermoneutral zone, the evaporative heat loss rises linearly due to sweating and its evaporation. To summarize, there is a steep rise in metabolic heat production when the ambient temperature falls below the thermoneutral zone, and there is a steep rise in evaporative heat loss when the temperature rises above the thermoneutral zone. Both the processes are at their minimum within the thermoneutral zone. The thermoneutral zone can therefore be defined as the range of ambient temperature in which a person neither shivers nor sweats.

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Hypothalamic thermoregulatory mechanisms The hypothalamus has two thermoregulatory mechanisms built into it; one for raising, and the other for lowering the body temperature (Fig. 109.5). Both the systems have their own cutoff temperature at which the heating or cooling mechanisms are activated or deactivated (Fig. 109.6). Antirise center The anterior (rostral) hypothalamus acts as a heat-loss (heat-dissipating or antirise) center and opposes any rise of body temperature. Stimulation of this region, especially the preoptic area, produces heat loss by cutaneous vasodilatation, sweating, panting, and probably by reducing heat production. The antirise center receives catecholaminergic afferents from peripheral and central thermoreceptors. Destruction of the rostral hypothalamus results in hyperthermia: it is called neurogenic fever. Catecholaminergic interneurons Antirise center

Antidrop center Serotonergic interneurons

From warmth thermoreceptors

From cold thermoreceptors

Central thermoreceptor for blood temperature

Fig. 109.5 Hypothalamic thermoregulatory centers.

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Regulation of Body Temperature

Set-point

Thermoregulatory Activity of the body

Cutoff for anterior hypothalamic activity

Posterior hypothalamic (heating) activity

Cutoff for posterior hypothalamic activity

Anterior hypothalamic (cooling) activity

37 C Body temperature

Fig. 109.6 Graph showing the hypothalamic set point and the cutoff temperatures for posterior and anterior hypothalamic activity.

Antidrop center The posterior (caudal) hypothalamus, near the mamillary body, is concerned with heat production (antidrop center). Stimulation of this region activates heat production through shivering and increased TSH secretion. It also reduces heat loss by causing cutaneous vasoconstriction. The antidrop center receives serotonergic afferents from the peripheral cold thermoreceptors. It does not have any direct input from the central thermoreceptors but it is inhibited by impulses from the antirise center that arise when the blood temperature rises. It is also stimulated by blood-borne pyrogens such as viruses and toxins.

Disorders of thermoregulation Hyperthermia Hyperthermia, also called fever or pyrexia, is an elevation of the body temperature above the normal range. Fever is presumably beneficial because many microbes grow best at a specific temperature, and a rise in body temperature inhibits microbial growth. Moreover, antibody production increases when body temperature is elevated. Before the advent of antibiotics, fever was artificially induced for the treatment of neurosyphilis and proved to be beneficial. Hyperthermia also slows the growth of some tumors. Hyperpyrexia is the rise of body temperature above 41°C. It is accompanied by tachycardia, tachypnea, weakness, headache, mental confusion, and finally brain damage with loss of consciousness. A persistent temperature of over 43°C is not compatible with life. In malignant hyperthermia, a defective ryanodine receptor leads to excess Ca2+ release during muscle contraction. The resulting muscle contracture

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greatly increases heat production, leading to hyperthermia which is fatal if not treated. Hypothalamic set point Fever mostly occurs when

the hypothalamic set point is reset to a higher temperature and the body activates heat-producing mechanisms to warm up to the set point. However, if the rate of heat production persistently exceeds the rate of heat loss, fever can occur even when the set point is unaltered, as in severe exercise and hyperthyroidism. Chills herald the onset of fever and are associated with heat-generating and heat-conserving mechanisms such as shivering and curling up, respectively. These mechanisms continue to be active until the body temperature rises to the elevated hypothalamic set point of fever. Crisis signifies the end of fever. It is characterized by sudden sweating. It occurs when the hypothalamic set point suddenly drops to normal and the heat-dissipating mechanisms are activated. The hypothalamic set point is elevated by feverproducing substances called pyrogens, which may be exogenous or endogenous. Exogenous pyrogens are the lipopolysaccharide endotoxins derived from bacterial cell membranes. Endogenous (leukocytic) pyrogens are the cytokines (1L-IB, IL-6, β-IFN, γ-IFN, and TNF-α) released from actively phagocytosing monocytes and macrophages. They act by inducing the synthesis and release of prostaglandin E2. Antipyretics such as aspirin prevent the formation of prostaglandin E2 from arachidonic acid. The cytokines act on the OVLT (organ vasculosum of lamina terminalis) which is outside the bloodbrain barrier. The activated OVLT, in its turn, raises the hypothalamic set point. The septal nuclei located anterior to the preoptic area serve as the antipyretic area. The area contains vasopressin-secreting neurons that reset the thermostat. Injection of vasopressin into this area reduces fever directly. Heat exhaustion and heatstroke Heat exhaustion occurs due to excessive sweating leading to circulatory failure. Heatstroke occurs at very high ambient temperatures that upset the normal thermal balance of the body, leading to a rise in body temperature. The hyperthermia impairs the thermoregulatory capability of the hypothalamus, leading to a further rise in body temperature. A vicious cycle is thus set off, culminating in loss of consciousness.

Hypothermia Thermoregulation fails at shell temperature < 32°C. Death usually occurs at core temperature < 25°C.

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Central Nervous System The temperature-regulating mechanism is often impaired with aging, which is why in cold countries many elderly people die each winter of hypothermia. Hypothermia tends to occur during surgery due to the use of anesthesia and muscle relaxants, both of which abolish shivering. Hypothermia of about 27°C is induced artificially so that the O2 demand of tissues is greatly reduced and circulation can be stopped for 15 to 20 minutes, permitting cardiovascular surgery. The patient is warmed up slowly during recovery. Ventricular fibrillation is a common complication of hypothermia.

Poikilothermia In poikilothermia, the body temperature becomes labile, rising and falling frequently: If the patient is covered with blankets, his body temperature quickly rises and may reach a dangerous level. Conversely, the body temperature falls quickly when exposed to cold. An experimental lesion of the caudal hypothalamus produces poikilothermia because efferents from both antirise and antidrop centers descend through the caudal hypothalamus. Thermoregulation is also impaired following a brain stem lesion that interrupts the descending hypothalamic fibers to the spinal cord.

REVISION QUESTIONS 1. From which part of the body is the following best recorded? (1) Shell temperature, (2) core temperature, and (3) intracranial temperature. 2. Is the diurnal fluctuation of body temperature related to the sleep–wake cycle? 3. What is the thermoregulatory role of the venae comites accompanying the limb arteries? 4. Which thermoregulatory effector mechanisms are sympathetically mediated? 5. Which type of patients are largely dependent on behavioral thermoregulatory mechanisms? 5. What is the mechanism of nonshivering thermogenesis? 6. What is the mechanism of shivering in response to cold?

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7. What is the difference between “thermoneutral zone” and “preferred ambient temperature”? 8. Where in the body are the central and peripheral thermoreceptors located? Where in the brain are the “antirise” and “antidrop” centers located? 9. What are the various endogenous and exogenous pyrogens and how do they produce fever? How does aspirin reduce fever? 10. What is the difference between “heat exhaustion” and “heat stroke?” 11. Hypothermia tends to occur during surgery. Why? 12. A lesion in the caudal hypothalamus produces poikilothermia. Why?

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110

Regulation of Food Intake

Feeding behavior The primitive goal of feeding be-

havior is to achieve homeostasis of the nutrient concentration in the body. Food intake depends on both internal and external factors. Internal factors such as hunger and satiety regulate food intake by producing a conscious sensation of the adequacy of the food consumed. External factors such as the taste and smell of food are necessary for discriminative appetite (see below) which helps in the consumption of a balanced diet. Thus, salt intake is known to be regulated through salt craving and a similar mechanism might exist for sweet carbohydrates. Hunger is a conscious sensation that stimulates feeding behavior for fulfilling the caloric requirements of the body. The conscious sensation that causes the cessation of eating is called satiety. The mechanisms of hunger and satiety are inborn. Appetite is an emotional desire to eat, which may or may not be associated with the need for food. Appetite is partly acquired and dependent upon past hedonic experiences. When hungry, an individual will eat almost any wholesome food as long as it is reasonably palatable. After he has reached a state of satiety, he might still be left with the appetite for some dessert, which is entirely unnecessary so far as caloric requirements are concerned.

Central regulatory mechanisms Neural regulation of feeding behavior Hypothalamic control The hypothalamus has a

feeding center and a satiety center. The feeding center is located in the lateral nuclei of the hypothalamus. It stimulates feeding behavior. Lesions of the feeding center produce marked reduction in food intake and body weight. The feeding center is composed of two parts: the midlateral and the farlateral. The midlateral hypothalamus controls the basic feeding behavior but does not provide the motivation to cross a difficult barrier to obtain the food. The farlateral hypothalamus, through which the medial forebrain bundle passes, is important in “hunger motivation” that is necessary for overcoming a barrier to obtain food. A lesion in the medial forebrain bundle fails to abolish the basic feeding responses but the animal will not “work” for this food. The satiety center is located in the ventromedial nucleus of the hypothalamus (VMH) (see Fig. 98.2).

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It inhibits feeding behavior by inhibiting the farlateral hypothalamus. Lesions of the satiety center cause overeating, leading to obesity. The overeating only if the lateral nuclei are intact, proving that the VMH acts by inhibiting the feeding center. The amount of weight gained following a VMH lesion depends on the starting weight. If the experimental rats are already obese, they do not overeat or gain much weight after the satiety center is lesioned. Thus, it seems that the feeding and satiety centers together determine the “set point” of food intake and body weight. The feeding center raises the set point while the satiety center lowers the set point. A lesion of the satiety center therefore raises the set point. However, if the animal is made obese by forced feeding before the experiment, its subsequent self-motivated food intake actually reduces even if its satiety center is lesioned. It is also observed that an obese person who has reduced to normal weight by strict dietary measures usually develops intense hunger that is far greater than that of the normal person. This indicates that the set point of the obese person’s feeding control system is at a higher level of nutrient storage than that of the normal person. The VMH is stimulated by the entry of glucose into it. The glucose uptake by the VMH cells is facilitated by insulin. The stimulated VMH inhibits insulin secretion and thereby completes a negative feedback loop (Fig. 110.1). In diabetes mellitus, the deficiency of insulin reduces the glucose uptake in VMH cells and therefore the satiety produced is less, resulting in polyphagia. Obesity of hypothalamic origin is also seen in humans and is called hypothalamic obesity. It is

Insulin secretion

-

Entry of glucose into VMH cells of the satiety center Stimulation of satiety center Decrease in food intake

Decrease in vagal discharge

Fig. 110.1 Feedback control of the satiety center.

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Central Nervous System attributable to a defect not only in the VMH but also in the paraventricular nucleus (PVN). A lesion in the PVN causes excess consumption of sweet carbohydrates. Hypothalamic obesity is reduced by vagotomy, indicating that the vagus plays an important role in obesity. Vagal discharge is stimulated by the feeding center and inhibited by the satiety center. The hunger contractions of the stomach that occur before meals are due to excessive vagal discharge triggered by the hypothalamic feeding center. The vagal discharge also produces hyperinsulinemia, which is known to coexist with hyperphagia (Fig. 110.2). Hence, a lesion of the VMH causes both hyperphagia (behavioral overfuelling) and hyperinsulinemia (cellular overfuelling). Other brain areas affecting feeding behavior include the brain stem, limbic cortex, and the neocortex. The basic mechanical features of feeding such as salivation, licking of lips, chewing of food, and swallowing are controlled by brainstem centers. The amygdala and the prefrontal cortex are important for discriminative appetite. Bilateral lesions of the amygdala produce psychic blindness in the choice of foods, that is, indifference to the type and quality of food. Psychic blindness is a feature of the Kluver– Bucy syndrome. The neocortex modifies feeding behavior through learning.

Hormonal regulation of feeding behavior Leptin (Greek: thin) is a protein hormone pro-

duced by fat cells. It acts on the hypothalamus to reduce food intake, decrease lipogenesis, and increase lipolysis, thereby reducing the body fat stores. Leptin thus regulates the size of the body’s fat deposits through a negative feedback mechanism (Fig. 110.3). The effect of leptin on appetite is mediated through α-melanocyte stimulating hormone (α-MSH), a proopiomelanocortin (POMC) derivative

Stimulation of feeding center or Lesion of the satiety center Increase in food intake

Hunger pangs

Fig. 110.2 Hypothalamic obesity.

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Increase in insulin secretion Hyperinsulinemia

-

Increase in leptin secretion

Decrease in food intake

Decreased lipogenesis

Increased lipolysis

Decrease in body fat

Fig. 110.3 Leptin feedback control of body fat stores.

(see Fig. 82.5). Leptin acts through a group-I hormonal mechanism to increase the synthesis of POMC which is converted into α-MSH. The α-MSH acts through melanocortin-4 receptors to depress appetite (Fig. 110.4). Leptin also inhibits the secretion of AgRP (see below). Plasma leptin levels are proportional to the amount of body fat and are therefore higher in women and obese individuals. A decrease in plasma leptin is interpreted by the body as a signal for caloric deficiency and is therefore associated with adaptive responses such as inhibition of the pubertal onset and thyroid function, and stimulation of glucocorticoid secretion. Neuropeptide Many of these which are also

present in the gut as gastrointestinal hormones are released when food enters the gastrointestinal tract and causes satiety. Neuropeptides inhibiting food intake include CCK (cholecystokinin), GRP (gastrinreleasing peptide), glucagon, somatostatin, CART (cocaine and amphetamine-regulated transcript), α-MSH (α-melanocyte stimulating hormone), and CRH (corticotropin releasing hormone). The CCK released from the gastrointestinal tract does not act directly on the brain: It

Pro-opiomelanocortin +

Increase in vagal discharge

Increased gastric motility

Increase in body fat

Proenzyme converatase-1

α-MSH +

Leptin receptor +

Leptin

-

AgRP

-

Melanocortin-4 receptor

Appetite

Fig. 110.4 Mechanism of leptin action on appetite.

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Regulation of Food Intake stimulates CCK receptors in the pylorus of the stomach. The signal is transmitted by vagal afferents to the satiety center, resulting in satiety. Hence, the anorexic effect of systemically administered CCK can be abolished by vagotomy as well as by CCK antagonists such as devazepide. CCK receptors are also present in the satiety center and CCK is the neurotransmitter in some of the vagal afferents to the satiety center. Hence, the satiety induced by CCK seems to involve both peripheral and central mechanisms. CCK seems to work synergistically with serotonin, which explains why antiserotonergic drugs such as fenfluramine are effective stimulants of appetite. Neuropeptides that increase food intake include NPY (neuropeptide Y), Agouti-related peptide (AgRP), melanin-concentrating hormone (MCH), galanin, orexins, and ghrelin. Neuropeptide Y is produced in the arcuate nucleus and paraventricular nuclei. In the arcuate nucleus, NPY is coreleased with AgRP which stimulates appetite by inhibiting the action of α-MSH. In the paraventricular nucleus, NPY is coreleased with norepinephrine which depresses appetite. Amphetamine, which increases the release of norepinephrine in the brain, suppresses appetite. NPY induces a strong appetite for carbohydrates. Melanin-concentrating hormone is a polypeptide found in the lateral hypothalamus. Galanin seems to stimulate fat intake in particular. Orexins are synthesized in the lateral hypothalamus. A defect in orexin receptor genes causes narcolepsy in dogs. This is interesting since narcolepsy and hyperphagia often coexist—recall Dickens’ fat sleepy boy Joe in Pickwick Papers! Ghrelin is released from the stomach in the fasting state. It increases hunger by inhibiting the VMH. It also stimulates GH secretion.

Gastrointestinal feedback Gastrointestinal filling Distension of the stomach stimulates stretch receptors located in the muscular wall of the stomach. Impulses from these receptors reach the brain through the vagus and inhibit hunger and appetite. Vagotomy abolishes the effect, leading to hyperphagia. Oral metering of food intake Oral receptors

related to feeding, such as chewing, salivation, swallowing, and tasting, inhibit the hypothalamic feeding center after a certain amount of food has passed through the mouth. This is demonstrable by sham feeding of an esophagostomized animal so that the food it ingests is drained out through an opening in the esophagus (Fig. 110.5). Although no food enters its stomach, the animal still stops eating after a time. If some of the food is allowed to enter the stomach, the sham feeding stops earlier. Hunger contractions contribute to, but are not solely responsible for, the hunger sensation. Cutting the splanchnic and vagus nerves abolishes hunger contractions but does not abolish hunger. The contractions cease immediately on gastric filling. Hunger contractions intensify as a fast is prolonged and therefore, emptiness of stomach cannot by itself be the cause of hunger contractions. Hunger contractions are induced and accentuated by insulin-induced hypoglycemia due to the direct action of low blood glucose on the hypothalamic feeding center.

Metabolic feedback

Peripheral feedback mechanisms

Metabolic feedback comprises the glucostatic feedback, that is, inhibition of food intake is initiated by glucose, and the lipostatic feedback, that is, the inhibition of food intake by adipose tissues. The roles of both are explained above together with the role of insulin and leptin. Glucose directly acts on

Peripheral feedback mechanisms that regulate food intake are broadly categorized into gastrointestinal feedback and the metabolic feedback. Gastrointestinal feedback is an instantaneous neural feedback initiated by the physical stimulation of the gut. It makes a person eat in frequent, small meals so as to optimize the rate of gastrointestinal transit, absorption, and postabsorptive assimilation. Metabolic feedback helps to maintain long-term constancy of nutrient stores in the body, preventing them from becoming too low or too high. It is initiated by the chemical stimulation of sensory receptors within or outside the central nervous system.

Fig. 110.5 Sham feeding.

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Central Nervous System the satiety center while the effect of adipose tissue is mediated by leptin. A thermostatic hypothesis holds that a fall in body temperature below a given set point stimulates appetite and a rise above the set point inhibits appetite. Considering the thermic effect of the food (p 496), it is possible that the rise in body temperature caused by the food may be a factor limiting further food intake.

Energy balance and obesity Obesity is caused by an excess of energy input over energy output. Muscular activity is by far the most important means by which energy is expended in the body, accounting for more than a third of the daily energy expenditure. Obesity results from a high ratio of food intake to daily exercise. For each 9 kcal of excess energy consumed, 1 g of fat is stored in the body. Excess energy input is required only during the developing phase of obesity. Once a person becomes obese, all that is required to remain obese is that the energy input equals the energy output. For the person to reduce weight, caloric input must be less than caloric output. Indeed, the food intake of most obese people whose weight has stabilized is about the same as that for normal people. Obesity is usually caused by abnormalities of the feeding regulatory mechanism. Excess eating results

in excess deposition of fats in the fat cells. Overeating in childhood is particularly harmful because it also increases the rate of formation of new fat cells. The number of fat cells is about three times more in obese children. Psychogenic obesity A large proportion of obesity results from psychogenic factors such as the commonplace belief that three meals a day is a physiological necessity. Eating also helps in the release of tension and therefore some people gain considerable weight during stressful situations such as bereavement, a severe illness, or melancholic depression. Neurogenic and endocrine obesity Frohlich syn-

drome causes obesity with hypogonadism due to hypothalamic dysfunction. Sometimes, it occurs due to a hypophysial tumor that presses on the hypothalamus. Endocrine disorders leading to obesity are Cushing syndrome and hypothyroidism. Genetic obesity Obesity definitely runs in families. Identical twins usually maintain weight levels within 1 kg of each other throughout life, if their lifestyles do not differ markedly. This might result partly from eating habits acquired during childhood, but it is likely that this close similarity between twins is genetically controlled. Genetic defects in leptin, leptin receptor, POMC, melanocortin-4 receptor, and proenzyme convertase-1 are all known causes of human obesity.

REVISION QUESTIONS 1. What is the difference between hunger and appetite? 2. What is the functional difference between the mid-lateral and far-lateral parts of the hypothalamic satiety center? 3. An obese person who has reduced to normal weight by strict dietary measures usually develops intense hunger that is greater than that of the normal person. Why? 4. A diabetic patient has polyphagia despite having hyperglycemia. Why?

6. Which parts of the brain are important for discriminative appetite? Which syndrome is associated with psychic blindness? 7. Leptin regulates the size of the body’s fat deposit. How? 8. The anorexic effect of systemically administered CCK is abolished by vagotomy. Why? 9. In sham feeding, no food enters the stomach and yet, the animal stops eating after a while. Why?

5. The “feeding center” of the hypothalamus stimulates vagal discharge. What is its physiological significance?

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111

Memory and Learning

Memory is the acquisition, storage, and retrieval of sensory information. Learning is an enduring change in behavior that results from sensory information. The change in behavior must satisfy three criteria: (1) It must last at least a few seconds to distinguish it from transient reactions to sensory stimuli. (2) It must be based on individual experience as opposed to species experience, for example, an infant learning to walk or a bird learning to fly (neither qualifies as learning). (3) It must have a teleonomic function, that is, it must serve a purpose. The premise that learning is the process of acquisition of sensory information while memory is the storage and retrieval of the same information is fallacious. There can be no acquisition without some form of temporary storage and therefore it is impossible to draw a line between acquisition and memory, both of which must occur simultaneously. Hence, it is important to incorporate a change in behavior as the critical element of learning (Fig. 111.1). Thus, Pavlov’s dog had not just “memorized” the sequence of bell and food but had actually “learnt” because it was salivating, that is, its behavior had changed. Memory is of two types: explicit (discussed below) and implicit (discussed on p 734).

Explicit memory Explicit memory is also called declarative or reflective memory. It is the memory of knowledge, that

Behave yourself! You have memorized the whole book but learnt nothing!

is, of facts and events that we are aware of. Explicit memory is of two types: (1) semantic memory, which is the memory of objects, facts, and concepts as well as words and their meaning, and (2) episodic memory, which is the memory of events and factual knowledge of people, places, and things and also the feelings they aroused. Semantic (factual) memory is distributed at multi-

ple sites in the brain. For example, the word “flute” conjures up in our mind several of its attributes: a visual memory of a long narrow cylinder, an auditory memory of its tonal quality, and a somatosensory memory that reminds us that it is light and has a smooth surface. Memories of each of these attributes that are perceived by our visual, auditory, and somatic senses are stored in different areas of the brain. Each time the knowledge about flute has to be recalled, the recall is built up from distinct bits of information, each stored in specialized and dedicated memory stores. As a result, damage to a specific cortical area can lead to loss of specific information and therefore, to a fragmentation of knowledge. Thus, damage to the posterior parietal cortex can result in associative visual agnosia, that is, patients cannot name objects (e.g., flute) but they can identify objects by selecting the correct drawing and can faithfully reproduce detailed drawings of the object. In contrast, damage to the occipital lobes and surrounding region can result in an apperceptive visual agnosia, that is, patients are unable to draw objects (e.g., flute) but they can name them if appropriate perceptual cues (its sound or its feel) are available. Episodic (autobiographical) memory is stored in

the prefrontal cortex. Patients with frontal lobe damage have a tendency to forget how a piece of information was acquired, a deficit called source amnesia. Patients with loss of episodic memory however retain the ability to recall vast stores of factual (semantic) knowledge. Such a patient may be able to name an old friend just by looking at his face but may fail to recall their past meetings and therefore, fail to recall his identity.

Processing of explicit memory Fig. 111.1 A school teacher chides the students, alluding to behavior as the essential difference between memory and learning.

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The storage of explicit memory proceeds through four stages: encoding, consolidation, storage, and retrieval of memory. Encoding is the process by

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Central Nervous System which newly learned information is attended to and processed when first encountered. Consolidation is the process that alters the newly stored and still labile information so as to make it more stable for long-term storage. Storage refers to the retention of memory at specific sites in the brain. It involves the expression of genes and synthesis of new proteins. Retrieval refers to the recall and use of stored information. Encoding of memory The briefest form of memory, lasting less than a second, is the sensory memory. Things we see, hear or feel continuously in our environment register only in our sensory memory, only to be forgotten in less than a second. A slightly longer form of memory is the primary or shortterm memory which lasts several seconds. A special type of short-term memory that is required for maintaining behavioral continuity is called the working memory. Working memory Both the initial encoding and the subsequent recall of memory are routed through the working memory, which has an attentional control system and two rehearsal systems, one for language and the other for vision and action (Fig. 111.2). The attentional allocation system is located in the prefrontal cortex and has a very limited capacity of less than 12 items. It regulates the apportioning of attention between the two rehearsal systems.

Sensory information

Learning

Sensory memory

Immediate or potential change in behavior

Working Memory Attentional control system V I S Rehearsal U systems A L

A U D I T O R Y

Primary memory Emotions

Secondary memory Tertiary memory

Fig. 111.2 Levels of memory and their relation with learning and emotions.

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The information processed in these rehearsal systems can then enter the primary memory. The rehearsal system for language is called the articulatory loop, which is a temporary storage circuit where memory for words and numbers can be held in mind only through repeated mental speech, as is often done with a new telephone number as one prepares to dial it. The rehearsal system for the visual characteristics and the spatial location of objects is the visuospatial sketchpad. For example, this system allows one to store the image of the face of a person one meets for the first time. Visual characteristics (details of what it is) are stored in the inferior temporal cortex while the spatial characteristics (details of where it is) are stored in the posterior parietal cortex. The importance of working memory in behavioral continuity becomes apparent when we consider that to do anything properly, it is important to remember what has just been done and what remains to be done. Similarly, to speak fluently, it is important to remember what has just been spoken and what remains to be spoken. The deficiency in working memory in monkeys with prefrontal lobectomy has been demonstrated as follows. A piece of food was hidden randomly under one of the two containers placed in front of the monkey. Although the monkey was allowed to observe where it was hidden, it was unable to discover it barely 5 seconds later. Consolidation and storage of memory A critical amount of time, about 5–10 minutes, is required for the transfer of short-term memory to long-term memory through a process called consolidation of memory. If this time is not allowed for the consolidation to occur, the data in short-term memory are completely forgotten. This is seen in patients of concussion and electroconvulsive therapy who are unable to recall the events immediately preceding the concussion or convulsion. This phenomenon is called retrograde amnesia. A similar retrograde amnesia occurs before the onset of sleep, which is the reason why one is unable to remember the precise time of one’s own sleep onset. For the same reason, damage to brain areas responsible for memory consolidation also results in anterograde amnesia in which new memory formation is impaired without affecting old memories. The area of brain responsible for the consolidation of memory is the medial temporal lobe (parahippocampal gyrus, entorhinal cortex, and hippocampus). The right hippocampus processes spatial memory and the left hippocampus processes verbal memory (see interhemispheric differences, p 634). The parahippocampal and entorhinal cortices process memory of object

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Memory and Learning attributes. In processing information for explicit memory storage in the hippocampus, the entorhinal cortex is a major relay station both for hippocampal input as well for hippocampal output (see Figs. 100.9 and 100.10). Polymodal information from the association cortices reaches the hippocampus through the entorhinal cortex which projects to the dentate gyrus via the perforant pathway. Also, the hippocampal output relays in the entorhinal cortex before reaching the polymodal cortices. Hence, memory impairments associated with damage to the entorhinal cortex are particularly severe and affect all sensory modalities. In fact, the earliest pathological changes in Alzheimer disease, which affects mainly explicit memory storage, occur in the entorhinal cortex. Memory that lasts for minutes to years is called secondary or intermediate-term memory. Memory that is permanent and lasts a lifetime is called tertiary or long-term memory. Our own name resides in our tertiary memory. The first word recalled by a patient recovering from coma is his own name. Consolidation of memory into long-term memory occurs when sensory experiences are associated with profound emotions. Hence, when we reminisce about our childhood days, the events recalled are only those that were associated with deep emotions. For the same reason, we remember even the trivial things we were doing moments before we received shocking news. This is the brain’s ways of deciding what is to be remembered and what is to be forgotten. Experiences with no emotional adjunct are better forgotten so that they do not take up memory space in the brain. The amygdala stores the components of memory concerned with emotions. Interhemispheric memory transfer If an experimental animal (cat or monkey) is conditioned to a visual stimulus presented only to the left eye, will the conditioned response occur subsequently if the visual stimulus is presented only to the other eye? Normally, yes. The response occurs even after the optic chiasma has been sectioned in the middle so that the visual stimulus is transmitted only to the ipsilateral visual cortex (Fig. 111.3). It suggests that the memory and associated learnt behavior are somehow transferred to the contralateral cerebral hemisphere. However, the intercortical transfer fails to occur if the training is imparted after sectioning the corpus callosum too (in addition to the optic chiasma). Such failure of intercortical transfer of learning and memory is also seen in patients with congenital absence of the corpus callosum or in those in whom the corpus callosum has been surgically sectioned in an effort to control epileptic seizures. Studies in these subjects indicate that

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Blindfolded

Optic chiasma sectioned

Posterior fibers of corpus callosum

Fig. 111.3 Interhemispheric transfer of visual memory occurs even with sectioning of the optic chiasma.

the transfer of visual memory occurs in the posterior part of the corpus callosum while transfer of auditory and somesthetic memory occurs in the anterior part of the corpus callosum.

Learning associated with explicit memory Incidental learning Almost any fact or event that is consigned to explicit memory has the potential to alter behavior at a later date. Such learning occurs in the absence of an identifiable instructive situation and is known as incidental learning because the individual acquires information while attending “incidentally” to sensory inputs and thereby develops the potential to behave differently. Incidental learning is often not apparent immediately. For example, consider a child who fears a burly stranger (Fig. 111.4). She remembers the stranger and his benign manners on several occasions (explicit

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Central Nervous System

Fig. 111.4 The child learns to make friends. An example of explicit memory with incidental learning.

memory). In the course of time, she tries to befriend him (incidental learning). Insight Explicit memory may also contribute

to the reorganization of internal representations, resulting in an “insight” into previously unresolved problems. Newton’s formulation of gravitation theory is a case in point. Newton had enunciated that a body continues to move in a straight line with uniform velocity till an external force is applied on it. He therefore wondered why the moon went round the earth instead of flying off in a straight line. As he brooded sitting under an apple tree, an apple fell in front of him. He suddenly realized that the same force that pulled the apple to the ground (gravity) was also keeping the moon in a circular orbit around the earth. That was insight! Newton had seen both earlier: the moon going round the earth and apples falling to the ground. But all of a sudden, this knowledge was “reorganized” to give him a new insight.

Implicit memory Implicit memory is also called nondeclarative or reflexive memory. These are memories of skills that

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we are never aware of and do not have to make any conscious effort to memorize or recall. Explicit memory often progresses to implicit memory. For example, learning to drive a car involves explicit memory of a series of coordinated movements. However, over a period of time, the memory of these movements becomes implicit and the driving behavior becomes reflexive. Unlike explicit memory which is not immediately associated with behavioral changes, implicit memory is associated with an immediate behavioral change that is called reflex learning. Implicit memory and reflex learning are therefore used synonymously. Unlike incidental learning where no clear instructive situation is identifiable, reflex learning is associated with well-defined instructive paradigms and helps in achieving the desired outcome in a novel situation. Although explicit memory stores the feelings associated with events, implicit memory stores the autonomic and somatic responses associated with events. The various types of reflex learning can be classified as shown in Fig. 111.5. The reflex centers for the different types of reflex learning (see below) are located in different parts of the brain: (1) Classical conditioning involves the activity of the cerebellum which mediates the motor responses (as in adaptive motor responses and the eye-blink reflex) and the amygdala which mediates the autonomic responses (as in fear conditioning). (2) Operant conditioning involves the striatum and the cerebellum. (3) Habituation and sensitization involve the reflex pathways in the spinal cord and brain stem.

Priming Priming means having a greater ability to identify an object or a word after a recent exposure. It is common experience that the more often we see something, the easier it is for us to identify it. This phenomenon is known as perceptual priming and it explains why we are able to quickly identify known faces, voices, currencies, gadgets, streets, and landmarks in comparison to the new and unknown ones. Similarly, the more often we read a word, the better we recall its meaning. This is known as semantic priming.

Procedural learning Procedural learning or memory refers to the learning of cognitive skills or motor skills. Learning to tell the time by looking at a clock is an example of cognitive skill. Learning to cycle, swim or even to handle a computer mouse are examples of motor skills. The

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Memory and Learning

735

Memory

Explicit memory

Semantic (factual) memory

Episodic (autobiographical) memory

Implicit memory or Reflex learning

Priming

Perceptual priming

Semantic priming

Procedural learning

Cognitive skills

Nonassociative learning

Associative learning

Motor skills and adaptations

Habituation Sensitization

Classical conditioning

Instrumental conditioning

Reward conditioning

Aversive conditioning

Avoidance conditioning

Biofeedback

Fig. 111.5 Classification of memory and learning.

presupplementary motor area (pre-SMA) is involved in the motor learning of complex sequences. A special kind of procedural learning is motor adaptation, which involves learning to adjust to a changing stimulus. It occurs when the earlier behavior stops having the desired effects. Adaptive motor responses are abolished if the cerebrocerebellum or the inferior olivary nucleus is lesioned. A common example of motor adaptation is observed in our handling of the computer mouse. Each time the speed and acceleration of the cursor produced by the mouse is changed, there is an adaptive motor response in which the hand movements adapt to the changes appropriately. A well-studied adaptive motor response is the abolition of the vestibuloocular reflex (VOR) on wearing prisms. The VOR ensures that any abrupt rotation of the head rotates the eye to the opposite side, thereby helping to keep the gaze fixated on an object. If the subject wears prismatic glasses so that the rotation of the eye fails to bring back the object to the fixation point, the VOR is eventually abolished.

Nonassociative learning Nonassociative learning is the most simple and elementary form of learning. It takes the form of

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either habituation through homosynaptic mechanism or sensitization through heterosynaptic mechanism. These have been mostly studied in the gill-withdrawal reflex in which the aplysia (sea slug) withdraws its gill when its siphon is touched or when a painful stimulus is applied to its tail or its mantle shelf. The neurotransmitter released at the synapse between the sensory and motor neuron is glutamate, which acts on the non-NMDA receptors present on the motor neuron. Habituation is learning not to respond to repeti-

tive, low intensity stimuli and ignore them as unimportant. It is a gradual diminution of response to a stimulus, following repeated presentation of the same (or a very similar) stimulus. Habituation is not due to fatigue; rather, habituation helps in avoiding fatigue. Habituation involves decline of existing responses but the acquisition of novel responses remains unaffected. Habituation thus helps in adaptation to the environment and prevents unnecessary defense responses, making it possible to devote more attention to novel stimuli than to familiar ones. Following habituation by repeated application of a stimulus, if this stimulus is withheld, the response recovers over time. If repeated series of habituation training and spontaneous recovery are given, habituation becomes successively more

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Central Nervous System rapid. The weaker the stimulus and more rapid the frequency of stimulation, the more rapid and pronounced is habituation. Strong stimuli may fail to produce habituation. Presentation of another, usually noxious stimulus results in recovery of the habituated response, that is, dishabituation. Habituation of the gill-withdrawal reflex occurs when the siphon of the slug is touched repeatedly, and the slug does not withdraw its gill anymore. Habituation is associated with a decrease in neurotransmitter release at the synapses, which in turn is due to the inactivation of Ca2+ influx at the axon endings (Fig. 111.6A). However, what causes the inactivation of the Ca2+ channels is not known. Sensitization is the augmentation of response to

nonspecific stimuli. More precisely, it is learning to intensify the response to any stimulus following an exposure to a strong or noxious (sensitizing) stimulus. Sensitization is termed nonassociative because it does not result from specific associations between particular stimuli, as opposed to associative learning. Rather, a sensitizing stimulus increases the responsiveness to a wide variety of stimuli. Thus, a man who has survived a

A

Sensory neuron of the siphon

Ca2+

Motor neuron of the gill

Before habituation Ca2+ After habituation B

Before sensitization

After sensitization

Fig. 111.6 Synaptic mechanism of [A] habituation and [B] sensitization.

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Associative learning Associative learning is the learning of relations among events, either among stimuli or among stimuli and effects. It is a more discriminatory form of learning than nonassociative learning. Conditioning can be either classical or instrumental. In classical conditioning, a stimulus that is physiologically unimportant becomes important and starts eliciting a specific behavior due to its close association with a physiologically important stimulus. In instrumental conditioning, a behavior that is feeble and inconsequential becomes intense when it starts producing an effect that is physiologically important. Conditioning and sensitization involve different receptors: The gill-withdrawal reflex, a conditioned reflex, requires Hebbian potentiation (p 657) involving the activation of NMDA receptors on motor neurons, as opposed to the non-NMDA receptors that are activated during sensitization. In the classical (Pavlovian) conditioning the organ-

Glutaminergic sensory neuron of the siphon

Serotonergic facilitatory neuron from the tail

snake bite might react sharply to just about anything serpentine, like a piece of rope. Sensitization increases arousal and attention and lowers the threshold of defensive responses. Repetitive exposure to noxious stimuli may lead to longterm sensitization, lasting weeks or more. Sensitization of the gill-withdrawal reflex occurs if a painful stimulus is applied to the tail repeatedly. Following sensitization, the slug withdraws its gill much more vigorously in response to an innocuous touch on the siphon. Sensitization occurs due to presynaptic facilitation of synaptic transmission by a facilitator neuron that synapses presynaptically on the sensory nerve terminal (Fig. 111.6B).

ism is first presented with a stimulus that evokes an instinctive behavioral response. The stimulus is called the unconditioned stimulus (US) and the response to the US is called the unconditioned response (UR). Another stimulus, neutral with respect to the UR, is then presented in association with the US. This stimulus is called the conditioned stimulus (CS). The association between the CS and US alters the response to the CS, resulting in a conditioned response (CR), which is identical to the UR. Successful conditioning is critically dependent on (1) the duration of the US and CS (both must be of adequate duration), (2) the frequency of the stimuli (should be frequent), (3) the interval between the US and CS (should be minimum), and (4) the sequence of their presentation (CS must precede US).

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Memory and Learning A classical conditioning in which there is skeletomotor response is the conditioned eyeblink reflex (CR) in which the unconditioned stimulus (US) is a puff of air in the eye and the unconditioned response (UR) is the eye blink. The conditioned stimulus (CS) is a tone (Fig. 111.7B). Pavlov classical conditioning (Fig. 111.7A) is an example of visceromotor response: When the dog was presented with food (US), there was salivation (UR). After the dog had been repeatedly presented with food immediately after ringing a bell (CS), it started salivating on hearing the bell (CR). Specific CRs are frequently associated with nonspecific responses. For example, when an innocuous CS is paired with an aversive US, specific motor CRs are accompanied with nonspecific visceral reactions signifying arousal and fear, for example, altered heart rate, blood pressure, and respiration (Fig. 111.7C). These visceral reactions are called conditioned emotional response or conditioned fear and are an important factor in the development of anxiety neurosis (p 703). Conditioning is sometimes possible even when there is an extensive delay between the CS and the US. These cases involve gustatory reflexes, in which a meal is followed hours later by vomiting and cramps. Nature seemingly has evolved a mechanism to ensure that when survival is at stake, conditioning tolerates a long delay between cause and effect. For example, a person falling ill shortly after consuming a food item frequently develops an aversion for that food even if it was not responsible for the illness (Fig. 111.7D). Deconditioning is the inhibition or abolition of a well-established conditioned reflex. There are two ways of deconditioning: (1) Presentation of the CS frequently without the US causes internal inhibition or extinction. (2) Disturbing the animal with an external stimulus immediately after the CS causes external inhibition. In instrumental (operant) conditioning an organism learns from the impact of its actions on its environment. In this type of learning, the presence or absence of a particular behavior is reinforced by the consequence of the behavior. Hence in instrumental conditioning, it is the consequence of a spontaneous behavior (or its absence) that acts as the reinforcer. The term “instrumental” denotes that the organism’s behavior is instrumental (i.e., necessary) in the delivery of the US. In instrumental conditioning, the organism learns which of its own actions presages the occurrence of a reinforcer. This is in contrast to classical conditioning in which the organism learns that an

Sircar_Chapter111_731-739.indd 737

A

Seeing or Hearing smelling a bell food

CS

B

Salivation

US

UR

Hearing a bell

Salivation

CS

CR

Puff of air Tone in the eye

CS

Eye blink

US

UR

Tone

Eye blink

CS

CR

C An explosion Sight of a in the switchboard switchboard

CS Sight of a switchboard

Running away (motor response) and Tachycardia, drying of mouth (non-specific visceral response)

US

UR Tachycardia, drying of mouth (non-specific visceral response)

CS

D Eating apples

CS

737

CR Nausea Having an and attack of appendicitis vomiting

US

UR

Eating apples

Nausea

CS

CR

Fig. 111.7 [A] Classical (Pavlovian) conditioning of a visceral response. [B] Conditioning of a skeletomotor response: the nictitating membrane reflex. [C] Conditioned fear response showing several nonspecific responses. [D] Visceral conditioning with a long interval between conditioned.

external event (US) predicts the occurrence of a reinforcer (CS). There are three main types of instrumental conditioning. In reward conditioning, a positive (rewarding) reinforcer is provided in response to a particular behavior, which consequently becomes

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Box 111.1 Thorndike paradigm and Skinner box Instrumental conditioning can be demonstrated in experimental animals too. In Thorndike paradigm, a hungry cat is placed inside a puzzle box and a piece of fish is kept outside in sight of the cat. The box has a complicated system of pulleys, strings, and levers designed to open its door. The cat initially manages to open the door by chance but its performance improves with time. The cat learns to associate its actions with the rewarding outcome. The cat can even be manipulated to scratch or lick itself to escape from the box! Thorndike paradigm led to the development of the Skinner box, a problem box in which an animal learns to press a key to get food (reward conditioning) or avoid electric shock (avoidance conditioning) or to avoid the pressing of a key that delivers an electric shock (aversion conditioning).

alcohol, he develops severe unpleasant reactions that serve as a punishing reinforcer, discouraging alcohol consumption. Aversion conditioning has also been attempted for stopping bedwetting in children. When the bed is soaked with urine, a sensor is activated and triggers a loud sound that wakes up the child. The loud sound in the middle of sleep acts as a punishing reinforcer to the child and discourages bedwetting. In avoidance conditioning, a punishing reinforcer is delivered in the absence of a particular behavior, which consequently becomes intensified. Drug dependence is the consequence of avoidance conditioning. Whenever attempts are made to give up drugs, it results in severe unpleasant symptoms called withdrawal symptoms that serve as negative reinforcers and encourage the continuance of drugs. Biofeedback is an example of operant conditioning

intensified. Addiction to drugs occurs as a result of reward conditioning: The consumption of the drug becomes a compulsive behavior due to the pleasure it gives. In aversive conditioning, a negative (punishing) reinforcer is delivered in response to a particular behavior, which consequently becomes infrequent. The use of disulfiram for alcohol deaddiction is an example of aversive conditioning. When an alcoholic on disulfiram therapy consumes

in which autonomic responses are conditioned. It is based on the premise that we have an innate ability to voluntarily influence the autonomic functions of our body. Biofeedback helps us to develop this innate ability and puts it to therapeutic use. For example, we must get a feedback about the state of our bodily functions such as blood pressure, heart rate, sweating, or the resting tone of our voluntary muscles if we are trying to control them voluntarily.

REVISION QUESTIONS 1. What is the difference between memory and learning? 2. What is the difference between explicit and implicit memory? Give an example where explicit memory naturally progresses to implicit memory. 3. What is the difference between semantic memory and episodic memory? 4. What is the difference between associative visual agnosia and apperceptive visual agnosia? 5. A patient is able to say the name of an old friend just by looking at him. However, he is unable to recall their past meetings and therefore, fails to recall his friend’s identity. What is wrong with the patient?

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6. What is working memory? 7. Patients of concussion are unable to recall the events immediately preceding the concussion. Why? 8. Damage to the entorhinal cortex causes the severest memory loss and affects all sensory modalities. Why? 9. Which aspect of memory is affected in Alzheimer disease? 10. We never forget even the trivial things we were doing moments before we received a shocking news. Why? 11. If an experimental animal is conditioned to a visual stimulus presented only to the left eye, will the conditioned response occur

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Memory and Learning

subsequently if the visual stimulus is presented to the right eye? 12. What is the difference between sensitization and conditioning?

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13. What is the physiological significance of habituation? 14. What type of conditioning is “biofeedback?”

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112

Language and Speech

Language

Aphasia

The collection of all the words in a given language is called the lexicon. The meanings of the words and sentences are called semantics. Memorizing words and their meanings is necessary for speaking a language. However, a language can never be spoken fluently till its structure is understood. The smallest unit of a language is the phoneme. Phonemes are fundamental sounds that are combined to form morphemes, the smallest meaningful units of words. A morpheme may be a base (“do” in “undo”), an affix (“un” in “undo” and “unfold” or “er” in “painter” and “washer”), or an inflectional form (“ing” in “doing” or “s” in “girls”). Morphemes may be words themselves or they may be combined to form words. Several words are strung together using certain rules called the syntax. The syntax can change the semantics, for example, “speed thrills but kills” versus “speed kills but thrills.” The semantics can also be modified by vocal intonation or prosody. The importance of prosody is illustrated by the following example. When a child is asked “What is this?” he replies “This is my toy.” When asked “Whose is this?” he replies “This is my toy.” When asked “Which one is yours?” he replies “This is my toy.” Each time, the answer remains the same but the prosody changes its meaning. Finally, the stringing together of sentences to form a meaningful narrative is called pragmatics. The term grammar mainly encompasses phonology (rules of phonemes), morphology (rules of morphemes), and syntax. These components of language are applicable not only to sound-based language but also to sign languages. For example, a morpheme in sign language is the smallest meaningful movement. Table 112.1 Structural components of a language Phonemes

Sound units whose sequence produces morphemes

Morphemes

Smallest meaningful unit of a word

Syntax

Grammatical combination of words in phrases and sentences

Prosody

Vocal intonation that can modify the meaning of words and sentences

Pragmatics

Linking of sentences into a narrative

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Aphasia refers to a disorder of language apparent in speech, writing, or reading. Aphasias must be distinguished from dysarthria, a disorder of speech due to motor defects in the muscles of articulation. Aphasias are categorized into nonfluent and fluent. In fluent aphasias, the speech is fluent but there is difficulty in the comprehension or repetition of words, phrases, or sentences spoken by others. In nonfluent aphasias, the speech is limited and effortful but there is fairly good comprehension of spoken speech. Discussed below are some of the commoner forms of aphasia. Wernicke aphasia Also called receptive, sensory,

or fluent aphasia, it is the inability to comprehend words or to arrange sounds into coherent speech. There is no dysarthria and the speech is fluent and indeed, the patient may speak a lot. Auditory comprehension is defective due to the inability in distinguishing the phonemes of the speech, a phenomenon called word deafness. An example will illustrate the point. In the Japanese language, the sounds l and r are not distinguished. Therefore, a Japanese-speaking person hearing English cannot distinguish the sounds l and r although this distinction is perfectly clear to English-speaking persons. A person with Wernicke aphasia has a similar problem in his or her own language. Visual comprehension or reading is affected too, that is, there is word blindness, because a person who has problems in distinguishing phonemes has problems with graphemes too. Graphemes are the pictorial or written representations of a phoneme that combine to form a word. The word blindness is associated with agraphia, that is, impairment of writing. Speech is fluent but is often associated with anomia, neologism, and paraphasias. Anomia is the difficulty in finding an appropriate word to express a thought. Neologism is using or creating new words or new meanings for established words. Paraphasias are syllables, words, or phrases that are spoken completely unintentionally (for example, “my mother” instead of “my wife”) or that represent a distortion of the intended word (for example, “lime” instead of “line”). Confusion associated with phonemes while speaking results in what has been called a word salad.

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Language and Speech There are two minor variants of Wernicke aphasia, an auditory form and a visual form, both of which are associated with relatively satisfactory speech. (1) The auditory form is called pure word deafness. It is associated with impaired auditory comprehension and inability to repeat what is said or write what is dictated. (2) The visual form results in dyslexia with agraphia, that is, impairment of reading and writing. This type of dyslexia must be distinguished from developmental dyslexia which is difficulty in learning to read. Dyslexic children do not have a well-developed planum temporale on the left side, suggesting that the basic defect in them may be the absence of hemispheric specialization for language. They also have an impaired development of the magnocellular visual pathway which results in their difficulty in processing fast, high-contrast visual stimuli, that is necessary for good reading. In Broca aphasia (also called expressive, motor,

or nonfluent aphasia), the patient speaks very slowly using only the key words and a simple syntax in Broca aphasia. Comprehension of speech is largely preserved and therefore Broca aphasia was long thought to be only a defect in speech production. However, it has been observed that the patient is unable to understand long-winding sentences with a complex structure. Analyzing the grammar of a long sentence would require a good working memory and it is now believed that the inability occurs due to the breakdown of the articulatory loop in the working memory. For the same reason, the patient often has no difficulty in pointing out the grammatical error in a simple sentence, for example, “I was called him.” Most patients also have agraphia. Conduction aphasia is a paradoxical deficit in

which individuals can speak easily, name objects, and understand speech, but they cannot repeat words. It is hypothesized that there is a disconnection between the thought of the words in Wernicke area and the production of the words in Broca area. However, there is no proof that cutting the arcuate fasciculus connecting Wernicke and Broca areas actually causes this syndrome. An impairment of short-term memory probably contributes to this condition. Global aphasia combines the features of Broca, Wernicke, and conduction aphasias. Comprehension, speech, and repetition are completely lost. In transcortical aphasia, individuals are able to repeat words in transcortical aphasia, which distinguishes it from the other aphasias (Table 112.2).

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Table 112.2 Main features of different types of aphasia Aphasia

Speech

Comprehension

Repetition

Broca

Nonfluent

Largely preserved

Impaired

Wernicke

Fluent

Impaired

Impaired

Conduction

Fluent

Largely preserved

Impaired

Global

Nonfluent

Impaired

Impaired

Transcortical

Variable

Variable

Intact

This type of aphasia is caused by defects in cortical areas outside the main language areas. The impairment of speech and comprehension is variable depending on whether the area affected is nearer to Wernicke or Broca area.

Neural basis of aphasias Wernicke–Geschwind model Aphasias were earli-

er explained on the basis of this model which was developed by studying the site of cerebral lesions in patients of aphasia. According to this model, spoken words are first perceived in the primary auditory area (areas 41 and 42) and then recognized and understood in Wernicke area (area 22), where thoughts and words originate. Written words are perceived in area 17 and are subsequently processed in visual association areas 18 and 19, and in the angular gyrus (area 39). Written words are fully understood when the information passes to Wernicke area. Thus, Wernicke area is concerned with the comprehension of both spoken and written language and the formation of ideas that are to be articulated in speech. The thought of words generated in Wernicke area is transmitted to Broca area (areas 44 and 45) through a neuronal tract called the arcuate fasciculus (Fig. 112.1). For writing, the information is passed to Exner center. The Broca area formulates the motor plan for words. The motor plan is forwarded to the primary motor cortex from where impulses are sent down to the muscles of articulation and the vocal cords, resulting in speech. Similarly, Exner center formulates the motor plans for writing, which are forwarded to the primary motor cortex and finally to muscles of the wrist and fingers. The Wernicke–Geschwind model explains why (1) comprehension is impaired in Wernicke aphasia but is largely preserved in Broca aphasia;

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Arcu la

te f a

3

19 17

18

40

1

cu

lu s

39

2

s ci

44 42 41

45 22

Fig. 112.1 The perisylvian speech areas and the arcuate fasciculus.

(2) speech is nonfluent in Broca aphasia but remains fluent in Wernicke aphasia; (3) conduction aphasia occurs when the arcuate fasciculus connecting Broca and Wernicke areas is destroyed. In conduction aphasia, speech remains fluent and comprehension remains intact but there is difficulty in repetition of spoken language. The modern framework of the neural basis of lan-

guage incorporates additional data that have come from positron emission tomography (PET), functional magnetic resonance imaging (fMRI), and event-related potential (ERP) studies on patients and normal subjects. A few important aspects of the modern view of language and aphasias are as follows. Most of the language functions, including the lexicon and grammar, are located in the left hemisphere, not only in right-handed but also in a large number of left-handed individuals. The right hemisphere is important in prosody and pragmatics but has no understanding of grammar. Left hemispherectomy in the adult causes severe speech and writing deficits but has less effect on reading.

Auditory comprehension is affected very little. If the left hemispherectomy is performed at an early age, the right hemisphere can acquire considerable language abilities. Right hemispherectomy only produces subtle changes in speech including dysprosody (flattening of the emotional tone of speech) and lack of comprehension of emotional tones in speech. A neurosurgeon operating on the brain would want to know the cerebral hemisphere to which speech functions are lateralized in the patient, so as to avoid any damage to it. The laterality of speech area in the patient can be determined by injecting sodium amobarbital into the carotid artery of one side. The injection causes temporary contralateral hemiplegia signifying that the ipsilateral hemisphere is anesthetized. If the speech is lateralized to the left hemisphere, which is usually the case, it is abolished by amobarbital injection into the left carotid artery. Language requires memory processes. Working memory is required for remembering words so that a long sentence can be understood. Long-term memory is required for storing words and retrieving them when required. Nouns are stored in the posterior temporal cortex while verbs are stored in the frontal cortex and cerebrocerebellum. Hence, damage to the temporal cortex results in anomia, that is, difficulty in finding nouns, whereas frontal lobe injuries result in verb-finding deficits. A patient with anomia, when shown a picture of a lock, might say, “I know what it does... I use it to lock my door.” Thus, although he uses the word “lock” as a verb, he is unable to use it as a noun. Automatic and well-practiced speech requires the insular cortex whereas novel speech generation requires the frontal (premotor) and posterior temporal cortex. As language ability increases, there is a reduction in the size of the posterior temporal speech area. Females have a smaller posterior temporal involvement in language and a larger frontal or insular involvement.

REVISION QUESTIONS 1. What do the following terms mean? (1) Phoneme, (2) morphene, (3) syntax, (4) prosody, and (5) pragmatics. Which of these constitute the subject of grammer? 2. What is aphasia? What is the difference between fluent and nonfluent aphasia?

Sircar_Chapter112_740-743.indd 742

3. Explain the meaning of the following terms: (1) word deafness, (2) word blindness, (3) agraphia, (4) anomia, (5) neologism, and (6) paraphasia. Name a condition that is associated with all these defects. 4. What are the anatomic correlates (in the brain) of a dyslexic child?

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Language and Speech 5. What are the characteristics of speech in Broca’s aphasia?

9. How can the laterality of speech be determined in a patient?

6. What is the main speech defect in conduction aphasia?

10. When a patient was shown a lock and asked to name it, he said “I know what it does ... I use to lock my door.” What type of speech problem does the patient have?

7. Which type of aphasia is associated with a complete loss of comprehension, speech, and repetition? 8. What distinguishes transcortical aphasia from other types of aphasia?

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11. As language ability increases, there is a reduction in the size of the posterior temporal speech area. Why?

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113

Special Senses

Functional Anatomy of the Eye

The Eye The eye (Fig. 113.1) has an outer protective layer called the sclera, which is modified anteriorly to form the transparent cornea. The junction of the cornea with the sclera is called the limbus. Interior to the sclera is the choroid, which is a layer containing blood vessels that nourish the inner structures, especially the retina. Interior to the posterior twothirds of the choroid is the retina, containing photoreceptor cells. The anterior part of the choroid is thickened into the ciliary body containing the ciliary muscles. The curvature of the lens can be changed through the action of the ciliary muscles. A circular ligament called the zonule is attached to the ciliary body. The zonule holds the transparent crystalline lens in place. In front of the lens is the pigmented and opaque iris, which encloses a central aperture called the pupil. The space between the lens and the retina is filled with a clear gelatinous material called the vitreous humor. The space between the lens and the cornea is filled with a clear liquid called the aqueous humor.

Cornea The cornea consists of five layers from outside in, viz., (1) the stratified layer of epithelial cells, (2) the basal

Canal of Schlemm

Suspensory ligament

Sclera Choroid

Aqueous humor

Retina

Cornea

Fovea

lamina of the epithelial cells (Bowman membrane), (3) the layer of stroma (substantia propria), (4) the basal lamina of the endothelial cells (Descemet membrane), and (5) the layer of endothelial cells. The cornea is sensitive to touch due to the dense nerve supply from the trigeminal nerve. The cornea has no blood vessels beyond the limbus so that it is dependent for its nourishment upon diffusion of fluid from the aqueous humor, the precorneal tear film, and the pericorneal limbal blood vessels. Corneal transparency The corneal stroma and the

collagen fibers in the stroma have different refractive indices. This should make the cornea opaque due to scattering of light by the corneal fibers. However, there is no scattering of light and the cornea is normally transparent because: (1) the stromal collagen fibers are arranged uniformly and do not scatter light; (2) the corneal epithelial cells are arranged uniformly; (3) blood vessels are absent in the stroma; and (4) myelin sheaths are absent in the corneal nerve fibers. The corneal stroma contains acid mucopolysaccharides which tend to absorb water through osmosis. This osmosis is minimized by the semipermeability of the corneal epithelium to water and electrolytes. Moreover, a Na+ pump located on the corneal endothelium constantly removes fluid from the stroma to prevent excessive rise in turgidity. The pump is temperature dependent and exposure to extremes of temperature results in corneal edema. If the corneal epithelial cells are damaged, they regenerate perfectly and the cornea remains transparent. However if the Bowman membrane is disrupted, the regeneration of the epithelial cells is imperfect and affects corneal transparency.

Lens Lens Iris Optic Nerve

Ciliary body Extraocular muscle

Optic Vitreous Disk humor

Fig. 113.1 Anatomy of the eye.

Sircar_Chapter113_744-748.indd 744

The lens is a biconvex mass of cells. Its central part consists of the oldest cells and its periphery or cortex is made of the youngest cells. In the course of its development, what was originally the surface of the epithelium comes to lie in the center of the lens, and the basal cells of the epidermis come to lie on the surface of the lens. Just as the epidermis grows by the proliferation of the basal cells with shedding of the old superficial cells, in the same way, the lens grows by the proliferation of its superficial cells.

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Functional Anatomy of the Eye The newly formed cells elongate into fibers. However, the older cells cannot be cast off since they lie deep inside: They accumulate in the center as the nucleus of the lens and undergo sclerosis. The lens is surrounded by a hyaline fibrous membrane called the lens capsule, which is attached to the zonule. The zonule is split medially into anterior and posterior laminae, which enfold the lens capsule and blend with it. Laterally the zonule is attached to the inner surface of the ciliary body. The main source of energy of the lens is glucose, most of which is metabolized through Embden– Mayerhof pathway with the HMP shunt pathway and citric acid cycle making smaller contributions. In hyperglycemia, the sorbitol pathway, which is normally negligible, metabolizes large amounts of glucose. The sorbitol produced is trapped inside the lens because the lens capsule is impermeable to sorbitol. The sorbitol retains water osmotically, causing swelling of the lens and resulting in cataract formation.

Uveal tract The uveal tract is made of highly vascular connective tissue and is innervated by sensory nerve fibers of the trigeminal as well as vasomotor fibers. Because of the presence of nociceptive fibers, the inflammation of the uveal tract (uveitis) is intensely painful. The uveal tract consists of three parts: the choroid, ciliary body, and the iris. The iris forms a circular diaphragm which, together

with the lens, partitions the aquous chamber into the anterior and posterior chambers. It encloses a central aperture called the pupil and contains two muscles that control pupillary movements: (1) The sphincter pupillae is a circular bundle of muscle fibers running round the pupillary margin. It is supplied by parasympathetic fibers from the oculomotor nerve. The pupillary aperture decreases when the sphincter pupillae contracts. (2) The dilatator pupillae has radially-arranged muscle fibers. It is innervated by sympathetic fibers from the cervical sympathetic ganglia. Contraction of the dilator pupillae increases the pupillary aperture. The ciliary body has an outer and an inner part. (1) The outer part of the ciliary body is composed of smooth muscle called the ciliary muscle. The muscle consists of the longitudinal and circular (sphincteric) parts with a common origin in the ciliary tendon, a structure that runs circumferentially round the globe blending with the scleral spur. (2) The inner part has tufts of blood capillaries. The anterior part of the inner surface of the ciliary body

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745

is thrown into folds called the ciliary processes, which secrete the aqueous humor. The choroid is an extremely vascular membrane

in contact with the sclera. On the inner side, the choroid is covered by a thin elastic membrane called the membrane of Bruch. Immediately beneath the membrane of Bruch is a plexus of the choriocapillaries. The outer choroid layers contain the medium-sized and large vessels.

Aqueous humor Aqueous humor is a clear transparent fluid, filling the anterior and posterior chambers of the eye. It provides nutrition and oxygen to the lens and the cornea, and also serves as a vehicle for elimination of metabolic waste products. Aqueous circulation The aqueous humor is secreted into the posterior chamber by the ciliary body (Fig. 113.2). It is formed mostly through active secretion though ultrafiltration also contributes. The aqueous humor flows from the posterior to the anterior chamber through the pupil. It then flows into the canal of Schlemm, a venous channel at the limbus (junction between the iris and the cornea) and thence, into the episcleral veins. The main resistance to the outflow of the aqueous humor is offered by the trabecular meshwork that forms the medial wall of the canal of Schlemm. Intraocular pressure (IOP) is the pressure of the aqueous humor in the anterior chamber of the eye. The normal IOP is between 10 and 21 mm Hg. It changes with posture, rising by up to 6 mm Hg when reclining from a sitting to supine position. It

Trabeculae Canal of Schlemm

Capillaries secreting aqueous humor

Fig. 113.2 Aqueous circulation

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Special Senses increases with age, especially after 40 years. Myopes and individuals with a family history of glaucoma tend to have a higher IOP. Glucocorticoids increase the IOP, and the diurnal changes in IOP is related to the diurnal fluctuations in glucocorticoid secretion.

Vitreous humor The vitreous humor is a transparent, hydrated gel containing over 90% water. A vitreoretinal barrier prevents the vitreous constituents from equilibrating with blood and surrounding fluids. The vitreous humor also contains hyalocytes which secrete hyaluronic acid and fibrocytes which secrete collagen fibrils.

Lacrimal Apparatus The lacrimal apparatus comprises the lacrimal glands which secrete tears and the lacrimal passages which drain the tears into the nasal cavity. The lacrimal glands of each eye consist of the superior (or orbital) gland, the inferior (or palpebral) gland, and the accessory lacrimal glands (also called Krause glands). All are serous acinous glands. Tear secretion is increased by

parasympathetic nerves and decreased by sympathetic nerves. A tear film has three layers (Fig. 113.3). (1) The outer lipid layer secreted by the meibomian glands in the eyelids. It prevents evaporation of the aqueous layer. (2) The middle aqueous layer secreted by the lacrimal glands. It lubricates the ocular surface, removes debris, oxygenates the cornea, and has an antimicrobial action. (3) The inner mucin layer is secreted by the goblet cells of the conjunctiva. The mucin layer is necessary for soaking the tears. In its absence, the eye becomes dry because the underlying corneal epithelium is hydrophobic. The condition is called xerophthalmia and is seen in vitamin A deficiency which causes malfunctioning of the goblet cells. Xerophthalmia is associated with corneal damage and repeated infections. Application of artificial tear fluids alleviates the condition. Methylcellulose solution and polyvinyl alcohol solution are the two main types of artificial tear supplements. The eyes can also be kept moist by occluding the lacrimal puncta to decrease the drainage of tears.

Glaucoma Glaucoma is an elevation of IOP with characteristic degenerative changes in the optic nerve head.

Tear film Corneal epithelium Bowman membrane

Lipid wax (0.1 µm)

Aqueous layer (0.7 µm)

Stroma

Mucus layer (0.02 µm)

Descemet membrane

Corneal epithelium

Endothelium

Fig. 113.3 (Left) Layers of the cornea. (Right) Layers of the tear film.

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Functional Anatomy of the Eye Patients with normal IOP can also show glaucomatous optic nerve changes: They are classified as normal tension glaucomas. On the contrary, patients with increased IOP may not show any glaucomatous changes in their optic nerve head: They are classified as ocular hypertensives. Therefore, the diagnosis of glaucoma is based, not on the elevated IOP but on certain characteristic glaucomatous changes in the optic nerve head. There are two distinct types of glaucoma, which differ considerably in their pathophysiology and treatment. They are called angle-closure glaucoma and open-angle glaucoma. The differentiation is based, as the names suggest, on the magnitude of the sclerocorneal angle (Fig. 113.4A), which can be assessed with an instrument called the gonioscope. In angle-closure glaucoma (Fig. 113.4B), the sclerocorneal angle (which is also equal to the angle of anterior chamber) is narrow and therefore easily occludable by the peripheral part of the iris. The occlusion, which may be slight initially, causes pooling of aqueous humor in the posterior chamber and further accentuates the occlusion by causing the iris to bulge out. This is called the appositional closure at the angle and results in a sudden rise in the IOP. Appositional closure is often relieved by peripheral iridectomy, that is, punching a small hole in the iris. The hole allows aqueous flow from the posterior to the anterior chamber and thereby relieves the IOP (Fig. 113.4C). Repeated attacks of appositional closure may be followed by irreversible closure of the angle due to synechiae (adhesions). This type of synechial closure is not relieved by peripheral iridectomy and may require trabeculectomy. This type of glaucoma is associated with a sudden rise in IOP: It is extremely painful and associated with red congested eye and corneal edema, thus accounting for its previous name of acute congestive glaucoma. In open-angle glaucoma (Fig. 113.4D), the anterior

chamber angle is not reduced, and the increased IOP is due to the increased resistance of the trabeculae to aqueous outflow. Increased trabecular resistance is often due to deposition of pigments and mucopolysaccharides in the trabecular meshwork. What causes such deposition is not known but some predisposing factors include myopes above 50 years of age, patients with diabetes and thyroid disorders, and patients with a family history of glaucoma. Such cases are diagnosed as having primary open angle glaucoma. Cases where the cause can be discerned are called secondary open angle glaucoma. This can be due to either an increased episcleral venous pressure or due to deposition

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747

A Normal

B

Narrow

Angle closure glaucoma Pupil dilated

Pupil constricted

Peripheral iridectomy C

D Aqueous outflow blocked by high trabecular resistance

Open angle glaucoma

Trabeculectomy

Fig. 113.4 [A] Normal (left) and narrow (right) sclerocorneal angle. [B] Obliteration of angle by pupillary dilatation in angle closure glaucoma. [C] Facilitation of aqueous drainage by peripheral iridectomy in angle closure glaucoma. [D] Facilitation of aqueous drainage by trabeculectomy in open angle glaucoma.

of pigment and exfoliative materials from the iris and lens capsule. Surgical treatment of open angle glaucoma involves trabeculectomy, that is, the creation of a fistula between the anterior chamber and the subconjunctival space. The treatment in both types of glaucoma comprises reducing the IOP with the help of hyperosmotic agents such as mannitol, glycerol,

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Special Senses sorbitrate or urea which causes shrinkage of the vitreous humor, and intravenous acetazolamide which reduces aqueous humor formation. Subsequent reduction in pressure can be maintained with drugs that reduce aqueous humor formation such as acetazolamide, β and α2 adrenergic blockers, cholinergic agonists, and PGF2α agonists. Medical management is the mainstay of treatment in open angle glaucoma. Miotics such as pilocarpine are useful in both types of glaucoma: (1) In angle-closure glaucoma, pupillary constriction flattens the iris and draws it away from the cornea, thus increasing the outflow of aqueous humor. (2) In open angle glaucoma, the ciliary muscle contraction pulls the scleral spur, thereby stretching the trabecular mesh and improving the outflow (Fig. 113.5). The patient requires surgery if medical therapy fails.

Longitudinal ciliary muscle

Trabeculae

Scleral spur

Longitudinal muscle contracts

Trabeculae 3 stretched

1

2 Scleral spur pulled

Fig. 113.5 Effect of miotics on open-angle glaucoma.

REVISION QUESTIONS

2. Hyperglycemia causes cataract. Why?

4. Angle-closure glaucoma occurs due to appositional closure of the sclerocorneal angle. What causes the appositional closure and how is it relieved?

3. The different layers of the tear film come from different sources. What are they, and which one is deficient in xerophthalmia?

5. Pilocarpine, a miotic drug, is useful in both angle-closure and open-angle glaucoma. How?

1. Exposure of the cornea to extremes of temperature results in corneal edema. Why?

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114

Visual Optics

Physiological optics The schematic eye (Fig. 114.1) shows that the eye is made of four optical media, each with a different refractive index. It assumes that light bends only when it passes from air to cornea, cornea to aqueous humor, and aqueous humor to vitreous humor. This is a gross simplification since in the actual eye; none of these media have a homogeneous refractive index. However, the schematic eye is good enough for understanding the broad principles of visual optics.

Reduced eye The degree of bending at an optical interface is proportional to the ratio of the refractive indices of the two media it separates. With light bending

Schematic eye

µ = 1.38 µ = 1.33 µ = 1.40

µ = 1.34

at multiple interfaces, the mathematical treatment of visual optics is complex. This is avoided by confining the mathematical approach to an even simpler model of the eye, called the reduced eye (Fig. 114.1), in which the cornea, aqueous humor, and vitreous humor are replaced with a single medium with a uniform refractive index of 1.336. The surface of this hypothetical ocular medium (the air–medium interface) is spherical (radius of curvature = 5.6 mm) and is located 1.4 mm behind the corneal surface. The nodal point or optical center of the medium is therefore located 5.6 mm behind the air–medium interface. Rays of light passing through the nodal point do not undergo any refraction. Angle gamma The line passing through the nodal point and the center of the pupil is called the optical axis. On the contrary, the line passing through the nodal point and the fovea centralis is called the visual axis. The two axes subtend a small angle between them, which is called the angle-γ (Fig. 114.2). When the optical axis intersects the retina medial to the fovea centralis, the angle γ is said to be positive. When the optical axis intersects the retina lateral to the fovea centralis, the angle γ is said to be negative. In emmetropes, the γ angle is 5 degrees. In hypermetropes, the angle is greater than 5 degrees. In myopes, the angle is 0 degree or even negative. The line of vision is the same as the visual axis. However, an external observer judges the direction of the line of vision by the position of the pupil. Hence, the greater the γ angle, the more the eyes will appear to look outward, and therefore squinted

Reduced eye Fovea Center of the pupil µ = 1.336 Visual axis

Nodal Point

Optical axis

5 degrees (γ angle)

5.6 mm 1.4 mm

17 mm

Nodal Point

24 mm

Fig. 114.1 Reduced eye of Listing.

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Fig. 114.2 Visual and optical axes of the eye.

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750

Special Senses (Fig. 114.3). As the normal angle γ is 5 degrees, we are accustomed to regard a 10 degrees divergence of the eye (5 degrees for each eye) as normal. Dioptric power of the eye Although, the refraction

of light first occurs at the air–medium interface, for all practical purposes, the entire refraction is assumed to occur at the plane of the nodal point as shown in Fig. 114.4. In an eye with normal dimensions and refractive power, all parallel rays come to focus on the retina. Thus, the focal length of the eye equals the distance between the nodal plane and the retina, which is equal to 17 mm. The relation between focal length and dioptric power is given by the following formula: 1 Power in diopters = Focal length in meters

Substituting:

u = Infinity, v = 17 mm f = 17 mm Power = 59 D

u = 100 mm v = 17 mm f = 14.5 mm Power = 69 D u = 100 mm

v = 17 mm

Fig. 114.4 Focal length of the eye, before (above) and after maximum accommodation (below). Observer

Power in diopters =

1 0.017

Visual axis

Optical axis

= 59 D

Although the calculations are based on the reduced eye, the dioptric power of the real eye too is 59 D. This power represents the combined refractive power of the cornea, aqueous humor, lens, and vitreous humor, wherein the contribution of the lens is 16 D.

Accommodation Far point Only rays that originate at infinity are parallel. In a relaxed normal eye, parallel rays are focusssed on the retina. In other words, the far point of the normal eye is infinity (∞). Near point The eye can focus divergent rays on the

Subject

Fig. 114.3 Apparent squint. The direction of gaze of a subject is determined by his visual axes. Hence, when he looks straight ahead (toward infinity), his visual axes are parallel. Because of the positive γ angle, his optical axes are divergent. The observer judges the direction of gaze by the optical axes. Therefore, the eyes of the subject appear divergent to the observer.

Sircar_Chapter114_749-759.indd 750

retina by increasing the dioptric power of the lens. This is known as accommodation, which enables the eye to clearly see objects very close to it. The closest distance at which the eye can see objects clearly (with maximum accomodation) is called the near point. It is about 10 cm. The near point is not the same as the working distance for near vision, denoted by D, which is taken to be about 30 cm. This is the distance at which near objects should be placed for viewing without unduly straining the eyes, that is without excessive accommodation. “D” is an important consideration in the design of optical instruments and even determines their magnification (see Ophthalmoscopy, p 756).

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Visual Optics Maximum accommodation occurs when the object is at the near point of the eye, that is “u” = 100 mm. The distance of the retinal image from the nodal plane “v” remains 17 mm. The focal length “f” of the maximally accommodated eye can be calculated using the following lens formula: 1 f

1 1 − v u 1 1 − 17 −100

= =

∴

f

∴

P

P

=

0.069

=

14.5 mm

= =

1 0.0145 69 D

Thus, the power of the eye can increase by up to 10 diopters, from 59 to 69 D. This increase in power is called the amplitude of accommodation, and it can be calculated by a general formula that is derived below. If Prel and Pacc are the powers of the eye in fully relaxed and fully accommodated states, respectively, then the amplitude of accommodation is given by Pacc minus Prel. According to the lens formula: Prel

=

1 1 − v far point

Pacc

=

1 1 − v near point

=

1 1 − far point near point

Pacc − Prel

If the far point is ∞, the amplitude of accommodation is the reciprocal of the near point. Thus, if the near point is 0.1 m in an emmetropic person (u = – 0.1), the amplitude of accommodation is 10 D. The amplitude of accommodation decreases in presbiopia (see below) as the near point recedes.

751

blurring of the retinal image, were it not for the iris, which keeps the periphery of the lens covered most of the time. In fact, the smaller the pupil, the less is the spherical aberration and the sharper the image (Fig. 114.5). Chromatic aberration When white light passes through the lens, light of different wavelengths comes to focus at different planes. This is called chromatic aberration. The eye tackles this problem by keeping the green-red wavelengths in focus while allowing the blue light to blur. As blue cones are absent in fovea and comprise less than 10% of all cones, vision is not much affected by the blurring of blue light (Fig. 114.5).

Refractive Errors An eye whose far and near points are normal is called an emmetropic eye. However, not every eye can see as far as infinity or as near as 10 cm. Accordingly, three common errors of refraction have been defined (Fig. 114.6). Myopia In the absence of any accommodation, parallel rays incident on a myopic eye comes to focus in front of the retina. This occurs either because of (1) higher dioptric power of the eye or (2) greater anteroposterior diameter of the eye (more common). Only divergent rays originating from a finite distance come to focus on the retina.

SPHERICAL ABERRATION

CHROMATIC ABERRATION

Physiological aberrations of image formation The refractive index of the lens of the eye is not uniform throughout: its central part has a higher refractive index than its periphery. Thus, rays passing through the periphery of the lens and the rays passing through the central part of the lens come to focus at different planes. This is called the spherical aberration and would cause

Spherical aberration

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Fig. 114.5 Spherical and chromatic aberrations.

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Special Senses

Myopia

Hypermetropia

More power

Less power

f < 17 mm

f > 17 mm

OR

OR

A-P diameter more

A-P diameter less

f = 17 mm

What is the far point in hypermetropia? In the absence of accommodation, hypermetropics can focus only converging rays on the retina. We know that the rays incident on the eye are highly divergent when the object is close to the eye. As the object recedes from the eye, the rays become less divergent. When the object is at infinity, the rays are parallel. Extrapolation of this logic suggests that convergent rays must originate from beyond infinity! Hence, the far point of a hypermetropic is beyond infinity. An alternative logic is also helpful. We know that the source of rays is always located at the point of their convergence. Since the convergent rays, which a relaxed hypermetropic eye can see clearly, would normally meet behind the eye, the far point of a hypermetropic is located behind the eye!

f = 17 mm

Corrected using concave lens

Corrected using convex lens

Fig. 114.6 Myopia, hypermetropia, and their correction using lenses.

Thus, the far point in myopes is less than ∞. If the accommodative power of the myopic subject is normal, the near point too comes closer to the eye (Table 114.1). Myopia can be corrected by wearing concave lenses. Myopes have no problems seeing near objects and have to use less accommodation for doing so. In fact, they see near objects bigger than emmetropes. Even then, young myopes are advised to wear their glasses during reading. This ensures that they continue to exercise their ciliary muscles Table 114.1 Far and near points in the normal eye and in refractive errors. Far point

Near point

Emmetropia

=∞

= 10 cm

Myopia

∞ (behind the eye)

> 10 cm

Presbyopia

=∞

> 10 cm

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Box 114.1 Far point in hypermetropia: Behind the eye? Beyond infinity?

and do not lose their power of accommodation at an early age. Hypermetropia In the absence of any accommodation, parallel rays incident on a hypermetropic eye come to focus behind the retina. This occurs either due to (1) lower dioptric power of the eye or (2) due to smaller anteroposterior diameter of the eye (more common). The near point recedes in hypermetropics and is always greater than 10 cm. Hypermetropia can be corrected by wearing convex lenses. The far point is behind the eye or beyond infinity in hypermetropia (Box 114.1). One might question the necessity of wearing corrective lenses when hypermetropia can be so easily corrected by using accommodation. However, a child with uncorrected (or undetected) hypermetropia who employs accommodation for distant vision can go blind! The reason is as follows: accommodation is always associated with some degree of convergence of the eyes (see near reflex, p 780). During distant vision, convergence is unnecessary and results in double vision. The child is thus left with a difficult choice—(1) either to use accommodation and have a clear but double-vision, or (2) not use accommodation and have a blurred vision. Mostly, the child opts for the first option, using accommodation to have a clear vision, and coping with double vision by seeing through one eye—usually the better eye. Whatever is seen through the other eye is ignored by the visual cortex. Such cortical suppression of vision makes the eye blind in the long run. Such blindness is called amblyopia ex anopsia (See Box 116.1). It is therefore of the utmost importance to detect hypermetropia early and correct it.

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Visual Optics Presbyopia is an inadequacy of the accommoda-

Astigmatism occurs when the refractory system of

tive power of the eye that occurs with aging, usually after the age of 40 years (Fig. 114.7). It occurs due to loss of lens elasticity though a change in lens curvature and weakness of ciliary muscles could also contribute. Because of reduced accommodation, the near point recedes (becomes greater than 10 cm) and approaches the far point. Presbyopia is corrected by wearing convex lenses for near vision.

the eye shows the properties of a cylindrical lens rather than that of a spherical lens. A cylindrical lens has different foci in the horizontal and vertical planes (Fig. 114.8). Thus, the vision is blurred along one axis but remains sharp along the other axis. The axis along which the vision is blurred can be tested using the astigmatic dial (Fig. 114.9).

753

Distance from the eye (m)

Pin-hole test and the stenopic effect 4 3 Near point

2 1

Ordinary working distance 0 0

10

20

30 40 Age (y)

50

60

Fig. 114.7 Regression of the near point with age.

Spherical lens Focal length in transverse plane

70

The refractive errors discussed above have one thing in common—they all cause blurring of the retinal image. They also have a common remedy—the pin-hole! Thus, if a patient with blurred vision can see clearly through a pin-hole, it indicates the presence of a refractive error. On the other hand, if the patient cannot see clearly through the pin-hole, it rules out refractive errors and points to other causes, such as retinal defects, which blurrs vision even when the retinal image is sharp. This is known as the pin-hole test and it works as follows. All rays originating from a point-sized object converge on a single point on the retina if the eye is

Cylindrical lens Focal length in transverse plane

in th ng l le ne a c a Fo l pl tica ver

in ce gen r e v con e No l plan a ic t r ve

Fig. 114.8 Spherical versus cylindrical lens.The spherical lens brings parallel beams to focus in both horizontal and vertical planes. The cylindrical lens shown here brings to focus only the parallel beams in horizontal plane.

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Special Senses

Superior 90o Meridian 5/330 Snellen scale: 0.1/60

180o Meridian Lateral

0o Meridian Medial

Blind spot

Fig. 114.9 Astigmatic dial. To an astigmatic subject, the meridian perpendicular to the axis of astigmatism would look blurred.

emmetropic but fall on multiple points on the retina, forming a blur circle, if there is any refractive error. A true pin-hole admits only a single ray of light from a point-object and therefore precludes the possibility of a blur circle: the image is low in brightness but sharp. Patients with uncorrected myopia often use the pin-hole effect unwittingly to have a clearer distant vision. They do so by lightly shutting the eyelids so as to admit fewer rays of light through the gaps between the eyelashes. This is known as the stenopic effect.

Visual field Fixation point Although it is rarely realized, the eye can see clearly only an extremely small area at a time. This point-sized area, which the eye focuses and looks directly at, is called the fixation point. The image of the fixation point forms on the fovea centralis. There is however no difficulty in seeing a large part of the world around because of the extremely efficient mobility of the eyes. Meridians and isopters A grid of meridians and

isopters is mapped onto the visual field so that every point on the field has a unique meridian and isopter. Meridians are radial lines centered at the fixation point: The 0, 90, 180 and 270 degrees meridians point nasally, superiorly, temporally and inferiorly, respectively (Fig. 114.10). Isopters are concentric circles centered at the fixation point: objects on the same isopter (say, a 50 degrees isopter) subtend the same angle (50 degrees) with the visual axis at the center of the cornea. Field of vision is the total area visible to the eye when it is fixated. The normal field of vision extends to the 60 degrees isopter medially (restricted by nose), 50 degrees isopter superiorly (restricted by eyebrow),

Sircar_Chapter114_749-759.indd 754

20o Isopter

90o 270o Meridian Isopter Inferior

1/330 Snellen scale: 0.6/60

Fixation point

1/1200 Snellen scale: 2/60

Fig. 114.10 The field of vision shrinks as the size of the object with which it is tested is made smaller. The fields shown here are of the right eye.

90 degrees isopter laterally (unrestricted), and 70 degrees isopter inferiorly (restricted by zygoma). The process of charting out the field of vision is called perimetry (Fig. 114. 11).

Visual acuity When two point-objects are brought very close together, they are no longer seen as separate. To be seen as discrete points, their images must form on two separate photoreceptors on the retina (see two-point discrimination, p 664). The distance between the two retinal images depend, not on the absolute distance between the two objects, but on the visual angle subtended at the nodal point of the eye. The minimum visual angle (or more commonly, the tangent of that angle) required for clear vision is called visual acuity. Areas of the retina where the photoreceptors are farther apart require a greater visual angle for clear vision and therefore have a low visual acuity. Conversely, areas where the photoreceptors are closely packed produce clear vision

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Visual Optics

0o isopter (fixation point)

330 mm 70o isopter 70o 90o isopter

Observer

Fig. 114.11 Perimetry. A subject is seated with his left eye in front of the center (fixation point) of the perimeter. The arc of the perimeter has a radius of 330 mm. This figure shows the arc as horizontal (0 degree meridian) but it can be placed vertically (90 degrees meridian) or inclined at any other angle. A test object can be slided along the arc, which is graduated in isopters: the position (isopter) of the object on the arc is given by the angle it subtends with the fixation point at the observer’s eye. As the test object is moved in along the arc kept at, say 0 degree meridian, the isopter at which the subject is first able to glimpse the object while keeping his gaze fixed on the fixation point gives the spatial limit of his peripheral vision in 0 degree meridian. When the procedure is repeated at several meridians, it charts out an area as shown in Fig. 114.13. If the object size is, say 5 mm, the area charted out gives the extent of peripheral vision with an acuity of 5/330 or higher.

755

distance can be considered parallel and therefore, the test is considered as appropriate for distance vision. A numerical fraction is used to express the visual acuity: the numerator denotes the distance (in meters) of the patient from the chart (usually 6), and the denominator is the number assigned to the smallest letters he can read. Normal vision is recorded as 6/6 though many have a higher visual acuity of 6/5, that is standing at a distance of 6 m, they can read smaller letters that an average person can read only from a distance of 5 m. On the contrary, a patient who cannot read below the top-most line marked 60 has a visual acuity of 6/60. Patients with poorer vision are asked to move closer to the chart till they are able to see the top-most line: if the patient can read it when he is 2 m away from the chart or nearer, his vision is recorded as 2/60. The visual acuity read out from the Snellen chart is a comparison with normal vision, for example 6/9, 6/60, 2/60, etc. These fractions should not be reduced. This avoids confusion with the direct method of expressing visual acuity that gives the tangent of the minimum visual angle, that is, the minimum object size visible divided by the distance it is kept at. According to this direct system, an acuity of 6/6 would correspond to 8.75/6000. In the readout of the Snellen chart, a small fraction denotes poor visual acuity whereas in the direct system, a small fraction denotes high acuity. The Snellen chart measures the acuity of foveal vision only. There is a sharp diminution of visual acuity immediately beyond the fovea centralis and it diminishes further towards the periphery, as discussed below.

Visual acuity in peripheral retina even when the visual angle is small, that is they have high visual acuity.

Visual acuity at fovea centralis Visual acuity is highest at the fovea centralis. For clear foveal vision, two point-objects must subtend a visual angle of at least 1 minute (1’) to be seen as separate. It can be calculated that a 1’ visual angle corresponds to a 4.95 μm separation of the coresponding retinal images (Fig. 114.12A): this much separation is enough to stimulate two discrete foveal cones. The Snellen chart (Fig. 114.12B) is used for routine evaluation of visual acuity at the fovea for distant objects. The patient stands at a distance of 6 m from the chart: rays incident on the eye from such

Sircar_Chapter114_749-759.indd 755

The field of vision shrinks with smaller objects. The field of vision shown in Fig. 114.10 is obtained in good light using a 5 mm object kept at a distance of 330 mm. The area charted out therefore represents the field with a visual acuity of 5/330 (about 0.1/60 in Snellen scale) or more. When a 1 mm object is used, the visual field constricts: The constricted field denotes the areas of the retina with a higher acuity of 1/330 (about 0.6/60 in Snellen scale) or more. The field constricts further when the 1 mm object is placed at a distance of 1200 mm: this highly constricted field has an even higher acuity of 1/1200 (about 2/60 in Snellen scale) or higher. Thus, the acuity of vision gradually increases from 0.1/60 at the peripheral retina (where the photoreceptors are distributed sparsely) to 6/6 at the fovea (where the photoreceptors are densely packed).

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756

Special Senses

A

B

nodal point 17,000 mm

1'

4.95 mm

H D = 60

A V D = 36

D = 24

LT J D = 24

V O A D = 24

5 min

H 60 m

T X A L D=9

H 36 m

O A N V Z

H 18 m

D=6

HH

H Z N V T U E H

12 9 6 m m m

D=5 N O H X E Z A U

Fig. 114.12 The distance between the nodal point and retinal is 17,000 mm (17 mm); [A] 1 minute is equal to 1/60 degrees, which is equal to 0.0167 degrees. The height of the retinal image can be calculated to be 17,000 × tan (0.0167) = 4.95 μm. Therefore, a visual angle of 1’ corresponds to a distance of about 5 mm on the retina. [B] The Snellen chart. The chart has rows of letters arranged in order of diminishing font-size. Each letter is of such a shape that it can be placed in a square, the sides of which are five times the stroke width. Hence, when the letters are read from the distance indicated alongside, the whole letter subtends an angle of 5 minutes at the nodal point of the eye but the stroke width of the letters and the gaps between the strokes subtend an angle of 1 minute. For example, the stroke-width of the largest letter will subtend 1 minute at the nodal point if it is placed 60 m from the eye. Those in the subsequent lines will subtend 1 minute if they are 36, 24, 18, 12, 9, and 6 m from the eye. A person with normal acuity of vision is able to read the topmost line at 60 m, the second at 36 m, the third at 24 m, and so on.

Blind spot The part of the visual field that is focused on the optic disk remains invisible to the eye and is called the blind spot (Fig. 114.13). Normally, the blind spot is located between the 12 and 18 degrees isopters, a little below the 180 degrees meridian, that is on the temporal side. Retinal disorders can cause the appearance of additional blind spots in the visual field. These are called scotomata (singular = scotoma).

Ophthalmoscopy If we look into the eye of a subject through his pupil, what do we see? Considering that we are

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seeing the retina through 59 diopters of refractive power, we should see a magnified image of the retina. Here, the refractive medium of the subject’s eye serves as our magnifying glass. A simplified ray diagram (Fig. 114.14) illustrates the situation. The focal length is taken as 17 mm (1/59 = 0.017 m). When the object is placed at the focal plane of a magnifying lens, the magnifying power of the lens is given by the following formula: Working distance for near vision (D) Focal length of the le ens (f )

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Visual Optics

757

f = 17 mm

Retina (object)

40 mm Observer

225 mm

17 mm Disk

Fovea 3 mm

Fig. 114.13 Blind spot. To appreciate the blind spot, close your right eye and hold the figure above vertically at a distance of about 30 cm in front of your eye. Fixate the blue cross with your left eye. You will still be able to see the red circle to your left, though less clearly. Slowly draw the figure nearer to you, keeping the cross fixated (and resisting the instinctive urge to fixate the circle). When the figure is about 22 cm from your eye,1 the circle suddenly disappears from your visual field, only to reappear when you draw the figure still nearer. What do we see at the spot where the red circle is located? We see “nothing” at the blind spot. The brain fills in the color of the background in the blind spot. Thus in a white background, the blind spot appears white while in the above figure, the blind spot appears green.

Substituting, we get:

Intraocular lens (mangifying glass) Power = 59 D

u = 17 mm Subject

Fig. 114.14 An observer looks into the eye of a subject. This creates an optical system in which the retina of the subject serves as the object, and his intraocular lens serves as a magnifying glass for the observer.

Thus, if we look through the pupil of a subject, we will see a retina that is about 17 times magnified. No external lenses are required for obtaining this magnification. This is the underlying principle of direct ophthalmoscopy (see Fig. 1.14). Although a sound proposition theoretically, it is not practically possible to see the retina as suggested above. The pupil is a very small window. If we look in through the pupil, we will block all the light that enters the eye. On the other hand, if we shine light through the pupil, we are left with no space to bring our eye in front of the pupil. Hence, for seeing the retina, an ophthalmoscope is required. An ophthalmoscope is a simple device that allows both the light source as well as the observer’s eye to come in front of the pupil of the subject. Essentially, the ophthalmoscope is a concave mirror with a central hole that the observer can look through. Usually, it is equipped with its own source of light—an electric bulb (Fig. 114.15). The ophthalmoscope is used to examine the fundus (interior) of the eye. During ophthalmoscopy, both the examiner and the patient have to take off their glasses. Hence, most ophthalmoscopes are equipped with an array of convex and concave lenses. These lenses are only corrective lenses meant for compensating the refractive errors of the subject and the observer.

30 cm = 17.5 (approx) 1.7 cm 1

Note the distance (say 22 cm) from your eye at which the blind spot is observed. Given that the distance between the cross and the circle is 4 cm, the distance between the optic disk and the fovea centralis can be calculated to be about 3 mm by applying the principle of similar triangles:

Retinal distance between disk and fovea 4 cm = Distance between len ns and fovea (17 mm) 22 cm

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758

Special Senses Example If the subject is wearing +3 diopters of lenses when the retinal image becomes completely blurred (endpoint), it means that the subject is 1 diopter myopic when wearing a +3 diopters (convex) lens. To make the subject emmetropic, another –1 diopter (concave) lens has to be added. Overall, the subject requires corrective lenses of +2 diopters (i.e., +3 plus –1).

Concave

mi rro r

Aperture for eye

Light source

Fig. 114.15 An ophthalmoscope projects a parallel beam of light while helping in bringing the visual axis in line with a beam of light.

Retinoscopy Retinoscopy (or more correctly, skiascopy, which means observing the shadow) makes it possible to objectively prescribe lenses of appropriate power to myopic and hypermetropic patients. In essence, the retinoscope is similar to the ophthalmoscope in that both are devices that help in bringing the axis of vision in line with a source of light. The procedure for retinoscopy can be summarized as follows. The observer places himself 1 m away from the subject and views through the retinoscope a small circular spot on the subject’s retina that is illuminated by the light from the retinoscope. He then adds lenses in front of the subject’s eyes till the image of the illuminated retina becomes completed blurred. At this stage, the subject with all the lenses he is wearing, is exactly 1 diopter myopic. Adding a concave lens of –1 diopter would now make him emmetropic.

Illuminated spot on the retina

Retinoscopy is based on the analysis of the optical system in which the subject’s retina serves as the object. The refractive medium of the subject’s eye acts as the converging lens of the optical system. Additional lenses that are placed in front of the subject eye help in forming a real image of his retina exactly at the pupil of the observer seated 1 m away (Fig. 114.16). When an image forms exactly at the pupil of the observer, the observer sees nothing but diffuse light. In this optical system, the distance of the image from the lens (v) is 1 m. The distance of the object from the lens (u) is given by fe, that is the focal length of the lens in the emmetropic eye. This is because in an emmetropic eye, the retina is always at the focus of the lens. Suppose, at endpoint, the eye power of the subject with lenses on is Psubject. Using the lens formula,

Psubject

Subject

=

1 1 − v u

=

1 1 − 1 −fe

=

1 + Pe

Observer

Blurred retinal image

u = fe

v=1m Power of lens is 1 D higher than normal

Fig. 114.16 Principle of retinoscopy. If the observer sees a completely blurred image of the subject’s retina, the subject must be 1 diopter myopic. The illuminated spot on the retina acts as the object.

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Visual Optics Thus, at the end point, the subject’s refractive power (with the added lenses) is 1 diopter greater than the power of an emmetropic eye. By tilting the retinoscope sideway, the observer can move around the illuminated spot on the retina. By doing so, the observer can have a preliminary idea as to whether the refractive error is hypermetropia or myopia. In hypermetropia, the retina is located within the focal length of the lens and therefore would form an erect, virtual image. Hence, if a spot of light moves across the retina from left to right, it would appear to move in the same direction to the observer too. In emmetropia, the retina is located at the focus of

759

the lens and therefore would form an erect, virtual image. Hence, in emmetropia too, if a spot of light moved across the retina from left to right, it would appear to move in the same direction to the observer. In subjects with myopia greater than 1 diopter, the retina is located beyond the focal length of the lens and therefore would form an inverted, real image. Hence, if a spot of light moved across the retina from left to right, it would appear to move in the opposite direction to the observer. If the myopia is 1 diopter or less, the image of the light is highly blurred as it is formed near the observer’s pupil.

REVISION QUESTIONS 1. A high γ angle causes “apparent” squint. Why? 2. In a subject with normal distant vision, the amplitude of accommodation is the reciprocal of the near point. Why?

13. What is amblyopia ex anopsia and what causes it? 14. What is the diagnostic utility of the pin-hole test?

3. Myopes see near objects bigger and better than hypermetropes. Why?

15. What is the “stenopic effect” and why does it occur?

4. Although myopes see near objects bigger and better than hypermetropes, they are advised to wear their glasses during reading. Why?

16. What is visual acuity? Which part of the retina has the highest visual acuity, and why?

5. In hypermetropia, the far-point is beyond infinity (behind the eye). Why? 6. A child with uncorrected hypermetropia, who employs accommodation for distant vision, can go blind (amblyopia ex anopsia). Why? 9. What is the difference between “near point” and “working distance for near vision?” 10. What is spherical aberration and why is vision not affected by it?

17. In the readout of the Snellen chart, a small fraction denotes poor visual acuity, whereas in the direct system, a small fraction denotes high acuity. What is the direct system of denoting visual acuity? 18. An ophthalmoscope is only a concave mirror with a central hole in it that the observer can look through. Why, then, does the retina look 17 times magnified on looking through the ophthalmoscope? 19. What is retinoscopy?

11. What is chromatic aberration and why is vision not affected by it? 12. Myopes have better near vision than emmetropes and yet, young myopes are advised to wear their glasses during reading. Why?

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115

Special Senses

The Retina and Phototransduction

The retina

Rod

The retina lies on the inner surface of the choroid. It has a purple tint because the rod cells of the retina contain visual purple or rhodopsin. Light rapidly bleaches the visual purple; in darkness, the color gradually reappears. The retina contains six types of cells, viz., photoreceptor cells, bipolar cells, ganglion cells, horizontal cells, amacrine cells, and Müller cells. These cells are organized into 10 layers (Fig. 115.1).

Cone

Disks

Outer segment

Sacs

Cilia Mitochondria

Inner segment

Nucleus

Synaptic terminal

Photoreceptors There are two types of visual receptors, the rods and the cones, located in the retina. In the retinal periphery, the photoreceptors are fewer, larger, and less evenly distributed. Photoreceptors are absent from the optic disk, which is the area where the optic nerve fibers exit the eye. Each photoreceptor (rod or cone) has an outer segment, an inner segment, and an innermost segment (Fig. 115.2). The outer segment contains stacks of membranous disks. The doublemembrane disks are formed by invagination of

incident light

Incident light

Fig. 115.2 Rods and cones.

the cell membrane. The disk membrane contains photopigment molecules “stitched” into it. The outer segment contains Na+ channels. The inner segment contains the nucleus, mitochondria, and Na+–K+ pumps. The outer and inner segments are

Choroid Rod Photoreceptors Cone .. Muller cell

The row of synapses between bipolar cells, ganglion cells and the amacrine cells

Horizontal cell

The row of nuclei of the bipolar cells

Bipolar cell Amacrine cell

OPTIC NERVE

Ganglion cell

The row of synapses between photoreceptors, bipolar cells, and the horizontal cells

Ten retinal layers Inner limiting membrane Layer of optic nerve fibers Ganglion cell layer Inner plexiform layer Inner nuclear layer Outer plexiform layer Outer nuclear layer Outer limiting membrane Layer of rods and cones Pigment cell layer

The row of nuclei of photoreceptor cells

Light

The row of zona adherens between the photoreceptors .. and the neuroglial Muller cells. It is not a membrane.

Sometimes considered to be a part of the choroid

Fig. 115.1 Retinal layers.

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The Retina and Phototransduction connected by an eccentrically placed modified cilium. The innermost segment is the synaptic zone. In darkness, it releases transmitters continuously. The difference between rods and cones are given in Table 115.1. The photoreceptor synapses with the bipolar cell, which in its turn synapses with the ganglion cell. The axons of the ganglion cells form the optic nerve, which leaves the eye to reach the brain. The horizontal and amacrine cells have important roles in image processing. Fovea centralis About 2.5 mm lateral to the optic

disk, the inner surface of the retina shows a shallow round depression called the fovea centralis, which contains a dense and orderly aggregation of cones (Fig. 115.3). The area around the fovea contains yellow pigment and is called the macula lutea or the “yellow spot.” Vision at the fovea is extremely clear (high visual acuity) for several reasons:

Table 115.1 A comparison of rods and cones Rods

Cones

The outer segment of a rod is a slender cylindrical structure.

The outer segment of the cone is a long conical structure.

In rods, the invaginated cell membrane becomes separated from the cell surface.

In cones, the invaginated cell membrane retains continuity with the cell surface.

The photopigment is rhodopsin, which mediates scotopic vision (vision in dim light). Can detect even a single photon of light!

The photopigment is photopsin, which mediates photopic vision (vision in bright light) and color vision.

Membrane proteins synthesized in the inner segments are assembled into new disks at the inner end of the outer segment. The newly formed disks slowly move toward the tip of the rod as additional disks are formed behind them.

Membrane proteins synthesized in the inner segment are inserted into the disk membranes throughout the outer segment. Disks do not move toward the pigment epithelium continuously as in rods.

The nucleus of the rod is smaller and its chromatin is more condensed.

The nucleus is larger and relatively pale staining.

The terminal part of the inner segment is narrower than that of cones.

The terminal part of the inner segment is expanded into a triangular cone pedicle.

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761

1 mm Layer 4 Choroid

Only cones High density of rods and cones Mostly rods

Fig. 115.3 Fovea centralis.

(1) There is a high concentration of photoreceptors at the fovea. All foveal photoreceptors are cones: There are no rods in the fovea. (2) The inner retinal layers are thinned out at the fovea exposing the cones better to light. In other areas of the retina, light has to pass through all the layers before it can strike the photoreceptors. (3) The fovea contains only fine arteries, veins, and capillaries. At the very center of the fovea, even the capillaries are absent, greatly increasing its transparency. (4) There is no convergence of the efferents of the foveal cones: Each foveal cone relays to a single ganglion cell. Hence, there is a disproportionately large foveal representation in the visual cortex.

Pigment epithelium The pigment epithelium is a sheet of heavily pigmented epithelial cells. The basement membrane of the pigment epithelium is considered by some as a part of the choroid because in retinal detachment, the separation occurs along the plane between the photoreceptors and the pigment epithelium. The pigment epithelium has several functions: (1) The tight junctions between adjoining pigment epithelial cells protect the retina from toxic metabolites that may be brought in by the choriocapillaries. (2) The pigment granules absorb light that traverses the photoreceptor layer and thereby prevents light reflection from the external ocular layers. (3) The membranous disks are continuously exfoliated from the tips of the outer segment of the rods, which are surrounded by processes of the pigment epithelium. The pigment epithelium phagocytoses exfoliated disks. In mice and rats, certain genetic disorders of photoreceptors are associated with reduced destruction of disks. These disorders resemble a disorder called retinitis pigmentosa in humans. (4) In the pigment epithelium, all-trans-retinal is reduced to all-trans-retinol (vitamin A), followed by its storage in the pigment cells, isomerization to 11-cis-retinol and regeneration of 11-cis-retinal (see Fig. 115.5). (6) Vitamin A derivatives move to the pigment epithelium during

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762

Special Senses light adaptation and return to the photoreceptors during dark adaptation.

Phototransduction Phototransduction is a unique example of sensory transduction that is associated with hyperpolarization and a reduction in the neurotransmitter release from the sensory receptor. The fact that light reduces neurotransmitter output should not be cause for confusion: It should be borne in mind that there are two types of bipolar cells—those that are depolarized (excited) by glutamate and those that are hyperpolarized, that is, inhibited by glutamate. The latter are disinhibited (i.e., excited) when the glutamate output from the photoreceptor decreases.

Na+ (Dark current)

Na+ K+

K+

Ca2+

Resting potential The photoreceptor cell has a

membrane potential of –40 mV. The K+ channels are located in the inner segment of the photoreceptors while the Na+ channels are located in the outer segments. The Na+–K+ pump is located in the inner segment. The presence of the Na+ and K+ channels at different locations on the cell does not make any difference to the basic mechanism of generation of membrane potential. Thus, the membrane potential is attributable largely to a greater outward diffusion of K+ than the inward diffusion of Na+. Dark current The Na+ channels remain open in

darkness due to the action of cGMP. Hence, in darkness, there is a steady Na+ influx into the outer segment of the photoreceptor. This inward depolarizing current is called the dark current (Fig. 115.4). Due to the dark current, the photoreceptor remains depolarized in the dark and a steady stream of neurotransmitter is released from its terminal. The neurotransmitter is glutamate. The Na+ channels close when light, which is trapped by photopigments, catalyzes the conversion of cGMP to 5’GMP and thereby decreases the cGMP concentration. (The process is similar to Group-IIB hormonal mechanism, Figs. 81.2 and 81.5B.) Visual cycle The photosensitive pigments, viz., rhodopsin and iodopsin, are composed of a protein moiety called opsin (scotopsin in rods, photopsin in cones) and 11-cis-retinal (retinal is also called retinene), an aldehyde of vitamin A. The G-protein (GTP-binding protein) in opsin is called transducin. When light falls on the photoreceptors, its energy is trapped in rhodopsin and photopsin (photopigments) present in the disks/sacs of the rods and cones (photoreceptors), respectively. The photopigments go through a cycle of transformations

Sircar_Chapter115_760-765.indd 762

Fig. 115.4 The dark current in a photoreceptor.

(the visual cycle) that culminates in the formation of metarhodopsin II followed by the regeneration of rhodopsin. Metarhodopsin II converts cGMP to 5′GMP. The lowering of 5′GMP concentration in the photoreceptor causes the closure of Na+ channels. The consequent reduction in Na+ current hyperpolarizes the photoreceptor to –70 mV and reduces its neurotransmitter output. The first step in the visual cycle is the lightinduced conversion of 11-cis-retinal to all-transretinal, forming prelumirhodopsin. This cis–trans transformation triggers a chain reaction (proceeding through lumirhodopsin, meta-rhodopsin I, and meta-rhodopsin II), that culminates in: (1) the separation of retinal from meta-rhodopsin II, leaving behind opsin (Fig. 115.5), (2) displacement of GDP from the α-subunit of transducin, (3) binding of GTP to the α-subunit of transducin, (4) conversion of cGMP to 5′GMP, (5) lowering of cGMP concentration, (6) closure of the Na+ channels, (7) hyperpolarization of the photoreceptor, and (8) reduction of neurotransmitter output from the synaptic zone of the photoreceptor. Role of vitamin A The 11-cis-retinal is regenerated

from all-trans-retinal by the enzyme retinal isomerase. Some of the all-trans-retinal is converted in the liver into all-trans-retinol (vitamin A) by alcohol dehydrogenase in the presence of NADH + H+. The all-trans-retinol is isomerized to 11-cis-retinol. The 11-cis-retinol thus produced, as well as that obtained as vitamin A from the diet, is converted

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The Retina and Phototransduction

Light

763

All-trans-retinal

γ β αs

γ β αs

GDP

Prelumi-rhodopsin

GDP

Lumi-rhodopsin

Guanylyl cyclase

11-cis-retinal

γ β αs

GDP

The visual cycle

Rhodopsin

Opsin

Meta-rhodopsin-I

γ β αs

GDP

Meta-rhodopsin-II 5'GMP Na

γ β αs

γ β

GDP

+

αs

cGMP GTP

as GDP

Retinal isomerase

11-cis-retinal Retinal reductase NADH + H+

NAD+

All-trans-retinal Pigment Epithelium

Retinal isomerase 11-cis retinol

All-trans-retinol (Vitamin A)

All-trans-retinal

Blood (in choroid plexus)

All-trans-retinal Alcohol dehydrogenase

Liver

All-trans-retinol (Vitamin A)

Fig. 115.5 The visual cycle. See also Figs. 81.3 and 81.5B.

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764

Special Senses to 11-cis-retinal, which is required for refurbishing the rhodopsin stock of the retina. As vitamin A is important for replenishing the retinal stores in photoreceptors, a dietary deficiency of vitamin A produces visual abnormalities. The earliest to appear is nyctalopia (night blindness) due to impaired function of rods. Impairment of cone function occurs later. Chronic avitaminosis A is associated with structural abnormalities in rods and cones followed by degeneration of other layers of the retina. Treatment with vitamin A restores retinal function if administered before the receptors are destroyed.

Blue

Red Photopic vision

450 nm

560 nm

650 nm

peak retinal sensitivity of cones

Blue

Red Scotopic vision

450 nm

500 nm

650 nm

Photopic and scotopic vision The human eye responds to a remarkable range of luminance. A white surface lit by a moonless night sky has a luminance of 10–6 Cd/m2 whereas in bright sunlight, the same surface has a luminance of 104 Cd/m2. Neither rods nor cones have the ability to provide effective vision over such a wide range of luminance. Rods function effectively in the range of 10–7 to 10–3 Cd/m2. Vision in this range of luminance is called scotopic vision. Cones function effectively in the range of 1 to 108 Cd/m2. Vision in this range of luminance is called photopic vision. Prolonged exposure to higher luminance damages the retina. Comfortable reading requires 30 Cd/m2. Purkinje shift is the difference in the luminosity

of colors in lights of different intensities. It occurs due to the difference between rods and cones in their peak spectral sensitivity, which is blue– green color (500 nm) for rods and the green– yellow color (560 nm) for cones. It is due to the Purkinje shift that at dusk, a blue flower glows but a red flower appears black. The reason is explained below. The peak spectral sensitivity of photopic vision (λ = 560 nm) is roughly equidistant from the wavelengths of red (λ = 650 nm) and blue (λ = 450 nm) light. Hence during daytime, when vision is photopic, a red and a blue flower have the same luminosity. However at dusk, vision becomes scotopic. The peak spectral sensitivity of scotopic vision (λ = 500 nm) is close to blue light and distant from red light (Fig. 115.6). Hence, in dim light, blue flowers glow while red flowers appear black . Light adaptation When one passes suddenly from a dim to a brightly lit environment, the light seems intense until the eyes adapt to the increased illumination. This adaptation occurs over a period of about 5 minutes and is called light adaptation. As already explained above, photoreceptors signal light by decreasing their neurotransmitter output.

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peak retinal sensitivity of rods

Fig. 115.6 Purkinje shift. In bright light, vision is photopic and occurs through cones, which are almost equally sensitive to blue and red light. In dim light, vision is scotopic and occurs through rods, which are poorly stimulated by red light.

In rods, the neurotransmitter output is reduced to zero by intense light so that no further decrease is possible. This renders rods useless for signaling bright light. In cones exposed to intense light, the neurotransmitter output decreases initially but in the continued presence of bright light, increases again, as explained below. Ca2+ plays an important role in this recovery of conal sensitivity to bright light. When light falls on the cone, there is closure of Na+ channels resulting in membrane hyperpolarization. The hyperpolarization causes closure of Ca2+ channels, resulting in a reduction in intracellular Ca2+. Intracellular Ca2+ normally inhibits guanylyl cyclase—the enzyme that converts GTP into cGMP. A low intracellular Ca2+ therefore elevates intracellular cGMP levels. The cGMP reopens the Na+ channels, leading to the depolarization of the outer segment and the resumption of neurotransmitter output. Dark adaptation If a person spends a considerable length of time in brightly lit surroundings and then moves to a dimly lit environment, the retina slowly becomes more sensitive to light as the individual becomes accustomed to the dark. This rise in visual sensitivity is known as dark adaptation (Fig. 115.7). It is nearly maximal in about 20 minutes. The time required for dark adaptation is the time required to build up the photopigment stores, which are constantly depleted in bright light. The dark adaptation response has two components: (1) The initial rapid but small rise in visual sensitivity is due to

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The Retina and Phototransduction

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the dark adaptation of cones. (2) The late, slow but large rise in visual sensitivity occurs due to the dark adaptation of rods. It occurs only in the peripheral retina and not in the fovea, which contains only cones. Aircraft pilots taking off into the night sky need quick dark adaptation immediately on take-off. Hence, they wear red goggles when on the ground in bright light. Red light (λ = 650 nm) causes minimal stimulation of rods which have peak spectral sensitivity at λ = 500 nm. However, red light stimulates cones adequately. Therefore, pilots wearing red glasses can see in bright light and yet their rods remain dark-adapted.

Electroretinogram Electroretinogram (ERG) is the record of the electrical potential generated by the retina in response to a brief flash of light. It is recordable outside the eye, usually at the cornea, with a contact lens electrode. The ERG is produced by the radially oriented

Inner retinal potential (oscillatory waves)

Fig. 115.8 The electroretinogram (red) and its component waves (green).

peripheral processes of the photoreceptors, bipolar, and Müller cells. The ganglion cells do not contribute to the ERG waves because their peripheral processes have a relatively tangential (not radial) orientation. Hence, the ERG is normal in optic atrophy despite the loss of ganglion cells. The ERG is useful in the diagnosis of certain retinal disorders, particularly retinitis pigmentosa. The typical ERG wave has three components (Fig. 115.7): (1) The photoreceptors generate the a-wave of the ERG, which is a cornea-negative (downward) wave. (2) The bipolar and Müller cells together produce the b-wave which is cornea-positive (upward). (3) Processes of the inner plexiform layer generate low-voltage oscillatory waves.

REVISION QUESTIONS 1. What are the reasons for the high visual acuity at the fovea centralis of the retina?

5. At dusk, a blue flower appears to glow whereas the red flower appears nearly black. Why?

2. What are the functions of the pigment epithelium of the retina?

6. Why does the electrooculogram show deflections when there are eye movements?

3. What is dark current?

7. ERG is normal in optic atrophy despite the loss of ganglion cells. Why?

4. When light falls on the photoreceptor, its neurotransmitter output decreases. How, then, does the photoreceptor transmit the signal?

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Visual Pathways and Image Processing

Visual pathways The visual field (p 754) is divided into temporal and nasal halves by a vertical line passing through the fixation point. Accordingly, the retina too is divided into nasal and temporal halves by a vertical line passing through the fovea centralis. The axons of the retinal ganglion cells run in four different pathways: (1) Ninety percent of the optic fibers reach the striate cortex via the lateral geniculate body, forming the geniculostriate pathway. The other pathways are the (2) colliculopulvinar pathway, (3) the accessory optic pathway, and the (4) retinohypothalamic pathway.

Geniculostriate pathway The axons of retinal ganglion cells relay in the lateral geniculate nucleus (LGN) of the thalamus. (1) Fibers from the nasal half of the retina decussate in the optic chiasma before relaying in the contralateral LGN. (2) Fibers from the temporal half of the retina relay in the ipsilateral LGN without decussating. The LGN has a lamellar structure comprising six layers numbered ventrodorsally. Each layer receives input from one eye only. The fibers from the temporal half of the retina relay to the ipsilateral LGN in layers 2, 3, and 5 while those from the nasal half relay to the contralateral LGN in layers 1, 4, and 6. Efferents from the LGN fan out as the optic radiation to terminate in the ipsilateral primary visual cortex, which is also known as area 17, striate cortex, or visual area 1 (V1). Fibers from the inferior half of the retina take a detour of the temporal lobe as Meyer loop before terminating in the cortex (Fig. 116.1). Lesions of the geniculostriate pathway All lesions of the geniculostriate pathway, other than those in the optic nerve, tend to cause hemianopia, that is, blindness in only one half of the visual field. The term homonymous is used when the hemianopia affects only the left halves or right halves of the visual field, while the term heteronymous is used when the hemianopia affects only the temporal halves (bitemporal) or nasal halves (binasal) of vision. The visual defects associated with lesions at different sites in the geniculostriate pathway are shown in Fig. 116.1. The fovea projects to a relatively large part of the striate cortex, and lesions of the striate cortex are rarely large enough to abolish macular (foveal) vision completely.

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Hence, hemianopia with macular sparing is characteristically seen in lesions of the striate cortex. Vision however may be impaired even when there is no defect in the retina, visual pathways, or visual cortices. The condition is called amblyopia or the “lazy eye” (Box 116.1).

Colliculopulvinar extrastriate pathway The second strongest retinal projection is to the superior colliculus of the midbrain, where they have a retinotopic representation. From there, the fibers project to the pulvinar of the thalamus, which in turn projects to the extrastriate cortex (Fig. 116.2). The extrastriate visual cortex projects back to the superior colliculus, which is important for saccadic movements of the eye and its coordination with the grasping reflex. When the geniculocalcarine pathway is damaged, this colliculopulvino-extrastriate pathway is responsible for the persistence of some very limited stimulus detection and eye movement toward objects in the visual field. This residual vision is called blindsight.

Accessory optic pathway Fibers of the accessory optic pathway relay in the pretectal nuclei, viz., the nucleus of the optic tract and the terminal nucleus. Efferents from these nuclei reach the contralateral vestibulocerebellum after relaying in the ipsilateral medial vestibular and inferior olivary nuclei (Fig. 116.2). The visual signals in the accessory optic pathway interact with vestibular signals at two sites: (1) the medial vestibular nucleus and (2) the cerebellum. These sites are important for the synergistic actions of the optokinetic reflex and the vestibuloocular reflex. The relative effects of the two reflexes can be readjusted by the cerebellum, resulting in a form of adaptive motor learning.

Retinohypothalamic pathway A very small number of axons terminate immediately above the optic chiasma in the suprachiasmatic nucleus of the hypothalamus (see Figs. 95.5, 98.2). This retinohypothalamic pathway provides information about light–dark cycles to the suprachiasmatic nucleus which generates circadian rhythms

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Visual Pathways and Image Processing

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Fig. 116.1 Lesions of the geniculostriate pathway. Note that the image formed on the left half of the retina represents the right half of the visual field, and vice versa. (1) Lesion of the optic nerve causes ipsilateral blindness. (2) Midsagittal lesion of the optic chiasma causes bitemporal hemianopia. (3) Lesion of the optic tracts causes contralateral homonymous hemianopia. (4) Lesion of the temporal lobe affects the fibers of Meyer loop coming from the lower half of the retina and causes contralateral homonymous upper quadrantanopia. (5) Lesion of the optic radiation causes contralateral homonymous hemianopia. (6) Lesion of the visual cortex causes contralateral homonymous hemianopia with macular sparing.

Box 116.1 Lazy eye Vision may be impaired even when there is no defect in the retina, visual pathways, or visual cortices. The condition is called amblyopia and the eye is called amblyopic or the “lazy eye.” It usually occurs if the retina is not exposed to clear images of diverse “visual forms” when vision is still developing, that is, usually up to the first 12 years of life. Such “form-sense” deprivation occurs when the retinal image is blurred (due to ptosis, uncorrected refractive error, corneal opacity, cataract, or vitreous hemorrhage) from birth. The amblyopia that occurs when binocular fusion is defective is called amblyopia ex anopsia.

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(1-day-long cyclic rhythms) in sleep and wakefulness, eating and drinking, physical activity, and melatonin and adrenocortical secretions (see Fig. 85.6).

Parallel processing of image M and P cells Starting from the ganglion cells, all

cells in the geniculostriate pathway up to the striate cortex and probably beyond are of two types: the M and P cells. However, cells of the colliculopulvinar pathway or the accessory optic pathway do not conform to either M or P cells: They have small to medium-sized cells with large dendritic field and thin axons.

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Fig. 116.2 Colliculopulvinar and accessory optic pathways. Note that the vestibular afferents meet the accessory optic pathway in the vestibular nucleus. Also shown are the geniculostriate pathway and the oculomotor circuit of the basal ganglia.

M cells are large with extensive dendritic field and thick axon. They have higher sensitivity to light contrast and higher temporal resolution—properties that result in a higher critical flicker-fusion frequency, which is the maximum rate at which stimuli can be presented and still be perceived as separate stimuli. In motion pictures, the perception of motion occurs only when individual picture frames are projected at a frequency exceeding the normal critical fusion frequency, which is about 16/s. P cells are small with small dendritic field and thin axon. P cells have higher sensitivity to color contrast and higher spatial resolution—properties that result in a higher visual acuity.

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Magnocellular and parvocellular pathways M cells constitute the magnocellular pathway and P cells constitute the parvocellular pathway. The two pathways are involved in parallel processing of the image, that is, analysis of different aspects of the image. Beyond the striate cortex, the magnocellular pathway extends to the middle temporal area (posterior parietal cortex) while the parvocellular pathway extends to the inferior temporal cortex.

Serial processing of image Successive cells in the geniculostriate pathway are involved in increasingly complex analysis

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Visual Pathways and Image Processing of the image. This is called sequential or serial processing.

Photoreceptors and bipolar cells The photoreceptors break up the image into small spots of light or darkness, quite like a digital camera that breaks down a picture into small pixels. Photoreceptors reduce their neurotransmitter (glutamate) output in response to light. As already mentioned above, there are two types of bipolar cells: (1) those that are depolarized (excited) by the glutamate and (2) those that are hyperpolarized (inhibited) by glutamate. The bipolar cells that are inhibited by glutamate are disinhibited (i.e., excited) when the glutamate output from the photoreceptor decreases.

Ganglion cells and LGN cells In the ganglion cells and LGN cells, the image is analyzed mostly in terms of the contours of the light–darkness boundaries, with areas of uniform light or uniform darkness eliciting very little neural response. It involves lateral inhibition (see Fig. 103.13) and yields a high-contrast outline of the original image (Fig. 116.3). The advantage in such a conversion is that fewer neurons are required for transmitting the distinctive features of the image to the brain. The accentuation of the image contrast is made possible by the center-surround organization of the receptive fields of the ganglion cells and LGN cells, as explained below.

Fig. 116.3 This black-and-white sketch has fewer details and shades than photograph in Fig. 55.2. Yet, both are nearly equally effective in conveying the scenery. This is because in the brain, the photograph is converted to a line sketch anyway (through lateral inhibition).

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Center-surround organization of receptor fields The

bipolar cells and the ganglion cells have concentric-antagonistic receptor fields. Depending on the stimulation mode of their receptor fields, the bipolar/ganglion cells are called on-center or off-center cells. An on-center cell is stimulated when light falls on the center of its receptor field and inhibited when light falls on the periphery of the field. Conversely, an off-center cell is stimulated when light falls on the periphery of the field and inhibited by light on its center. Similar concentric-antagonistic receptor fields are present in the LGN cells too. The mechanism of an on-center response in a bipolar cell is as follows: The bipolar cells of the on-center receptor field are inhibited by glutamate. Hence, they are disinhibited (stimulated) when the glutamate output of photoreceptors decreases, as occurs in the presence of light. Also, the synapse between the photoreceptor and the bipolar cell is presynaptically inhibited by the horizontal cells. Therefore, when light falling on the periphery stimulates the horizontal cell, the bipolar cell is inhibited. The reverse occurs in an off-center field (Fig. 116.4).

Visual area 1 (V1) Visual area 1 (V1) is variously known as the primary visual cortex, Brodmann area 17, and the striate cortex. The name “striate” comes from the prominent stripes seen on a cross section of cortex produced by the myelinated fibers of the LGN that terminate there. V1 is situated along the lips and walls of the posterior part of the calcarine sulcus. The peripheral part of the retina is represented in the anterior part of area 17. Its upper quadrants project to the upper wall of the calcarine sulcus and its lower quadrants, to the lower wall of the sulcus. The macular part of the retina projects mainly to the posterior part of area 17 and anteriorly, to a thin strip along the calcarine sulcus. The macular area occupies nearly one-third of area 17 (Fig. 116.5). The striate cortex is made of six layers of cells numbered 1 to 6. Layer 4 is further subdivided into four sublayers (Fig. 116.6). Afferents from the LGN enter layer 4. The magnocellular afferents from the LGN enter layer 4Ca. The parvocellular afferents enter layer 4Cb from where they project to the blobs and interblobs (see below). Layers above 4C project to higher visual cortices such as V2, V4, and V5 and, through the corpus callosum, to the contralateral visual areas. Layers below 4C project to subcortical areas: Thus layer 5 projects to the superior colliculus, pons, and pulvinar, and layer 6 projects back to the LGN and to the claustrum.

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optimally only to stimuli that have linear properties, such as a line or bar. These cells belong to two major groups, the simple and the complex cells. The simple and complex cells receive input from both the M and P pathways, both pathways contributing to the primal sketch, that is, the initial two-dimensional approximation of the shape of a stimulus.

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Simple cells have a receptor field that is oblong in shape. They are best stimulated by lines and edges with the same orientation as the long axis of their oblong receptive field. Simple cells also have excitatory and inhibitory zones in their field. Complex cells have larger receptive fields. They respond to linear stimuli with specific orientation but the precise position of the stimulus within

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Visual Pathways and Image Processing

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stimulated when an edge of light moves across their receptor field in one direction but not in the reverse direction. P-type complex cells respond not only to lines of specific orientation but also to lines of specific length. This is made possible by their ability to respond to right-angled edges that indicate where a line ends. Given their ability to detect both the orientation and length of lines and edges, the complex P cells are able to analyze the detailed form and texture of an object. Hypercolumns in the striate cortex Each receptor

field of a retinal ganglion cell is represented in the striate cortex by a hypercolumn, which occupies an area of 1 mm2 and processes multiple aspects of the image, viz., orientation, binocular interaction, color, and motion. Accordingly, the hypercolumn has three components: the orientation columns, the ocular dominance columns, and the blobs. Orientation columns (Fig. 116.7) are columns of simple cells that respond to stimuli with a specific orientation. The columns are disposed perpendicular to the cortical surface. The optimal stimulus orientations of adjacent columns are progressively tilted, and within a width of 1 mm, all orientations are represented. Ocular dominance columns (Fig. 116.7) Cells of these columns receive inputs from the corresponding points (Fig. 116.10) of both retinas and thereby enable stereopsis, that is, binocular vision. The inputs from the two eyes in most cases are not equal, and usually, the effect from one of the eyes dominates. Columns of cells that are dominated by the same eye form the ocular dominance columns. Dominance alternates between output from the left and right eye at intervals of about 0.5 mm. Columns of blobs are apparent in V1 when it is stained with cytochrome oxidase. Blobs and the intervening interblobs are sites of color processing and are prominent in layers 2, 3, and 4A of the striate cortex. The blobs contain color-opponent neurons (see below).

Visual area 2 (V2) Fig. 116.6 Magnocellular and parvocellular pathways from the lateral geniculate ganglion to the visual cortices.

the receptive field is less crucial because there are no clearly defined “on” or “off” zones. Thus, movement of image across the receptive field is a particularly effective stimulus for certain complex cells. M-type complex cells respond better to moving edges than stationary edges of light. Some of them are directionally sensitive. These cells are

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Visual area 2 (V2) is also called the secondary visual cortex. It occupies much of area 18 but is not coextensive with it. Cells in V2 are sensitive to the orientation, color, and binocular disparity of the stimulus. V2 carries out more complex analysis of contours than V1 and can respond even to illusory contours, such as the Kanizsa triangle (see Fig. 103.16). Staining with cytochrome oxidase gives a striped appearance to the V2 cortex. The stripes are of two types: the thick stripes and the thin stripes. The interstripe regions are sometimes called pale

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stripes. The stripes receive their input from different areas of V1. The thick stripes project to V5. The thin and pale stripes project to V4 and onward, into the inferior temporal cortex.

Visual area 4 (V4) Visual area 4 (V4) lies mainly within area 19 anterior to visual area 3 (V3). (V3 is a narrow strip adjoining the anterior margin of V2, still within Brodmann area 18. Its functions are not well defined.) Its major input is from the thin and pale stripes of V2. V4 cells are responsive to both color and form. V4 cells are also responsible for color constancy, that is, the ability of the visual system to identify different colors under different illumination conditions. V4 is a key relay station for the ventral (parvocellular) pathway to the inferior temporal cortex.

Visual area 5 (V5): middle temporal (MT) area The cortical area that is dedicated to detection of motion across the visual field is designated as V5. In the simian brain, it is located toward the posterior end of the superior temporal sulcus and has been called the middle temporal (MT) area. In the human brain, the area corresponds to the junction of the parietal, temporal, and occipital cortices, lying in Brodmann area 19, but no separate name has

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been assigned to it. Since most of the experimental work is done in monkeys, the name MT area is widely used. The MT area receives a strong input from the directionally sensitive M-type complex cells in V1. MT cells show a more complex directional sensitivity than the V1 cells. The latter respond only to moving lines and edges and are therefore called component direction-selective. MT cells respond to moving objects and forms and are therefore called pattern direction-sensitive. The receptor field of the MT cell is 10 times larger than that of the V1 M cell. This enables the MT cell to detect entire objects that move across its large receptor field. A few MT cells are sensitive to form and color. They help in detecting motion of colored spots and shapes. A cortical area adjacent to MT, called the medial superior temporal area (MST), contains neurons that respond to visual motion. These neurons may process a type of global motion in the visual field called optic flow, which is important for detecting a person’s own movements through the environment.

Inferior temporal cortex (Area 20) The inferior temporal cortex is located in inferior temporal gyrus, the temporal pole and the lateral and medial occipitotemporal gyri. The most prominent visual input to the inferior temporal cortex is from visual area-4 (V4). The cells of this area have a very large receptor field, sometimes including the

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Visual Pathways and Image Processing

Color vision The three primary colors, viz., red, blue, and green, when added in appropriate proportions can create all other colors (Fig. 116.8). Hence, they are also called additive colors. This can be demonstrated by projecting overlapping primary colors on a white screen. The area where all the three colors overlap looks white. The screen appears black when no light falls on it. Colored pigments do not follow the same rules as colored lights and are called subtractive colors. A red pigment looks red because it absorbs (subtracts) all other colors from the white light that falls on it. Similarly a blue pigment reflects only blue light and absorbs all other colors. When red and blue pigments are smeared together, they subtract all colors from white light and therefore look black. The three subtractive colors are cyan, magenta, and yellow which, when mixed in appropriate proportions, produce pigment colors of all hues. Trichromatic coding The simplest explanation of the existence of primary colors is the trichromatic coding theory of Young and Helmholtz. Lights of different colors have different wavelengths and they excite different types of cones in the retina. There are three types of cones, namely, the L cone for red (λ = 650 nm) color, M cone for green (λ = 530 nm) color, and S cone for blue (λ = 440 nm)

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entire visual field. Importantly, the fovea is always represented in every receptor field. Such large fields enable position invariance, that is, the ability to recognize the same object regardless of its location in the visual field. Some inferotemporal cells respond only to specific complex stimuli, such as the hand or face. For cells that respond to a hand, the fingers are especially critical since these cells do not respond when there are no spaces separating the fingers. However, all orientations of the hand elicit similar responses. Among neurons selective for faces, the frontal view of the face is the most effective stimulus for some, while for others it is the side view. Moreover, whereas some neurons respond preferentially to faces, others respond preferentially to specific facial expressions. Some cells are activated even by two dots and a line appropriately positioned, for example, .. Some cells respond to facial dimensions (distance between the eyes) while others respond to familiar faces. Cells responding to similar facial features are probably organized in columns. Although the proportion of cells in the inferior temporal cortex responsive to hands or faces is small, lesions of this region lead to prosopagnosia, that is, deficits in face recognition.

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Fig. 116.8 (Above) The primary colors red, blue, and green produce magenta, cyan, and yellow when added in pairs. Addition of all the three primary colors produces white light. (Below) Wavelength sensitivity of retinal cones according to the Young–Helmholtz theory.

color. The letters L, M, and S denote the long, middle, and short wavelength of light absorbed by the cones. All colors are coded at the receptor by differential stimulation of these three types of cones. This is known as trichromatic coding. Opponent color coding Simple trichromatic color

coding occurs only at the receptor level. In the ganglion cell, there is opponent color coding, which occurs in the blobs of the striate cortex. There are three distinct opponent mechanisms, which are formed by summation or subtraction of signals from the three types of cones. Summation of signals occurs when the photoreceptors facilitate each other while subtraction occurs when one photoreceptor inhibits the other. The red–green opponent mechanism occurs by the subtraction of signals of the M and L cones, that is, L– M. It is excited by red light and inhibited by green light and thereby captures red–green variation in the image. The yellow–blue opponent mechanism occurs by the subtraction of S cone signals from the summated signals of M and L cones, that is, S – (M + L). It is excited by blue light and inhibited by yellow light and thereby captures blue–green variation in the image. The

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Special Senses achromatic opponent mechanism occurs by the summation of signals from all the three cones, that is, S + M + L. It is excited by light and inhibited by dark and thereby captures the achromatic (light– dark) variations in the image. All signals from cones, color signals as well as the achromatic signals about image brightness, are transmitted through parvocellular pathways. The P cells are very densely distributed, especially in and around the fovea. The activation of the opponent mechanism requires the stimulation of several cones in the receptor field and therefore the mechanism is not activated when light falls on a small point on the retina and stimulates a single cone. The cones themselves respond to a wide range of wavelengths and, on their own, signal the brightness of the light rather than its color. Hence, the P cell detects the brightness of the finest dots in the image and detects shades of color in larger fragments of the image. Further color processing occurs in V4. In these neurons, maximum response occurs to those hues for which the human languages have separate words, that is, the seven colors of the rainbow.

Color blindness Color blindness is common in men (8%) and uncommon in women (0.4%). It is inherited as an X-linked recessive character. Though hereditary color blindness is much more common, defects of color vision can also be acquired, and occur in diabetes mellitus or disease of the retina, optic nerve, or visual cortex. The detection of color blindness is important in selecting candidates for jobs requring the ability to distinguish colors. A convenient quick test is the Ishihara chart (Fig. 116.9). Color blind individuals may be monochromats, dichromats, or trichromats. Monochromats are unable to distinguish any color. There are two kinds of monochromats. Rod monochromats lack normally functioning cones and have poor vision in bright light, quite like a dark-adapted subject exposed suddenly to bright light. Cone monochromats lack functioning rods and have poor vision in dim light, quite like a light-adapted subject who enters an unlit room. Monochromats, especially cone monochromats, are rare. Dichromats, who can see two colors, are of three kinds. The protanopes (red-blind) and deuteranopes (green-blind) are often grouped together as “red–green” blind. They confuse red and green objects, though they can usually distinguish yellow objects. Tritanopes, sometimes called “blue-blind,” are rare. They have little ability to distinguish blue from green.

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Fig. 116.9 The Ishihara chart. A color blind person may not be able to see the green figure of five hidden in the red and yellow dots.

Anomalous trichromats can see all colors but still have defective color vision. The cause of anomalous trichromacy is unknown, though they might have abnormal pigments.

Depth processing Monoocular mechanisms At distances greater than about 30 m the retinal images in each eye are almost identical, so that looking at a distance, we are practically one-eyed! Nevertheless, we can perceive depth with one eye by relying on a variety of monocular depth cues, which are as follows: (1) Familiarity with the size of a person helps in judging the person’s distance. (2) When there is partial occlusion of one person by another, we assume the person in front is closer. (3) Parallel lines, such as those of railway track, appear to converge with distance. The greater the convergence of lines, the greater is the impression of distance. (4) If two similar objects appear different in size, the smaller is assumed to be more distant. (5) Patterns of light and dark can give the impression of depth, for example, brighter shades of colors tend to be seen as nearer. In painting this distribution of light and shadow is called chiaroscuro. (6) As we move our head or body from side to side, objects nearer than the fixated plane move quickly and in the direction opposite to our own movement, whereas more distant objects move slowly and in the same direction as our movement. This relative movement of objects at different distances is called parallax. (7) The depth of accommodation required

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Visual Pathways and Image Processing for focusing an object gives an idea of its distance from the eye.

775

Z Y X W V U T G F E D C B A NM L K J

T1 U1 V1 W C 1 A1 B H1

X 1 Y I1 D 1 E 1 Z 1 J1 1 K1 L F 1 G 1 1 M1 N 1

When the eyes fixate an object, its image is formed on the retina of each eye. The two retinal points on which the images of a fixated point-object are formed are called corresponding points. Conversely, when two identical images are formed on the corresponding points, the brain interprets them as originating from the same object. However, not all images formed on corresponding points are identical. This occurs with objects that are located either behind or in front of the fixation plane. The displacement of the images from corresponding points, called binocular disparity, is proportionate to the distance of the object from the fixation plane (Fig. 116.10). Cells sensitive to binocular disparity are found in V1, V2, and V3. These cells are organized into ocular dominance columns. MT cells are even able to judge whether an object is nearer or farther away from the plane of fixation. There are specific cells that respond to objects in front of the fixation plane (near cells) or behind the plane (far cells). The importance of stereopsis in depth perception can be easily appreciated through a simple experiment. Hold both your arms straight out in front, keeping them wide apart. Now, bring a finger of each hand together so that their tips meet. First,

I H

W 2 M E2 F X 2 Y 2 Z 2 2 N2 2 G 2

Binocular mechanisms (stereopsis)

1

V2 T2 U2 D A 2 B 2 C 2 L2 H 2 I2 J2 K2

Fig. 116.10 Corresponding points and depth perception. The corresponding points on the retina are A1 and A2, B1 and B2, C1 and C2, till G1 and G2. When identical images form on corresponding points, they are perceived as single. When the images on corresponding points are nonidentical, they are interpreted as two different objects. When the eyes are fixed on the letters ABCDEFG (the middle plane), the images of all the letters in that plane fall on corresponding points. The letters in the rear and front planes do not cast their images on corresponding points and therefore appear doubled, providing depth cues.

try to do it with one eye closed and then, with both eyes open.

REVISION QUESTIONS 1. Lesions of the striate cortex causes hemianopia with macular sparing. Why?

7. Which part of the visual cortex detects motion across the visual field?

2. What is amblyopia? What is blindsight?

8. What is optic flow? What is position invariance? What is color constancy? Which areas of the brain enable these?

3. Which part of the brain coordinates the optokinetic reflex and vestibuloocular reflex during synergistic action? 4. What is the function of the retinohypothalamic pathway? 5. What are the M cell and P cell? Which one has (1) higher sensitivity to light contrast, (2) higher temporal resolution, (3) higher sensitivity to color contrast, and (4) higher spatial resolution acuity? 6. The on-center and off-center responses increase the image contrast. Which cells show these responses and where are they located?

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9. What is prosopagnosia? A lesion of which area of the brain causes it? 10. Trichromatic color coding occurs only at the receptor level. What type of color coding occurs beyond receptors? 11. Monochromats are of two types and dichromats are of three types. What are these types? 12. What are the monocular mechanisms of depth perception?

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117

Special Senses

Oculomotor Mechanisms

Extraocular motor mechanisms The skeletal muscles attached to the eyeball externally are called extraocular muscles. They rotate the eye around the center of rotation, which lies about 12 mm behind the center of the cornea. Three types of rotation are possible around this center of rotation (Fig. 117.1): (1) Horizontal rotation around the vertical axis can be either abduction (temporal rotation) or adduction (nasal rotation). (2) Vertical rotation around the horizontal axis can be either elevation (upward rotation) or depression (downward rotation). (3) Cyclic rotation around the anteroposterior axis can be either intorsion (inward rotation) or extorsion (outward rotation). Each pair of muscles that help in directing the eye toward any of the six cardinal directions of gaze are known as yoke muscles. Each pair of yoke muscles are an agonist–antagonist pair that are reciprocally innervated. Electrooculogram (EOG) is the record of the po-

tential difference called corneoretinal potential that exists between the cornea and the retina (i.e., the opposite poles) of the eyeball. The potential results from the metabolic activity of the cornea, lens, and the retinal pigment epithelium. Normally, the cornea is up to 10 mV positive with respect to the back of the eye. The potential recorded changes vectorally with eye movements and is therefore used for monitoring ocular movements.

For recording the EOG, electrodes are placed at the inner and outer canthi. When the eyes move to the right, the positive cornea comes closer to one of the electrodes, which accordingly records a more positive potential than the other electrode. The opposite happens when the eyes move to the left (Fig. 117.1). The EOG sensitivity to ocular movements is utilized in polysomnography (p 716) for identifying REM sleep by recording nystagmus. EOG is also routinely recorded simultaneously with the EEG (see Fig. 107.8): When the eye blinks, the eyes roll upward (Bell phenomenon) and therefore the EEG potentials, especially in the frontal leads, become more positive. This positive drift of the EEG potential caused by the blink is called the blink artifact. It is necessary to identify the blink artifacts in the EEG so as not to confuse them with seizure activity. Due to the retinal contribution to the corneoretinal potential, the EOG is sensitive to light and dark adaptations. Hence, although primarily meant for monitoring ocular movements, the EOG has been put to diagnostic use in certain rare retinal disorders.

Versions and vergences A visual target is normally foveated with both eyes and therefore requires synergistic binocular

IO

IO

SR

SR

LR SO Inferior oblique (IO)

Superior rectus (SR)

Lateral rectus (LR)

SO

Abduction

Elevation

Intorsion

SR

Medial rectus (MR)

IO MR

Superior oblique (SO)

Inferior rectus (IR) Right eye

IR Adduction

SO

IR Depression

IR Extorsion

Fig. 117.1 Monocular movements.

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Oculomotor Mechanisms movements. Such movements may be conjugate (version) or disjuate (vergence). In conjugate movements, the eyes move in the same direction. In disjugate movements, the eyes move in opposite directions. Conjugate movements (versions) may be horizontal or vertical. The lateral gaze center is present in the paramedian pontine reticular formation. Stimulation of the lateral gaze center produces conjugate version to the same side and therefore pontine lesions result in the conjugate deviation of the eye to the opposite side. The vertical gaze center is present in the mesencephalic reticular formation, or more precisely, in the rostral interstitial nucleus of the medial longitudinal fasciculus. It produces vertical versions. Pure vertical versions require bilateral activity of the gaze centers. Oblique versions are produced by combining the activities of the lateral and vertical gaze centers (Fig. 117.2). Disjugate movements (vergences) may take the form of convergence and divergence. They are observed when the eyes are fixed on a target that moves nearer to or farther away from the eye and are mediated by the near reflex (see below).

Fixation of visual target Eye movements are meant for foveating or fixating a visual target, that is, ensuring that a steady image of the visual target is formed on the fovea of the retina. The image tends to slip away from the fovea whenever there is a relative movement between

-

+

+

Fig. 117.2 The principle of electrooculogram. See also Fig. 107.8

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the visual target and the observer. This slippage of the foveated image is prevented by different types of reflex eye movements: (1) The vestibuloocular and optokinetic reflexes keep the eye stationary in space when the head is moving. (2) The smooth pursuit movement keeps a moving visual target foveated. (3) When the visual target approaches or recedes from the eye, it is kept foveated by vergence movements. (4) A different kind of movement, called saccadic movement, occurs when the eye fixation shifts from one object to another. Saccadic movements are quick and brief, and employ a neural mechanism that is quite different from the other reflex eye movements. The vestibuloocular reflex (VOR) is triggered when the eye is fixated on a target and the head moves suddenly. The direction of the head movement is sensed by the semicircular canals of the vestibular apparatus. Afferents from the semicircular canal reflexly activate corrective ocular movements in the opposite direction (Fig. 117.3). Were it not for the VOR, our vision would become blurred during a jerky ride in a car. The VOR has its strengths and weaknesses vis-a-vis the optokinetic reflex (see below): (1) The drawback of the VOR is that the semicircular canals, which senses the head movement, receive no feedback on whether or not the corrective eye movements are adequate. Hence, the reflex cannot ensure perfect stabilization of foveation, which is possible only through the optokinetic reflex. (2) However the latency of the optokinetic reflex (80 ms) is much longer than that of the VOR (12 ms) and therefore during rapid jerks, the stabilization of the foveal image is maintained almost entirely by the VOR. (3) Also, the VOR can operate even in the dark because it is not dependent on vision. (4) Finally, VOR is suppressed during shifting of gaze, be it a saccade or a smooth pursuit. The suppression is caused by the vestibulocerebellum. The VOR can be demonstrated easily in a subject seated on a rotating stool. When the stool rotates fast, the subject is unable to fix the eyes on any particular target. Nonetheless, if the subject rotates clockwise, the eyes will rotate anticlockwise due to the VOR. When the eyes reach about 60 degree version, they jump back to the opposite end in a saccadic motion resulting in oscillatory eye movements called nystagmus. The nystagmus thus has two components: a slow vestibular component and a fast saccadic component. A postrotatory nystagmus occurs for a few seconds after rotation ceases. It occurs as the endolymph in the semicircular canals continues to flow due to inertia even after rotation has stopped. The VOR forms the basis of the vestibular function tests (p 797).

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778

Special Senses

Right eye

Left eye

Dextroversion (DV)

Right eye

Left eye

Levoversion (LV) III

LR

MR

MR

LR

SR

SR

MR

MR

IR

IR

IO

IO

IV SO

IO

Dextroelevation (DE) SR

SO IV Medial longitudinal fasciculus

Levoelevation (LE) SR IO Vertical gaze center

Dextrodepression (DD)

DE

DD

LD

LE

Levodepression (LD)

LR VI

VI LR SO

IR

III

IR

SO Lateral gaze center

DV

LV

Fig. 117.3 Versions, elevations, and depressions. (Left) Conjugated movements produced by pairs of yoke muscles. (Right) The lateral and vertical gaze centers and their connections with the nuclei of the yoke muscles.

The optokinetic reflex is triggered by the slippage

of the foveated image when the head moves. The velocity of slippage is calculated by the cells of the nucleus of the optic tract (see accessory optic pathway, p 766) in the pretectum. The information is passed on to the medial vestibular nucleus, which cannot distinguish between the velocity signals conveyed from the retina and those coming from the vestibular apparatus. The corrective motor response therefore is the same in both cases. The velocity signal coming from the retina disappears when the visual target is foveated again. Humans and primates have an additional, phylogenetically newer mechanism of optokinetic reflex in which the velocity signal is generated by the magnocellular visual pathways in the lateral geniculate nucleus, striate cortex, middle temporal cortex, and the medial superior temporal cortex. The velocity signal generated in these areas is transmitted to the vestibulocerebellum and two brain stem nuclei, viz., the medial vestibular nuclei and the nucleus prepositus hypoglossi. These centers convert the velocity signal into appropriate motor signals to the extraocular muscles which are relayed through the brainstem gaze centers. Smooth-pursuit movement occurs when there

is a relative motion between the target and the observer, and the observer tries to keep the target foveated. Thus, it can occur when (1) a stationary

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subject tracks a moving target or when (2) a moving subject keeps a stationary target fixated. It can be argued that a smooth-pursuit movement is only a series of saccades that repeatedly fixate a moving target. That, however, is not true: When a subject is asked to perform a smooth pursuit movement by imagining a moving object, the result is a series of jerky saccades and not a smooth eye movement. Essential to a smooth-pursuit movement is the “velocity signal” generated from the perpetual “slippage” of the foveated image of a moving object. It can also be argued that a smooth-pursuit movement is no different from the optokinetic reflex since both respond to a slippage of the foveated image. However, there are important differences. (1) Smooth-pursuit movement depends on a “velocity”-signal generated from the slippage while optokinetic reflex depends on a “displacement”-signal generated from the slippage. (2) In smooth pursuit, the velocity signal is generated only by the higher centers in the magnocellular visual pathway and not by the nucleus of the optic nerve. (3) The frontal eye field is necessary for the initiation of smooth pursuit but not for its continuation. Smooth-pursuit movements underlie the physiological nystagmus that would be seen, for example, in a person looking out of the window of a moving train. The person tends to fixate any object

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Oculomotor Mechanisms of interest outside the window and follow it all the way as it moves back, with the eyes moving in smooth pursuit. Just after it passes by, the eyes fixate a new object, moving in a saccade, and again follow it all the way back, resulting in an oscillatory movement that has two components: a slow component due to smooth pursuit and a fast component due to saccade. Saccadic movements Saccades are quick jumps of the eyes from one fixated target to another. The saccades can be small, as in reading or they can be large, in which case they are associated with movement of the head too. Visual perception is momentarily suppressed between saccades. This prevents blurring of vision during the interval in which the eyes jump from one target to fixate another. The effector mechanism for producing saccades resides in the superior colliculus (see Fig. 116.2). The deeply located cells in the superior colliculus produce saccades when stimulated: Each cell produces a saccade directed toward a different spot in the visual field. When attention is directed to a particular spot in the visual field, it results in the stimulation of the appropriate deep collicular cell that produces a saccade in the direction of that spot. During saccade, there is no movement of the visual target and therefore there is no velocity signal to guide the saccade. Saccades are guided toward the source of a sound, sight, or a touch by the sensory signals originating respectively in the visuotopic, audiotopic, and somatotopic maps of the exterior that are present in the superficial layers of the superior colliculi: The sensory signal is generated only when attention is directed at a particular spot on the map. The posterior parietal cortex, which is the cortical area for sensory attention, is therefore important for saccades. The motor signals that drive the collicular cells are generated in the vestibulocerebellum, medial vestibular nuclei, and the nucleus prepositus hypoglossi. The tectospinal tract descending from the superior colliculus to the cervical segments of the spinal cord brings about the turning of the head that is associated with a large saccade. The initiation of saccades depend on the frontal eye field, which is connected to the deep collicular cells through two distinct pathways, one direct and the other indirect through the oculomotor circuit of the basal ganglia. The indirect pathway comprises three neurons, two of which are inhibitory (see Fig. 116.2). The collicular cells are kept inhibited by the neurons of the substantia nigra. Neurons in the caudate nucleus inhibit the substantia nigra and therefore disinhibit the deep collicular cells. The frontal eye field inhibits the substantia nigra and therefore helps in

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initiating saccades. The dorsolateral prefrontal circuit is important for making saccades to targets recalled from memory.

Strabismus Squint or strabismus is a misalignment of the visual axes of the two eyes, resulting in diplopia (double vision). Sometimes the eyes may look squinted even though there is no misalignment of the visual axes. This is called pseudostrabismus or apparent squint and occurs when there is a high γ angle between the visual and optical axes (see Figs. 114.2 and 114.3). There is no diplopia in apparent squint. However, due to the high divergence of the optical axes, the eyes look squinted to the observer. A true squint is always associated with diplopia. It occurs when one or more extraocular muscles are paralyzed. Such a squint is called paralytic squint. Squint can also occur even when the extraocular muscles are not paralyzed. Such a squint is called concomitant squint and is due to a defect in the central coordinating mechanism for fixating a target, that is, in the conjugate horizontal movements of the eyes. To some extent, it is possible through continuous voluntary effort to correct the misalignment of the visual axes and thereby avoid diplopia. Such voluntarily corrected concomitant squint is called latent squint. Latent squint is readily detected by the cover test as follows. When the squinted eye of the patient is covered, it immediately becomes misaligned with the other eye. This is because in the absence of the possibility of diplopia, there is a relaxation in the voluntary effort for alignment of visual axes. When the squinted eye is uncovered again, it jumps back to the aligned position through voluntary effort in order to prevent diplopia. The “jump” is briefly visible to the examiner when the eye is uncovered, and it proves the presence of concomitant squint.

Intraocular motor mechanisms The intraocular muscles are smooth muscles. They include the ciliary muscle, which is responsible for the process of accommodation, and the iris muscles, which control the pupillary diameter. The iris contains two sets of smooth muscles: (1) the sphincter pupillae, a circular bundle running round the pupillary margin, and (2) the dilator pupillae, arranged radially near the root of the iris. The intraocular muscles are supplied by sympathetic and parasympathetic fibers that reach the eyeball through the ciliary nerves.

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780

Special Senses

Accommodation Accommodation is the ability of the eye to focus on objects at varying distances. This is made possible by the change in curvature of the anterior surface of the lens. The radius of curvature of the anterior surface of the lens is 12 mm when the eye is focused for distant vision (resting position) and 6 mm when the eye is maximally accommodated for near vision. The radius of curvature of the posterior surface of the lens remains nearly unchanged at 6 mm. The anterior lens surface bulges forward when the ciliary muscle contracts and pulls the ciliary body closer toward the rim of the lens, thereby reducing the tension exerted by the zonule on the lens capsule. Paralysis of accommodation is called cycloplegia and can be induced by cycloplegics such as atropine and homatropine, which anesthetize the parasympathetic fibers to the ciliary muscle. A simple experiment demonstrates that it is the anterior and not the posterior surface of the lens that increases in curvature during accommodation (Fig. 117.4). When a lighted candle is held in front of a subject’s eye, three images, called the Purkinje–Sanson images, can be seen in the reflection—two upright and one inverted. The smaller of the two upright images is reflected from the cornea and the larger image is reflected from the anterior surface of the lens. The inverted image, which is faint and small, is formed by reflection from the posterior surface of the lens. The image formed at the anterior surface of the lens becomes smaller with accommodation while the other two images show no change with accommodation.

Pupillary reflexes Light reflex When light is shone in one eye, there is simultaneous constriction of the ipsilateral pupil (direct light reflex) and the contralateral pupil (consensual light reflex). The afferent pathway of the reflex is through the optic nerve and the efferent pathway is through the oculomotor nerve (Fig. 117.5), as detailed below. The afferents from the retinal ganglion cells run in the optic nerve and partly decussate to enter the optic tract. The fibers pass through the lateral geniculate body uninterrupted and enter the superior colliculus to relay in the pretectal nucleus. Fibers originating in the pretectal nucleus partly decussate in the midbrain and enter the Edinger– Westphal (EW) nucleus on both sides. The EW nucleus is one of the several cell groups in the oculomotor nucleus (see Table 96.3). Parasympathetic fibers originating in the EW nucleus leave the midbrain through the oculomotor nerve and relay in the

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1 3 Left eye

Right eye

VI

III

III

VI

-

+

-

+

Lateral gaze center for left eye

Lateral gaze center for right eye

Vestibular nuclei

2

Vestibular ganglia

Semicircular canal

Fig. 117.4 Vestibuloocular reflex. (1) The head rotates to the left. (2) The horizontal semicircular canals rotate to the left. (3) The eyes reflexly rotate to the right.

ciliary ganglion. Postganglionic parasympathetic fibers leave the ciliary ganglion through short ciliary nerves to innervate the pupillary sphincter. The consensual light reflex occurs because (1) the optic fibers from each eye reach the pretectal nuclei of both sides due to incomplete decussation at the chiasma and (2) each pretectal nucleus innervates the EW nuclei bilaterally. The near reflex or the accommodation reflex occurs when an object, on which the eye is fixed and focused, is moved nearer to the eye. It is characterized by the triad of (1) convergence, (2) accommodation, and (3) pupillary constriction. The reflex is triggered by any of the several monocular and binocular visual cues of depth perception that suggest that the object is moving closer to the

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Oculomotor Mechanisms

781

Before accommodation

3 2 Zonule relaxes

Anterior surface of lens bulges out

After accommodation

1

Circular ciliary muscle contracts; comes nearer to the zonule

Fig. 117.5 Accommodation reflex and the Purkinje–Sanson images.

eye. The afferents travel through the geniculostriate pathway to the visual cortex from where they reach the frontal eye field through the long association fibers. Projection fibers from the frontal eye

Short ciliary nerves

field descend through the internal capsule and terminate on the oculomotor nuclear complex where they stimulate the nucleus of medial rectus and the EW nucleus (Fig. 117.6).

Light

Frontal eye field

Ciliary ganglion 3rd nerve 3rd nerve nucleus

Midbrain Lateral geniculate body

Oculomotor nucleus Geniculostriate tract

Pretectal Lateral nucleus Brachium of geniculate superior colliculi body

Fig. 117.6 Light reflex.

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Long association fibers

Visual cortex

Fig. 117.7 Near reflex.

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782

Special Senses Psychosensory reflex If, while the eye is maximally

constricted, the examiner observes the pupillary size when there is a sudden stimulus such as pain or a loud noise, the pupils dilate due to stimulation of the sympathetic fibers and inhibition of the EW nucleus.

Abnormal pupillary reflexes Argyll–Robertson pupil (ARP) A lesion of the

pretectal nucleus, which is almost always due to tertiary syphilis, results in the abolition of the pupillary light reflex. However, the accommodation reflex is unaffected. Thus, the pupil constricts in the accommodation reflex but not in the light reflex, and

is called the Argyll-Robertson pupil (ARP = accommodation reflex present). Marcus–Gunn pupil An unilateral optic nerve

lesion diminishes the ipsilateral direct pupillary reflex and the contralateral consensual reflex. When the swinging-flashlight test is performed on such patient, that is, when light is shone alternately in both eyes every 2 to 3 seconds, the affected eye shows pupillary dilatation when light is shone into it. Such a pupil is called the Marcus–Gunn Pupil. The paradoxical pupillary dilatation in response to light actually signifies the cessation of the consensual light reflex elicited in the opposite eye a few seconds earlier.

REVISION QUESTIONS 1. What are the different types of versions and vergences? 2. What is the physiological basis of electrooculography? 3. Which are the two reflexes that help fixate a visual target? What is the merit of each reflex? 4. In which type of situations are saccadic movements seen? Why is the posterior parietal cortex important for saccades? 5. What is apparent squint and why does it occur? 6. What is the difference between paralytic squint, concomitant squint, and latent squint? How is latent squint detected?

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7. How can it be demonstrated that the accommodation of the eye occurs due to bulging of the anterior surface of the lens? 8. What is consensual light reflex and why does it occur? 9. What are the three motor effects of the near reflex? 10. In a patient, pupillary constriction is observed when the accommodation reflex is tested but is absent when the light reflex is tested. What is the patient suffering from? 11. In a patient, when light was shone alternately in both eyes every 2 to 3 seconds, it was observed that the pupil of the right eye dilated each time light fell on it. What could be the reason?

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118

Auditory Mechanisms

The ear The ear consists of external, middle, and internal parts. Except the pinna, all parts of the ear are located inside the petrous part of the temporal bone. The external ear comprises the pinna and the external auditory canal, which is 2.5 cm in length. Sound waves are deflected by the pinna into the meatus which channels the waves to the tympanic membrane, about 1 cm in diameter, that separates the external and middle ear. The middle ear or tympanic cavity contains an ossicular chain comprising the malleus (hammer), incus (anvil), and stapes (stirrup). The middle ear communicates with the internal ear through the oval and the round windows. The base of the stapes is attached to the circumference of the oval window (Fig. 118.1). The internal ear comprises the cochlea (concerned with hearing) and the vestibular apparatus (concerned with equilibrium).

Middle ear The vibrations of the tympanic membrane are transmitted by the malleus and incus to the stapes. When the stapes vibrates, it moves rhythmically in and out of the oval window, setting up pressure waves in the cochlear fluid. The waves travel to the secondary tympanic membrane covering the round window. Acoustic impedance matching The sound waves in air can set up pressure waves in the cochlear

Malleus

fluid as described above only if there is proper impedance matching. The acoustic impedance of water (i.e., the resistance to the passage of a wave through water) is much higher than that of air and without impedance matching, most of the sound reaching the cochlea will be reflected back instead of being transmitted into the cochlear fluid. Impedance matching requires pressure gain, which is brought about in two ways. (1) As the force exerted by sound on the tympanic membrane is funneled into a smaller area of the stapes footplate, it results in pressure gain. (2) The mechanical advantage of the ossicle chain is greater than 1, which produces further pressure gain. The pressure gains ensure that more than half the sound energy striking the tympanic membrane is transmitted to the cochlea. When middle ear function is impaired, the threshold of hearing increases by up to 20 dB. The auditory (Eustachian) tube connects the mid-

dle ear to the nasopharynx. It usually remains collapsed so that debris and infectious agents cannot pass from the oral cavity to the middle ear. Children suffer from middle ear infections more than adults because the direction of the auditory tube is nearly horizontal in children. When open, the auditory tube equalizes the air pressure in the middle ear with the atmospheric pressure. When driving up a mountain, the tympanic membrane bulges out due to the low atmospheric pressure. Swallowing relieves the bulge with a popping sensation in the ears as it opens the auditory canal, allowing air to flow out from the higher pressure in the middle ear to the lower pressure in

Incus

Stapes Oval window

Scala vestibuli Reissner membrane

Tympanic membrane

Scala media Round window

Eustachian tube

Scala tympani

Basilar membrane

Helicotrema

Fig. 118.1 Schematic anatomy of the middle and inner ear.

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Special Senses the nasopharynx. The auditory tube also opens up during chewing, yawning, and sneezing. Acoustic reflex The two muscles present inside

the middle ear are the tensor tympani and the stapedius. These muscles are attached to the malleus and stapes, respectively. Loud sounds initiate reflex contraction of these muscles. The reflex is called the acoustic (or tympanic) reflex and it prevents ear damage due to continuous loud sound as explained below. However, the reflex is not quick enough to prevent damage to middle and inner ears when there is a sudden explosion unless it is anticipated. The mechanism of dampening is as follows: (1) Contraction of the tensor tympani makes the tympanic membrane taut by pulling the malleus medially. Therefore, the amplitude of tympanic vibrations decreases. (2) Contraction of the stapedius pulls the footplate of the stapes out of the oval window so that the sound waves are not conducted to the internal ear.

Modiolus

Osseous spiral lamina

Reissner membrane

Inner ear Cochlea The membranous cochlea is about 35 mm long in humans and takes approximately 22/3 turns from base to apex. It is compartmented by the vestibular (Reissner) membrane and the basilar membrane into three spiraling tunnels: (1) the scala vestibuli, (2) the scala media (or the cochlear duct), and (3) the scala tympani (Figs. 118.1, 118.2, 118.3). The cochlear duct ends blindly. It does not extend till the apex of the cochlea and therefore leaves a small gap between its tip and the cochlear wall. The scala vestibuli and the scala tympani communicate through this gap, which is called the helicotrema. The inner edge of the basilar membrane is attached internally to the spiral lamina that arises from the modiolus, the bony core around which the cochlea is wound. Externally, the basilar membrane is anchored to the wall of the cochlea by the spiral ligament. Contained within the spiral ligament is a vascular structure called the stria vascularis which secretes the endolymph into the scala media. Organ of Corti The sensory hair cells are located on

the basilar membrane, surrounded by supporting cells with a small amount of perilymph intervening between them. The apex of the hair cells bears stereocilia, which are bathed in endolymph. Near the apex, the hair cells have tight junctions with the supporting cells. These tight junctions prevent the mixing of the perilymph that bathes the base of the hair cells with the endolymph into which their stereocilia project (Fig. 118.8). This separation is important physiologically, as explained later.

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Outer hair cells Osseous spiral lamina Inner hair cells

Tunnel of Corti

Basilar membrane

Fig. 118.2 Schematic anatomy of the cochlea and the tunnel of Corti. The cochlear tube is shown as it winds around the modiolus. The osseous spiral lamina, the basilar membrane, and the organ of Corti are partly visible through its open proximal end. The entire osseous spiral lamina is also shown separately, as it winds around the modiolus.

The hair cells are arranged in rows. There is a single row of inner hair cells and three rows of outer hair cells. Between the rows of inner and outer hair cells are the inverted Y-shaped rods of Corti which enclose the tunnel of Corti. The stereocilia of the outer hair cells are embedded within a gelatinous tectorial membrane that overhangs the hair cells. The stereocilia of the inner hair cells barely touch the tectorial membrane. The entire assembly of the basilar membrane, the tectorial membrane, and the hair cells with their sensory afferents is called the spiral organ or the organ of Corti (Fig. 118.3). Cochlear fluids The scala media is filled with the

endolymph secreted by the stria vascularis. The

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Auditory Mechanisms

Scala vestibuli (Perilymph)

iss Re

ne

rm

em

e an br

Tectorial membrane

785

Scala media (Endolymph) Outer hair cells

Inner hair cell

Bas ilar mem bran e Tunnel of Corti Ciliary ganglia

(Scala tympani) Perilymph

Rod of Corti

Cochlear nerve fibers

Fig. 118.3 The organ of Corti.

composition of the endolymph resembles intracellular fluid, that is, it has high K+ and low Na+ concentration. The scala vestibuli and scala tympani contains the perilymph, which has a composition similar to that of extracellular fluid, that is, high Na+ and low K+ concentration. The perilymph of the scala vestibuli and scala tympani is continuous at the apex of the cochlea through the helicotrema. The tunnel of Corti is filled with perilymph because the basilar membrane is relatively permeable to perilymph in the scala tympani. The bases of the hair cells are also bathed in perilymph but the apices of the hair cells are bathed in endolymph. The scala media is electrically positive (+80 mV) relative to the scala vestibuli and scala tympani. This positive endolymphatic potential occurs because the amount of K+ secreted by the stria vascularis exceeds the amount of Na+ it reabsorbs. Cochlear nerve Ninety-five percent of the neurons in the cochlear nerve are afferent fibers originating in the inner hair cells. The cell bodies of these neurons are present in the spiral ganglion, which is located inside the modiolus. The remaining 5% of the neurons are efferent fibers that each innervate several of the more numerous outer hair cells.

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Auditory pathway The cochlear nerve terminates tonotopically, that is, in an orderly sequence representing the various frequencies in the cochlear nuclei in the medulla. The fibers of the cochlear nuclei pass to the superior olivary nuclei that receive inputs from both ears. From each olivary nucleus, fibers ascend in the lateral lemniscus to project to the ipsilateral inferior colliculus and thence to the medial geniculate body of the thalamus. From the medial geniculate body, auditory fibers project to the primary auditory cortex. Auditory fibers decussate at several levels in the brain stem. The trapezoid body is formed by decussating auditory fibers in the medulla (Fig. 118.4). The primary auditory cortex lies principally in area 41 in the anterior transverse temporal (Heschl) gyrus, situated on the upper surface of the superior temporal gyrus along the floor of the posterior ramus of the lateral sulcus (Figs. 95.6 and 100.5). It also extends into the lateral border of the temporal lobe, over much of the insular cortex and into the lateral portion of the parietal operculum. The primary auditory cortex projects to the auditory association area (area 42) formed by the posterior transverse temporal gyrus. The rest of the superior temporal gyrus

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Special Senses

Heschl gyrus

Midbrain

Medial geniculate body Inferior colliculus

Pons

Medulla

Nucleus of lateral lemniscus

Superior olivary nuclei Trapezoid body

Fig. 118.4 Auditory pathway. Only the trapezoid decussation is shown. Decussations higher up are not shown for clarity.

frequency < 20 Hz and therefore these waves take a detour through the helicotrema to reach the round window. Waves with higher frequency make the basilar membrane oscillate and therefore are able to take a shorter route across the scala media. The highest audible frequency of 20,000 Hz makes the membrane oscillate maximally near its base while the lowest audible frequency of 20 Hz makes the membrane oscillate maximally near its apex (Fig. 118.5). Traveling wave It might seem from the above account that the basilar membrane resonates at a specific site in response to a specific frequency. The pressure wave does not cause resonance of the basilar membrane: Rather, it sets the basilar membrane into a ripple that travels along the membrane. This ripple, which is a transverse wave, has been called the traveling wave. The amplitude of the ripple increases till it reaches its maximum at a specific site on the membrane and then declines rapidly, somewhat like an ocean wave that gradually gains in height till it lashes on the shore. Its entire progression can be conveniently depicted by superimposing the waveforms at regular intervals into a single “envelope” (Fig. 118.6). The oscillatory characteristics of the basilar membrane are attributable to its structure: It is made of transverse fibers that are shorter at the base and longer at the apex, which make the base stiff and the apex floppy.

2,000–20,000 Hz

behind areas 41 and 42 forms the Wernicke area (area 22), which is concerned with the interpretation of sounds and comprehension of spoken language. 200–2,000 Hz

Auditory processing Vibration of basilar membrane The vibrations produced at the oval window by movements of the stapes set up a pressure wave within the scala vestibuli. This pressure wave ultimately finds its way to the round window where it causes bulging of the secondary tympanic membrane, thereby releasing the pressure into the middle ear. From the middle ear the pressure wave is released into the atmosphere through the Eustachian tube. The route taken by the pressure wave from the oval to the round window depends on the frequency of the sound wave. The basilar membrane does not oscillate in response to waves with

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20–200 Hz

< 20 Hz

Fig. 118.5 The traveling wave on the basilar membrane.

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Auditory Mechanisms

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Basilar membrane 0 ms 1 ms 2 ms 3 ms 4 ms 5 ms 6 ms 7 ms 8 ms 9 ms 10 ms

Fig. 118.7 The vibration of the basilar membrane is associated with bending of the sterocilia due to the shearing movement between the hair cells and the tectorial membrane. Envelope of the traveling wave

Fig. 118.6 The traveling wave on the basilar membrane. As an example, in the first 9 milliseconds, the wave gradually gains in amplitude as it travels on the basilar membrane. In the 10th millisecond, the amplitude diminishes markedly. A convenient way of depicting all the waves across time is to represent them on the same baseline and enclose them in a common outline called the envelope.

Auditory transduction When the basilar membrane oscillates, it results in a shearing force between the basilar membrane and the tectorial membrane. The shearing force bends the stereocilia of the hair cells (Fig. 118.7), which produces a potential called the generator potential, in the inner hair cells (Box 118.1). The greater the displacement of the basilar membrane and the bending of the stereocilia, the greater is the generator potential produced, and the greater is the frequency of action potentials in the cochlear afferents issuing from the base of the hair cell. A higher frequency of action potentials is perceived as a louder sound. Transduction channels Atop each hair cell, the stereocilia are arranged in rows of increasing length. The tips of adjacent stereocilia are connected to each other by fine filaments called tip links. These links control the opening of mechanosensitive

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Box 118.1 Inner hair cells: A high-pass filter The stereocilium bends only when its tip is held in place while its base moves with the hair cell. The stereocilia of outer hair cells are embedded in the gelatinous tectorial membrane and therefore they bend when the hair cells tilt. The stereocilia of the inner hair cells just “touch” the tectorial membrane. What is its physiological significance?

The question is best answered by considering what would happen if the tectorial membrane were less viscous. Such a membrane would not hold the stereocilia firmly in place except for a brief, initial period. Thereafter, the stereocilia would straighten by moving through the membrane. The situation is similar when the stereocilia just touch the tectorial membrane. The implications of such a response—of a brief flexion followed by straightening—are obvious: The stereoclia will flex only while the basilar membrane moves. A sustained or slow displacement of the basilar membrane will not be associated with stereociliary flexion. In other words, low-frequency sounds that cause slow oscillations of the basilar membrane do not result in auditory transduction and are thereby filtered out. However, high-frequency sounds will cause rhythmic flexion of the stereocilia resulting in high-fidelity auditory transduction.

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Special Senses cation channels in the stereocilia (Fig. 118.8). These “mechanoceptive” channels are called transduction channels to distinguish them from other ion channels at the base of the hair cells. Deflection of the stereocilia toward the tallest stereocilium fully opens these transduction channels, causing depolarization of the hair cell. Conversely, when the stereocilia are bent away from the tallest stereocilium, the tension in the links reduces and the transduction channels close completely, causing hyperpolarization of the hair cell. Cochlear action potentials Since the intracellu-

lar fluid of the hair cells and the endolymph have similar composition, there is no diffusion gradient of ions between them. Hence, when the transduction channels open, it is the large potential difference of 150 mV existing between the endolymph (+80 mV) and the hair cell interior (–70 mV) that drives the cations (K+ and Ca2+) into the stereocilia, causing depolarization of the hair cell. The depolarization causes voltage-gated Ca2+ channels at the base of the hair cells to open, allowing more Ca2+ to enter the cell. The influx of Ca2+ causes the release of neurotransmitter, probably glutamate, from the hair cells. The neurotransmitters depolarize of the sensory afferents.

Hair cell depolarization also opens up voltagesensitive K+ channels at the base of the hair cell. Since the base of the hair cell is bathed in perilymph which has a low K+ concentration, there is K+ efflux through the voltage-sensitive K+ channels into the perilymph. The efflux of K+ ions causes repolarization of the hair cell. The Ca2+ that enters the hair cell during depolarization is pumped out to the exterior by a Ca2+ pump. Cochlear amplification of sound Low-intensity

sound waves entering the inner ear do not have adequate energy in them to cause the vibration of the basilar membrane after overcoming the inertia of the cochlear fluids. It seems therefore that the outer hair cells amplify the sound that enters the cochlea, a possible mechanism of which could be as follows: The initial, feeble movement of the basilar membrane depolarizes both the inner and the outer hair cells. While the depolarization of the inner hair cells triggers action potentials, the depolarization of the outer hair cells causes them to contract and pull on the basilar membrane. The movements of the basilar membrane are thereby amplified. The contractions of the outer hair cells are probably responsible for otoacoustic emissions, which

Transduction channel

Ca

+

K

+

Endolymph Tip link

Kinocilium

Tight junction

Voltage-sensitive Ca2+ channel

Voltage-sensitive K+ channel

Ca2+

K+

Ca2+ Ca2+ -sensitive

Ca2+ pump

K+

K+ channel

Supporting cell

Perilymph

Fig. 118.8 The hair cells and auditory transduction. (Left) A hair cell in the resting state. (Right) The stereocilia are bent toward the kinocilium. The tip links pull open the mechanosensitive cation channels. The K+ and Ca2+ entering the stereocilia leave through channels and pumps present in the cell body.

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Auditory Mechanisms may be evoked or spontaneous. (1) In response to a click sound, the ear produces a sound of the same frequency after a latency of 5 to 20 ms. These evoked otoacoustic emissions have been recorded in neonates as a screening test for the functional integrity of the cochlea. (2) Spontaneous otoacoustic emissions are recordable in neonates. They are sometimes loud enough to be audible directly. Efferent cochlear control The cochlear sensitiv-

ity to specific frequencies can be voluntarily controlled. It is a common experience that in a noisy radio channel, we are able to selectively hear the music or speech of our interest and ignore the rest (Fig. 118.9). To some extent, this is made possible by tuning the inner hair cells to the selected frequency. Such tuning is made possible by the olivocochlear fibers to the outer hair cells. Masking The presence of one sound decreases the au-

dibility of other sounds. This phenomenon is known as masking. It is believed to be due to the relative refractoriness of previously stimulated auditory receptors and nerve fibers to other stimuli. Masking is an important consideration in the tests for hearing (see below). Cortical auditory processing shows the follow-

ing characteristics: (1) The cortical neuronal response to acoustic stimuli is brief, seen mostly at the onset and at the termination of the stimulus. The phenomenon is analogous to the accentuation of contrast of a visual stimulus and helps in identifying any change in the sound quality. (2) There is tonal localization in the primary auditory cortex. Low tones are represented anterolaterally and high

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tones posteromedially in the auditory cortex. (3) A portion of posterior superior temporal gyrus called the planum temporale is larger in the left cerebral hemisphere, particularly in right-handed individuals (see Fig. 100.5). This area is important for language-related auditory processing. The asymmetry is greater in musicians and others who have perfect pitch—a rare ability to tell the pitch of a sound without reference to a standard pitch.

Sound discrimination Pitch discrimination The brain infers the pitch of a sound from the place on the basilar membrane which responds with the maximum displacement, stimulating the hair cells located on it. The apex of the basilar membrane, which is broad, responds maximally to low pitch sound while its base, which is narrow, responds maximally to high-pitch sound. There are different versions of this “place theory,” each offering a different explanation for the cause of the maximal vibration at a specific site on the basilar membrane. Thus, the resonance theory held resonance as the cause. The current theory is the traveling wave theory described above. It posits that all sound waves travel all the way down to the apex of the basilar membrane but registers its maximum amplitude at a specific distance along its path where the membrane stiffness best matches the sound frequency (Fig. 118.6). Timbre discrimination The timbre or quality of a sound depends on the various overtones that are present in addition to the fundamental frequency (p 13). The basilar membrane breaks down a sound into all its component frequencies, fundamental as well as overtones, with each frequency registering its maximum amplitude at a different place on the membrane. The ensemble of the frequency components coded by the cochlea are identified in the auditory cortex as a single sound with a distinct timbre.

Sound localization Sound delays Humans can localize the source of

sound with considerable accuracy because the two ears are located about 15 cm apart and a sound originating on the left side has to travel an extra 15 cm to reach the right ear. The sound therefore reaches the right ear about 0.4 ms after it reaches the left. The medial superior olivary nucleus uses the time delay as a cue for localizing a sound. Fig. 118.9 Two boys listening to the radio, each trying to concentrate on his favorite broadcast, as four different channels are mixed up. The situation signifies the role of efferent cochlear control.

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Sound-shadows The head casts a sound-shadow, which gives rise to an intensity difference for the sounds arriving at the two ears, especially for

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Special Senses sounds with wavelength smaller than the dimensions of the head. The intensity difference indicates if the sound is coming from left or right. Similarly, the sound-shadow cast by the pinnae provides clues on whether the sound orginates from front or behind the head. Also, the convolutions at the upper part of the pinnae provide information on whether the sound originates from above or below the head. The intensity differences are processed by the medial superior olivary nucleus.

0 20 y 30 y Hearing loss (dB)

790

40 y

20

50 y 40 60 y

Deafness Deafness is expressed as the difference in sound pressure level (in dB) between the patient’s threshold of hearing and that of a normal healthy subject. If the threshold intensity of a particular tone is 20 dB higher than that of normal subjects, it is described as 20 dB hearing loss. Conductive deafness results from a failure of the external and middle ear to transmit sound efficiently to the inner ear. It can result from various causes, such as: (1) wax or foreign body in the external ear, (2) infection of the middle ear (otitis media), or (3) otosclerosis, in which the movement of the footplate of the stapes is impeded by the growth of bone around the oval window.

100

1,000 Frequency (Hz)

Fig. 118.10 Age-related sensorineural deafness (presbycusis).

timbre and the interpretation of temporal sequences of sound, which are important in music and speech.

Tests for hearing Tuning fork tests Tuning fork tests provide a convenient method of determining whether deafness is of the conductive or sensorineural type. The tuning fork used should be large and made of stainless steel, so that the sound is not damped quickly. Its frequency should be 512 Hz. It should have an expanded base for application to the skull. The sound of a vibrating tuning fork can be heard in two ways: (1) When its prongs are held in front of the ear, its sound must pass through air to the tympanic membrane and across the middle ear to reach the cochlea. Such conduction of sound is called air conduction. (2) When the base of the vibrating tuning fork is pressed firmly against the skull, the sound is transmitted through the bones of the skull to the cochlea, bypassing the middle ear. Such conduction of sound is called bone conduction (Fig. 118.11).

Bo ne ion uct nd co

Sensorineural deafness results when some part of the cochlea or auditory nerve is damaged. (1) Traumatic damage to the cochlea can result from overamplified music. A special variant of traumatic damage is boiler-maker’s disease which occurs on prolonged exposure to continuous highintensity sounds of a particular frequency. Such sounds are typically produced in industrial processes. Only those hair cells that are tuned to the sound frequency are damaged. (2) Presbycusis is an age-related sensorineural deafness that specifically affects the high frequencies (Fig. 118.10). (3) Loss of hair cells can be caused by ototoxic drugs (e.g., streptomycin, neomycin, frusemide). (4) A very distressing but common cause of hearing loss is tinnitus, a continuous buzzing sound generated within the ear itself, that masks the natural sound reaching the ear.

20,000 10,000

20

Central deafness The auditory pathways are exten-

sively crossed at all levels above the cochlear nuclei. Hence, unilateral damage to the auditory cortex does not result in deafness, although the affected person may have difficulty in localizing sounds. Extensive damage to the auditory cortex of the dominant hemisphere leads to difficulties in speech recognition. Extensive damage to the auditory cortex of the nondominant hemisphere affects recognition of

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Air conduction

Fig. 118.11 The paths of air-conducted and bone-conducted sound.

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Auditory Mechanisms In Rinne test, the base of a vibrating tuning fork is

placed on the mastoid process (Fig. 118.12). When the subject no longer hears it, it is held in air next to the ear on the same side. A normal subject is still able to hear the sound, indicating that his air conduction is better than bone conduction. Rinne test is said to be positive in a normal person. A patient with conductive deafness has better bone conduction than air conduction and Rinne test is said to be negative. In sensorineural deafness, air conduction remains better than bone conduction and therefore Rinne test remains positive. In severe unilateral sensorineural deafness, Rinne test is false negative. Air conduction is absent but bone conduction may be good because the sound is transmitted to the opposite cochlea through the skull bones. This observation misleads the examiner into making a wrong diagnosis of conductive deafness. In this situation, Weber test is important. In Weber test, the base of vibrating tuning fork is

placed on the vertex of the skull, allowing its sound to reach both ears through bone conduction. A normal subject hears equally on both sides. A hearing deficiency in one ear indicates either an ipsilateral sensorineural deafness or a contralateral conductive deafness. Bone-conducted sound is better heard in the ear with conductive deafness because of reduced background noise conducted through air. The sound is less clearly heard in the normal ear due to the masking effect of background noise. Schwabach test is the comparison of bone conduc-

tion of the patient versus the examiner, assuming that the latter has a normal hearing. The base of the vibrating tuning fork is placed first on the mastoid of the patient till he stops hearing the sound. The examiner then places the tuning fork on his own mastoid. If the examiner still hears the sound,

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it indicates that the patient’s bone conduction is impaired, presumably due to sensorimotor deafness. The reliability of the test is higher if the tragus of both subject and examiner are occluded during the test. This is called the absolute bone conduction test or the modified Schwabach test.

Audiometric tests There are different types of audiometric tests such as pure tone audiometry and speech audiometry. In pure tone audiometry, a pure tone audiometer delivers tones of variable frequency and intensity. Both air conduction and bone conduction are measured. For each frequency, a series of tone pips are delivered at increasing intensities (beginning from subthreshold) and the patient is instructed to signal every time he hears a sound. The frequencies tested are at octave steps, that is, 125, 250, 500, 1,000, 2,000, 4,000, and 8,000 Hz. Each frequency is tested in the intensity range of 10 to 120 dB. The results are charted as an audiogram (Fig. 118.13).

Auditory evoked potentials These are the objective tests of hearing in which the conscious response from the patient is not required. It includes electrocochleography and brain stem auditory evoked potentials. Electrocochleography measures the electrical ac-

tivity generated in the cochlea in response to a click stimulus. A needle electrode is passed through the tympanic membrane and held against the promontory (an elevation on the medial wall of the middle ear, overlying the base of the cochlea). The responses obtained include the cochlear microphonics and the compound action potential of the vestibulocochlear

Fig. 118.12 The tuning fork tests for hearing.

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Special Senses

-20

Normal

-10 0 10 20 30 40 50 60 70 80 90 100

-20

Conductive deafness

-10 0 10 20 30 40 50 60 70 80 90 100

-20

Sensorineural deafness

-10 0

nerve. Its main clinical use is in threshold estimation in children, who cannot be tested by other means. Cochlear microphonics develop in the hair cells of the cochlea before the development of action potentials in auditory nerve fibers. They are called “microphonics” because when these potentials are fed into a speaker through an amplifier, the original sound is accurately reproduced. This proves that the waveform of cochlear microphonic potential is an exact replica of the sound wave that produces it. Cochlear microphonics are produced through the piezoelectric effect, a property exhibited mostly by certain crystals that generate electricity when subjected to mechanical stresses. The following observations indicate that cochlear microphonics are not of biological origin. (1) They do not have a latent period. (2) They do not have a refractory period. (3) They do not show fatigue and are resistant to ischemia and hypoxia. (4) Their frequency can be unusually high for any biological signal. (5) They persist several hours after death! Cochlear microphonics do not have a significant physiological role in the hearing mechanism. At best, they might have a role in boosting receptor excitation. Cochlear microphonics have been put to clinical use for testing the integrity of the cochlea since they disappear when the hair cells are damaged. Brainstem auditory evoked potentials (BAEP) com-

prise short- and mid-latency waves. The shortlatency (< 10 ms) waves are observed in the auditory evoked potentials (p 792). They originate in the brain stem. They are also called vertex potentials because they are recorded from the vertex (Cz) with reference to one of the ear lobes. The midlatency (10–50 ms) responses are thought to reflect activity arising in the thalamocortical radiations, the primary auditory cortex, and the early association cortex.

10 20 30 40 50 60 70 80 90 100 125

250

500

1,000 2,000 4,000 8,000 16,000 Tone frequency (Hz)

I

Air conduction Bone conduction

Fig. 118.13 Audiogram in normal subjects and patients with conductive and sensorineural deafness. (Above) In the normal audiogram, the threshold for hearing through air conduction is nearly 0 dB and the threshold for bone conduction is slightly higher. (Middle) In conduction deafness, air conduction is impaired but bone conduction is normal. The threshold for air conduction is higher than bone conduction. (Below) In sensorineural deafness, air conduction and bone conduction are impaired with equal severity and therefore the threshold for bone conduction remains slightly higher than bone conduction.

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II

III

IV V

VI

VII

0.2 mV

0

2

4

ms

6

8

10

Auditory stimuli: 60 dB at 10 Hz

Fig. 118.14 Brain stem auditory evoked response.

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Auditory Mechanisms The BAEP waves are named I to VII (Fig. 118.14). Waves I, III, and V primarily represent the electrical activity from the acoustic nerve, pons, and midbrain respectively. The interpeak

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latencies (latencies between these three waves) give a measure of the conduction velocities in the corresponding segments of the central auditory pathway.

REVISION QUESTIONS 1. The middle ear ensures that there is proper impedence matching between the external and internal ear. What is impendence matching and how is it brought about? 2. Children suffer from middle ear infections more than adults. Why? 3. When driving up a mountain, the tympanic membrane tends to bulge out. Why? Swallowing relieves the bulge with a popping sound. Why? 4. The acoustic reflex prevents ear damage due to continuous loud sound. How? It cannot prevent ear damage due to sudden loud sound. Why? 5. What is the function of the efferent cochlear control? 6. A sound of the highest audible frequency makes the basilar membrane oscillate near its base while the lowest audible frequency makes the membrane oscillate maximally near the apex. Why?

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7. The stereocilia of the hair cells bend when the basilar membrane oscillates. Why? 8. Where are the auditory “transduction channels” located and how are they gated? 9. What is the function of the outer hair cells? 10. What is the function of the olivocochlear fibers? 11. The basilar membrane is narrow and stiff at its base and is wider and more flexible toward the apex. What is its physiological significance? 12. What is the importance of the medial superior olivary nucleus in sound localization? 13. What is boiler-maker’s disease? 14. In severe unilateral sensorineural deafness, Rinne test is false negative. Why? 15. What are cochlear microphonics and what is their clinical use?

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Vestibular Mechanisms

Vestibular apparatus

vestibular nucleus in the brain stem (see Figs. 95.9, 96.4, and 116.2). Afferents from the vestibular apparatus terminate in the vestibular nuclei in the upper medulla. The vestibular nuclei have vestibulocollicular, vestibuloreticular, vestibulospinal, vestibulocerebellar, and vestibulothalamocortical connections with the superior colliculus, reticular formation, spinal cord, flocculonodular lobe of the cerebellum, and thalamus, respectively (Fig. 119.4). There are two vestibulospinal tracts, medial and lateral, which descend respectively from the medial and lateral vestibular nuclei and are present in the anterior funiculus of the spinal cord. The medial vestibulospinal tract descends only to the cervical and upper thoracic segments of the spinal cord and controls only the muscles of the neck and upper limbs. The lateral vestibulospinal tract extends down to the sacral segments and controls the muscles of trunk and lower limbs.

The vestibular apparatus is a membranous structure consisting of the otolith organs, three semicircular canals and the endolymphatic duct, which are interconnected through the utriculosaccular duct (Fig. 119.1). The saccule is connected to the cochlea through the ductus reuniens. The vestibular apparatus is lined internally with an epithelium. At certain small areas of this epithelium, the epithelial cells are specialized into hair cells bearing stereocilia. Unlike the cochlear hair cells, however, the vestibular hair cell has an additional nonmotile “true” cilium known as a kinocilium. The structure of the hair cells and the mechanism of hair cell transduction are described on p 787 (see Fig. 118.8). The first-order neurons originating from the hair cells have their cell bodies in the vestibular ganglion. The central ends of these neurons constitute the vestibular nerve and terminate in the

Ductus utriculosaccularis Ductus endolymphaticus Utricle Anterior canal

Saccule Ductus reuniens Cochlea

Lateral canal Posterior canal

A nt er io r

Po st er io r

45 o

m niu cra he t f o Base

30o

Fig. 119.1 Schematic representation of the vestibular apparatus showing the orientation of the three semicircular canals in relation to the base of the cranium. The vestibular apparatus has been expanded for clarity. The inset shows a diagram of the vestibular apparatus.

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Vestibular Mechanisms The endolymphatic duct is the site where the endolymph is reabsorbed. It is also the site through which leucocytes and macrophages gain entry to the endolymph and clear up cellular debris in the endolymph. Damage or blockage of the endolymphatic duct causes accumulation of endolymph in the membranous labyrinth, affecting both vestibular and cochlear functions.

Otolith organs The otolith organs comprise The utricle and saccule. They detect linear acceleration. In the otolith organs, the epithelium bearing the hair cells is called the macula. It is covered with a gelatinous layer called the otolith membrane. Embedded in the membrane are numerous small crystals of Striola A

Otolith membrane

Hair cells

B

Hair cells Kinocilium Stereocilia

ola Stri

C

Utricular macule

Saccular macule

Fig. 119.2 [A] Sensory receptors in the utricular macula. [B] Sensory receptors in the otolith organs. The arrows indicate the axis of the hair cells. [C] The macula in vertical position (left) and horizontal position (right).

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calcium carbonate called otoconia. The cilia of the underlying hair cells project into the otolith membrane (Fig. 119.2). Stereocilia and kinocilia The row of stereocilia and the kinocilium present on the hair cell lends to the cell a polarity (axis) that is directed toward its kinocilium (Fig. 119.2A, B). A hair cell depolarizes when the stereocilia bend toward the kinocilium (i.e., along the axis) and hyperpolarizes when the stereocilia bend away from the kinocilium (i.e., opposite to the axis). If the cilia bend in a direction perpendicular to the axis, the hair cell will neither depolarize nor hyperpolarize in accordance with vectorial principles. The axes of the numerous hair cells in the macula are in different directions so that at least some of them are depolarized regardless of the direction of the shearing force. When the head is erect, the utricular macula is horizontal while the saccular macula is vertical. In the supine position, the reverse is true (Fig. 119.2C). At any point of time, the macula (utricular or saccular) that is more horizontal responds more to horizontal acceleration while the macula that is more vertical responds more to vertical acceleration including gravity. When the macula is subjected to acceleration, the hair cells accelerate quickly while the otolith membrane, owing to its higher density and consequent inertia, lags behind. This results in a shearing movement between the otolith membrane and the hair cells. The shearing movement bends the cilia, thereby exciting the hair cells and triggering action potentials at frequencies proportional to the acceleration.

Semicircular canals The semicircular canals detect rotatory acceleration. They are three in number: lateral (or horizontal), anterior (or superior), and posterior. The lateral canals are horizontal only when the head is tilted 30 degrees forward. The two vertical canals (anterior and posterior) share a common origin from the utricle. The dilated end of each canal is called the ampulla and it opens in the utricle. The three canals on each side are mutually perpendicular. Also, the corresponding vertical canals (superior and posterior) on opposite sides are perpendicular to each other. Together, the six canals on both sides form three sets of functional pairs that lie in the same plane: (1) the left and right horizontal canals, (2) the right anterior and left posterior canals, and (3) the left anterior and right posterior canals. Crista ampullaris In the semicircular canals, the epithelium bearing the hair cells is called the

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796

Special Senses

Cupola

Resting

Utricle

Horizontal semicircular canal Stimulation

Rotation about the horizontal axis has opposite effects on the left and right semicircular canals. When the head rotates to the right, the cupula bends toward the left, bending the cilia of the hair cells toward the left. Since the kinocilia in the horizontal semicircular canal are located toward the utricle, the stereocilia in the right semicircular canal move toward the kinocilia, triggering action potentials in the vestibular afferents. Simultaneously, the discharge frequency in the left vestibular afferents reduces. The combined pattern of discharge in the two vestibular afferents (right stimulated and left inhibited) results in the conscious interpretation of head rotation to right.

Vestibular functions

Inhibition

Fig. 119.3 Sensory receptors in the horizontal semicircular canals. Note that the kinocilium is present toward the utricle.

crista ampullaris. It is covered with a gelatinous dome called the cupula. At its free end the cupula is in light contact with the wall of the ampulla. The cupula therefore comes in the way of flowing endolymph and is deflected by endolymphatic flow. The cupula does not contain any crystals. The cilia of the underlying hair cells project into the cupula. In the horizontal semicircular canal, the kinocilium is located toward the utricle, while in the anterior and posterior semicircular canals, it is directed away from the utricle (Fig. 119.3). When the head rotates about a vertical axis, the endolymph in the horizontal canal flows in a circular motion. Starting and stopping rotation have different effect on the stimulation of hair cells. When the head begins to rotate, the endolymph initially remains stationary due to inertia, resulting in its relative motion in the opposite direction. The effect occurs in both the horizontal canals simultaneously, stimulating the crista ampullaris on one side and inhibiting it on the other (Fig. 119.3). The reverse occurs when the head suddenly stops rotating because the endolymph continues to flow for sometime due to inertia.

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The central connections of the vestibular nuclei coordinate the various vestibular functions, which are as follows: (1) The vestibular apparatus stabilizes the eye in space when the head is moving or jerking, thereby preventing any blurring of vision. This function is enabled by the vestibuloocular reflex (VOR) and optokinetic reflexes (p 778). The pathway of these reflexes includes the

Vestibulothalamocortical tract

Superior colliculus

Thalamus

Lateral gaze center Vestibuloreticular tract

Vestibulocollicular tract

Flocculus

Medial vestibulospinal tract Lateral vestibulospinal tract

Vestibulocerebellar tract Medial vestibular nucleus

Fig. 119.4 Efferent connections of the vestibular nuclei.

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Vestibular Mechanisms

797

a Barany chair, rotated 10 times in 20 seconds and then abruptly stopped. The presence of postrotatory nystagmus for about 30 seconds indicates a normal vestibular function, at least on one side. In the caloric nystagmus test, the auditory canal is rinsed with warm saline after tilting the head 60 degrees backward (i.e., if the subject is seated) so that the horizontal canals are in the vertical plane. The heat from the auditory canal is conducted to the horizontal semicircular canal and produces convection currents in the endolymph, resulting in nystagmus to the same side. In the same way, irrigation of the auditory canal with cold saline results in caloric nystagmus to the contralateral side1. When there is unilateral damage to the vestibular apparatus, the caloric test cannot be elicited on the affected side.

vestibuloreticular fibers to the gaze centers and the vestibulocerebellar fibers to the flocculonodular lobe (see Fig. 116.2). (2) When the head moves, the vestibular apparatus readjusts the posture to stabilize it against gravity. This function is enabled by the tonic labyrinthine reflexes which involve the vestibulospinal tracts. Simultaneously, the direction of the gaze is also readjusted through appropriate saccadic movements: The reflex pathway includes the vestibulocollicular fibers. (3) The vestibular apparatus also provides us with conscious senses of head tilt and head rotation. This is enabled by the vestibulothalamocortical fibers which reach the cerebral cortex after relaying in the ventrolateral and ventroposterior thalamic nuclei. Vestibular function tests The functional integrity of

the vestibular apparatus is tested clinically by eliciting the VOR. The test is also one of the several tests that is used to establish whether a comatose patient is brain dead. There are two ways in which the VOR is elicited in the laboratory (Fig. 119.5). In the postrotatory nystagmus test, the patient is seated on

Vestibular disorders Motion sickness occurs due to excessive and

repeated stimulation of the vestibular apparatus. This usually happens due to rapid and repeated change in motion while traveling. The person has

componen Quick t

k component Quic

compone Slow nt

compone nt Slow

R

L

Rotation of the head

1

2

L

3

R

Heat

y

atic

fl o w

Horizontal semicircular canals

fl o

ol

ph

ic

End

m

w

Cold

E n d oly m

ph

at

Fig. 119.5 Slow rotation of the eye to the left with nystagmus to the right is caused by (1) rotation of the head to the right, (2) cold saline in the left ear, or (3) warm saline in the right ear. 1

A mnemonic that helps to remember the direction of caloric nystagmus is ACTH (Away Cold, Toward Hot).

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798

Special Senses nausea, vomiting, sweating, headache, and disorientation. It can be prevented by avoiding greasy and bulky food before travel and by taking antiemetic drugs. Motion sickness may be due to conflicts in visual and vestibular signals. Hence, motion sickness is reduced or eliminated by the surgical removal of flocculonodular lobe, which receives both optokinetic and vestibular signals. Meniere disease is associated with endolymphatic hydrops, an abnormal distension of the membra-

nous labyrinth due to an increase in endolymph volume. It probably occurs due to the hyperactivity of the secretory cells in the membranous labyrinth and the endolymphatic duct. The disease is associated with attacks of dizziness, vertigo, and vestibular nystagmus, which are frequently accompanied by nausea and vomiting. There is hearing impairment of low-frequency sounds. The condition is relieved by implantation of a small tube into the swollen endolymphatic duct.

REVISION QUESTIONS 1. What are the three major functions of the vestibular apparatus? 2. Which are three such functional pairs of semicircular canals? Why are they called so? 3. Why are the hair cells stimulated when the macula is subjected to linear acceleration? 4. How does the crista ampullaris detect rotatory acceleration?

vestibulocerebellar tracts, (3) vestibulospinal and vestibulocollicular tracts, and (4) vestibulothalamocortical fibers 6. Which are the two ways in which the vestibuloocular reflex is elicited in the laboratory? 7. Motion sickness is reduced or eliminated by the surgical removal of flocculonodular lobe. Why?

5. What are the functions of (1) the vestibulospinal tract, (2) vestibuloreticular and

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120

Olfactory and Gustatory Mechanisms

Olfaction Olfactory mucosa Olfactory stimuli are detected when odorant molecules come in contact with the olfactory mucosa, a small patch of sensory epithelium located in the roof of the nasal cavity near the septum. Because of its location high in the nasal cavity, the olfactory mucosa is not directly exposed to the flow of inspired air entering the nose. Odorant molecules come in better contact with the olfactory mucosa when the airflow in the nasal cavity is turbulent. Sniffing makes the airflow turbulent and therefore helps in olfaction. The olfactory mucosa contains olfactory receptor cells, supporting cells, basal lamina cells, and Bowman cells. The basal lamina cells are rapidly dividing progenitor cells that replace the aged olfactory receptor cells. The Bowman cells secrete the mucus that forms a layer on the olfactory mucosa. Unlike the mucus layer on the adjacent nasal epithelium which is kept moving by rhythmic ciliary motion, the mucus layer on the olfactory epithelium is stagnant. Odorant molecules must pass through this stagnant mucus layer to stimulate the olfactory receptor cells. Certain odorant-binding proteins present in the olfactory mucosa help in transferring the odorant molecules to the receptors. The olfactory mucosa is innervated mainly by the olfactory nerve. It is also innervated by the trigeminal nerve which is stimulated by the irritative odors of ammonia, menthol, and peppermint. Odorant molecules are

mostly small, having < 20 carbon molecules. They must dissolve in the mucous layer lining the nose before they can come in contact with the olfactory receptors. Hence, an odorant molecule must be: (1) volatile, so as to diffuse in air and be transported into the nose, (2) water-soluble, to be able to penetrate the watery mucous layer to reach the receptor cell membrane, and (3) lipid-soluble, to penetrate the cell membranes of the olfactory receptor cells for stimulating them.

Olfactory pathway The olfactory receptor cell has a dendrite that is modified into the olfactory rod. The olfactory rod bears cilia that project into the mucus layer. The axon of the receptor cell terminates in the olfactory bulb after passing through the cribriform plate as the olfactory nerve fibers (Fig. 120.1).

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The olfactory bulb contains the mitral cells, the dendrites of which synapse with the olfactory nerve ending to form the olfactory glomerulus. The axons of the mitral cell form the lateral and medial olfactory stria that terminate in the olfactory cortex located in the pyriform area. Olfactory fibers also project to the orbitofrontal cortex (involved in discrimination of odors), amygdala (involved in emotional responses to olfactory stimuli), and the entorhinal cortex (involved in olfactory memory).

Olfactory processing Olfactory transduction The adsorption of odorant molecules to the plasma membrane of the cilia of the receptor cells activates group-IIA hormonal mechanisms (see p 507), resulting in the opening of Cl– channels. The ECl of the cell is less negative than the resting potential of the olfactory cell and therefore the opening of the Cl– channels depolarizes the receptor cell. Olfactory sensation adapts very rapidly with continued exposure to an odorant. The adaptation occurs partly in the receptor cells and partly in the central neurons. Neural encoding of different odors An odorant

substance usually stimulates a large number of olfactory receptors. No two odorant substances stimulate the same set of olfactory receptors, although individual receptors can respond to more than one odorant substance. Thus, it seems that the brain interprets the odor from the pattern of receptor cells stimulation. An analogy can be drawn here with the auditory mechanism in which an endless variety of sound quality can be appreciated from the spatial pattern of basilar membrane vibration. The electrical response recorded from the olfactory mucosa in response to an olfactory stimulus is called an electroolfactogram. The amplitude of the electroolfactogram increases when the intensity of the stimulus increases. The electroolfactogram is useful in the diagnosis of anosmia (absence of olfactory sense), hyposmia (diminished olfactory sense), and dysosmia (distorted olfactory sense).

Gustation Gustatory (taste) stimuli are detected by taste receptors within the tongue, mouth, and

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800

Special Senses

Olfactory bulb

Olfactory tract

Olfactory bulb Olfactory nerves

Olfactory nerves

SNC Middle nasal concha

Inf. nasal concha

Cribriform plate

Supporting cell Olfactory receptor cell Olfactory rod Viscous mucus Watery mucus

Fig. 120.1 (Left) Olfactory nerves, bulb, and tract. (Right) Olfactory epithelium, showing the olfactory receptor cells with their olfactory rods.

pharynx. “Taste” must be distinguished from “flavor,” which includes the olfactory, tactile, and thermal attributes of food in addition to taste.

Palatine tonsil Lingual tonsil Root of tongue

Foramen cecum

Sapid substances Sapid (taste-producing) substances must dissolve in the saliva before they can stimulate the taste receptors. All taste sensations result from various combinations of four basic tastes: A sweet taste is produced by various classes of organic molecules, including sugars, glycols, and aldehydes. Saccharin (o-sulfobenzimide) and aspartame (amino acid) are sweet substances with low calorific content. The tip of the tongue is the area most sensitive to sweet stimuli. A bitter taste is produced by alkaloids such as quinine and caffeine. The back of the tongue is the area most sensitive to bitter stimuli. A salty taste is produced by the anions of ionizable salts. The anterolateral part of the tongue is the area most sensitive to salty stimuli. A sour taste is produced by acids. The posterolateral part of the tongue is the area most sensitive to sour stimuli.

The tongue Gustatory papillae Three of the four types of papil-

lae on the tongue have gustatory functions. These gustatory papillae may be fungiform, circumvallate or foliate. Fungiform papillae are located in the anterior two-thirds of the tongue. Circumvallate papillae are arranged in a V-shaped row on the posterior part of the tongue. Foliate papillae are located on the lateral border of the tongue anterior to the circumvallate papillae (Fig. 120.2). The

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Terminal sulcus Vallate papillae Foliate papillae

Body of tongue

Filiform papillae Fungiform papillae

Tip of tongue Lingual tonsil Filiform papillae Fungiform papillae Vallate papilla Taste buds Taste pore Microvilli Epithelial cells

Taste cell Supporting cell

Sensory neuron

Fig. 120.2 (Above) The tongue, showing the location of the different types of papillae. (Middle) Structure of the different types of papillae. (Below) Structure of a taste bud.

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Olfactory and Gustatory Mechanisms fourth type, called the filiform or mechanical papillae, have a role in breaking up food particles in the mouth. Taste buds are located on the sides of the gustatory papillae. They are also present on the hard and soft palate, epiglottis, and in the pharynx. Each taste bud is a cluster of about 50 taste cells and several supporting and basal cells. Each taste bud contains a taste pore that allows substances to reach the interior of the taste bud. The taste receptors are located on the microvilli that project from the taste cells into the taste pores (Fig. 120.2).

801

epiglottis are innervated by fibers of the vagus nerve (Fig. 120.3). Gustatory fibers of the facial, glossopharyngeal, and vagus nerves terminate in the nucleus of tractus solitarius (NTS) in the brain stem. Second order neurons originating in the NTS ascend in the contralateral medial lemniscus to terminate in the ventroposterior medial nucleus (VPM) of the thalamus. The third order neurons originate from the VPM and terminate in the cerebral cortex, at the border between the anterior insula and its frontoparietal operculum, near the foot of the postcentral gyrus.

Gustatory processing Gustatory pathway

Gustatory transduction There are different mecha-

Taste cells are innervated by branches of the facial, glossopharyngeal, and vagus nerves. (The tactile and temperature receptors of the mouth, tongue, and pharynx are innervated by the trigeminal nerve.) The taste buds in the anterior two-thirds of the tongue are innervated by lingual branches of the facial nerve. The cell bodies are located in the geniculate ganglion. The taste buds in the posterior third of the tongue are innervated by the glossopharyngeal nerve. Taste receptors in the pharyngeal part of the tongue and on the hard palate, soft palate, and

nisms of sensory transduction for different taste substances. Sweet substances depolarize taste cells by closing K+ channels through the group-IIA hormonal mechanism. These K+ channels are cAMP-dependent. Bitter substances activate the group-IIC hormonal mechanism, causing a rise in intracellular Ca2+ that triggers neurotransmitter release. Salty substances depolarize taste cells by activating an amiloride-sensitive Na+ channel. Sour substances (e.g., citric acid) depolarize taste cells by raising the intracellular H+ ion concentration, which causes closure of K+ channels.

To foot of postcentral gyrus and to insula Posteromedial ventral nucleus of thalamus Dorsal tegmental nucleus

Dorsal trigeminothalamic tract Dorsal longitudinal fasciculus

Medial parabrachial nucleus Oval nucleus Solitary nucleus, gustatory part VII Solitary nucleus, cardiorespiratory part Spinal nucleus of trigeminal nerve

IX

X

Dorsal nucleus of vagus nerve Area postrema

Chorda tympani Sweet, salty, sour

Bitter VII

Fig. 120.3 Gustatory pathways.

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Special Senses Neural encoding of tastes Each nerve fiber of the gustatory nerves responds to more than one taste stimulus. However, each fiber responds best to one of the four primary taste qualities. Therefore, the coding of a gustatory sensation, such as that of the olfactory system, seems to depend on the pattern of nerve fibers activated by a particular stimulus. The intensity discrimination of taste, such as that of odor, is quite poor. Certain sapid substances, such as miraculin, leave an after-effect. After tasting miraculin, acids

taste sweet. There are also genetic differences in taste perception, as revealed by the dichotomy with regard to the taste of phenylthiocarbamide (PTC). About 70% Caucasians find PTC to be sour while the rest find it tasteless. Abnormalities of taste include ageusia (loss of taste sensation), hypogeusia (diminished taste sensation), and dysgeusia (distorted taste sensation).

REVISION QUESTIONS 1. Sniffing helps in olfaction. Why? 2. Ammonia has a pungent odor. Why? Ammonia is never used for testing olfaction in patients with anosmia or hyposmia. Why? 3. An odorant molecule has to be volatile, watersoluble and lipid soluble. Why? 4. What is the physiological significance of olfactory projections to the orbitofrontal cortex, amygdala and entrorhinal cortex?

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5. Which type of papillae on the tongue have a role in breaking up food particles in mouth? 6. Where in the taste buds are the taste receptors located? 7. What is the mechanism of sensory transduction for (1) sweat, (2) salty, (3) sour, and (4) bitter tasting substances? Which of them have poor intensity discrimination?

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Index A Abdominal adipose tissue, 555 Abdominal paradox, 320 Abdominal vs. thoracic breathing, 320 Abductor muscles, 313 ABO system, 158, 158t agglutination test for, 159, 159f agglutinogens and agglutinins, 159–160 genotypes and inheritance of, 159, 159t ABP. See Androgen-binding protein; Arterial blood pressure Absolute bone conduction test, 791 Absorptive pinocytosis, 40 Abstinence, 577 Acceleration due to gravity, 3 Acclimatization, 366–367, 366t Accommodation (optics), 9 Accommodation reflex, 780 ACE. See Angiotensin-converting enzyme Acetylcholine, 644, 652 binding to ligand-gated ACh receptors, 125 binding with acetylcholine receptors, 94 effect on cardiac pacemaker, 128, 128f effect on smooth muscles, 125 inactivation of, 93 release of, 93 and Ca2+ influx, 96 drugs affecting, 94–95 postjunctional potentials and, 94 synthesis of, 93 Acetylcholine receptors autoantibodies to, 96 drugs blocking, 95–96 on smooth muscles, 125 Acetylcholinesterase, 93 drugs inhibiting, 95, 95f Acetyl coenzyme A (Acetyl CoA), catabolism of electron transport chain, 485, 486 Krebs cycle. See Krebs cycle ACh. See Acetylcholine Achalasia, 466, 466f AChE. See Acetylcholinesterase Achromatic opponent mechanism, 774 Acid–base balance, renal correction of acidosis, 405 alkalosis, 405 compensatory responses, 405, 406 respiratory vs renal compensation, 405 Acidophils, 512 Acidosis, 286, 403, 429 CNS functions in, 405 and oxygen dissociation curve, 349 and potassium ion secretion, 408 renal correction of, 405 respiratory correction of, 360

Sircar_Chapter BM_803-836.indd 803

Acid phosphatase, 31 Acquired immunity active immunity, 188 definition of, 187 hapten, 187–188 passive immunity, 188 Acquired immunodeficiency syndrome, 189–190 Acromegaly, 514–515, 515f Acrosin, 574 Acrosin inhibitor, 571 Acrosome, 562 ACTH. See Adrenocorticotropic hormone Actin filament, 58 Action potentials all-or-none law, 76, 76f biphasic, 111, 111f definition of, 69, 76 and graded potentials, differences between, 80, 80t ionic changes during, 78f ionic conductances during, 77–78, 77f, 78f membrane excitability during, 76–77, 77f monophasic, 111, 111f origin and spread of, 77 phases of, 76, 77f propagation of, 87 refractory periods of, 77f setup for recording of, 77f in single-unit smooth muscles, 125, 125f temperature effects on, 78, 78f triphasic, 111, 111f Activated partial thromboplastin time, 175 Activation heat, 100 Active immunity, 188 Active immunization, 188 Active insufficiency, 119 Activity-dependent synapse modification, 651 Actomyosin-ADP-Pi complex, 97 Acute mountain sickness, 366 Acute phase proteins, 135 Acute renal failure, 428 Acute retrograde (chromatolytic) response, 65 Acute tubular necrosis, 428 Adaptive immunity. See Acquired immunity Adaptive motor learning, 620, 687 ADCC. See Antibody-dependent cell-mediated cytotoxicity; Antigen-dependent cellmediated cytotoxicity Addison disease. See Primary adrenal insufficiency Adenohypophysis, 511–512, 511f, 512f ADH. See Antidiuretic hormone ADH secretion and cortisol, 539 Adjuvants, 189

Adluminal compartment, 561 Adrenal androgen-stimulating hormone, 560 Adrenal cortex, 534, 537, 542 Adrenal glands, 534, 534f Adrenal insufficiency, 541 Adrenal medulla blood supply to, 544 chromaffin granules, 544f Adrenergic receptors, 125, 545, 644 Adrenergic transmission, MAO inhibitors, 653f Adrenocortical dysfunctions adrenal insufficiency, 541 Cushing syndrome, 540–541, 541f hyperaldosteronism, 542 Adrenocortical hormones glucocorticoids, 290, 538–540 mineralocorticoids. See Mineralocorticoids Adrenocorticosteroid therapy, 542 Adrenocorticotropic hormone, 538 Adrenogenital syndrome, 536 Adrenomedullary dysfunctions, 546 Adult ventricles in series, 247b Adynamic ileus, 467–468, 468f Afferent neural control, 354–355 After-depolarization, 76, 77f, 83, 83f Afterload, cardiac, 104, 234 Aganglionic megacolon. See Hirschsprung disease Agglutination, 196 Agglutination test, 159, 159f Agglutinogens and agglutinins, 158 ABO system, 159–160 Rhesus (CDE) systems, 160 Aggregate-free antigens, 190 Agonist, 118 Agranulocytes, 176 A:G ratio, 135b AIDS. See Acquired immunodeficiency syndrome Air-conditioned hall genesis of temperature oscillations in, 25f temperature-regulatory system in, 24, 24f Air embolism and gravity, 257 Airflow rates, 336–339 Airway closure, mechanism of, 325f Airway resistance, 320 and COPD, 370–371 Akinesia, 629 Albinism, 512, 513 Alcohol intake, 718 Aldosterone effect on potassium balance, 416 fluid and electrolyte balance, 397 physiologic actions of, 541 and potassium ion secretion, 408 relative importance of, 416f renal effects of, 415 secretion control, 540 Alimentary canal, 437, 437f Alkaline phosphatase, 526

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804

Principles of Medical Physiology Alkalosis, 403 CNS functions in, 405 renal correction of, 405 respiratory correction of, 360 Allocortex, 632 All-or-none law, 76, 101 Alpha-Latrotoxin and ACh release, 94 Alveolar dead space, 340 Alveolar gas exchange diffusion capacity, 344–346 exercise effect on, 346 flow-limited vs. diffusion-limited transport, 344 Alveolar perfusion, 343 Alveolar stabilization, 329 Alveolar ventilation alveolar air composition, 341, 341f alveolar perfusion, 343 definition of, 341 gravity effect on, 341–343 ventilation–perfusion ratio, 343, 344 Alveoli, 314 Amblyopia, 766 Amidopyridines and ACh release, 94 Amino acid catabolism, 492f Amino acid neurotransmitters, 650 gamma-amino butyric acid, 651 glutamate, 650–651 glycine, 652 Aminophospholipids, 37 Ammonia buffers, 403 Ammonia, detoxification of, 492f Amphetamine, 654, 728 Ampholyte, 23 Amygdala, central nucleus, 702t Amylase, 440 Anabolic states growth, 498, 499, 499f obesity, 498 postabsorptive state, 496, 497f, 498f Anabolism vs. catabolism, 494 Anaphylaxis, 191, 191f Anatomic dead space, 340, 340f Anchoring proteins, 57, 59 Androgen-binding protein, 561, 561f Androgens, 534 Anemia definition of, 139 etiological classification of, 139–140, 140f laboratory classification of, 140 Anemia hypoxia, 161 Anemic hypoxia, 360, 589 Anesthesia, 661, 675 Anesthesia dolorosa, 661 Angiotensin-converting enzyme, 317 Angiotensin-II, 415 Angiotensinogen, 415 Angiotensin receptors, 415 Angle of His, 439f Anion gap, 406 Anisocytosis, 134, 136 Ankyrin, 139

Sircar_Chapter BM_803-836.indd 804

Anomalous trichromats, 773 Anomia, 740 ANP. See Atrial natriuretic peptide ANS. See Autonomic nervous system Antagonist, 118 Anterior corticospinal tract, 611 Anterior hypothalamus, 718 Anterior pituitary, 511f, 512, 512f Anterolateral abdominal muscles, 320 Anthropometry BMI, 481, 481t circumferences, 481, 482 definition of, 482 skinfold thickness, 482 weight, 481, 481f, 481t Antiarrhythmic drugs, 220 Antibody-dependent cell-mediated cytotoxicity, 196 Antibody-mediated cytotoxicity, 191f, 192 Anticancer drugs, 44 Anti-ChE drugs. See Anticholinesterase drugs Anticholinergic drugs, 630 Anticholinesterase drugs, 95, 95f, 652 Anticoagulants, 171, 173f Anti-D antibodies, 158 Antidepressants, 655, 702, 703 Antidiuretic hormone, 397, 414 Antigen-dependent cell-mediated cytotoxicity, 183 Antigenic blindfolding, 187 Antigen processing, 193 Antigen shedding, 193 Antigravity muscle tone, 691 Antigrowth effects, 539 Antihemostatic mechanisms, 170, 170f blood coagulation, factors inhibiting antithrombin–heparin system, 171 exogenous anticoagulants, 171 protein C pathway, 170, 171, 172f fibrinolysis, 171–172 platelet aggregation, 170 Antihypertensive drugs, 285 Anti-immunity effects, 538 Anti-inflammatory effects, 538 Antioxidants, 571 Antiport, 38 Antipyretics, 725 Antisperm antibodies, 571 Antithrombin–heparin system, 171 Antithyroid drugs, 523–524 Anuria, 423 Aortic pressure, 227 Aortic pressure curves, 294f APB. See Atrial premature beats Aphasia, 740 Broca aphasia, 741 conduction aphasia, 741

features of, 741t global aphasia, 741 neural basis, 741 modern framework, 742 Wernicke–Geschwind model, 741 transcortical aphasia, 741 Wernicke aphasia, 740–741 Apical skin, 307–308 Apnea after hyperventilation, 356b Apneustic breathing, 353, 354 Apocrine sweat glands, 308, 308t Apolactoferrin, 177 Apoptosis definition of, 47 induction of, 199 by lysosomal enzymes, 31 and mitosis, 48 phases of, 48 Appetite, 727 APTT. See Activated partial thromboplastin time Aquaporins, 38 Aqueous tension, 18–19 Arachidonic acid-activated K+ channels, 129 Archicerebellum, 615 ARF. See Acute renal failure Arneth count, 176 Arnold theory, 700 Arterial blood pressure, 235 Arterial pressure, effect of gravity on, 256f Arteries, 248–249, 250f pressure drop along, 255f Arterioles, 249 in apical skin, 307, 308 pressure drop along, 255f resistance offered by, 255b Arteriovenous (A-V) anastomoses, 250, 308 Artificial breathing, 331f Ascites, 312 Asphyxia, 361b Aspiration pneumonia, 313 Aspirin and platelet aggregation, 170 Assisted ventilation, 330 Association nuclei, 623 Astrocytes, 57, 57f Ataxic breathing. See Biot breathing Atelectasis, 372 Atlantooccipital joint, 120 Atmospheric pressure, 4 ATP and muscle contraction, 99 Atria, 224 Atrial fibrillation, 221, 222f Atrial flutter, 221, 222f Atrial natriuretic peptide, 271, 416 Atrial premature beats, 222f Atrial septal defect, 247 Atrial systole, 227 Atrioventricular node, 206 Atrioventricular (AV) valves, 224 Audiogram, 792f Audiometric tests, 791

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Index Auditory area I, 637 Auditory association area, 785 Auditory evoked potentials, 791 brainstem auditory evoked potentials, 792–793 electrocochleography, 791 Auditory information, 612 Auditory mechanisms, 783 ear, 783 inner ear cochlea, 784 cochlear fluids, 783–784 cochlear nerve, 785 corti, organ of, 784 middle ear, 783 acoustic impedance matching, 783 acoustic reflex, 784 Eustachian tube, 783 Auditory pathway, 785, 786f Auditory processing auditory transduction cochlear action potentials, 788 cortical auditory processing, 789 efferent cochlear control, 789 masking, 789 sound, cochlear amplification, 788 transduction channels, 787–788 basilar membrane, vibration of traveling wave, 786 Auditory transduction, 787f Augmented limb leads, 209 Autocatalysis, 447, 447f Autoimmune diseases, mechanism of, 190t Automatic cardiac fibers, action potentials of, 128–129, 128f Autonomic dysreflexia, 434 Autonomic fibers, 607 Autonomic function tests, 646–647 Autonomic ganglia, neurotransmitters of, 646t Autonomic nerve impulses circulating catecholamines, 645t–646t Autonomic nerve stimulation and saliva secretion, 440f Autonomic nervous system, 646 parasympathetic nervous system, 643 sympathetic nervous system, 643f Autonomic neurotransmission autonomic dysfunctions, 647 ganglionic neurotransmission, 644–646 parasympathetic neurotransmission, 642–646 sympathetic neurotransmission, 644 Autonomic neurotransmitters and junctional potentials, 125 Autophagic vacuoles, 31 Autoregulation of blood flow, 310

Sircar_Chapter BM_803-836.indd 805

Auxotonic contraction, 117 Average capillary hydrostatic pressure, 263 Axonal growth, trophic factors affecting, 63–64 Axon diameter and conduction velocity, link between, 87–88 Axonotemesis, 66, 66t Axon reflex, 91 Axoplasmic resistance, 86 Axoplasmic transport, 56–57 Azurophilic granules, 176, 177

B Bacillus Calmette–Guerin, 189 BAEP. See Brainstem auditory evoked potentials Balance of currents, 71, 71f Balint syndrome, 637 Ballistic movements, 681, 687 Ballistocardiography, 233 BAO. See Basal acid output Baroreceptor reflex, 275f, 286 activated by venous pooling, 275, 276f afferents, efferents, and centers of, 274f carotid, 275 reflex correction of blood pressure, 275 Baroreceptors, 274, 274b, 274f inhibition, 278 mechanism of blood pressure regulation, 281–282 Barr body, 580 Basal acid output, 447 Basal electric rhythm, 458 Basal ganglia, 596, 626 anatomy of, 626f caudate loops, 627f choreoathetosis chorea, 630, 630f Huntington chorea, 630 Wilson disease, 630 circuits of, 626–627 cortical origin, 627 striatal/thalamic relays, 627, 627f disorders of, 629 hemiballismus, 630 neuronal damage, 630f neurotransmitters, 626 pallidum, 626 Parkinson disease, 628, 629f hypokinesia, 629 patient posture, 629f rigidity, mechanism of, 629f treatment, 630 tremor, 630 putamen loops, 627f skeletomotor circuit, 627–628 skeletomotor loop of, 628f substantia nigra, 626 Basal metabolic rate definition of, 496

805

factors influencing, 496, 496f during postabsorptive period, 496 in thermoneutral ambient temperature, 496 Basilar membrane traveling wave, 786, 786f vibration, 787f Basolateral nucleus, 702 Basopenia, 180 Basophilia, 180 Basophils, 176, 179f, 180, 180t, 512 BCG. See Bacillus Calmette–Guerin BEAM. See Brain electrical activity mapping Bell phenomenon, 776 BER. See Basal electric rhythm Bereitschaft potential, 686 Bernoulli’s principle, 8, 252–253 Bicarbonate buffers, 403 Bicarbonate reabsorption, 403 Bicarbonates, 404 Bilateral prefrontal leucotomy, 638 Bile and pancreatic ducts, 448f Bile juice, 448 Bile salts, 448, 449–450, 449f Biliary secretion, regulation of, 449 Bilirubin excretion of, 146 formation of, 145–146, 145f serum level of, 146 Biological membranes, tonicity of, 22 Biot breathing, 355f, 356 Bipolar neurons, 56, 56f Bipolar vs. unipolar recording, 208 Bladder efferent nervous controls of, 433t and sphincters, motor innervation of, 432 Bladder distension, sensation of, 432, 432f Bladder pain, sensation of, 432f Blind loop syndrome, 469 Blood composition of, 133, 133t plasma proteins. See Plasma proteins functions of, 133 normal values for cellular elements in, 133t sludging of, 287 specific gravity of, 133 viscosity of, 256 Blood–brain barrier vs. blood–CSF barrier, 301, 301f deficiency of, 301 functions of, 300 structures outside, 301 Blood buffers, 404 Blood cells, cortisol effect on, 538. See also Red blood cells; White blood cells Blood coagulation and coagulation factors, 166, 166t extrinsic pathway. See Extrinsic pathway

2/14/14 2:39 PM

806

Principles of Medical Physiology intrinsic pathway, 166, 167 in vitro, 166, 167 in vivo, 167 Blood coagulation, factors inhibiting antithrombin–heparin system, 171 exogenous anticoagulants, 171 protein C pathway, 170, 171, 172f Blood–CSF barrier vs. blood–brain barrier, 301, 301f Blood flow characteristics of flow rate vs. flow velocity, 253, 253b, 254f laminar vs. turbulent flow, 254–255 effect of vessel characteristics on, 253b intrarenal distribution of, 377, 378 measurement, 258 resistance in vascular beds, 14 to tonic and phasic muscles, 308 Blood glucose, postprandial surge in, 455, 456 Blood group systems, 159 ABO system, 158, 158t and cross-matching, 160–161 familial blood groups, 158 importance of, 160 and Landsteiner’s law, 158 Rhesus (CDE) systems, 158–159, 158t Blood pressure clinical classification of, 285t determinants of, 280 in exercise, 281 fluctuations in normotensive patient, 284 recording using direct manometry, 280 Blood pressure changes during Valsalva maneuver, 278, 278f Blood pressure measurement direct manometry, 258–259, 258f sphygmomanometry, 260, 260f Blood pressure regulation, mechanisms of, 281, 281t baroreceptor mechanism, 281–282 capillary fluid shift mechanism, 282 chemoreflex and CNS ischemic response, 282 electrolytes in blood volume regulation, 283 pressure natriuresis, 282f, 283 renin–angiotensin mechanism, 282 salt-loading curve, 283–284, 283f stress-relaxation mechanism, 282 Blood reservoirs, 250, 250f Blood transfusion autologous, 160 complications of, 161

Sircar_Chapter BM_803-836.indd 806

Blood vessels, 249f parasympathetic innervation of, 273 sympathetic innervation of, 273 B-lymphocytes, 183, 184t differentiation of, 194f, 195 BMI. See Body mass index BMR. See Basal metabolic rate BNP. See Brain natriuretic peptide Body calcium balance, 528, 528f Body cooling mechanisms behavioral mechanisms, 722 cutaneous vasodilatation/ sweating, 722 insensible perspiration, 722 nonevaporative heat loss, 722 Body fluid compartments volume measurement approaches, 132, 132f volumes, 132, 132f Body fluids osmolarity of, 132–133, 133t volume of, 132 Body mass index, 481, 481t Body osmolarity important contributors to, 132, 133t total, calculation of, 132–133 Body pH, regulation of blood buffers and, 404 Body sodium balance, 396 Body temperature regulation, 24, 720 core/shell temperatures, 721f diurnal variation, 720f heat exchange with exterior, 721 heating mechanisms behavioral mechanisms, 722 chemical/nonshivering thermogenesis, 722 cutaneous vasoconstriction, 722 horripilation, 722 shivering, 722 heat loss, 720b hypothalamic set point, 725f hypothalamic thermoregulatory centers, 724f normal body temperature core/shell temperatures, 721f diurnal variation, 720f physiological variations, 720–721 oxidative dephosphorylation, uncoupling, 723f temperature maintenance, 720b thermoregulatory effector mechanisms, 721t thermoregulatory mechanisms, 721, 721t, 724f Body water balance, 396 Bohr effect, 144 Bone accretion, 526 calcitriol effect on, 530

composition of, 525 cortical (compact), 525 estrogens, physiological actions, 557 trabecular (spongy), 525 Bone calcium pool, 528 Bone cells, 525f, 526 Bone changes, 430 Bone disorders, 527–528, 527f Bone marrow, 140 age changes in, 203 biopsy, 203, 203f, 204 color of, 203 reserve capacity, 203 reticulum cells and reticulin fibers, 203 sinusoids, 203 Bone matrix, 525, 526 Bone remodeling. See Bone turnover Bone resorption by osteoclast, 526, 526f Bone turnover, 526 Botulinum toxin (Botox) and ACh release, 94 Bowman’s cells, 799 Bowman’s membrane, 744 β-Oxidation of fatty acids, 490, 491f Boyle’s law, 18 BR. See Breathing reserve Bradyarrhythmias atrioventricular block, 217 bundle-branch block, 217–218 sick-sinus syndrome, 217 Bradykinesia, 629 Bradykinin, 269, 269f, 665 Brain anteroinferior view, 601f brainstem, posterior aspect, 603f caudate nucleus, 600f cerebellum/fourth ventricle, 602f cerebral hemisphere, 595f cerebral hemispheres, 595–604 corpus callosum, 598f cranial nerves/spinal cord/spinal nerves, 604f fornix, hippocampus/fimbria of, 599f, 600f schematic view of, 597f spinal cord, 604 subdivisions of, 596f Brain electrical activity mapping, 711 Brain natriuretic peptide, 416 Brainstem, 609 Brown–Sequard syndrome, 607t, 608f cranial nerve nuclei, 610t–611t, 612, 612f extrapyramidal tracts, 612 general sensory tracts, 612 pyramidal tract, 609f, 612 special sensory tracts, 612 spinal cord lesions, 612 spinal cord, transverse section of, 608f

2/14/14 2:39 PM

Index spinal tracts, physiology, 607t supranuclear motor lesions, 612–613 Brainstem auditory evoked potentials, 792–793 Brainstem auditory evoked response, 712, 792 Breast, 558 Breastfeeding, nutritional requirements in, 483, 484 Breathing cardiovascular effects of, 278 chemical control of, 27 chemical regulation of, 359 acidosis, correction of, 360 alkalosis, correction of, 360 exercise-induced hyperventilation, 360 respiratory equilibrium maintenance, 359, 360 pressure-volume changes during, 327–328 thoracic vs. abdominal, 320 work of, 328, 329f Breathing cycle, 327–328, 328f Breathing during sleep, 355 Breathing reserve, 339 Breath sounds, 374–375, 375t Bretylium, 654 Broca area, 741 Brodmann areas, 632 Bronchial asthma, 369–370 Bronchial epithelium, 316f Bronchiectasis, 33 Bronchioles, 314 Brown–Sequard syndrome, 607, 608f neurological deficits, 608t Bucket-handle movement, 318 Buffering power, 22 Buffers, 21–22 Bundle of His, 206 Buoyancy, 6, 298

C CAH. See Congenital adrenal hyperplasia Ca2+-induced Ca2+ release, 124 Calcineurin, 658 Calcitriol, 529, 530, 530b effect on bone, 530 effect on intestine, 531 effect on kidney, 531 and PTH, relationship between, 530f synthesis of, 531, 531f Calcitropic hormones, 416, 528–529 calcitonin, 529, 530f calcitriol. See Calcitriol parathyroid hormone. See Parathyroid hormone Calcium-activated K+ channels, 710 Calcium and phosphates imbalances, 429–430

Sircar_Chapter BM_803-836.indd 807

tubular reabsorption of, 413 Calcium balance disorders hyperparathyroidism, 532 hypervitaminosis D, 532 hypoparathyroidism, 531–532, 532t hypovitaminosis D, 532 Calcium ion and membrane excitability, 83, 83f voltage-gated, 96 Calcium ion concentration in L-tubule, 98 sarcoplasmic, 98 Calcium pulse, 98–99 Calculus, 1–2 Caloric nystagmus test, 797 Calsequestrin, 98 CAMs. See Cell adhesion molecules Capacitance, 12, 13 Capacitor, 13 Capillaries, 249, 249f pressure drop along, 255f structure of, 262, 262f types of, 262 Capillary circulation, 262 Capillary exchange diffusion across capillary wall, 264, 264f filtration and reabsorption, 262– 264, 263f readjustments in, 396, 396f starling forces of, 263f Capillary fluid shift mechanism, 282 Capillary hydrostatic pressure, 263f Capillary hydrostatic pressure and edema, 266 Capillary permeability and edema, 266 Capsaicin receptor, 665 Carbaminohemoglobin, 350 dissociation curves of, 350f Carbohydrate metabolism cortisol effect on, 540 and glucagon, 549, 549f gluconeogenesis, 486f, 487–488 glycogenesis, 487, 487f glycolysis Embden–Meyerhof pathway, 487 glucose–sorbitol–fructose pathway, 487, 487f HMP pathway, 487, 487f growth hormone effect on, 514 and insulin, 548–549, 548f in postabsorptive state, 496, 497f TH role in, 521 Carbohydrates, 473–474 absorption of, 455, 456 digestion, 451, 452, 455 Carbon dioxide dissociation curve, 350, 350f transport in blood as carbaminohemoglobin, 350 as dissolved CO2, 350

807

as plasma bicarbonate, 349–350, 350f Carbonic acid, 403 Carbonic-anhydrase independent reabsorption, 403 Carbon monoxide poisoning, 360–361 Carboxyhemoglobin, 144, 360 Cardiac action potentials. See also Action potentials abnormal potassium currents, 129, 129t in automatic cardiac fibers, 128–129, 128f in nonautomatic cardiac fibers, 127–128, 127f Cardiac contractility, 404 Cardiac contraction cross-bridge cycling, 129 ephaptic conduction, 130 excitation–contraction coupling, 129, 129f staircase effect, 130, 130f Cardiac cycle arterial and venous events, 227–228 definition of, 224 duration of, 228–229, 228t phases of, 226f diastole, 224, 225, 227 duration of, 225t systole, 224, 225 ventricular pressure-volume loop of, 5, 6f Cardiac depression, 286 Cardiac dipoles, 206–207 Cardiac excitation, 207 all-or-none law, 205 conductive system of heart, 205–206, 205f Cardiac excitation, abnormalities of bradyarrhythmias, 217–218 tachyarrhythmias, 218–223 Cardiac failure compensated, 242 decompensated, 242 diastolic, 243 high-output, 242 left-sided, 242 right-sided, 242 systolic, 243 treatment of, 243, 243f Cardiac function curves, 239–240, 240f, 241f Cardiac index, 231 Cardiac muscles, 60–61 contractility, modulation of, 129–130, 129f epinephrine action on, 128–129 types of, 127 Cardiac output and central venous pressure, interdependence of, 240–241, 240f definition of, 231, 231b

2/14/14 3:26 PM

808

Principles of Medical Physiology in dynamic exercise, 238, 238f effect of heart rate on, 239b in fitness test, 239 graphic analysis of, 239–241, 239f, 240f measurement methods, 231, 231b ballistocardiography, 233 cineradiographic technique, 233 Doppler technique, 233 dye-dilution technique, 232– 233, 233f Fick principle, 231, 232f pressure changes associated with, 235 in static exercise, 238, 238f TH role in, 521 Cardiac output, control of cardiac pump function, 235 circulatory load on heart, 234 CVP measurement, 233–234 myocardial contractility, 235 vascular functions, 235–237 Cardiac pump function, 235 Cardiac syncope, 296 Cardiac tissue, conduction velocity of, 205, 206t Cardiac vector, 206, 207f Cardiac wave in blood pressure tracing, 280, 280f Cardiogenic shock, 289 Cardiovascular control centers, 274, 275 Cardiovascular receptors, 273–274, 274f Cardiovascular reflexes bainbridge reflex, 276–277 baroreceptor reflex, 275f activated by venous pooling, 275, 276f afferents, efferents, and centers of, 274f carotid, 275 reflex correction of blood pressure, 275 chemoreceptor reflex baroreceptor inhibition, 278 experimental stimulation, 277–278 hypoxic stimulation, 277 effectors of, 273 Cardiovascular responses to venous pooling, 276t Cardiovascular system efferent control of, 273 sympathetic control of, 278–279 Cardiovascular system, chemical control of endocrine control, 271–272 paracrine control, 268–271 Carotid baroreceptor reflex, 275 Carotid sinus syncope, 297 Carpopedal spasm, 531f Carrier-mediated transport, 39f energy for, 38

Sircar_Chapter BM_803-836.indd 808

inhibitors of, 40 mechanism of, 40 passive, 38 primary-active, 38–39 rate of, 39–40 secondary-active, 39 types of, 38 Catabolic states exercise catabolic reactions, 499, 499f grading of, 500, 500b oxygen debt, 499, 499f starvation, 500, 501f Catabolism vs. anabolism, 494 Catecholamines, 271, 544, 544f, 653 effect on smooth muscles, 125 hyposecretion of, 546 and insulin secretion, 547–548 and metabolic rate, 545 metabolism of, 545f and potassium balance, 545 Cathodal stimulation, 78–79 CBF. See Cerebral blood flow CBG. See Cortisol-binding globulin Cell cell organelles. See cell organelles definition of, 28 Cell adhesion molecules, 34, 34f, 36, 64 Cell cycle definition of, 44 meiosis. See Meiosis mitosis. See Mitosis phases of, 44, 44f Cell homeostasis, restoration of, 74–75, 74f Cell lysis through complement, 196f Cell-mediated immunity cytotoxic T cells, 199 definition of, 196 helper cells, 199 Cell membrane. See Membrane Cell organelles apparatus for metabolic reactions, 30–31 apparatus for protein synthesis, 28–29 cytoskeletal apparatus, 31–33 definition of, 28 digestive apparatus, 31 secretory (exocytic) apparatus, 29–30 separation by centrifugation, 28 Cellular overfuelling, 728 Central chemoreceptors, 358–359, 359f Central evaluative component, of emotions, 638 Central inspiratory activity (CIA) neurons, 352 Central nervous system, 56, 595 anteroinferior view, 601f brainstem, posterior aspect, 603f caudate nucleus, 599f cerebellum/fourth ventricle, 602f

cerebral hemispheres, 595–604, 595f corpus callosum, 598f cranial nerves/spinal cord/spinal nerves, 604f fornix, hippocampus/fimbria of, 599f, 600f schematic view of, 597f spinal cord, 604 Central respiratory neurons organization of, 352f Central venous pressure and cardiac failure, 242–243 cardiac pumping effect on, 235 measurement of, 233–234 vascular factors affecting, 240–241 and venous return, 236b Central venous pressure and cardiac output, interdependence of, 240–241, 240f Centrioles, 32, 32f Centrosome, 32, 32f Cerebellum, 615 anatomic subdivisions of, 615f cerebellar dysfunctions, 620, 620f cerebrocerebellar dysfunction, 620–621 spinocerebellar dysfunction, 620–621 vestibulocerebellar dysfunction, 620 cerebrocerebellum, 619–620 connections of, 620f coordination, 617 experiments, 619f functional lobes, 615f hemispheres, 615 internal cerebellar structure cerebellar afferents, 616 cerebellar cortex, 615 cerebellar medulla, 616 internal structure, 615f learning, 617 paravermal part, connections, 620f spinocerebellum, 618 afferents, 618 efferents, 618–619 somatotopy, 618, 618f spinal tracts, 618f vermal part, connections of, 619f timing/comparison, 617 vestibulocerebellum, 617 connections of, 617f Cerebral arteries, 295, 295f Cerebral blood flow, 295 factors affecting, 296 measurement of, 295 regional, metabolic regulation of, 296, 296f total, autoregulation of, 295–296 Cerebral cortex, 595, 632 cerebral hemisphere, sulci/gyri, 632f

2/14/14 2:39 PM

Index cerebral laminae, 633f cortical areas cytoarchitecturally, 632 phylogenetically, 632 cortical cells, 632 cortical projection fibers, 633 interhemispheric differences, 634 left cerebral hemisphere, 633f motor areas, 634 brain, horizontal section of, 635f nonprimary motor areas, 635–636 primary motor area, 634 multimodal sensory areas amygdala, 640 hippocampus, 638 limbic association area, 638–640 nucleus accumbens, 640 parietooccipitotemporal association area, 637–638 prefrontal association area, 638 sex differences, 634 unimodal sensory areas general sensory areas, 636 special sensory areas, 637 Cerebral edema, 366 Cerebral vasodilatation, 296 Cerebral ventricles, 596 Cerebrocerebellum, 687 Cerebrospinal fluid abnormalities in, 299 absorption, 298 analysis, 299, 299f circulation, 297f, 298 constituents, 299, 299t functions of, 298 physical characteristics of, 299, 299t pressure, 299–300 subarachnoid space, 297 Cervical stimulation, 591 Cervix, 557 CFC. See Colony-forming cells Channel blockers, specific, 83 Channel currents, 69 Channel density in neuron, 90t Channel modulators, nonspecific, 83 Charcot–Marie–Tooth disease, 33 Charged particles, simple diffusion of, 38 Charles’ law, 18 Chemical equilibrium, 22–23 Chemoreceptor reflex, 286 baroreceptor inhibition, 278 experimental stimulation, 277–278 hypoxic stimulation, 277 Chemoreceptors, 273, 661, 665 static vs. dynamic sensitivity of, 26, 26f Chemoreflex and CNS ischemic response, 282 Chemotaxis, 177

Sircar_Chapter BM_803-836.indd 809

Chest (precordial) leads, 209, 210f Chest wall dimensions, changes in, 318 Cheyne–Stokes breathing, 27, 27f, 289, 355, 355f, 356 Chloride current, 72 Chloride ions and membrane conductance, 71f, 72 secretion of, 445 Chloride shift, 350f Cholagogues, 449 Cholera toxin, 507 Cholesterol, 35, 37 in bile juice, 448 and membrane fluidity, 36, 37 Cholesterol gallstones, 471 Choline-containing phospholipids, 37 Cholinergic PGO-on cells, 718 Chordae tendinae, 224, 224f Choreoathetosis chorea, 630, 630f Huntington chorea, 630 Wilson disease, 630 Choriocapillaries, 745 Chromaffin granules, 544f Chromatin, 28 Chromatolysis, 65 Chromophils, 512 Chromophobes, 512 Chromosomal nondisjunction, 581 Chromosomal sex, 580 abnormalities, 582f Klinefelter’s syndrome, 581–582, 582f true hermaphrodites, 583 Turner syndrome, 582, 582f Chromosome, 28 Chronaxie, 80 Chronic bronchitis, 370 Chronic granulomatous disease, 179 Chronic mountain sickness, 367 Chronic obstructive pulmonary disorder, 370, 371 Chronic renal failure, 428–429 Chronic retrograde atrophic response, 65 CICR. See Ca2+-induced Ca2+ release Cilia and flagella, 32–33 Ciliary muscle, 745, 779 Ciliary nerves, 779 Cineradiographic technique, 233 Cineradiography, 458 Circulating blood, energy gained by, 252–253 Circulating vasoconstrictors, 271–272 Circulation, accelerative force effect on g forces, 257–258, 258f gravity, 256, 257, 258, 258f Circulatory beds, 13f Circulatory load on heart, 234 Circulatory overload, 161

809

Circulatory pathway in adult, 245 circulatory changes at birth, 246, 246f, 247, 247f congenital defects in, 247 in fetus, 245, 245f, 246f Circulatory shock causes of, 288–289 clinical features of, 289 definition of, 286 stages of, 287f, 288f irreversible, 288 nonprogressive, 286 progressive, 286, 287 symptoms, 286 treatment of, 289–290 Circumferences, measurement of, 481, 482 Clarke column, 618 Class-III lever, 120–121, 120f Class-II lever, 120, 120f Class-I lever, 120, 120f Closed-loop control system, 24 ‘Closest-fit theory’ of ion channel specificity, 42f Clot retraction, 175 Cloudy swelling, 20 CNP. See C-type natriuretic peptide CNS. See Central nervous system CNS ischemic response, 286 Coagulation disorders, 172f, 174t hemophilia, 173 tests for, 174–175 vitamin K deficiency, 173 von Willebrand’s disease, 173 Cobalamin. See Vitamin B12 Cochlear microphonics, 791 Cochlea, schematic anatomy, 784f Codon for amino acids, 50, 50t for STOP codons, 50t Cog-wheel rigidity, 629 COHb. See Carboxyhemoglobin Coitus interruptus, 577 Cold receptors, 663 Cold stress, 722 Collagenase, 177 Collateral ganglia, 642, 643f Collecting lymphatics, 265 Colon feces in, 460, 460t nerve supply of, 458 pressure changes in, 458 sodium and water absorption in, 459–460 wall of, 458 Colonic motility, 458 Colonic reflexes defecation reflex, 459, 459f gastrocolic reflex, 459 Colonic transit, 458–459 Colony-forming cells, 200 Colony stimulating factors, 201 Combined control, 25–26 Communicating hydrocephalus, 300

2/14/14 2:39 PM

810

Principles of Medical Physiology Compensatory pause, 222f Compensatory poststenotic dilatation, 293 Compensatory responses, renal correction of, 405 Competitive inhibitor, 40 Complement fixation, pathways of, 198f Complement system, 198, 198t Complex waves, 11 Computerized axial tomography, 706 Conation, 703–704 cataplexy, 704 catatonias, 704 disorders of, 703 mutism, 704 obsessive-compulsive disorder, 704 Concave lens, focal point of, 8, 8f Concentric contraction, muscle tension vs. muscle excursion in, 117 Condoms, 578 Conduction, 8 Conduction abnormalities, 215 Conductive tissues, conduction velocity of, 205, 206t Cone monochromats, 774 Congenital adrenal hyperplasia enzyme defects in, 537t hypertensive form of, 537 salt-losing form of, 536 Congenital atransferrinemia, 153 Congenital heart diseases, 248f Congenital myeloperoxidase deficiency, 179 Congestive glaucoma, acute, 747 Conjugated bilirubinemia causes of, 147, 148 vs. unconjugated bilirubinemia, 146t Conn syndrome, 542 Conscious sensations, 660 Constipation, 469–470 Constitutional hyperthermia, 721 Consumption coagulopathy, 174 Contact junctions, 61f, 62 Contraception barrier contraceptives, 578f behavioral methods, 577 female contraceptives barrier contraceptives, 577 implants, 578 intrauterine contraceptive devices, 578 long-acting injectables, 578 oral contraceptives, 577 tubectmy, 578 fertilization, stages of, 575f interstitial implantation, 577f male contraception azoospermic agents, 579 condoms, mechanical devices, 578 reversible inhibition of sperm under guidance (RISUG), 578

Sircar_Chapter BM_803-836.indd 810

thermal methods, 578 vasectomy, 578f vas-occlusive plugs, 578 male reproductive tract, 570f morula into blastocyst, 576f seminiferous tubules/rete testis/ epididymis, 570f female reproductive tract, 573f spermatozoon, capacitation, 574f sperm moves, pH changes, 571f two-cell stage embryo, formation of, 576f Contractile proteins, 57 Contralateral hemianesthesia, 624 Contralateral sensory neglect, 636 Control system, 24 Convection, 8 Convergence-projection theory, 674 Convex lens, focal point of, 8, 8f Cooperative binding kinetics, 144 COPD. See Chronic obstructive pulmonary disorder Cori cycle, 500f Coronary angioplasty, 293 Coronary artery bypass grafting, 293 Coronary blood flow, regulation of, 291–292 Coronary blood vessels on sternocostal surface, 291f Coronary chemoreflex, 292 Coronary insufficiency cause of, 292 myocardial infarction, 292 myocardial ischemia consequences of, 292–293 risk of, 294 treatment of, 293, 293f Coronary steal, 293f Coronary vasodilator reserve, 293–294 Corpus callosum, 595, 596 Corpus hemorrhagicum, 568 Cortex, 376 Cortical (compact) bone, 525 Cortical nephrons, 376, 379f Cortical peritubular capillaries, 377 Cortical sensory processing, 671, 672f cortical pain areas, 672 posterior parietal cortex sensory cortex, plasticity of, 671 primary sensory cortex (S-I), 671 secondary sensory cortex (S-II), 672 Corticobulbar fibers, 612 lateral gaze center, 613f VII cranial nerve, superior part, 612f Corticosteroids, 534 biosynthesis of, 535–536, 535f biosynthetic defects, 536–537, 537f chemical structure of, 536f transport and metabolism, 537–538 Corticosteroid therapy, 542

Corticotropin-releasing hormone, 538 Corti, organ, 785f Cortisol-binding globulin, 537 Cotranslational insertion, 29 Cotransport. See Symport Coughing and sneezing, 316–317 Countercurrent exchanger system changes in osmolarity of tubular fluid due to, 392–394, 393f in vasa recta, 394, 395, 395f Countercurrent exchanges in villi, 310, 310f Countercurrent multiplier system, 392 Countertransport. See Antiport CP. See Compensatory pause Craniosacral outflow, 642 Craniosacral parasympathetic outflow, 607 C-reactive proteins, 135 CRF. See Chronic renal failure CRH. See Corticotropin-releasing hormone Critical temperature, 723 Cross-bridge cycling in cardiac muscle, 129 dark and light bands, 98 initiation and termination of, 98–99 power stroke, 97 steps in, 97, 97f Cross-matching and blood grouping, 160–161 CRP. See C-reactive proteins Cryptorchidism, 563 CSF. See Colony stimulating factors C-type natriuretic peptide, 416 Cumulus oophorus, 574 Cushing reflex, 296 Cushing’s syndrome, 284, 540, 541f Cushioning and cerebrospinal fluid, 298 Cutaneous blood vessels, organization of, 308f Cutaneous circulation, 307–308 Cutaneous receptors, 662f location of, 662f morphology of, 662f static/dynamic responses, 663f CVP. See Central venous pressure Cyanosis, 361 Cyanotic heart defects, 247 Cycloplegia, 780 Cystometry, 434–435, 435f Cytoarchitecturally, 632 Cytokeratin, 32 Cytokinesis, 44 Cytoplasmic dense bodies, 60 Cytoskeletal apparatus centrosome, 32, 32f cilia and flagella, 32–33 intermediate filaments, 32 microtubules and microfilaments, 31–32 Cytotoxic drugs, 44

2/14/14 2:39 PM

Index

D D agglutinogen, 158 Dalton’s law of partial pressure, 18, 18f Dark and light bands, 98 Davenport diagram, 406, 406f D cells, 446, 547 Dead spaces, 340, 340f Deafness central, 790 conductive, 790 sensorineural, 790 Decerebrate posturing, 683f Decibel scale, 3 Decompression sickness, 365 Deconditioning, 737 Decorticate posture, 693, 694f Defective kinetic automatism, 629 Defects in tubular transport Fanconi syndrome, 428 nephrogenic diabetes insipidus, 428 renal glycosuria, 427, 428, 428f renal tubular acidosis, 428 Defensins, 176 Defibrination syndrome, 174 Deficiency anemias, 140 Deglutition coordination center of, 437–438 phases of, 438, 438f Dehydroepiandrosterone, 554 Delayed-type hypersensitivity, 191f, 192 Demyelination, nerve conduction failure by, 91 Dendrites, 54–55 Dentate gyrus, 638 Deoxyadenosylcobalamin, 157 Deoxyribonucleic acid, 49 Depolarization, 76, 77f Depolarizing neuromuscular blocker, 95–96 Depot effect, 189 Dermatomes, 666, 666f Dermographism, 307 Desmosome, 33 DHEA. See Dehydroepiandrosterone DHF. See Dihydrofolate DHP. See Dihydropyridine receptors DHT. See Dihydrotestosterone Diabetes insipidus, 414 Diabetes mellitus diagnosis of, 553 metabolic consequences of hyperglycemia, 551–552, 551f, 552f hyperkalemia, 553 hyperlipidemia, 552, 552f ketoacidemia, 552f ketosis, 552, 552f polyphagia, 552 treatment of, 553 type 1 diabetes, 550, 551t type 2 diabetes, 550–551, 551t

Sircar_Chapter BM_803-836.indd 811

Diabetic ketoacidosis, 409 Dialysis, 430 Diapedesis, 178 Diaphragm, 577 Diaphragmatic paralysis, 320 Diarrhea, 470 due to intestinal hypermotility, 470 due to reduced absorption, 470 osmotic, 470 secretory, 470 Diastasis, 225, 226f, 227 Diastasis and atrial systole, 227 Diastole, 224, 225, 227 Diastolic murmurs, 229 Diastolic perfusion of myocardium, 294 Diastolic pressure–time index, 294 DIC. See Disseminated intravascular coagulation Diencephalon, 596, 622 pineal body, 622 thalamus, 622 Dietary fibers components of, 479 physiological effects of, 479 sources of, 479 Dietary heme iron, 151 Dietary nonheme iron, 151 Dietary planning balanced diet, 483 consumption units, 482–483, 483t dietary guidelines for diabetic patient, 553 recommended daily allowance, 483, 483t reference man and woman, 482, 482t special nutritional requirements, 483 Differential calculus, 1–2 Differential leukocytic count, normal values for, 133t Diffuse junction, 62 Diffusion across capillary wall, 264, 264f of solutes, 19–20, 20f of solvent, 20–21, 20f Diffusion capacity and COPD, 371 of lungs, 344–346 Diffusion-limited transport, 344 Diffusion potential definition of, 69 of multiple ions, 70–71, 71f origin of, 69–71 of single ion, 70, 70f Diffusion rate, 346 Digestive events, 447 Digestive events in mouth, 440 Dihydrofolate, 154 Dihydropyridine receptors, 99 Dihydrotestosterone, 554 vs. testosterone, 555t Dilatator pupillae, 745

811

Dilutional hyponatremia, 414 2,3 Diphosphoglycerate (DPG), hemoglobin reaction with, 144 Diplopia, 779 Dipole, electric, 15 Direct manometry, 259, 259f Direct-reacting bilirubin, 147 Discriminant responses, 716 Discriminative appetite, 640, 728 Dishabituation, 736 Disseminated intravascular coagulation, 174 Distal tubular functions tests, 425 Distributive shock, 289 Disuse osteoporosis, 527 Diuretics definition of, 390 mechanism of action of, 390t, 391f osmotic diuretics, 390, 391 side effects of, 390t Diurnal fluctuation, 720 DM. See Diabetes mellitus DNA. See Deoxyribonucleic acid DNA cloning, 53 DNA fingerprinting, 52–53 DNA helicase, 50 DNA polymerase, 50 DNA replication, 50, 51f DNA synthesis folate role in, 154, 155f Dopamine, 271 Doppler flow meters, 258 Doppler technique, 233 Dorsal column nucleus, 670f Dorsal columns, 667 Dorsal horn gating, 669f Dorsal respiratory group of neurons, 352 Dorsal thalamic nuclear groups, 622 anterior group of nuclei, 623 intralaminar nuclei, 623 lateral group of nuclei, 623 medial group of nuclei, 623 midline nuclei, 623 nuclei, ventral group, 622–623 reticular thalamic nucleus, 623 Dorsolateral prefrontal circuits, 627 DPTI. See Diastolic pressure–time index DRG. See Dorsal respiratory group of neurons Drumstick-like appendage, 580 DTH. See Delayed-type hypersensitivity D-tubocurarine, 95 Dual insufficiency, 119 Dual-label Schilling test, 453 Dumping syndrome, 467 Duodenal secretions bile juice, 448, 448f pancreatic juice, 449–450, 449f Dust cells, 317 Dye-dilution technique, 232–233, 233f

2/14/14 2:39 PM

812

Principles of Medical Physiology Dynamic airway compression, 326 Dynamic airway obstruction, 370–371 Dynamic exercise, 234 blood pressure in, 281 cardiac output in, 238, 238f Dynamic lung compliance, 324–325 hysteresis of, 325 static vs., 322 Dynamic lung volumes airflow rates, 336–339 expiratory flow rates, 336–339, 337f, 338f forced expiratory volume, 336 ventilatory capacity, 339 Dynamic sensors and static, 26, 26f Dynein, 32 Dysdiadokokinesia, 621 Dysmetria, 617 Dyspnea, 328 Dyspneic index, 339

E Eccentric contraction, 117 E-C coupling. See Excitation– contraction coupling Eccrine sweat glands, 308, 308t ECF calcium pool, 528 ECF volume expansion, 395 Edema causes of, 266, 266f extracellular, 266 intracellular, 266 EEG. See Electroencephalography Effective refractory period, 77 Efferent visceral nervous system, 642 Einthoven’s hypothesis, 208f Einthoven’s law and equation, 208b Einthoven’s triangle, 1, 207, 208, 208f Electrical charge, 12 Electrical silence, 214 Electric current, 12 Electric field, 14, 14f Electricity and fluid dynamics, similarity between, 13–14, 14f Electric potential, 12 Electrocardiogram, 207 baseline of, 215f changes in myocardial infarction, 214f, 215 changes in myocardial ischemia, 213–215, 214f, 215f ECG waves duration and amplitude of, 210t intervals and segments, 211 P wave, 210, 210f QRS complex, 210, 210f, 211, 212f T wave, 210, 210f, 211 U wave, 210, 210f, 211 vectorial basis of, 211, 211f, 212

Sircar_Chapter BM_803-836.indd 812

isoelectric potential, 215–216, 215f Electrocardiography, 207 calibration, 209, 210 recording in frontal plane augmented limb leads, 209, 209f orientation of lead lines, 207, 208, 208f standard limb leads, 209, 209f recording in transverse plane, 209 unipolar vs. bipolar recording, 208 Electroconvulsive therapy, 703 Electroencephalogram alpha waves, 706 beta waves, 707 delta waves, 707–708 theta waves, 707 Electroencephalography, 706 alpha block, 708f analysis of, 706 averaging, principle of, 711f blink artifact, 710f electrode placement, international system, 707f epilepsies, 713 focal seizures, 713 generalized seizures, 713 epileptiform EEG discharges, 708–709 important waves, 708f montages, 708f pyramidal cell, apical dendrite of, 709f quantitative analysis, 710 data reduction, 710–711 event-related potentials, 712–713 evoked potentials, 712 recording technique, 706 electrode derivations, 706 electrode placement, 706 montage, 706 reticular nucleus, 710f synchronous paroxysm, 712f thalamic relay neurons, 710f waves origin, 709 ionic mechanism, 710 synchronization, 709 Electrolytes absorption of, 457 in bile juice, 448 in blood volume regulation, 283 disturbances, 161 metabolism and insulin, 548f, 549 Electromagnetic flow meters, 258 Electromechanical coupling, 124 Electromechanical systole, 229, 230 Electromyogram, normal, 112–113, 112f end-plate noise, 113 insertion activity, 112–113 recruitment patterns, 113 Electromyography definition of, 112

MUP. See Motor unit potential during muscle contraction, 114, 114f during muscle relaxation, 113 recording, 111, 111f standard protocol for, 112 Electroneurography, 114–115 Electron transport chain, 485, 486, 486f Electroolfactogram, 799 Electrophoresis, 23 Electrophoresis apparatus, 23f Electrophoretic mobility, 23 Electrotonic and local potentials, 79f Electrotonic conduction, 86–87 definition of, 86 factors affecting, 86, 87 Embden–Meyerhof pathway, 137, 138, 138f, 487 Emboli, 174 Emergent property model, 352–353, 353f EMG. See Electromyography Emotions, 699 Arnold theory of, 700f Cannon–Bard theory, 700 James–Lange theory, 699–700 neural substrates of, 700 amygdala, 702 cerebral cortex, 700–701 hypothalamus, 700 Emphysema, 325, 370 lung compliance in, 325 Emulsification, 450, 450f Endocrine control circulating vasoconstrictors, 271–272 circulating vasodilators, 271 Endocytosis, 40 Endogenous opioid peptides, 655 Endogenous pyrogens, 725 Endolymph, 784 Endolymphatic hydrops, 796 Endolymphatic potential, 785 Endometrium, 557 Endoneurium, 63 Endoplasmic reticulum, peptides synthesized on rough, 28, 28f Endothelins, 269–270 Endplate potential, 93 Energy, 5 Energy balance, 494 Enlongation factor, 51 Enterochromaffin-like (ECL) cells, 446 Enterogastric reflexes, 443 Enterogastrone, 464b Eosinopenia, 180 Eosinophilia, 180 Eosinophilic cationic protein, 179 Eosinophilic count, 180 Eosinophilic granules, 179 Eosinophils, 176, 179f Ephaptic conduction, 91–92 Ephrins, 64

2/14/14 2:39 PM

Index Epicritic sensations, 661 Epilepsies, 713 focal seizures, 713 generalized seizures, 713 Epinephrine, 544 action on cardiac muscle, 128– 129 adrenergic receptors, 545 cardiovascular effects of, 272, 272t metabolic effects of carbohydrate metabolism, 545 fat metabolism, 545 Epineurium, 63 EPP. See Endplate potential EPSP. See Excitatory postsynaptic potential Equal pressure point theory, 325f, 326 Equilibrium potential of membrane, 70 ERP. See Effective refractory period; Event related potentials Erythroblastosis fetalis, 161–162 Erythrocytes. See Red blood cells Erythrocytic sedimentation rate, 133–134 Erythroid hyperplasia, 140b Erythropoiesis, 138 in bone marrow, 138 cytoplasmic changes during, 202f microcytes and macrocytes, 202 normoblasts, 201, 202 nutritional requirements for, 138 pronormoblast, 201 reticulocyte, 202 Erythropoietin, 138, 555 Esophageal reflux, pevention of, 438, 439 ESR. See Erythrocytic sedimentation rate Estradiol, 557 physiological effects, 557t progesterone, physiological actions of, 557t Estrogen, 125–126, 534 biosynthesis of, 554f Estrogenic phase, 567 Estrone, 557 ET. See Endothelins Event related potentials, 713 Excitation–contraction coupling in cardiac muscle, 129, 129f definition of, 99 in skeletal muscle, 99, 99f Excitatory amino acids, 669 Excitatory postsynaptic potential, 656f vs. inhibitory postsynaptic potential, 656, 656f spatial summation of, 657f Exercise, 410, 553 blood pressure in, 281 effect on alveolar gas exchange, 346

Sircar_Chapter BM_803-836.indd 813

effect on oxygen dissociation curve, 349 and muscle circulation, 308–309 and pulmonary circulation, 305 RQ in, 495 sympathetic effects in, 278 Exercise-induced hyperventilation, 360 Exocytosis, 40–41 Exogenous anticoagulants, 171 Exogenous pyrogens, 725 Expiration diaphragm position in, 318, 318f muscles of, 319–320, 319f Expiratory flow rates, 336–339, 337f, 338f Expiratory reserve volume, 333 Expiratory vital capacity, 333 Exportins, 28 External hydrocephalus, 300 External intercostal muscles, 319 External longitudinal resistance, 87 External urinary sphincters, 431–432 Extracellular body fluid, osmolarity of, 132 Extracellular ionic concentrations, effect of changes in, 73, 73f, 73t Extrapersonal space, 637 Extrapyramidal fibers, 688 Extrapyramidal symptoms, 704 Extravascular hemolysis, 138, 145, 149 Extrinsic nerves, 437 Extrinsic pathway activation of factors VII, VIII, and V, 167–168, 168f activation of factor X, 168, 168f factor IV, 169 fibrin monomers, 168, 168f initiation of, 167 thrombin formation, 168, 168f Extrinsic rhabdomyosphincter, 431–432 Exudate, 264 Eye, anatomy of, 744f Eye blink reflex, 619 Eye, functional anatomy of aqueous circulation, 745 aqueous humor, 745 circulation, 745 intraocular pressure, 745 cornea, 744 corneal transparency, 744 layers of, 746f glaucoma in angle-closure glaucoma, 747 in open-angle glaucoma, 747 lacrimal apparatus, 746 lens, 744–745 open-angle glaucoma, miotics, 747f sclerocorneal angle, 747f tear film, layers of, 746f

813

uveal tract, 745 choroid, 745 ciliary body, 745 iris, 745 vitreous humor, 746

F Facial nerve, 801 Facilitated diffusion. See Passive carrier-mediated transport Facilitatory reticular formation, 682, 683 Fallot tetralogy, defects in, 248f Familial blood groups, 158 Farlateral hypothalamus, 727 Fasciculation potentials, 113, 114f Fasciculus cuneatus, 667 Fasciculus gracilis, 667 Fast axoplasmic transport, 56 Fast twitch fibers, 103 Fat digestion, 451–452, 452f, 455 Fat metabolism β-Oxidation of fatty acids, 490, 491f cortisol effect on, 540 fatty acid synthesis, 488–490, 490f and glucagon, 549, 549f growth hormone effect on, 514 and insulin, 548f, 549 lipogenesis, 491, 492f lipolysis, 491, 492f in postabsorptive state, 496, 498f TH role in, 521 Fats, 473 absorption of, 456, 456f, 457 metabolism of. See Fat metabolism Fat-soluble vitamins, 475 Fatty acid and membrane fluidity, 36 synthesis, 488– 490, 490f Fatty liver, 501 F cells, 547 Fecal fat test, 453 Feces, 460, 460t Feed-forward inhibition, 617 Feeding behavior, 727 hormonal regulation leptin, 728 neuropeptide, 728–729 neural regulation brain areas, 728 hypothalamic control, 727–728 hypothalamic obesity, 728f Feeding center, 727 Female contraceptives barrier contraceptives, 577 implants, 578 intrauterine contraceptive devices, 577 long-acting injectables, 578 oral contraceptives, 577 tubectmy, 578

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814

Principles of Medical Physiology Female gametogenesis folliculogenesis antral/Graafian follicle, 565 ovulation, 564 primordial follicles, 565 secondary follicles, 565 tertiary follicles, 565 oogenesis, 564 Female pronucleus, 575 Female pseudohermaphroditism, 537 Feminine fat deposition, 560 Feminization, 537 Ferritin, 152f, 153, 153t Fertilization, 573 penetration of egg investments cumulus oophorus, 574 zona pellucida, 574 stages of, 575f Fetal ABO hemolytic disease, 162 Fetal circulation, 245, 245f, 246f Fetal hemoglobin, 142, 143 Fetal respiratory movements, 355 Fetal ventricles in parallel, 247b Fetus, sexual differentiation, 580 aberrant sexual differentiation, 581 chromosomal sex Barr body, 580, 580f chromosomal sex, abnormalities, 582f Klinefelter’s syndrome, 581– 582, 582f true hermaphrodites, 583 Turner syndrome, 582, 582f DHT effect on external genitalia, 582t external genitalia, 581 female pseudohermaphroditism, 583t gonadal differentiation, 580f gonadal sex, 580 internal genitalia, 581, 581f female internal genitalia, 581, 581f male internal genitalia, 581, 581f male pseudohermaphroditism, 583t normal, 580 phenotypic sex, abnormalities complete androgen resistance syndrome, 584 female pseudohermaphrodite, 583 male pseudohermaphrodite, 584 persistent Mullerian duct syndrome, 584 sexual differentiation, 582f FEV. See Forced expiratory volume FF. See Filtration fraction FFA. See Free fatty acid Fibrillation potentials, 113–114, 113f Fibrinolysin. See Plasmin

Sircar_Chapter BM_803-836.indd 814

Fibrinolysis, 172, 569 Fibrosing alveolitis. See Interstitial lung disease Fick principle, 231, 232f FIGLU. See Formiminoglutamate Filtration fraction, 421–422 Firing level, 82, 82f Firing level (threshold potential) and conduction velocity, 88 Fitness test, cardiac output in, 239 Flanking sequences, 53 Flare, 307 Flexion, definition of, 690b Flocculonodular lobe. See Archicerebellum Flow-induced vasodilatation, 268, 269f Flow-limited transport, 265f vs. diffusion-limited transport, 344 Flow rate vs. flow velocity, 253, 253b, 254f Flow–volume loop, 337–338 Fluid analogy of electricity, 13–14, 14f Fluid and electrolyte homeostasis disruption and restoration of, 399f effectors of, 397–398 homeostatic mechanisms, 396–397 receptors for fluid osmolarity and volume, 397 Fluid and electrolyte imbalances, 399f, 429 hypertonic fluid loss, 400 hypertonic saline intake, 400 hypotonic fluid intake, 398 hypotonic or isotonic fluid loss, 400 isotonic fluid intake, 398 water fluid intake, 398 Fluid flow, 7 Fluid mosaic model of membrane structure, 36–37, 37f Fluid-phase pinocytosis, 41 Fluid pressure, 4, 13 Fluid resistance, 13 Folate deficiency common causes of, 154, 155 test for, 155–156 Folic acid action of, 154 nutritional aspects of, 155t in plants, 154 structure of, 154, 154f Follicle-stimulating hormone (FSH) secretion, 563 Follicular cell in hormone synthesis, 517 Follicular phase, 567 Folliculogenesis antral/Graafian follicle, 565 ovulation, 564 primordial follicles, 565 secondary follicles, 565 tertiary follicles, 565

Food digestion, 454 Food intake regulation, 727 appetite, leptin action mechanism, 728f central regulatory mechanisms, 727 energy balance/obesity, 730 genetic obesity, 730 neurogenic/endocrine obesity, 730 psychogenic obesity, 730 feeding behavior, 727 feeding behavior, hormonal regulation leptin, 728 neuropeptide, 728–729 feeding behavior, neural regulation brain areas, 728 hypothalamic control, 727–728 hypothalamic obesity, 728f hypothalamic obesity, 728f leptin feedback control, 728f peripheral feedback mechanisms gastrointestinal feedback, 729 metabolic feedback, 729 satiety center, feedback control of, 727f sham feeding, 729f Force, 3 Forced expiratory volume, 336 Forced vital capacity, 333 Formiminoglutamate, 155–156 Fornix, 596 Fourier transform, 12 Frank–Starling law of heart, 234 FRC. See Functional residual capacity Free fatty acid, 488 Free-water clearance, 419, 420 F-response, 115, 115f Freund’s adjuvant, 189 Frontal eye field, 634, 778, 779 Functional residual capacity, 333–335 estimation methods helium dilution (closed circuit) technique, 334 nitrogen washout (open circuit) technique, 334–335 plethysmography, 334f, 335 FVC. See Forced vital capacity

G Galactokinesis, 591 Galactose tolerance test, 502 Galactosuria, 424 Galactosyl transferase, 593 Galanin, 729 Gallstones, 471–472, 471f, 589 Galvanic skin resistance, 646 Gamma-amino butyric acid, 651 Ganglion, 56 Gap junctions, 33, 33f Gastric (hydrochloric) acid, 447

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Index Gastric acid output, 446–447 Gastric acid secretion mechanism of, 444–445, 444f phases of, 446, 446f regulation of, 445–446, 445f vagus effect on, 446 Gastric effects, 539 Gastric emptying, 443 Gastric enzymes, 447 Gastric mucosa, gastric glands of, 443, 444, 444f Gastric mucus, 444 Gastrocephalic axis, 462 Gastroesophageal reflux, 466 Gastroileal reflex, 454 Gastrointestinal-associated organs, disorders of, 470–471 Gastrointestinal disorders, lower constipation, 469–470 diarrhea, 470 disorders of intestinal transit, 467–468 malabsorption syndrome, 468–469 Gastrointestinal disorders, upper disorders of lower esophageal sphincter, 466 peptic ulcers, 467 Gastrointestinal feedback, 729 Gastrointestinal hormones cholecystokinin, 462, 462t, 463 feedback control, 465, 465f gastric inhibitory peptide, 463 gastrin, 462, 462t, 463 gastrin-releasing polypeptide, 465 guanylin, 465 and insulin, 547 motilin, 464 neurotensin, 465 peptide YY, 464 secretin, 462, 462t, 463 types of, 462 vasoactive intestinal peptide, 464 G cells, 446 Genetic code, 49–50 Germline (selective) theory of immune specificity, 195 Gestational diabetes insipidus, 414 G forces, 3 and circulation, 257–258, 258f GFR. See Glomerular filtration rate GH. See Growth hormone Ghrelin, 729 Gibbs–Donnan equilibrium, 20, 20f Gill-withdrawal reflex, 736 Glaucoma in angle-closure, 747 in open-angle, 747 Glomerular capillaries, Starling forces operating at, 382 Glomerular filtration autoregulation of, 383, 383f, 384 of fluids, 383 of solutes, 382, 383 and Starling forces, 382, 382f

Sircar_Chapter BM_803-836.indd 815

Glomerular filtration rate, 396 expression for, 383 factors affecting, 383 and inulin clearance, 421–422 measurement, 425 rate of Cl- filtration into, 389 and renal sympathetic discharge, 385, 385f Glomerular function tests, 424–425 Glomerular proteinuria, 423 Glomerulotubular balance, 389–390 Glossopharyngeal nerve, 801 Glucagon, 549, 549f anticipatory secretion of, 464f, 465 and insulin secretion, 547 Glucocorticoids for circulatory shock, 290 metabolic effects of, 539, 539f physiologic actions of, 538–540 secretion control, 538, 538f Gluconeogenesis, 157, 486f, 487–488 Glucose and insulin, 547 renal handling of, 411 renal threshold for. See Renal threshold for glucose Glucose 6-phosphate dehydrogenase (G6PD) deficiency, 139, 176 glucose–sorbitol–fructose pathway, 487, 487f Glucose tolerance test, 553 GLUcose Transporter, 411 GLUT. See GLUcose Transporter Glutamate, 650–651, 762 excitotoxicity, 650 receptors, 650 Glycine, 652 Glycogenesis, 487, 487f Glycolipids, 37 Glycolysis, 100 Embden–Meyerhof pathway, 487 glucose–sorbitol–fructose pathway, 487, 487f HMP pathway, 487, 487f Glycosphingolipids, 35 γ-Motor discharge, 678 GnRH. See Gonadotropin-releasing hormone Goitrogens, 520 Goldblatt hypertension, 284 Goldman equation, 70 Golgi apparatus, 29, 29f nonconstitutive or constitutive pathways, 30 peptides synthesized on, 28, 28f Golgi bottle neurons, 689 Golgi tendon organ, 679 Golgi tendon reflex, 679, 682 reflex arc of, 680f Golgi-tendon reflex, 677 Golgi type-I, 632 and type-II neurons, 56 Gonadotropin-independent precocity, 561

815

Gonadotropin-releasing hormone, 555, 560, 560f Graafian follicle, 564, 564f Graded potentials and action potentials, differences between, 80, 80t definition of, 80 Grand mal epilepsy, 713 Granular cortex, 632 Granulocytes, 176 maturation of, 202 Granuloma formation, 192 Granulosa cells estrogens from androgens, 556f hormones secretion, 556f Gravitational force, 3 Gravity alveolar ventilation, 341–343 and jugular venous pressure, 256, 257, 257f pulmonary circulation, 305 vascular factors, 238 Group-I hormonal action, mechanism of, 504, 504f Group-I hormones, 505t Group-II hormones, 505t classification of, 504, 507t group-IIA hormones, 505t, 507 group-IIB hormones, 507, 508f group-IIC hormones, 508, 508f group-IID hormones, 508–509 hormonal receptors, 505 membrane-located enzyme activation by, 506f water-soluble peptide hormones, 504 Growth and maturation, TH role in, 521 Growth hormone IGF and insulin, interrelationship between, 514f physiologic effects of carbohydrate and fat metabolism, 514 insulin-like effects, 514 protein metabolism, 514 skeletal growth, 514 secretion, control of, 513, 513f Growth hormone disorders gigantism and acromegaly, 514–515, 515f pituitary dwarfism, 515 Growth of organs, 498, 498f GSR. See Galvanic skin resistance GTP-binding protein, 762 GTT. See Glucose tolerance test Guanadrel, 654 Gustation gustatory pathway, 801 gustatory processing, 801 gustatory transduction, 801 tastes, neural encoding, 802 sapid substances, 800 tongue gustatory papillae, 800–801 taste buds, 801

2/14/14 2:39 PM

816

Principles of Medical Physiology Gustatory fibers, 640 Gustatory pathways, 801f Gustatory processing, 801 gustatory transduction, 801 tastes, neural encoding, 802 Gustatory sweating, 647 Gustatory transduction, 801

H Hair cell depolarization, 788 Hair cells, 787f Hair follicle receptors, 661 Haldane effect, 350 Hallucination, 672 Harvard step test, 239 Haustral shuttling, 458 HbF. See Fetal hemoglobin HCG. See Human chorionic gonadotropin Head righting reflex, 694 Hearing tests age-related sensorineural deafness, 789, 790f air-conducted and boneconducted, 790f audiometric tests, 791 auditory evoked potentials, 791 brainstem auditory evoked potentials, 792–793 electrocochleography, 791 efferent cochlear control, 789, 789f inner hair cells, 787b middle/inner ear, schematic anatomy, 783f tuning fork tests, 790, 791f Rinne test, 791 Schwabach test, 791 Weber test, 791 Heart, 291f circulatory beds in series and parallel with, 13f circulatory load on, 234 conductive system of, 205, 205f atrioventricular node, 206 bundle of His, 206 internodal and interatrial pathways, 205 intrinsic automaticity, 205 Purkinje system, 206 sinoatrial node, 205 as demand pump, 237f instantaneous electrical axis of, 206–207 level in manometry, 259b mean electrical axis of, 212–213, 213f sympathetic innervation of, 273 work done by, 252 Heart block, 217–218, 218f Heart rate and cardiac cycle, 228 Heart sounds loud/split, 228 murmurs, 228 produced by heart valves, 228

Sircar_Chapter BM_803-836.indd 816

Heart valves, 224f Heat, 8 exhaustion, 725 pathway of blood through, 224 Heating mechanisms behavioral mechanisms, 722 chemical/nonshivering thermogenesis, 722 cutaneous vasoconstriction, 722 horripilation, 722 shivering, 722 Heat nociceptors, 664 Heat transfer, 8, 86 Heavy meromyosin, 58 Hebbian potentiation, 658 Helicotrema, 783f, 784 Helium dilution (closed circuit) technique, 334 Helper cells, 199 Heme pigments, 424 Hemicholiniums and ACh release, 94 Hemidesmosome, 33 Hemochromatosis, 154 Hemodialysis, 430 Hemodilutional anemia, 140, 588 Hemodynamics and Poiseuille– Hagen formula, 7 Hemoglobin, 403 concentration at different ages, 142, 142f estimation of, 142 reactions of buffering of hydrogen ions, 144 carbamino hemoglobin, 144 with carbon monoxide, 144 with DPG, 144 glycosylation, 144 oxygenation, 144 structure of, 142, 143f synthesis, 142–143, 143f Hemoglobin breakdown bilirubin, 145–146, 145f urobilinogen, 146, 146f Hemoglobin disorders hemoglobinopathies hemolytic anemia, 145 sickle cell anemia, 144–145 vasoocclusive crisis, 145 thalassemias, 145 Hemoglobinemia and hemolysis, 148–149 symbolic cascade of, 149f Hemoglobinopathies hemolytic anemia, 145 sickle cell anemia, 144–145 vasoocclusive crisis, 145 Hemoglobinuria, 149 Hemolysis and hemoglobinemia, 148–149 Hemolytic anemia, 139, 140 Hemolytic disease of newborn erythroblastosis fetalis, 161–162 fetal ABO hemolytic disease, 162 Hemolytic reactions, 161

Hemopexin, 149 Hemophilia, 173 Hemopoiesis, extramedullary sites of, 200, 200f Hemopoietic cells, 201f growth and differentiation of, 200 Hemopoietic cytokines, 200, 201 Hemopoietic pathways, 201f Hemorrhagic anemia, 140 Hemorrhagic disorders coagulation disorders, 172f hemophilia, 173 vitamin K deficiency, 173 von Willebrand’s disease, 173 platelet disorders, 172 thrombotic disorders, 173–174 vascular disorders, 172–173 Hemosiderin, 153, 153t Hemosiderinuria, 149 Hemosiderosis, 153, 161 types of, 154 Hemostasis, 164f clot retraction, 164 constriction of damaged vessel, 164f fibrinolysis, 164 platelet plug formation, 164 Henderson–Hasselbalch equation, 22 Henneman (size) principle, 105–106, 105f Hepatic acinus, 311, 311f Hepatic artery, hydrostatic pressures in, 311f Hepatic cellular integrity, tests for, 502 Hepatic circulation oxygen supply, 311–312 portal venous and hepatic arterial systems, 311 Hepatic conjugation and excretion, tests for, 502 Hepatic detoxification, 30 Hepatic encephalopathy, 460 Hepatic lobule, 311, 311f Hepatic metabolic reaction, tests for, 502 Hepatic microsomal enzymes, 28 Hepatic sinusoids, 311 Hepatic synthesis, tests for, 502 Hepatic vein, hydrostatic pressures in, 311f Hepatocellular diseases, 173 Hepatolenticular degeneration. See Wilson’s disease Hereditary cerebellar ataxias, 620 Hereditary spherocytosis, 38 Hermaphrodites, 583 Herring bodies, 414 Heschl gyrus, 785 Heterometric mechanism of cardiac contractility, 234 Hexose monophosphate shunt pathway, 138, 487, 487f High-altitude hypoxia, compensatory responses to, 366t

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Index High-fiber supplements, 479 High-pressure breathing breath-holding, 364 breathing air from container, 364 problems of, 364–365 through snorkel, 364, 364f High-pressure nervous syndrome, 365 Hippocampus, 599 Hirschsprung disease, 469–470 Histamine, 268 Histamine receptors, 315 Histotoxic hypoxia, 361 HMM. See Heavy meromyosin HMP pathway. See Hexose monophosphate shunt pathway Hollander insulin test, 447 Homeostasis, 24 Homeothermic, 720 Homometric mechanism of cardiac contractility, 234 Homosynaptic plasticity hebbian potentiation, 658 late LTP, 658 long-term depression, 658 long-term potentiation, 657 posttetanic potentiation, 657 Homosynaptic processes, 657 Hormonal action, mechanism of control of cellular activity, 504 paracrine/autocrine, 504 Hormonal feedback control, 464, 464f, 465 Hormone action ‘kit,’ 506f Hormones, 504. See also Specific types and neurotransmitters, difference between, 504 Hormone-sensitive lipase, activation of, 492f Horner syndrome, 647 HPNS. See High-pressure nervous syndrome H-response, 115, 115f Human chorionic gonadotropin, 554 Humoral immunity complement system, 198, 198t definition of, 196 and immunoglobulin. See Immunoglobulin Hunger, 727 Huntington chorea, 630 Hyaline casts, 424 Hyaline membrane disease, 330 Hyaluronidase, 574 Hydrocephalus, 299–300 Hydrogen ion secretion. See Proton secretion Hydrostatic pressure, 3–4, 4f Hydroxyproline, 527 Hyperaldosteronism, 284, 542 Hyperbaric 100% O2, 361, 362

Sircar_Chapter BM_803-836.indd 817

Hyperbilirubinemia conjugated bilirubinemia. See Conjugated bilirubinemia unconjugated bilirubinemia. See Unconjugated bilirubinemia Hypercapneic respiratory drive, effect of arousal state on, 356f Hypercapnia, 359 and respiratory acidosis, 362 Hyperchromia, 136 Hypereffective heart, 235, 239 Hypergammaglobulinemia, 502 Hyperglycemia, 501, 745 Hyperinsulinemia, 728 Hyperkalemia, 161, 409 Hypermetropia, 752b, 759 Hyperosmolar solution, 21 Hyperparathyroidism, 532 Hyperphagia, 722 Hyperpnea, 362 Hyperproteinemia, 135 Hyperpyrexia, 725 Hypersecretory hydrocephalus, 300 Hypersensitivity reactions, 191–192, 191f Hypersplenism, 186 Hypertension adverse effects of, 285 clinical, 284–285 clinical classification of, 285t definition of, 283 experimental, 284 treatment of, 285 Hyperthermia, 725 heat exhaustion, 725 heatstroke, 725 hypothalamic set point, 725 Hypertonic fluid loss, 400 Hypertrophic areflexic bladder, 434 Hyperventilation, 361 exercise-induced, 360 Hypervitaminosis, regulatory mechanism preventing, 532f Hypnic myoclonia, 719 Hypocalcaemia, 161 Hypocapnia and respiratory alkalosis, 362–363 Hypochromia, 136 Hypoeffective heart, 235 Hypoglycemia, 501 Hypokalemia, 408, 409 Hypokinesia, 629 Hypoosmolar solution, 21 Hypoparathyroidism, 83 Hypophysiotropic hormones, 510 Hypoproteinemia, 135, 383 Hypothalamic autonomic center, 274, 275 Hypothalamic control “arm,” 510f Hypothalamic diseases, 561 Hypothalamic hormones, 510–511 Hypothalamic–hypophysial control of adrenocortical secretion, 538f

817

Hypothalamic obesity, 728 Hypothalamic thermostat, 721 Hypothalamo-hypophyseal portal system, 625 Hypothalamo-hypophyseal tract, 625 Hypothalamo-hypophysial control, 510–511, 511f Hypothalamo-hypophysial portal system, 511, 512 Hypothalamus, 625, 642 connections of, 625 diencephalon, 624 limbic cortex, 625 functions of, 625 schematic representation, 624f Hypotonic fluid intake, 398 Hypotonic fluid loss, 400 Hypoventilation, 362 Hypovitaminosis D, 532 Hypovolemia, 309 Hypovolemic shock, 289 Hypoxia, 90, 360–361 Hypoxic hypoxia, 360 Hypoxic stimulation, 277 Hysteresis loop. See Pressure–volume loop

I ICSI. See Intracytoplasmic sperm injection Icterus. See Jaundice IDDM. See Insulin-dependent diabetes mellitus Ideomotor apraxia, 685 Idiopathic constipation, 470 IGFs. See Insulin-like growth factors IGT. See Impaired glucose tolerance Ileocecal transit, 458–459 Image formation, physics of, 9, 9f Immune complex disorder, 191f, 192 Immune paralysis, 190 Immune reaction hypersensitivity reactions. See Hypersensitivity reactions Immune response cell-mediated immunity. See Cellmediated immunity central phase of, 194 B-cell differentiation, 194f, 195 blast transformation, 194 T-cell differentiation, 194–195, 194f effector phase of stages of, 196 humoral immunity. See Humoral immunity initial phase of, 193 Immune specificity, theories of, 195–196, 195f Immune surveillance as natural immunity, 187 Immune tolerance specific, 190 tolerance to fetus, 190 tolerance to self, 190

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818

Principles of Medical Physiology Immunity acquired. See Acquired immunity definition of, 187 natural. See Natural immunity Immunodeficiency, 189–190 Immunoelectrophoresis, 425 Immunoglobulin, 197f components of, 196–197 immunoglobulin-A (IgA), 197, 317 immunoglobulin-D (IgD), 197 immunoglobulin-E (IgE), 197 immunoglobulin-G (IgG), 197 immunoglobulin-M (IgM), 197, 197f Immunological protection, 317 Immunomodulation immunoenhancement, 188–189 immunosuppression, 189 Immunosuppression, 189 Immunotherapy, 188–189 Impaired glucose tolerance, 553 Importins, 28 Indirect-reacting bilirubin, 147 Inertia, concept of, 3 Infant respiratory distress syndrome, 330 Infants, nutritional requirements of, 483 Inferotemporal cortex, 637 Infertility, 33 Inflammation as natural immunity, 187 Inhibitory postsynaptic potential, 656, 656f spatial summation of, 657f Inhibitory reticular formation, 682 Initial lymphatics, 265 Initiation codon, 51 Initiation factors, 51 Innate immunity. See Natural immunity Inner ear cochlea, 783 cochlear fluids, 784–785 cochlear nerve, 785 corti, organ of, 785f Inner hair cells, 786 ‘Innocent bystanders,’ 192 Inside-out asymmetry, 37 Inspiration diaphragm position in, 318, 318f muscles of, 318–319, 319f work done on and by lungs during, 5, 6f Inspiratory ramp, 353 Inspiratory reserve volume, 333 Inspiratory vital capacity, 333 Insula, 599, 600f Insulin, 449 anticipatory secretion of, 464f, 465 glucagon, and somatostatin secretion, interrelationship between, 550f metabolic actions of

Sircar_Chapter BM_803-836.indd 818

carbohydrate metabolism, 548–549, 548f electrolyte metabolism, 548f, 549 fat metabolism, 548f, 549 protein metabolism, 548f, 549 secretion control, 547–508, 547f structure of, 547f synthesis of, 547 Insulin-dependent diabetes mellitus, 550, 551t Insulin-like growth factors, 514 Insulin therapy, 553 Integral calculus, 2 Integral proteins composition of, 35–36 functions of, 36 polar residues of, 36f Integrator neurons, 353 Integrins, 64 Intensity of sound wave, 11 Intercellular junctions, 33–34 Interkinesis, 47 Intermediate filaments, 32 Intermediate lobe of pituitary, 512 Intermittent photic stimulation, 709 Internal capsule, 599 Internal hydrocephalus, 299 Internal intercostal muscles, 320 Internal urinary sphincters, 431 Internodal and interatrial pathways, 205 Interstitial lung disease, 372, 372f Interstitial lung disorders, 360 Interstitial oncotic pressure and edema, 266 Intestinal bacteria, 460 Intestinal digestion, 454 Intestinal mucosa, transport across, 455f Intestinal obstruction, 468 Intestinal transit, disorders of, 467–468 Intestine, calcitriol effect on, 531 Intestinointestinal reflex, 454 Intracranial temperature, 720 Intracristal space, 30 Intracytoplasmic sperm injection, 577 Intraesophageal spaces, 326f Intrapleural pressure, 327–328 Intrapleural spaces, 326f Intrapulmonary pressure, 327, 328, 329f Intrapulmonary relaxation pressure, 322, 323 Intrathoracic spaces, 326f Intravascular hemolysis, 149 Intrinsic automaticity, 205 Intrinsic leiomyosphincter, 431 Intrinsic rhabdomyosphincter, 431 Inulin clearance and GFR, 421–422 In vitro coagulation, 166, 167 In vivo coagulation, 167 Involutional osteoporosis, 527

Iodide trapping, 519 Iodide uptake, 518 Iodotyrosines, coupling of, 519 Ion channels agents altering, 83 classification of, 41–42 electrical conductance measurement patch clamp technique, 84–85, 84f voltage clamp technique, 84, 84f integral membrane proteins, 41 molecular structures of, 85, 85f specificity of, 41–42, 42f structural characteristics of, 41, 41t Ionic conductances, 77–78 Ionic currents, calculation of, 72t Ionic distribution, 19, 19f at Gibbs–Donnan equilibrium, 20f, 20t Ionotropic GABA A receptors, 658 IPSP. See Inhibitory postsynaptic potential Iris muscles, 779 Iron, 151 absorption mechanism of, 151 regulation of, 152, 152f nutritional aspects of, 151t storage, 153 transport in plasma, 152 Iron cycle, 152, 152f Iron deficiency anemia, 140, 141 Iron excess, disorders of, 153–154 Islets of Langerhans, 547f Isoelectric pH, 23 Isometric contraction, 97 energy expenditure in, 109 initial phase of, 108 isotonic and, comparison of, 109, 109t muscle tension vs. muscle excursion in, 117 Isoosmolar solution, 21 Isoosmotic solution, 21 Isopters, 754 Isosthenuria, 423 Isotonic contraction, 97 intermediate phase of, 108 isometric and, comparison of, 109, 109t muscle tension vs. muscle excursion in, 117 Isotonic fluid loss, 400 Isovolumetric ventricular contraction, 225, 226f Isovolumetric ventricular relaxation, 225, 226f, 227

J Jacksonian epilepsy, 713 Jaundice, 146 Jendrassik maneuver, 690

2/14/14 2:39 PM

Index Jugular venous pressure, 227–228, 257f and gravity, 256, 257, 257f Junctional potentials, 125 Juxtaglomerular apparatus, 379, 379f, 380 Juxtaglomerular (JG) cells, 379 Juxtamedullary nephrons, 376, 379f Juxtapulmonary (J) receptors, 354, 355, 355f JVP. See Jugular venous pressure

K Kartagener’s syndrome, 32 Karyopyknotic index, 567 Kayser–Fleischer ring, 479, 479f KE. See Kinetic energy Ketonuria, 424 Kety method, 295 Kidney calcitriol effect on, 531 functions of, 376 nephrons. See nephrons partial longitudinal section of, 376f renal blood vessels. See Renal blood vessels structure of, 376, 376f, 377f Kinetic energy, 5 Kininogens, 269 Kinins, 269 Kinocilium, 794 Klinefelter’s syndrome, 47, 581–582, 582f, 583f Kluver–Bucy syndrome, 640 Korotkoff sounds phases of, 260, 260t and turbulence, 260, 260f Korsakoff psychosis, 640 KPI. See Karyopyknotic index Krause’s glands, 746 Krebs cycle, 100, 485, 485f Kussmaul breathing, 404 Kwashiorkor and marasmus, comparison of, 474–475, 474f, 475t Kyphoscoliosis, 320

L Lacis cells, 380 Lactation amenorrhea, 594 Lactation hormones on breast development, 593f hyperprolactinemia, 591 milk ejection, control, 594f oxytocin, 591 phases of galactokinesis, 593 galactopoiesis, 593–594 lactogenesis, 593 mammogenesis, 593 pregnancy/suckling, prolactin levels, 594f prolactin, 591 relaxin, 591

Sircar_Chapter BM_803-836.indd 819

Lactosuria, 424 Lambert-Eaton myasthenic syndrome, 96 Lamellipodium, 178 Laminar vs. turbulent flow, 254–255 Laminins, 64 Language, 740, 740t Laplace’s law, 6f, 252 physiological phenomena and, 6–7 statement, 6 Large intestine. See Colon Large uncharged polar molecules simple diffusion of, 38 Laron-type dwarfs, 515 Larynx, 313 Latch mechanism, 122–123, 123f Lateral dorsal nucleus, 623 Lateral premotor area, 635 Law of inertia, 3 Laws of motion, 3 LBBB. See Left bundle-branch block L-dopa, 630 Leader sequence, 29 Lead hemifield, concept of, 212 Lead pipe rigidity, 629 Leak currents, 69 Learning classification of, 735f nonassociative habituation, 735 sensitization, 736 Left bundle-branch block, 218, 219f Left-to-right shunting, 247 Left ventricular failure, 306–307 Left ventricular hypertrophy, 285 LEMS. See Lambert-Eaton myasthenic syndrome Lengthening contraction. See Eccentric contraction Length-servo mechanism, 681 Leukocyte casts, 424 Leukocytes, 176 Leukocytic pyrogens, 725 Leukocytosis, 177 Leukopoiesis, 202 Lever mechanical advantage of, 4 in musculoskeletal system, 119– 121, 120f physics of, 5f Leydig cells, 555, 581 LH. See Luteinizing hormone Ligand-binding sites, 43f Ligand-gated cation channel structure of, 42t Ligand-gated channels, 42 Light and dark bands, 98 Light meromyosin, 58 Light, refraction of, 8 Limbic cortex, 642 Limbic system, 638 Lipase, 440 Lipid bilayer, 35–36, 36f Lipogenesis, 492, 492f

819

Lipolysis, 491, 492f Lipostatic feedback, 729 Liver blood storage in, 312 dual blood flow to, 311, 312 estrogens, physiological actions, 557 extirpation of, 501 functional unit of, 310 functions of, 501 oxygen supply to, 312 role in metabolism, 501 Liver function tests, 502 LMM. See Light meromyosin Load handling, 123b, 123f Lobuloalveolar growth, 593 Local anesthetics ion channel blockage by, 83, 84 nerve conduction failure by, 90 Local circuit neurons, 55–56 Local current circuit, 86, 87f Local potentials. See Graded potentials Logarithms, 2–3 Long-loop stretch reflex, polysynaptic, 679 Long-term depression, 658 Loop diuretics, 389 Loudness of sound wave, 11 Lower esophageal sphincter, disorders of, 466 Lower respiratory tract alveoli, 314 blood supply, 315 tracheobronchial tree, 313–314, 314f Low-pressure breathing acclimatization, 366–367 acute exposure to high altitude, 366 acute mountain sickness, 366 chronic mountain sickness, 367 signs and symptoms at high altitudes, 365, 366t LPA. See Lateral premotor area LTD. See Long-term depression Lumbar puncture, 299, 299f Luminal antibiotics, 460 Lung compliance, 322f definition of, 320 dynamic. See Dynamic lung compliance in emphysema, 325 hysteresis of, 324f, 325–326 measurement of, 321f specific, 322 static. See Static lung compliance “train” of, 321f Lung irritant receptors, 354 Lungs, 318 diffusion capacity of, 344–346 metabolic and endocrine functions, 317 nonrespiratory functions of immunological protection, 317

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820

Principles of Medical Physiology physical protection, 315–317 work done on, during breathing, 5, 6f Lung–thorax combine compliance of, 320, 322 static compliance of, 322–224 Lung–thorax–diaphragm analog model, 328f Luteal phase, 569 Luteinizing hormone, 554, 561 Luteolysis, 568 Lymph, 265 Lymphagogues, 265 Lymphatic circulation, 245, 264–266 Lymphatic obstruction, 469 Lymphatic vessels, 265–266, 265f Lymphedema, 266 Lymph node, 184–185, 185f Lymphoblasts, 202 Lymphocyte count, 183 Lymphocytes, 183, 183f Lymphocytic processing, 183–184 Lymphocytosis, 183 Lymphoid tissue central or primary, 184 definition of, 184 lymph node, 184–185, 185f peripheral or secondary, 184 spleen, 185–186, 185f thymus, 184 Lymphopenia, 184 Lymph vessels, 265f Lysophospholipase, 179 Lysosomal enzymes, 31 Lysosomal storage disorders, 31 Lysosomes, 31 Lysyl-bradykinin, 269

M Macrocytic anemias, 140 Macronutrients carbohydrate, 473–474 fat, 473 protein, 474 Macroreentrant circuits, 219, 220, 221f Macula, 795 Macula adherens, 33 Macula densa, 380 Macula lutea, 761 Magnocellular neurosecretory system, 510 Major basic protein, 179 Major histocompatibility molecules role in T-cell differentiation, 194– 195, 194f and tissue grafting, 193 Malabsorption syndrome, 468–469 Male contraception azoospermic agents, 579 condoms, mechanical devices, 578 reversible inhibition of sperm under guidance (RISUG), 578 thermal methods, 578 vasectomy, 578 vas-occlusive plugs, 578

Sircar_Chapter BM_803-836.indd 820

Male gametogenesis spermatogenesis, 562 temperature, 563, 563f testosterone, 563 spermiogenesis, 562–563 testes structure, 561 blood–testes barrier, 561 seminiferous tubules, 561 sertoli cell, 561 sperm, 561 Male pronucleus, 575 Male pseudohermaphroditism, 583t Malignant hyperthermia, 725 MAO. See Maximal acid output; Monoamine oxidase Marasmus and kwashiorkor, comparison of, 474–475, 474f, 475t Mast cells, 180, 180t Mastication, 437 Maternal changes, pregnancy, 588 amenorrhea, 588 circulation, 588–589 gall bladder, 589 glucose tolerance, 589 hormones, effects of, 588 hyperventilation, 588 plasma proteins, 589 Matrix space, 30 Maximal acid output, 447 Maximum breathing capacity, 339 Maximum midexpiratory flow rate, 337 Maximum voluntary ventilation, 339 MBC. See Maximum breathing capacity MBP. See Major basic protein MCH. See Mean corpuscular hemoglobin MCHC. See Mean corpuscular hemoglobin concentration MCV. See Mean corpuscular volume Mean blood pressure, 280 Mean corpuscular hemoglobin, 137 Mean corpuscular hemoglobin concentration, 136, 137 Mean corpuscular volume, 137 Mechanical advantage, 4 Mechanical ventilators, 330 Mechanomechanical coupling, 124 Mechanoreceptors, 273, 661, 664 Medial reticulospinal tract, 614 Medial superior olivary nucleus, 790 Medial superior temporal area, 772 Medial vestibular nuclei, 778 Medial vestibulospinal tract, 794, 796f Mediastinal shift, 374 Medulla, 376, 609 Medulla oblongata, 604 Medullary chemoreceptors. See Central chemoreceptors Medullary chemoreceptor trigger zone, 654

Medullary neurons, 352–353 Medullary parasympathetic center, 274 Medullary sympathetic center, 274 Megakaryoblast, 202, 203 Megakaryocytes, 202, 203f Megaloblastic anemia, 140, 157 Megaloblasts, 155 Meiosis definition of, 45 male vs. female, 47f stages of, 45–47, 46f, 47f Meiotic chromosomal nondisjunction, 47, 47f Meiotonic contraction, 117 Meissner corpuscles, 661, 663b Melanin, 512 Melanin-concentrating hormone, 729 Melanocytes, 512 Melanocyte-stimulating hormone, 512 Melanophores, 512 Melanosomes, 512 Melatonin, 622, 719 Membrane accommodation, 79 asymmetry, 37 capacitance, 13, 87 composition, 35 hyperpolarization and conduction velocity, link between, 88 perforation of, 199 space constant of, 89 time constant of, 89–90 tonicity, 21–22 Membrane conductance measurement, 84–85, 84f, 85f Membrane currents, 71–73 Membrane disorders, 37–38 Membrane excitability during action potential, 76–77, 77f and calcium ion, 83, 83f indices of, 79–80 Membrane lipids, 35 amphipathic, 35 closed bilayer, 35, 36f Membrane-located enzymes, activation of, 506f Membrane phospholipids, 35, 35f Membrane potential, 71 definition of, 69 effects on channel permeability, 81 general principles of, 69 Membrane potential, effect of channel permeability on, 82f after-depolarization, 83 destabilizing effect, 82 firing level, 82 stabilizing effect, 82 Membrane proteins, 35 and membrane fluidity, 37, 37f

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Index Membrane pump and exchanger, 130, 130f Membrane resistance, 87 Membrane stimulation cathodal stimulation, 78–79 and membrane accommodation, 79 strength–duration curve, 79, 79f Membrane structure fluid mosaic model, 36–37, 37f lipid bilayer, 35–36, 36f Membrane transport carrier-mediated, 39f energy for, 38 inhibitors of, 40 mechanism of, 40 passive, 38 primary-active, 38–39 rate of, 39–40 secondary-active, 39 types of, 38 endocytosis, 40–41 exocytosis, 41 simple diffusion, 38 Memory associative learning, 736 biofeedback, 738 instrumental/operant conditioning, 737 Pavlovian conditioning, 736, 737f child learning, 733 classification of, 735f explicit processing, 731 consolidation/storage, 732–733 encoding of, 732 episodic/autobiographical memory, 731 incidental learning, 733 insight, 734 interhemispheric memory transfer, 733 semantic/factual memory, 731 working memory, 732 implicit memory, 734 learning, differences, 731f learning, levels of, 732f nonassociative learning habituation, 735 sensitization, 736 priming, 734 procedural learning, 734–735 synaptic mechanism, 735, 736f visual memory, interhemispheric transfer of, 733f Menopause, 569 Menstrual cycles, 566 basal body temperature/hormonal concentrations, 566f cervical mucus, ferning of, 567f ovarian/endometrial changes, 568f ovulation tests for, 567 phases of, 566f

Sircar_Chapter BM_803-836.indd 821

postovulatory period breast changes, 569 cervical changes, 569 hormonal changes, 568 ovarian changes, 567–568 uterine changes, 568 vaginal changes, 569 preovulatory period, 566 breast changes, 569 cervical changes, 569 hormonal changes, 566–567 ovarian changes, 568 uterine changes, 568 vaginal changes, 569 MEPP. See Miniature endplate potential Mercury manometer, 4, 4f Mesenteric circulation, 310–311 Mesolimbic pathway, 654 Mesopontine cholinergic system, 652, 718f Messenger RNA, 49 Metabolic acidosis, 410. See also Acidosis causes of, 404t graphic analysis of, 406, 406f Metabolic alkalosis, 404, 404t. See also Alkalosis Metabolic rate BMR, 496 estimation of, 495 resting, 495 TH role in, 521 Metabolic syncope, 297 Metabolism anabolic and catabolic states, 494, 494f anabolism vs. catabolism, 494 carbohydrate. See Carbohydrate metabolism energy balance, 494 estrogens, physiological actions, 557 fat. See Fat metabolism nitrogen balance, 494 protein. See Protein metabolism Metabotropic GABAB receptors, 658 Metallothioneins, 478 Metarterioles, 249, 249f Methemalbuminia, 149 Methemoglobin, 144 Methemoglobinemia, 144 Methotrexate, 155 Methylmalonic aciduria, 157 MHC molecules. See Major histocompatibility molecules Micelles, 450 Microcytes and macrocytes, 202 Microepididymal sperm aspiration, 577 Microglial cells, 57, 57f Microminerals, 478 Micronutrients mineral nutrients, 478 vitamins, 476t, 477t, 478t

821

categorization of, 475 fat-soluble, 475 role in metabolic reactions, 475, 479f water-soluble, 475 Microreentrant circuits, 219, 220f Microsomes, 28 Microtubules and microfilaments, 31–32, 31f Micturition centers basal ganglia, 433 cerebral cortex, 433 pontine micturition center, 432–433 sacral micturition center, 432 Micturition, mechanism of, 433–434 Midbrain, 602f Middle ear, 783 acoustic impedance matching, 783 acoustic reflex, 784 Eustachian tube, 783 Migrating motor complexes, 442– 443, 443f, 454 Milieu intérieur and cerebrospinal fluid, 298 Milk–alkali syndrome, 404 Mineral nutrients, 478 Mineralocorticoid escape, 416 Mineralocorticoids, 540 Miniature endplate potential, 94 Minipill, 578 Miraculin, 802 MIS. See Mullerian inhibiting substance Mitochondria, 29f mitochondrial genome, 30 outer and inner membrane of, 30 structure of, 30 Mitosis chromosomal nondisjunction in, 45, 46f definition of, 44 stages of, 44–45, 45f Mitotic nondisjunction, 45, 46f MMCs. See Migrating motor complexes MMEFR. See Maximum midexpiratory flow rate Molecular chaperones, 29 Molecular motors, 32 Molecular techniques DNA cloning, 53 DNA fingerprinting, 52–53 polymerase chain reaction, 52f, 53 Southern blotting, 52 Monge disease, 367 Monoamine oxidase, 649, 653 Monoaminergic transmitters, neurotransmitters, 652–655 cocaine, 654 dopamine cells, 653–654 epinephrine, 654 histamine, 654 norepinephrine, 653 serotonin, 654

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822

Principles of Medical Physiology Monoblast, 202 Monochromats, 774 Monocytes, 182–183, 182f, 202 Monocytosis, 182 Mononuclear phagocytic system constituents of, 182 functions of, 183 Monophasic combined pill, 577 Monosynaptic reflex, 679 gain, 679 group-Ia afferents, motor recruitment, 679 spindle sensitivity to stimulus, 679 Monosynaptic reflex, gain, 679 group-Ia afferents, motor recruitment, 679 spindle sensitivity to stimulus, 679 Monro–Kellie doctrine, 296 Mood disorders anxiety, 703 mania, 703 melancholic depression, 702 Mossy fibers, 617 Motility of empty stomach, 442–443 Motility of fed stomach, 443 Motor adaptation, 735 Motor cortex ankle joint, positive supportive reaction, 692f antigravity muscle tone, 691 crossed extensor reflex, 692f crossed extensor reflexes, 691 decorticate posture, 694f locomotion rhythm, 695f motor programming, role, 687f occlusion, 691f positive supporting reaction, 691 postural reflexes, 691t rescue reactions, 691, 693 reverberating circuits, 691f tonic labyrinthine reflexes, 691, 694f tonic neck/labyrinthine reflexes, 692 α-Motor discharge, 678 Motor fibers, 315 Motor homunculus, 636 γ-Motor neurons, 678 Motor paralysis, 696t Motor planning, 685 ballistic movement, 687, 688 electroencephalogram, 685 ideational apraxia, 685f preparatory-set activity, 685 Motor unit definition of, 104 innervation ratio, 104–105 motor recruitment, 105–106, 106f territory, 105, 105f type-I, 106, 106t type-II, 106t, 107 Motor unit potential amplitude of, 112

Sircar_Chapter BM_803-836.indd 822

definition of, 112 duration of, 112 Mouth-to-mouth breathing, 330 MPS. See Mononuclear phagocytic system M-response, 115, 115f mRNA. See Messenger RNA MSH. See Melanocyte-stimulating hormone MST. See Medial superior temporal area Mucokinesis, 316 Mucosa, 437, 437f, 437f Mucosal absorptive defects, 469 Mucosal block theory, 152, 152f Müllerian duct inhibiting substance, 561 Mullerian duct syndrome, 584 Mullerian inhibiting substance, 581 Müller-Lyer illusion, 673f Multiorgasmic, 572 Multipolar neurons, 56, 56f Multipotent progenitor cells, 200 Murmurs, 228 Muscle. See also Specific types functional role in movement, 118 internal architecture of, 117–118, 117f Muscle action components of, 118, 118f integrated, 118 laws of, 118 two-joint muscles, 119, 119f Muscle cell, sarcoplasmic reticulum in, 58 Muscle circulation, 308–309 Muscle contraction activity associated with, 113 agonist-antagonist muscle pairs, 689f ATP role in, 99 EMG during, 114, 114f energy source for, 99–100 reciprocal inhibition, 689f subliminal fringe, 689f and Z-lines, 58 Muscle excursion vs. muscle tension, 117, 118t Muscle fatigue, 103 Muscle fibers contraction of, 57 cytoskeletal proteins in, 58–60 slow and fast twitch, 103 types of, 57, 57t Muscle heat, 100 Muscle length regulation, 681 constant muscle length, maintenance of stretch reflex, 680 desired length, muscle contraction alpha-gamma coactivation, 681 alpha-led activation, 680 gamma-led activation, 681 Muscle loading, 104, 104f

Muscle pump, 237–238, 310 Muscle relaxation ATP role in, 99 with cross-bridge cycling termination, 99 EMG during, 113–114 Muscle spasticity, 682 Muscle-Specific tyrosine Kinase, 68 Muscle spindle, 677 loading/unloading, 678, 678f through α-motor discharge, 678 through γ-motor discharge, 678 through muscle stretch, 678 monosynaptic reflex arc, 677f motor innervation, 678 sensory innervation, 677–678 static/dynamic spindle responses, 678 Muscle tension vs. muscle excursion, 117, 118, 118t Muscle tone, 681 supraspinal control of, 682, 682f Muscle tone abnormalities decerebrate rigidity, 683 classical decerebration, 683 decerebrate rigidity, mechanism of, 683 ischemic decerebration, 683 decorticate rigidity, 683–684 flaccidity/spasticity/rigidity, 682 spinal shock, 682 Muscular activity, 730 MuSK. See Muscle-Specific tyrosine Kinase Mutation, 50 MVO2. See Myocardial oxygen consumption MVV. See Maximum voluntary ventilation Myasthenia gravis, 38, 96 Myelination of neurons, 55–56, 55f and saltatory conduction, 88–89, 88f, 89f Myeloperoxidase, 177 Myocardial contractility, 235 Myocardial hibernation, 292 Myocardial infarction consequences of, 292 ECG changes in, 214f, 215 Myocardial interstitial tissue pressure, 291, 292f Myocardial ischemia, 285 consequences of, 292–293 ECG changes in, 213–215, 214f, 215f risk of, 294 treatment of, 293, 293f Myocardial oxygen consumption, 293–294 Myocardial oxygen demand, 291 Myogenic autoregulation, 296 of muscle circulation, 308–309 Myoglobin, 349 Myometrium, 557

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Index Myopathic disorders, 114 Myopia, 759 Myosin cross-bridges, phosphorylation of, 122 Myosin filaments, 59f composition of, 58 fragments of, 58–59 Myotrophic effect, 555

N Na+-activated K+ channels, 129 Na+–K+ ATPase, 39–40, 40f Na+–K+ pump, 69 activity and ion concentration, 73–74 analogy for understanding, 74 electroneutral, 74 role in membrane potential, 73–74 Narcolepsy, 719 Natriuresis, 429 Natural immunity immune surveillance, 187 inflammation, 187 Natural killer, 201f Negative pressure breathing, 330 Negative stretch reflex, 677 Neocerebellum, 615 Neocortex, 632 Neonatal jaundice, 147 Neostigmine, 95, 96 Nephritic syndrome, 427, 427t Nephrogenic diabetes insipidus, 414 Nephrogenic proteinuria, 424 Nephron, parts of Bowman capsule, 377–378, 378f juxtaglomerular apparatus, 379, 379f, 380 tubular cells, 380, 381f uriniferous tubule, 379, 379f Nephrons, 376 Nephrotic syndrome, 427, 427t Nernst equation, 2 Nernst potential, 19, 70, 70f Nerve conduction axon reflex, 91 ephaptic conduction, 91–92 mechanism of electrotonic conduction, 86–87 propagation of action potential, 87 myelination and saltatory conduction, 88–89, 88f, 89f traveling flame analogy of, 86, 86f Nerve conduction failure factors causing, 89–90, 89t in myelinated neuron, 89 Nerve conduction velocity factors affecting, 87–88 measurement compound action potential, 114–115 F-response, 115, 115f H-response, 115, 115f M-response, 115, 115f

Sircar_Chapter BM_803-836.indd 823

Nerve degeneration anterograde, 64, 65f retrograde, 64–65 Nerve fibers, strength-duration curves of, 79f Nerve growth factor, 63–64 Nerve impulse, conduction of, 69 Nerve injury, classification of, 66, 66t Nerve regeneration, 65, 66f Nerves chromatolytic changes in soma of, 65f connective tissue sheaths, 63 growth cone of, 63–64, 64f Nervous system, 405, 596f Netrins, 64 Neural control of mesenteric circulation, 310 of muscle circulation, 309 Neural sharpening, 616 Neuregulin, 68 Neurofibrillary tangles, 54 Neurofibrils, 54 Neurofilaments, 32, 54 Neurogenic diabetes insipidus, 414 Neurogenic fever, 724 Neurogenic shock, 289 Neuroglia astrocytes, 57, 57f functions of, 57 microglial cells, 57, 57f oligodendrocytes, 57, 57f Neurohormonal controllers of gastric acid secretion, 445, 445t Neurohormonal reflexes, 396, 397, 397f Neurohypophysis, 511, 513 Neuromuscular junction in smooth muscle, 61f, 62 synapse, 61, 61f Neuromuscular transmission drugs affecting, 94–95 steps of, 93, 93f Neuromuscular transmission, diseases of Lambert-Eaton myasthenic syndrome, 96 myasthenia gravis, 96 Neurons axon of, 54 cytoskeleton of, 54 dendrites, 54–55 morphological classification of, 56 myelination of, 55–56, 55f organization of, 56 soma, 54 structure of, 54, 54f Neurons, order, 666 anterolateral-spinothalamic pathway, 667 dorsal column-medial lemniscal pathway, 667 spinal tracts, for pain, 668 trigeminal lemniscus, 668

823

Neuropathic bladders autonomic dysreflexia, 434 comparison of, 434t flaccid, 434 hypertrophic areflexic bladder, 434 spastic, 434 Neuropathic disorders, 114 Neuropeptides, 649, 655–656, 669 neuropeptide Y, 729 vs. neurotransmitters, 655t Neuropraxia, 66, 66t Neurosecretions, 510 Neurotemesis, 66, 66t Neurotransmitters, 124, 769 acetylcholine, 652 acetylcholine, sites, 652f amino acid, 650 gamma-amino butyric acid, 651 glutamate, 650–651 glycine, 652 ATP as, 649 classification of, 649, 649f criteria of, 649 false neurotransmitters, 649 GABA A/B receptors, 652t glutamate cotransport, into nerve terminals, 650f glutamate-induced EPSP, late components, 651f and hormones, difference between, 504 monoaminergic transmitters, 652–655 cocaine, 654 dopamine cells, 653–654 epinephrine, 654 histamine, 654 norepinephrine, 653 serotonin, 654 vs. neuropeptide, 655t small molecule, 649 type-1/type-2 neurons, 650t Neurotrophins, 63–64 Neutropenia, 177 Neutrophilia, 177 Neutrophilic count, 177 ways to increase, 176 Neutrophilic granules azurophilic granules, 177 specific granules, 177 Neutrophils, 176 frequency distribution of, 176 functions of activation, 178 chemotaxis, 178 diapedesis, 178, 178f disorders of, 179 margination, 178, 178f migration to tissue, 176 size and shape of, 176 Newtonian fluid, 7 NGF. See Nerve growth factor NIDDM. See Non-insulin-dependent diabetes mellitus

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824

Principles of Medical Physiology Nigrostriatal pathway, 654 Nipple erection, 572 Nissl bodies, 54 Nitric oxide actions of, 269f physiological functions of, 268–269 Nitric oxide synthetase, 268 Nitrogen balance, 494 Nitrogen narcosis, 365 Nitrogen washout (open circuit) technique, 334–335 Nociceptors, 661, 663–665 Nocturnal enuresis, 719 Nonadrenergic, noncholinergic (NANC) parasympathetic fibers, 315 Nonapical skin, 308 Nonautomatic cardiac fibers, action potentials of, 127–128, 127f Noncardiac syncope, 297 Noncommunicating hydrocephalus, 300 Noncompetitive inhibitor, 40 Noncyanotic heart defects, 247 Nondeclarative, 734 Nondepolarizing neuromuscular blocker, 95 Non-insulin-dependent diabetes mellitus, 550–551, 551t Nonionic diffusion and diffusion trapping, 412f, 4125 Nonrapid eye movement, 715 Nonspirometric lung volumes, 333 Norepinephrine adrenergic receptors, 545 cardiovascular effects of, 272, 272t synthesis, secretion, and inactivation, 653f Normoblasts, 201, 202 Normocytic anemias, 140 Northern blotting, 52 NOS. See Nitric oxide synthetase NREM. See Nonrapid eye movement NTS. See Nucleus of tractus solitarius Nuclear pores, 28 Nucleic acids basic subunits of, 49 digestion, 452, 455 Nucleolus, 28, 28f Nucleosome, 28, 28f Nucleotides, 49 Nucleus, 28, 28f Nucleus basalis, of Meynert, 652 Nucleus dorsalis. See Clarke column Nucleus interpositus, 616 Nucleus of tractus solitarius, 273, 801 Nutritional assessment anthropometry. See Anthropometry criteria for, 481

Sircar_Chapter BM_803-836.indd 824

O Obesity, 498 Obstructive airway disorders bronchial asthma, 369–370 chronic bronchitis, 370 chronic obstructive pulmonary disorder, 370–371 emphysema, 370 flow-volume loops in, 368, 369t large airway obstruction, 368 small airway obstruction, 368, 369 Obstructive lung disorders and restrictive lung disorders, comparison of, 368, 368t Obstructive shock, 289 Ocular dominance columns, 771 Oculomotor circuit, 627 Oculomotor mechanisms abnormal pupillary reflexes Argyll–Robertson pupil, 782 Marcus–Gunn pupil, 782 accommodation, 780 accommodation reflex, 780f electrooculogram, principle of, 777f extraocular motor mechanisms, 776 intraocular motor mechanisms, 779 light reflex, 781f monocular movements, 776f near reflex, 781f pupillary reflexes, 780 light reflex, 780 near reflex, 780–781 psychosensory reflex, 782 Purkinje–Sanson images, 780, 781f strabismus, 779 versions/elevations/depressions, 778f versions/vergences conjugate movements, 777 disjugate movements, 777 vestibuloocular reflex, 780f visual target, fixation optokinetic reflex, 778 saccadic movements, 779 smooth-pursuit movement, 778 vestibuloocular reflex, 777 Ohm’s law, 12 Olfaction odorant molecules, 799 olfactory mucosa, 799 olfactory pathway, 799 olfactory processing neural encoding, 800 transduction, 799 Olfactory bulb, 799 Olfactory epithelium, 800f Olfactory nerves, 800f Oligodendrocyte, 55 Oligodendrocytes, 57, 57f

Oliguria, 366, 423 Oogonium, 564 Open-loop control system, 25 Ophthalmoscope, 757 Ophthalmoscopy, 756–758 Opsonization, 196 Optic radiation, 766 Oral ammonium chloride test, 425 Oral water-loading test, 425 Orexins, 729 Organic acids, 404 renal handling of, 412 Orthopnea, 328 Orthostatic proteinuria, 423 Osmolar clearance, 419 Osmolarity changes in tubules, 392, 392f Osmoles, osmolarity, and osmolality, 21–22 Osmoreceptors, 397 Osmosis, 20 Osmotic coefficient, 21 Osmotic diuretics, 390, 391 Osmotic pressure, 20–21, 20f Osteitis fibrosa cystica, 528 Osteoblasts, 527 Osteocalcin, 527 Osteoclasts, 526, 526f Osteocytes, 526 Osteomalacia and rickets, 527, 527f Osteopetrosis, 528 Osteoporosis, 527, 527f Osteosclerosis, 528 Outward current, 72 Ovarian cycle, 566 preovulatory phase, 566 Ovarian follicles, 564f Ovary hormone, 125 endocrine cells of granulosa cells, 555–556 luteal cells, 556 thecal cells, 555 estrogens, estradiol (E2), 556–558 hormonal control of, 558, 558f progestagens, 558 physiological effects, 558 Overflow proteinuria, 423, 424 Overshoot, 620 Ovulation, 564 Ovum, activation, 575 Oxygen delivery, 347t, 404 Oxygen-rich gas mixture, 361–362 Oxygen therapy for circulatory shock, 290 Oxygen toxicity, 362, 365 Oxygen transport in blood dissolved form in plasma, 347 oxygen dissociation curve, 347, 348f acidosis effect on, 349 coefficient of utilization, 347–348 exercise effect on, 349 of myoglobin, 349f shifts in, 348, 348f, 349 as oxyhemoglobin, 347

2/14/14 2:39 PM

Index Oxygen transport in tissues, 349 Oxygen treatment, 361–362 Oxytocin, 593

P Pacemaker potentials, 124, 125 in automatic cardiac muscle fiber, 128, 128f Pacemakers classification of, 223, 223t definition of, 223 Pacinian corpuscles, 663, 666f PAH clearance and renal plasma flow, 420–421 PAI. See Plasminogen activator inhibitors Pain, supraspinal control, 670f Pale muscles, 103 Pallesthesia, 661 Pallidum, 626, 627f PAM. See Pulmonary alveolar macrophages Pancreas, 547 Pancreatic enzymes, actions of carbohydrates digestion, 451, 452 fat digestion, 451–452, 452f nucleic acids digestion, 452 protein digestion, 450 Pancreatic function tests digestion product analysis, 453 pancreatic juice analysis, 452–453 Pancreatic juice analysis, 452–453 Pancreatic polypeptide, 550 Pancreatic secretion, regulation of, 449–450 Panhypopituitarism, 515 Pansystolic murmurs, 228 Papez circuit, 623, 702f Papilledema, 300 Paracrine control endothelins, 269–270 kinins, 269 nitric oxide, 268–269, 268f prostaglandins, 270–271, 270f Paradoxical sleep, 715 Parallax, 774 Parametric control system, 25–26 Parametric feedback control, 25 Parametric feedforward control, 25 Paraplegia, 608 Parasympathetic cholinergic fibers, 315 Parasympathetic innervation of bladder, 432 of blood vessels, 273 Parasympathetic nervous system, sympathetic and, 643f Parasympathetic stimulation, 440 Parathyroid hormone, 528f bone resorption, 528, 529 calcium homeostasis, 528–529 phosphate homeostasis, 529 Parathyroid hormone-related protein, 528 Parietal lobe, 595

Sircar_Chapter BM_803-836.indd 825

Parkinson disease, 628, 629, 629f hypokinesia akinesia, 629 patient posture, 629f rigidity, 629 rigidity, mechanism of, 629f treatment, 630 tremor, 629–630 Parkinsonism, 628 Paroxysmal supraventricular tachycardia, 220, 222f Partial pressure, 18 Partial pressure of CO2 (PCO2), alveolar and blood, 27 Parturition hormones initiation of high E:P ratio, 593 parturition reflex, 593 phases of, 591 uterine phase, 591–592 stages of, 592f birth of newborn, 592f Parvocellular neurosecretory system, 510–511 Parvocellular pathways, 774 Passive carrier-mediated transport, 38 Passive immunity, 188 Passive immunization, 188 Passive insufficiency, 119 Patch clamp technique, 84–85, 85f Patent ductus arteriosus, 247 Pavlov’s classical conditioning, 736 PCR. See Polymerase chain reaction PE. See Potential energy Peak expiratory flow rate, 337 PEFR. See Peak expiratory flow rate PEI. See Physical efficiency index Penile detumescence, 572 Pennate muscles, excursion and tension in, 117, 118 Pentaglutamyl conjugate, 154 Pentose phosphate pathway, 138 Pentosuria, 424 Pepsinogen secretion, regulation of, 447 Peptic ulcers, 467 Peptide chain, elongation of, 51 Peptides, renal handling of, 411 Peptidyltransferase, 51 Perceptual priming, 734 Percussion note, 374 Perilymph, 784 Perimenopause, 569 Perineurium, 63 Peripheral chemoreceptor afferents, O2 effects on, 359, 359f Peripheral cyanosis, 289 Peripheral lymphoid tissue, 184t Peripheral myelination, 55, 55f Peripheral nerves connective tissue sheaths, 63 structure of, 63f Peripheral nervous system, 56 Peripheral proteins, 37

825

Peripheral thermoreceptors, 724 Peristaltic reflex, 454 Peristaltic waves, 438, 454 Peritoneal dialysis, 430 Pernicious anemia, 157 Peroxisomes, 29f, 30 Persistent hyperventilation, 367 PFTs. See Pulmonary function tests p53 gene mutation, 44 Phagocytic vacuoles, 31 Phagocytosis, 40, 178 Phantom limb, 674 Phantom limb pain, 669 Pharmacomechanical coupling, 124 Phase transition temperature, 36 Phasic smooth muscles, excitation and inhibition of, 123 pH disturbances effects of, 404–405 graphic analysis of, 406, 406f, 407 metabolic causes of, 404 Phenobarbital, 147 Phenolphthalein test, 300, 300f Phenylethylamines, 649 Phenylthiocarbamide, 802 Pheochromocytoma, 284, 546 Phineas Gage, 701b skull/brain of, 701f Phoneme, 740 Phosphate, 404 buffers, 403 imbalances, 429 tubular reabsorption of, 413 Phosphene, 664 Phospholamban, 129 Phospholipid transfer, 30f Phosphoric acid, 403 Phosphorylation, cardiac excitation– contraction coupling machinery of, 130–131 Photopic/scotopic vision dark adaptation, 764–765 electroretinogram, 765 light adaptation, 764 Purkinje shift, 764 Photoreceptors, 664 fovea centralis, 761 outer segment, 760 Phototherapy for neonatal jaundice, 147 Phototransduction, 763 dark adaptation, 764, 765f dark current, 762 electroretinogram, 765, 765f resting potential, 762 visual cycle, 762 vitamin A, role of, 762 pH scale, 3 Physical efficiency index, 239 Physiological dead space, 340–341 Physiological shunt, 245, 315f Piebaldism, 513 Pigment gallstones, 471 Pill hypertension, 285 Piloerection, 722

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826

Principles of Medical Physiology Ping-pong mechanism of carriermediated transport, 39f, 40 Pinhole test, 755–754 Pinocytosis, 264 Pitch of sound, 11 Pituitary gland anterior pituitary, 512 hormones secreted by, 512f hypothalamo-hypophysial portal system, 511, 512 intermediate lobe of, 512 origin of, 511 parts of, 511f posterior pituitary, 513 Placental gas transfer, double Bohr effect in, 350, 350f Placental hormones, pregnancy estrogens, 586 human chorionic gonadotropin, 585–586 human chorionic somatomammotropin, 586 human chorionic thyrotropin, 586 progesterone, 586 relaxin, 586 Placental membrane, 585 Plantar flexion against resistance, 120f Plasma anion gap, 406 Plasma bicarbonate, 349, 350 Plasma concentration and clearance, 420 Plasma, constituents of, 133, 133t Plasma oncotic pressure and edema, 266 Plasmapheresis, 135 Plasma proteins, 404 functions of, 134, 134f properties of, 134 synthesis of, 135 types of, 134–135 Plasma urea and creatinine, 425 Plasmin, 171 Plasmin activators, 171–172 Plasminogen activator inhibitors, 172 Platelet canalicular system, 163, 163f Platelet count, 164 Platelet disorders, 172, 173, 174t tests for, 174–175 Platelets, 203 activation, 164, 165f adhesion, 164, 165, 165f aggregation, 165–166 factors affecting, 170 and vasoconstrictor release, 268 contraction, 166 functions of, 163 granules, 163, 163f integrins, 163–164, 163f normal values for, 133t plug formation, 164–166, 165f structure of, 163–164, 163f Plethysmography, 258–259, 258f, 334f, 335

Sircar_Chapter BM_803-836.indd 826

Pleural circulation, 306 Pleural effusion, 373 Pneumocytes, 314 Pneumothorax, 372, 372f, 372t PNS. See Peripheral nervous system Poikilocytosis, 134, 136 Poikilothermic, 720 Poiseuille–Hagen formula, physiological relevance of, 7 Polycythemia, 136 Polymerase chain reaction, 52f, 53 Polymodal nociceptors, 663 Polymorphonuclear leukocyte. See Neutrophils Polyribosomes, 29 Polysomnography, 716 Polysynaptic reflex, 689 Polyuria, 423 POMC. See Proopiomelanocortin Portal lobule, 311f Portal vein, hydrostatic pressures in, 311f Portocaval anastomosis, 312 Positive pressure breathing, 330 Postabsorptive state, 496, 497f, 498f Postcapillary venules, 250 Posterior hypothalamus, 718 Postganglionic neurons, 642 sympathetic preganglionic, 644f Post-hyperventilation periodic breathing, 356 Postjunctional differentiation, 68 Postjunctional membrane, transient depolarization of, 93 Postjunctional potentials, 94 Postovulatory period, menstrual cycles breast changes, 569 cervical changes, 569 hormonal changes, 568 ovarian changes, 568 uterine changes, 568 vaginal changes, 569 Postsynaptic potentials, 656 excitatory postsynaptic potential, 656 inhibitory postsynaptic potential, 656 initial spike/action potential, 657 synaptic integration, 656–657 Posttranslational modification, 29 Postural syncope, 297 Potassium absorption, 457 Potassium balance, 429 aldosterone effect on, 416 and catecholamines, 546 disturbance, disorders of, 409– 410 external, 409, 409f internal, 409, 409f Potassium currents normal and abnormal, 129, 129t stabilizing effect of, 82 Potassium ion channel agents altering, 83

membrane conductance, 84, 84f membrane potential effect on, 81 opening and membrane potential, 82 opening of, 507f structure of, 41, 42t, 85, 85f Potassium ion concentration and membrane conductance, 71f, 72 Potassium ion reabsorption cellular mechanism of, 408, 408f sites in nephron, 408, 408f Potassium ions, 665 Potassium ion secretion cellular mechanism of, 408, 408f factors affecting, 408 sites in nephron, 408, 408f Potassium ion transport, mechanisms of, 408, 408f Potential energy, 5 Power of lens, 8 Power stroke, 97, 97f PP. See Pancreatic polypeptide Precapillary sphincter, 262 Precocious pseudopuberty, 561 Preejaculatory fluid, 571, 572 Preganglionic sympathetic neurons, 642 Pregnancy, 585 cardiovascular changes, 589f diaphragmatic elevation, effects, 589 fetoplacental unit, 586 estriol, placental synthesis of, 588 estrone/estradiol, placental synthesis of, 586 progesterone, placental synthesis of, 586 fetoplacental unit, hormone synthesis, 586, 587f Gravindex test, immunological basis, 588f hormonal concentration, 587f luteal-placental shift, 586f maternal changes, 588 amenorrhea, 588 circulation, 588–589 gall bladder, 589 glucose tolerance, 589 hormones, effects of, 588 hyperventilation, 588 plasma proteins, 589 nutritional requirements in, 484 placenta, 585 placental hormones estrogens, 586 human chorionic gonadotropin, 585–586 human chorionic somatomammotropin, 586 human chorionic thyrotropin, 586 progesterone, 586 relaxin, 586

2/14/14 2:39 PM

Index placenta structure, 586f pregnancy diagnostic tests, 588 uterine cavity, blastocyst, 585f Prejunctional differentiation, 68 Prejunctional membrane, 61 Preload, cardiac, 104, 234 Preovulatory period, menstrual cycles, 566 breast changes, 569 cervical changes, 569 hormonal changes, 566–567 ovarian changes, 568 uterine changes, 568 vaginal changes, 569 Preparatory-set activity, 685 Pre:post capillary resistance ratio, 263, 263f Prepotential, 76 Prepropressophysin, 414 Presbycusis, 790 preSMA. See Pre-supplementary motor area Pressure, 3–4 Pressure drop, 255f Pressure natriuresis, 282f, 283 Pressure on axons, nerve conduction failure by, 90 Pressure–volume curve, 322 Pressure–volume loop, 5 Pre-supplementary motor area, 636, 687f Presynaptic facilitation, 658f Presynaptic inhibition, 658f Primary-active carrier-mediated transport, 38–39, 39f Primary adrenal insufficiency, 541 Primary auditory area. See Auditory area I Primary hyperaldosteronism, 541 Primary hyperparathyroidism, 532 Primary immune responses, 188, 188f, 188t Primary peristaltic waves, 438 Primary thrombocytopenic purpura, 164 Progenitor cells, 200 Progestagens, 558, 577 physiological effects, 558 brain, 558 breast, 558 cervix, 558 endometrium, 558 fetus, 558 kidney, 558 myometrium, 558 vs. progesterone, 558 sex steroids, biosynthesis of, 554f Progestational phase, 568 Progesterone, 592 effect on uterine smooth muscle, 125–126 estradiol, physiological actions of, 557t Prohemostatic mechanisms, 170f, 172

Sircar_Chapter BM_803-836.indd 827

Prolactin, 593 Pronormoblast, 201 Proopiomelanocortin, 512 Prostacyclin synthesis in endothelial cells, 171f and thomboxane A2, comparison of, 170, 170t Prostaglandins functions of, 270 receptors for, 270 synthesis of, 270, 270f Prostate, 571 Prostate-specific antigen, 571 Protamine, 171 Protein C pathway, 170, 171, 172f Protein-energy malnutrition kwashiorkor and marasmus, 474–475, 474f, 475t outcome of, 475b Protein-losing enteropathy, 470 Protein metabolism, 491, 497f, 497f cortisol effect on, 540 and glucagon, 549, 549f growth hormone effect on, 514 and insulin, 548f, 549 in postabsorptive state, 496, 497f products of, 376 TH role in, 521 Proteins, 474 digestion, 450, 455 folding, 29 and nucleic acids, absorption of, 456 renal handling of, 411 Protein synthesis posttranslational modification. See Posttranslational modification in ribosomes, 29 on rough ER, 28, 28f Prothrombin time, 175 Protodiastole, 227 Proton secretion, 444–445 and bicarbonate reabsorption, 403 factors affecting, 402–403 mechanism of, 402, 402f tubular sites of, 402, 402f and urinary buffers, 403 Protopathic sensations, 661 Proximal tubular functions tests, 425 PSA. See Prostate-specific antigen Pseudohermaphroditism, 584 Pseudounipolar neurons, 56, 56f Psychic blindness, 640, 728 Psychoneural effects, 539 PT. See Prothrombin time PTC. See Phenylthiocarbamide PTH. See Parathyroid hormone PTHrP. See Parathyroid hormonerelated protein Pubertal onset, abnormalities of delayed puberty, 561 precocious puberty, 561 Puberty

827

pubertal onset, abnormalities of delayed puberty, 561 precocious puberty, 561 pubertal onset, control of gonadotropin-releasing hormone, 560 leptin, role of, 560 secondary sexual characteristics female secondary sexual characteristics, 560 male secondary sexual characteristics, 560 Pulmonary alveolar macrophages, 152, 317 Pulmonary arterial pressures, 303, 304t Pulmonary baroreceptors, 304 Pulmonary blood pressure, 303 Pulmonary blood volume, 304 Pulmonary capillary dynamics, 304–305 starling forces, 304, 304f Pulmonary circulation, 245, 303, 303f control of, 304 factors affecting exercise, 305 gravity, 305 left ventricular failure, 306–307 zones of, 305, 305f Pulmonary edema, 306, 366 Pulmonary function tests, 368 Pulmonary hypertension and COPD, 371 Pulmonary stretch receptors, 354 Pulmonary tissue resistance, 320 Pulmonary transit time, 304 Pulmonary vasoconstriction, 304 Pulmonary ventilation CO2, O2, and pH effects on, 359, 359f measurements of dynamic lung functions, 332 dynamic lung volumes. See Dynamic lung volumes function residual capacity, 333–335 nonspirometric lung volumes. See Nonspirometric lung volumes static lung functions, 332 static lung volumes. See Static lung volumes Pulmonary wedge pressure, 303, 303f Pulvinar, 623 Pump current with channel current, balancing, 75 Pump-handle movement, 318 Purkinje cell layer, 615, 617 Purkinje–Sanson images, 780 Purkinje shift, 764f Purkinje system, 206 Putamen loop, 687 Pyramidal cells, 632 Pyramidal decussation, 612

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828

Principles of Medical Physiology

Q Quadratus lumborum, 319 Queckenstedt test, 300

R Rab proteins, 650 Radiation, 8 Radical mastectomy, 266 Radioactive iodide uptake, 523 RAGS, 64 Rahn diagram, 323, 324f Ramp movement, 687 Ramp movements, 681 Rapid eye movement sleep, 715, 718 RBBB. See Right bundle-branch block Reactive hyperemia, 309 Receptor-mediated pinocytosis. See Absorptive pinocytosis Receptors. See also Specific types for fluid osmolarity and volume, 397 static vs. dynamic sensitivity of, 26, 26f Recovery heat, 100 Recovery sleep, 717 Red blood cells biconcave shape of, 136 chromicity of, 136 definition of, 136 erythropoiesis. See Erythropoiesis importance of, 136 normal values for, 133t rouleaux formation, 136 Red cell destruction extravascular hemolysis, 138 fragility, 138–139, 139f G6PD deficiency, 139 spherocytosis, 139 Red cell fragility, 38 Red cell indices, 137 Red cell metabolism Embden Meyerhof pathway, 137, 138, 138f pentose phosphate pathway, 138 Red eye reflex, 10, 10f Red muscles, 103 Red reaction, 307 Reflexes, 454–455 Reflex hyperventilation, 359 Reflex learning, 734 Reflex salivary secretion, 440 Refraction of light, 8 Refractive index, 8 Regional asymmetry, 37 Regulatory control, 24 Regulatory proteins, 58 Regulatory system air-conditioned hall, 24, 24f closed-loop control system, 24 combined control, 25–26 open-loop control system, 25 oscillations in, 26–27 principles of, 24 static vs. dynamic sensors, 26, 26f

Sircar_Chapter BM_803-836.indd 828

Regurgitation hyperbilirubinemia. See Conjugated bilirubinemia Relaxation heat, 100 REM sleep. See Rapid eye movement sleep Renal acidification tests, 425 Renal blood flow (RBF) and oxygen consumption, 377, 378 Renal blood vessels, 377, 377f Renal clearance free-water clearance, 419, 420 inulin clearance and GFR, 421–422 osmolar clearance, 419 PAH clearance and renal plasma flow, 420–421 plasma concentration and clearance, 420 urea clearance, 422 Renal function tests distal tubular functions tests, 425 glomerular function tests, 424–425 proximal tubular functions tests, 425 Renal medullary hyperosmolarity countercurrent exchanger in vasa recta, 394, 395, 395f countercurrent multiplier in tubule, 392–394 dissipation of, 392 factors affecting, 395 Renal plasma flow and PAH clearance, 420–421 Renal sympathetic discharge, 385, 385f Renal threshold for glucose definition of, 418 estimation of, 418, 418f “splay,” 419 TmG, 418, 418f Renal water handling, tests for, 425 Renin–angiotensin–aldosterone system, 414–415 Renin–angiotensin mechanism of blood pressure regulation, 282 Renin–angiotensin system, 271 Renin degranulation, principal regulators of, 414 Renshaw cell inhibition, 688f Replacement therapy, 289 Repolarization, 76 Repulsive axon guidance signals, 64 RES. See Reticulo-endothelial system Reserpine, 654 Residual air, 333 Residual volume, 333 Resistance, electric, 12 Respiration, 313 Respiratory acidosis, 410 graphic analysis of, 406, 406f, 407 and hypercapnia, 362 Respiratory alkalosis and hypocapnia, 362

Respiratory burst, 178 Respiratory centers, classical concept of, 354f Respiratory chemoreceptors central, 358–359, 359f peripheral, 358, 358f Respiratory disequilibria hypercapnia and respiratory acidosis, 362 hypocapnia and respiratory alkalosis, 362–363 hypoxia, 360–361 oxygen toxicity, 362 oxygen treatment, 361–362 Respiratory dysrhythmias breathing during sleep, 356 Cheyne–Stokes breathing, 355, 355f, 356 post-hyperventilation periodic breathing, 356 Respiratory equilibrium maintenance, 359 Respiratory membrane, 344, 344f Respiratory minute volume, 339 Respiratory passages lower respiratory tract alveoli, 314 blood supply, 315 tracheobronchial tree, 313–314, 314f upper respiratory tract, 313, 313f Respiratory pump, 237, 237f Respiratory quotient definition of, 494–495 effect of foodstuffs oxidized on, 495 in exercise, 495 Respiratory reflexes, 355 Respiratory resistance, 320 Respiratory rhythm generation of apneustic breathing, 353, 354 emergent property model, 352–353, 353f respiratory centers, 352 Respiratory vs. renal compensation, 405 Respiratory waves in blood pressure tracing, 280, 280f Resting channels, 43 Resting heat, 100 Resting membrane potential definition of, 69 of smooth muscle cell, 124 Resting metabolic rate, 496 Restriction endonuclease, 52 Restriction fragment length polymorphism, 52 Restriction fragments, 52 Restrictive lung disorders atelectasis, 372 clinical diagnosis of, 373–375 clinical signs in, 374t common causes of, 372t consolidation, 372

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Index flow-volume loops in, 368, 369t interstitial lung disease, 372, 372f and obstructive lung disorders, comparison of, 368, 368t pleural effusion, 373 pneumothorax, 372, 372f, 372t Retention hyperbilirubinemia. See Unconjugated bilirubinemia Reticular activating system, 614 Reticular formation lateral reticular formation, 613–614 medial reticular formation, 614 ascending reticular formation, 614 descending reticular formation, 614 subdivisions of, 615f Reticulocytes, 202 Reticulo-endothelial system, 182 Retina fovea centralis, 761f image, 9–10, 10f photoreceptor, dark current, 760–761 photoreceptors fovea centralis, 761, 761f outer segment, 760 pigment epithelium, 761–762 rods/cones, 761t visual cycle, 762, 763f Retinal layers, 760f Retinoscopy, 758 in emmetropia, 759 hypermetropia, 759 optical system, analysis, 758 Retrograde amnesia, 717 Retrograde transneural degeneration, 65–66 Rexed’s laminae, 606f Reynolds number, 7 Rheobase, 80 Rhesus agglutinogen, 158 Rhesus (CDE) systems, 158–159, 158t agglutination test for, 159, 159f agglutinogens and agglutinins, 160 genotypes and inheritance of, 159, 159t Rheumatic heart disease, 190 Ribonucleic acid, 49 Ribosomal RNA, 49 Ribosomes of eukaryotes and prokaryotes, 29 free or bound, 28, 29 Right bundle-branch block, 218, 219f Right-to-left shunting, 247 Rigor mortis, 99 RMP. See Resting membrane potential RMV. See Respiratory minute volume RNA. See Ribonucleic acid RNA polymerase, 51

Sircar_Chapter BM_803-836.indd 829

RNA primer, 50 RNA synthesis, 50–51, 50f Romberg sign, 674, 688 Rouleaux formation, 134, 136 RQ. See Respiratory quotient rRNA. See Ribosomal RNA Ruffini end organs, 662f RV. See Residual volume Ryanodine (RYR) Ca2+-release channels, 99

S Safety factor, 90 Saliva composition of, 439, 439t functions of, 439 and salivary glands, 439 secretion of, 439 autonomic nerve stimulation and, 440f regulation of, 440 Salivary acini and ducts, 439, 439f Sallowing. See Deglutition Saltatory conduction and myelination, 88–89, 88f, 89f Salt craving, 398 Salt depletion, 400–401 Salt-loading curve, 283, 283f SAM (S-adenyl methionine) production, 157 SAOAF. See Sperm-associated oocyte-activation factors Sarcomere, 58, 59 Sarcoplasmic reticulum, 31, 58 Saxitoxin, 83 Schaffer collateral pathway, 657 Schematic eye, 749, 749f Schilling test, 156 Schizophrenia, 704 antipsychotic drugs, 704 brain abnormalities, 704 nonpsychotic state, 704 psychomimetic drugs, 704 psychotic episodes, 704 Schwann cells myelination of peripheral neurons by, 55, 55f regeneration, 65, 66f Scintiscanning, 522 Scopolamine, 652 Scotomata, 756 Secondary adrenal insufficiency, 541 Secondary granules, 176 Secondary hyperaldosteronism, 542 Secondary hyperparathyroidism, 532 Secondary immune responses, 188, 188f, 188t Secondary sexual characteristics female secondary sexual characteristics, 560 male secondary sexual characteristics, 560 Secretory diarrhea, 470

829

Segmental propulsion (peristalsis), 458 Segmentation contractions, 454 Semaphorins, 64 Semen analysis, 571–572 seminal plasma, 571 Semenogelin, 571 Seminal vesicle, 571 SEMs. See Slow eye movements Sensorineural deafness, 791 Sensory ataxia, 694 Sensory disorders, 674 cortical lesions, 675 representational neglect, 675f spatial neglect, 675f syringomyelia, 674–675 tabes dorsalis, 674 Sensory fibers in bronchial epithelium, 315 Sensory homunculus, 636, 669 Sensory mechanisms, 660 conscious sensations, 660 cortical sensory processing, 671–672 disorders, 674–675 pathways, 666 perception, 672–673 projection, 673 receptors, 660–664 subcortical sensory processing, 669–671 transduction, 664–665 unconscious senses, 660 Sensory nerve fibers, classification of, 667t Sensory pathways, 667 neurons, order, 666 anterolateral-spinothalamic pathway, 667 dorsal column-medial lemniscal pathway, 667 spinal tracts, for pain, 668 trigeminal lemniscus, 668 Sensory perception, 672 sensory conflict, 672–673 specific nerve energies, doctrine of, 673 Weber-Fechner law, 673 Sensory projection, 673, 674f Sensory receptors, 660–664 classification of, 660, 660f fine vs. crude touch, 661 general exteroceptors, 661 pain receptors, 663 stimulus energy, 661 stimulus source, 660–661 tactile receptors, 661–662 temperature receptors, 663 receptor field, 664f sensory acuity, 664 Sensory transduction, 664–665 mechanism of, 664 primary hyperalgesia, 665 receptor adaptation, 666

2/14/14 2:39 PM

830

Principles of Medical Physiology stimulus intensity, coding, 664–665 Sequestered self-antigen, 190 SER. See Smooth endoplasmic reticulum Serotonin, nerve endings synthesis, secretion, and reuptake, 655f Serotonin promoting arousal, 654 Sertoli cells, 554, 561, 581 Serum, 133 Serum electrolytes, 404 Servo control, 24 Sex chromatin, 580 Sex steroids, biosynthesis of, 554f Sexual flush, 572 Sexual infantilism, 537 SGLT. See Sodium-dependent glucose transporter Shearing force, 3, 3f Shear rate, 7 Shell temperature, 720 Shift-leukocytosis, 177 Shift reticulocytes, 140 Shortening heat, 100 SIADH. See Syndrome of inappropriate ADH secretion Sideroblasts, 153 Siderosis, 153 Siderotic granules, 153 Signal peptidase, 29 Signal peptide, 29 Signal recognition particle, 29 Simple diffusion, 19, 38 Single-breath N2 method, 340 Single muscle twitch effect of temperature on, 103 isometric, 102–103 isotonic, 101–102, 102f isotonic and isometric recording, 101 muscle contractility, 104 preload vs. afterload, 104 summation of, 103 tetanic tension, 103 Sinoatrial node, 205 Sinus arrhythmia, 278 Situational syncope, 297 Skeletal and smooth muscle fibers, structural differences between, 60t Skeletal growth dual effect on, 555 growth hormone effect on, 514 Skeletal muscle contractile mechanism cross-bridge cycling. See Crossbridge cycling E-C coupling in, 99, 99f elastic and contractile components, 107–108 Skeletal muscle contraction and elasticity three-compartment model, 107f, 108

Sircar_Chapter BM_803-836.indd 830

two-compartment model, 107–108, 107f force–velocity relationship, 109 isometric and isotonic contraction, 109 motor unit definition of, 104 innervation ratio, 104–105 motor recruitment, 105–106, 106f territory, 105, 105f type-I, 106, 106t type-II, 106t, 107 phases of, 108–109 single muscle fiber all-or-none law, 101 characteristics, 101 single muscle twitch. See Single muscle twitch Skeletal muscle fibers, 57, 58f cell membrane, 57–58 length-tension relationship in, 103, 104f Skeletal muscles and smooth muscles, differences between, 122 Skeletomotor response, 737 Skiascopy, 758 Skinfold thickness, 482 Skin, superficial receptors sense of, 664f Sleep, 715 discriminant responses, 716b neural centers, 718f nonrapid eye movement, 715, 715f polysomnography, recording scheme for, 716f rapid eye movement, 715 retrograde amnesia, 717b sleep cycles, 717 sleep onset behavioral responses, 716 electrophysiological responses, 716 intellectual functions, 716–717 stage distribution age, effect of, 717 drugs, 717–718 sleep history, 717 typical night’s sleep, sleep cycles, 717f Sleep onset behavioral responses, 716 electrophysiological responses, 716 intellectual functions, 716–717 Sleep spindles, 715 Sleep–wakefulness, neuronal systems chemicals mediating, 718 disorders of, 719 hypothalamus, 718 nucleus reticularis pontis oralis, 718

Slope, 1–2, 2f Slow axoplasmic transport, 56–57 Slow eye movements, 716 Slow-growing tumors, 44 Slow twitch fibers, 103 Slow vital capacity, 333 SMA. See Styrene malic anhydride; Supplementary motor area Small intensely fluorescent (SIF) cells, 654 Small intestinal motility, 454 Small-molecule neurotransmitters, 649 Small uncharged polar molecules, simple diffusion of, 38 Smooth endoplasmic reticulum, 30–31 Smooth muscle cells, resting membrane potential of, 124 Smooth muscle fibers skeletal and, structural differences between, 60t structure of, 60f Smooth muscles acetylcholine effect on, 125 catecholamines effect on, 125 contraction mechanism cross-bridge cycling, 122–123, 123f plasticity, 123 excitation and inhibition of, 123 excitation-contraction coupling in, 123–124, 124f multiunit, 60 and skeletal muscles, differences between, 122 vs. striated muscles, 60 visceral, 60 SN. See Substantia nigra Sneezing and coughing, 316–317 Snoring, 719 Snorkeling, 364, 364f Sodium absorption, 457 Sodium current, destabilizing effect of, 82 Sodium-dependent glucose transporter, 411, 455 Sodium ion channel, voltage-gated agents altering, 83 gates of, 81 inactivation of, 81, 81f membrane conductance, 84, 84f membrane potential effect on, 81 opening and membrane potential, 82 structure of, 41, 42t, 85, 85f Sodium ion concentration and membrane conductance, 71f, 72 Sodium ions, tubular reabsorption of chloride-driven sodium transport, 388, 388f, 389 factors affecting, 389 Na+-H+ exchange, 387f, 388 sodium-chloride cotransport, 389

2/14/14 2:39 PM

Index sodium cotransport with chloride and potassium ions, 387f, 389 with organic substrates, 387f, 388 from tubular segments, 387, 387f unitransport of Na+, 387f, 388 Sodium sulfate infusion test, 425 Soma-dendritic (SD) spike, 657 Somatic motor innervation, 432 Somatic mutation (clonal selection) theory of immune specificity, 195–196 Somatosensory pathways, 668f Somatostatin, 550, 550f Sound discrimination pitch discrimination, 789 timbre discrimination, 789 Sound localization sound delays, 789 sound-shadows, 789–790 Sound pressures at auditory threshold, 2t as multiples of hearing threshold, 2f Sound wave, characteristics of, 11–12 Source amnesia, 731 Southern blotting, 52 Sparse interference pattern, 114 Spastic neuropathic bladders, 434 Spatial memory, 638 Spatial summation, 656 Speech, perisylvian, 741t Sperm, 561 motility, 570, 571 structure of, 562f Sperm-associated oocyte-activation factors, 575 Spermatogenesis, 562, 562f heat, countercurrent exchange of, 563f temperature, 563, 563f testosterone, 563 Spermatozoa, immune protection of, 571 Spermatozoon. See Sperm Spermicidal cream, 577 Sperm transport across sexes excitement, phase, 572 orgasm, 572 plateau phase, 572 resolution phase, 572 assisted reproduction intrauterine insemination (IUI), 577 in vitro fertilization (IVF), 577 contraception, behavioral methods, 577 early embryonic development, 575–577 implantation, 576 meiosis II, metaphase of, 575 female tract, sperm migration, 572–573

Sircar_Chapter BM_803-836.indd 831

fertilization, egg investments penetration cumulus oophorus, 574 zona pellucida (ZP), 574 in male tract, 570 ovum, activation polyspermy, blocking, 575 passage through epididymis, 570 spermatozoa, decapacitation, 571 spermatozoa, immune protection of, 571 sperm maturation, 571 sperm storage, 571 passage through rete testis, 570 semen semen analysis, 571–572 seminal plasma, 571 sperm passage through urethra, 571 Spherocytes, 136 Spherocytosis, 138, 139 Sphincter of Oddi, 448 Sphincter pupillae, 745 Sphincter vesicae, 431 Sphygmomanometric blood pressure, 260b Sphygmomanometry, 260, 260f Spike potential, 76 Spinal cord spinal gray matter dorsal/posterior horn, 606 lateral/intermediate horn, 606 ventral/anterior horn, 607 spinal lesions, 607 Brown–Sequard syndrome, 607 cord, complete transection of, 607–608 spinal cord, subacute combined degeneration of, 608 spinal nerve, 607 spinal white matter, 607 Spinal nerves, 604 Spinal shock, 682 Spinal sympathetic center, 274 Spinal transection, 695 Spindle loading/unloading, 678f, 681 Spinocerebellum, 618 afferents, 618 efferents, 618–619 somatotopy, 618, 618f spinal tracts, 618f vermal part, connections of, 619f Spinohypothalamic tract, 669 Spinomesencephalic tract, 668 Spinoolivary tract, 612 Spirograms, 332, 332f, 368f Spirometer, 332, 332f Spirometric lung volumes, 332–333 Splanchnic circulation hepatic circulation, 311–312 mesenteric circulation, 310–311 “Splay,” 419 Spleen, 185–186, 185f Splenectomy, 186

831

Splenic circulation, 185 SRP. See Signal recognition particle Stagnant hypoxia, 361 Staircase effect, 130, 130f Standard limb leads, ECG recording with, 209, 209f Stapedius, 784 Starling forces, 382, 382f Starvation, metabolic events during, 500, 501f Static exercise blood pressure in, 281 cardiac output in, 238, 238f Static lung compliance calculation of, 322, 323 dynamic vs, 322 hysteresis of, 326 lung–thorax combine, 322–224 Static lung volumes factors affecting, 335–336 functional residual capacity. See Functional residual capacity nonspirometric, 333 spirometric, 332–333 Static vs. dynamic sensors, 26, 26f Stem cells, 200 Stenopic effect, 754 Stimulus-related potentials, 712 Stomach functions of, 442 interior of, 442, 442f parts of, 442, 442f Stool examination, 453 ‘Stop’ codon, 50 Strap and fusiform muscles, excursion and tension in, 117 Strength–duration curve, 79, 79f Stress adaptation, 538, 539 Stress-relaxation mechanism, blood pressure regulation, 282 Striatal GABAergic neurons, 651 Striated muscles dark and light bands in, 98, 98f vs. smooth muscles, 60 Strychnine, 652 STX. See Saxitoxin Styrene malic anhydride, 578 Subclavian steal, 297f Subcortical sensory processing dorsal column nuclei, 670 lateral inhibition, 670 lateral inhibition, 670f spinal cord, dorsal horn of, 669 dorsal horn gating, 669–670 secondary hyperalgesia, 669 stress-induced analgesia, 670 thalamus, 670 pain processing, 671 selective attention, 671 Subliminal fringe, 690 Subsarcolemmal dense plaque, 60 Substantia gelatinosa, 606 Substantia nigra, 626 Subthalamic movement center, 275 Subzonal insemination, 577

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832

Principles of Medical Physiology Succinylcholine, 95 Sulfuric acid, 403 Supplementary motor area, 636 Suppressor T cells, 187 Suprachiasmatic nucleus, 766 Supraspinal control centers for micturition, 433f Supraventricular tachyarrhythmias, 220–221 Supraventricular tachycardia, 221 Surface-connected canalicular system, 163 Surface tension, 6 Surfactant deficiency of, 330 definition of, 328 functions of, 329–330 Surgical menopause, 569 SUZI. See Subzonal insemination SVC. See Slow vital capacity Swallowing reflex, 355 Sweat glands, differences between, 308, 308t Sweet taste, 800 Swinging-flashlight test, 782 Sydenham chorea, 630 Symbiotic colonic bacteria, 460 Sympathetic adrenergic failure, 646–647 Sympathetic “adrenergic” fibers, 315 Sympathetic discharge, 241, 304, 309, 398 and insulin secretion, 548 Sympathetic innervation of bladder, 432 of blood vessels, 273 of heart, 273 Sympathetic stimulation, 440 Sympathetic vasodilator fibers, 309, 309f Sympathomimetic drugs, 289–290 Symport, 38 Synapse en passant, 61, 61f Synaptic contact, 54 Synaptic mechanisms chemical/electrical, 648t chemical versus electrical synapse, 648 synapse, 648 synaptic delay, 648 synaptic transmission, 648 Synaptic plasticity, 657 heterosynaptic plasticity, 658 in presynaptic facilitation, 658 in presynaptic inhibition, 658 homosynaptic plasticity hebbian potentiation, 658 late LTP, 658 long-term depression, 658 long-term potentiation, 657 posttetanic potentiation, 657 mechanisms, 657f Synaptic stripping, 65 Synaptic transmission, 93 Synaptic transmission, steps, 648f

Sircar_Chapter BM_803-836.indd 832

Synaptogenesis, 68 Syncope, 296–297 Syncytiotrophoblast, 585 Syndrome of inappropriate ADH secretion, 414 Synergist, 118 Syringomyelia, 674f Systemic circulation, 245, 245f Systole, 224, 225 Systolic multihaustral propulsion, 458 Systolic murmurs, 228

T Tachyarrhythmias common types of, 218 and reentrant circuits, 218–219 in SA node, 218 Tandem repeats, 52 Tay–Sachs disease, 31 T–B cooperation, 195 TDF. See Testis-determining factor TEA. See Tetraethylammonium Tectorial membrane, 784 Template (instructive) theory of immune specificity, 195 Temporal lobe epilepsy, 713 Temporal lobe seizures, 640 Temporal summation, 656 Temporo-mandibular joint, 120 Tendon jerk, 682 TENS. See Transcutaneous electrical stimulation Tension pneumothorax, 372 TEPD. See Transepithelial potential difference Terminal buttons, 61 Testes hormonal control of, 555f hormone-secreting cells, 554 structure, 561 blood–testes barrier, 561 seminiferous tubules, 561 sertoli cell, 561 sperm, 561 Testicular hormone, 554 androgens, physiological actions of, 555 feedback inhibition of LH, 555 follicular-stimulating hormone, 555 feedback inhibition of, 555 human chorionic gonadotropin, 554 Testicular sperm extraction, 577 Testis-determining factor, 580 Testosterone, 581 countercurrent exchanger mechanism, 563f vs. dihydrotestosterone, 555t Tetanic contraction, 108f Tetanus toxin, 652 Tetraethylammonium, 83 Tetraiodothyronine (T4) and triiodothyronine (T3), comparison of, 517, 518t

Tetrodotoxin, 83 TGT. See Thromboplastin generation test TH. See Thyroid hormone Thalamic GABAergic neurons, 651 Thalamic phantom limb, 623 Thalamocortical fibers, 633 Thalamus, 622 dorsal thalamic nuclear groups, 622 anterior group of nuclei, 623 intralaminar nuclei, 623 lateral group of nuclei, 623 medial group of nuclei, 623 midline nuclei, 623 nuclei, ventral group, 622–623 reticular thalamic nucleus, 623 functions of, 623 nuclear groups, schematic representation of, 622f specific/nonspecific nuclei, 623 thalamic syndrome, 624 Thalassemias, 145 TH cells. See Helper cells Thermal nociceptors, 663 Thermocycler, 53 Thermodilution technique, 233 Thermoneutrality/thermal comfort hypothalamic thermoregulatory mechanisms, 724 antidrop center, 725 antirise center, 724 temperature receptors, 724 thermoneutral zone, 723–724 Thermoreceptors, 661 Thermoregulation, 8 Thermoregulation disorders, 725 hyperthermia, 725 heat exhaustion, 725 heatstroke, 725 hypothalamic set point, 725 hypothermia, 725–726 poikilothermia, 720 Thermostatic hypothesis, 730 THF recovery and SAM production, 157 Thirst, 397, 398 Thoracic breathing, abdominal vs., 320 Thoracic resistance, 320 Thoracolumbar outflow, 642 Thoracolumbar sympathetic outflow, 606 Thought processes, 699 Three-compartment model of muscle, 107f, 108 Threshold of hearing, 11 Threshold stimulus, 76 Thrombasthenia, 172 Thrombin, 172 Thrombin time, 175 Thrombocytes. See Platelets Thrombocytopenic purpura, 172 Thrombocytosis, 164 Thromboplastin generation test, 174

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Index Thrombopoiesis, 202, 203 Thrombosis, 173 Thrombotic disorders, 173–174 Thunberg illusion, of pain, 671 Thymus, 184 Thymus independent (TI) antigens, 195 Thyroglobulin iodination of, 518 secretion and reabsorption of, 517, 517f Thyroid disorders goiter, 521–522 hyperthyroidism, 523 hypothyroidism, 522–523, 522f Thyroid functions, control of goitrogens, 520 hypothalamic–hypophysial– thyroid axis, 519–520 iodine effect on, 520, 520f Thyroid function tests hormonal feedback control, 523 of thyroid activity, 523 thyroid damage, 523 Thyroid gland, 517, 517f follicle, 517 iodothyronine secretion, 517 secretion and reabsorption of thyroglobulin by, 517f Thyroid hormone biosynthesis and secretion, 518, 519 physiologic actions of, 520–521 release, 519 structure of, 519f transport, metabolism, and excretion, 519 types of, 517 Thyroid suppression test, 523 Thyrotropin-releasing hormone, 519 TIBC. See Total iron-binding capacity Tidal volume, 332–333 Timbre, 11–12 Tinel sign, 66 Tissue grafting and MHC molecules, 193 Tissue-type plasmin activator, 171 Titration curve of buffer mixture with alkali, 23f TLC. See Total lung capacity T-lymphocytes, 183, 184t differentiation of, 194–195, 194f TmG. See Transport maximum for glucose Tongue gustatory papillae, 800 papillae, 800f taste buds, 800f, 801 Tonic and phasic muscles, blood flow to, 308–309 Tonic contractions, 454 Tonicity, 21–22 Tonic labyrinthine reflexes, 691 Tonic neck reflexes, 693 Tonic smooth muscles, excitation and inhibition of, 123

Sircar_Chapter BM_803-836.indd 833

Tonic spasm, 713 Total bilirubin concentration, 147 Total iron-binding capacity, 153 Total lung capacity, 333 Tourniquet test, 174 Toxic metabolites, 429 t-PA. See Tissue-type plasmin activator Trabecular (spongy) bone, 525 Trabeculectomy, 747 Tracheobronchial tree, nerve supply of, 315 Transcellular fluid, 132 Transcortical reflex, 634 Transcription, 50–51, 50f Transcutaneous electrical stimulation, 669 Transepithelial potential difference, 380, 381f, 390 Transferrin iron transport by, 152–153 synthesis of, 152 Transfer RNA, 49 Translation definition of, 51 steps in, 51, 51f Translational diffusion, 36 Transmission mode, 709 Transneuronal degeneration, 64 Transport maximum for glucose, 418, 418f Transudate, 263 Transverse waves, 11 Trauma, 307 Traveling flame mechanism, 86, 86f Trendelenburg position, 290, 290f TRH. See Thyrotropin-releasing hormone TRH stimulation test, 523 Tricuspid valve, 224 Trigeminal pathways, 668f Triiodothyronine (T3) and tetraiodothyronine (T4), comparison of, 517, 518t Triolein breath test, 452–453 Tripeptide hydrolysis test, 453 tRNA. See Transfer RNA Tropomyosin, 58, 59, 98 Troponin, 59, 98 Trypterigium wilfordii, 579 TSH secretion, 519 TT. See Thrombin time T–T cooperation, 195 TTX. See Tetrodotoxin Tuberal region, 624 Tubular cells, 380, 381f Tubular handling of solutes distal, 384, 385 proximal, 384 Tubular intestinal glands, 454 Tubular potentials, 380, 381 Tubular proteinuria, 423 Tubular reabsorption of water, 384 Tubules

833

osmolarity changes in, 392, 392f transverse and longitudinal, 59f Tubuloglomerular feedback, 383, 389 Tumor cells and immunological surveillance, 187 Tunica muscularis, 437, 437f Turner syndrome, 582, 583f Two-compartment model of muscle, 107–108, 107f Two-joint muscles, actions of, 119, 119f Tympanic cavity, 783

U Unconditioned stimulus, 737 Unconjugated bilirubinemia binding sites for bilirubin, 147 causes of, 147 vs. conjugated bilirubinemia, 146t jaundice in, 146 Unipolar vs. bipolar recording, 208 Uniport, 38 Unipotent progenitor cells, 200 Universal donor, 160–161 Universal gas law, 18 Unmyelinated axons, 55 Upper airway obstruction, 313f Upper airway patency, maintenance of, 313 Upper respiratory tract, 313 Urea clearance, 422 concentration in urine, 395 renal handling of, 411–412, 412f Urea cycle, 492f Uric acid, renal handling of, 412, 412f Urinary bladder, mucous membrane of, 431 Urinary buffers, 403 Urinary excretion of estriol, 588 of solutes, 420 Urinary 17-ketosteroids, 538 Urinary proteins, electrophoresis of, 424–425 Urinary sphincters comparison of, 431t external, 431 internal, 431 Urinary tract, sensory innervation of, 432 Urine anion gap, 406 color and turbidity, causes of, 423, 423t urea concentration in, 395 Urine examination chemical analysis abnormal constituents, 424 proteins, 423–424 microscopic examination, 424 physical examination, 423 Uriniferous tubule, 379, 379f

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834

Principles of Medical Physiology Urobilinogen, 146f formation and excretion of, 146 US. See Unconditioned stimulus Uterine smooth muscle, ovarian hormone effect on, 125–126 Uterotonins, 591 Uveal tract, 745 choroid, 745 ciliary body, 745 iris, 745

V Vaginal cycle, 566 Vaginal epithelium cells, 558, 567 Vaginal lubrication, 572 Vagotomy, 443 Valsalva maneuver, 646 blood pressure changes during, 278, 278f Van den Berg test, 147, 147f Vanilloid receptor, 665 Varicocele, 563 Vasa recta, 377 Vascular disorders, 172, 174t tests for, 174–175 Vascular effects, 539 Vascular factors, 235 affecting CVP, 240–241 gravity, 238 mean systemic filling pressure, 236–237 peripheral resistance, 235–236, 238 venous pumping, 237–238 Vascular function curves, 239f, 240–241, 241f Vascular resistance, 254, 255 Vascular system arteries, 248–249 arterioles, 249 arteriovenous anastomoses, 250 capillaries, 249, 249f metarterioles, 249 postcapillary venules, 250 veins, 250, 250f Vascular tone, 404 Vasoactive intestinal peptide, 271, 454 Vasoconstriction, pulmonary, 304 Vasodilatation, 268, 269f vs. venodilatation, 236b Vasodilators, 271 Vasomotor failure, 287 Vasopressin, 271, 272 Vasovagal syncope, 297 Vectorcardiogram, 207 Vectorcardiogram of QRS complex, 212, 212f Vectors, 1, 1f, 53 Veins, 250, 250f Velocity ratio, 4 Venous occlusion plethysmography, 258–259, 258f Venous pooling, cardiovascular responses to, 276t

Sircar_Chapter BM_803-836.indd 834

Venous pumping, 237–238 Venous return, 236b Venous valves and muscle pumping, 250, 250f Ventilation–perfusion mismatch, 362, 371 Ventilation–perfusion ratio, 343, 344 Ventilatory capacity, 339 Ventral anterior (VA) nucleus, 622 Ventral posterior (VP) nucleus, 622 Ventral posterolateral (VPL) nucleus, 623 Ventral posteromedial (VPM) nuclei, 623 Ventral respiratory group of neurons, 352 Ventricles, 5, 6f, 224 Ventricular diastole. See Diastole Ventricular ejection, 225 Ventricular extrasystole, 221, 223 Ventricular fibrillation, 221, 222f Ventricular flutter, 222f Ventricular premature beat, 222f Ventricular pressure–volume loop, 229, 229f Ventricular septal defect, 247 Ventricular systole. See Systole Ventricular tachyarrhythmias, 221, 223 Ventricular tachycardia, 221 Ventrolateral nucleus of tractus solitarius, 352 Ventromedial frontal cortex, 701 Ventromedial nucleus, 727 Ventroposterior (VP) nuclei, 669 Vertex sharp wave, 715 Vesicular and bronchial breath sounds, difference between, 375t Vestibular apparatus disorders meniere disease, 798 motion sickness, 798 endolymphatic duct, 795 eye, slow rotation, 797f otolith organs, 795–796 schematic representation, 794f semicircular canals, 795–796 sensory receptors, in horizontal semicircular canals, 795f utricular macula, sensory receptors, 795f vestibular functions, 796–797 Vestibular nuclei, efferent connections of, 796f Vestibulocerebellum, 615, 766 Vestibuloocular reflex, 26, 617, 735, 796 Vestibulothalamocortical fibers, 796, 797 Villous countercurrent system, 310–311, 310f VIP. See Vasoactive intestinal peptide Viscosity, 7 Visual acuity

blind spot, 756 at fovea centralis, 754 in peripheral retina, 755 Snellen chart, 755 Visual angle, 9 Visual optics, 749 accommodation far point, 750 near point, 750–751 apparent squint, 750f astigmatic dial, 754f blind spot, 757f eye, focal length, 750f eye, optical axes, 750f far/near points, 752t image formation aberrations, 751 chromatic aberration, 751 spherical aberration, 751 listing, reduced eye, 749f myopia, hypermetropia, 752f nodal point, distance, 756f observer looks, 757f ophthalmoscope projects, 758f perimetry, 755f physiological optics, 749 pin-hole test, 753–754 reduced eye, 749 angle gamma, 749 dioptric power, 750 refractive errors, 751 astigmatism, 753 hypermetropia, 752, 752b, 752f, 752t myopia, 751–752 presbyopia, 752t, 753 retinoscopy, principle, 758f spherical/chromatic aberrations, 751f spherical versus cylindrical lens, 753f stenopic effect, 753–754 vision shrinks, 755–756 visual field, 754 fixation point, 754 meridians/isopters, 754 Visual pathways, 766 accessory optic pathway, 766 black-and-white sketch, 769f colliculopulvinar/accessory optic pathways, 768f colliculopulvinar extrastriate pathway, 766 color blindness, 774 color vision, 773–774 opponent color coding, 773 trichromatic coding, 773 depth perception, corresponding points, 775f depth processing binocular mechanisms, 775 monoocular mechanisms, 774–775 ganglion cell, on-center/off-center responses, 770f

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Index geniculostriate pathway, lesions, 766, 767f image processing, parallel magnocellular/parvocellular pathways, 768 M/P cells, 767–768 image processing, serial ganglion cells/LGN cells, 769 photoreceptors/bipolar cells, 769 receptor fields, center-surround organization, 769 inferior temporal cortex, 772–773 Ishihara chart, 774f Lazy eye, 767b magnocellular/parvocellular pathways, 771f ocular dominance/orientation columns, 772f, 775 retinohypothalamic pathway, 766 visual area 1 (V1) hypercolumns, in striate cortex, 771 simple/complex cells, 770 visual area 2 (V2), 770–771 visual area 4 (V4), 772 visual area 5 (V5), 772 middle temporal (MT) area, 772 visual area 1 (V1) medial lateral surfaces, 771f Young–Helmholtz theory, 773f Vital capacity, 333 Vitamin B12 deficiency causes of, 157 main effects of, 157 Vitamin K cycle, 173f Vitamin K deficiency, 173 Vitamin K-dependent proteins, 173 Vitamins, 476t, 477t, 478t absorption of, 457 categorization of, 475 fat-soluble, 475

Sircar_Chapter BM_803-836.indd 835

metabolism, TH role in, 521 role in metabolic reactions, 475, 479f vitamin A, 761 vitamin B12 absorption and storage, 156, 156f actions of, 157 nutritional aspects of, 155t structure of, 154f synthesis of, 156 water-soluble, 475 VKDP. See Vitamin K-dependent proteins VLN-TS. See Ventrolateral nucleus of tractus solitarius Vocal resonance, 374 Voltage clamp technique, 84, 84f Voltage-gated channels, 41 Voltage-gated channel, structure of, 41f Volume of gaseous diffusion, 346 Volume of packed red cells, 137 Volume receptors, 274, 397 Vomiting, 466–467, 467f von Willebrand factor, 163 von Willebrand’s disease, 173 VOR. See Vestibuloocular reflex VPB. See Ventricular premature beat VPRC. See Volume of packed red cells VRG. See Ventral respiratory group of neurons vWF. See von Willebrand factor

Wave, 11, 11f Wave motion, 11, 11f Weaning, 484b Weber-Fechner law, 673f Weight-for-age, 481 Weight-height indices, 481 Wernicke–Geschwind model, 741 Western blotting, 52 Wheal, 307 White blood cells, 133t White coat hypertension, 284 Whole blood clotting time (CT), 175 Wilson’s disease, 478, 630 Withdrawal bleeding, 569 Wolff–Parkinson–White (WPW) syndrome, 219 Work done expression for, 5 by fluid, 5 by heart, 252 on lung during breathing, 5, 6f by ventricle during cardiac cycle, 5, 6f Working memory allocation, 713

W

Z

Waist/hip ratio, 482 Wallerian degeneration, 64, 65f Water absorption, 457 Water-deprivation test, 425 Water fluid intake, 398 Water-soluble vitamins, 475

Zero potential, 12b Zona adherens, 33 Zona fasciculata, 534 Zona glomerulosa, 534 Zona occludens, 33 ZP3 receptors, 571 Zwitterion. See Ampholyte

835

X Xerophthalmia, 746 Xerostomia, 470–471

Y Yellowing of sclera, 147 Yoke muscles, 776

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Sircar_Chapter BM_803-836.indd 836

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