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Neuroscience for Psychologists: An Introduction [1 ed.]
 9783030476441, 9783030476458

Table of contents :
Preface
Acknowledgments
Contents
Contributors
1: Introduction
1.1 What Is “Psychology”?
1.2 Science and Psychology
1.2.1 Definitions and Characterizations
1.2.2 “Truth” and “Reality”
1.2.3 The Scientific Process
1.2.4 Psychology as Science and Profession
1.3 Neuroscience and Psychology
1.3.1 Theoretical Considerations
1.3.2 Practical Considerations
References
I: Basics
2: Electrical Signals in the Nervous System
2.1 From Physics to Signals: Some Basics for the Exploration of Nervous Systems
2.1.1 The Four Interactions and the Atom
2.1.2 Living Systems
2.1.3 Function
2.1.4 Information and Signals
2.1.5 Detour: What Does “Meaning” Mean?
2.1.6 Electrical Signals Are Useful
2.2 How Do Electrical Signals Originate in Biological Cells?
2.2.1 The Basic Parameters of Electricity: Electric Charge, Current, Voltage, and Resistance
2.2.2 Diffusion and the Second Law of Thermodynamics
2.2.3 Ions and the Biological Membrane
2.2.4 Ion Channels: Properties and Classification
2.2.4.1 Ion Channels Can Be Open or Closed
2.2.4.2 Ionic Channels Are Specific for Certain Ions
2.2.4.3 Ion Channels in the Nervous System
2.2.5 Passive Flow Versus Active Transport
2.2.6 The Generation of Cellular Electrical Signals
2.2.6.1 The equilibrium voltage for a certain ion
2.2.6.2 Membrane voltage as result of contributions from various equilibrium potentials
2.2.7 Electrical Signaling Is Achieved by Closing or Opening Ion Channels
2.2.8 Detour: Capacitance – Why Are Biological Electrical Signals So Slow (Compared to Those in Technical Devices)?
2.3 Neurons and Other Cells Found in the Nervous System
2.4 Neurons and Synapses
2.5 Electrical Signals in Neurons
2.5.1 Neurons Generate Essentially Two Types of Electrical Signals: Postsynaptic and Action Signals
2.5.2 “Passive” Spread of Electrical Signals in Neuronal Processes
2.5.3 The Action Signal: Threshold, Explosion, and Feedback
2.5.4 Sodium Channel Inactivation Generates a Refractory Period for Action Signal Generation
2.5.5 How Do Action Signals “Travel” Along the Axon?
2.5.6 Action Signals Are the Form in Which Information Is Conveyed over “Long” Distances in the Nervous System
2.5.7 The Chemical Synapse: Transduction of Action Signals into Postsynaptic Signals
2.5.8 The Integration of Postsynaptic Signals in the Neuron
2.6 “Thinking” Implies Energy Consumption: Transporters of Ions in the CNS
References
3: Basics of Neuropharmacology
3.1 The Chemical Bonds
3.1.1 Asymmetric Bonds Make for High Solubility in Water; Symmetric Bonds Tend to Be Soluble in Lipids
3.2 Acids and Bases
3.3 Amino Acids
3.4 Biological Macromolecules
3.4.1 Proteins and Peptides
3.4.2 DNA and Other Biological Macromolecules
3.5 The Molecular Receptor
3.5.1 Binding and Specificity
3.5.2 Unspecific Pharmacological Interactions
3.5.3 Specificity
3.5.4 Receptors and Receptor Sites
3.5.5 Ligand Binding and the Concept of Affinity
3.5.6 Studying Binding
3.5.7 Agonism, Antagonism, Partial Agonism, and Inverse Agonism
3.5.8 Efficacy and Potency
3.6 Pharmacological Modulation of Synaptic Transmission
References
4: The Transmitters
4.1 What Is a (Neuro)Transmitter?
4.2 Classification of Neurotransmitters
4.3 Principal or “Classical” Transmitters
4.3.1 Glutamate: the Activator
4.3.2 Detour: Glutamate, Synaptic Plasticity, Learning, and Memory
4.3.3 Glutamate as a Killer
4.3.4 Glutamate Uptake
4.3.5 GABA and Glycine: Putting on brakes; slow down and relax
4.3.5.1 The Ionotropic Receptor GABAA
4.3.5.2 The Metabotropic Receptor GABAB
4.3.5.3 Glycine
4.3.6 Monoamine Transmitters: The Modulators
4.3.6.1 Adrenaline/Noradrenaline (Epinephrine/Norepinephrine): Activation and Plasticity
4.3.6.2 Dopamine: Madness, Pleasure and “Free Will”
4.3.6.3 Serotonin: Feeling Great or Suffering?
4.3.6.4 Histamine: Staying Awake and Alert
4.3.7 Acetylcholine: Mediating Behavior, Regulating Body Organs, and Modulating Functions in the Brain
4.4 Co-transmitters
4.4.1 Neuropeptides: From Digestion to Bliss
4.4.1.1 The Opioid Family
4.4.1.2 Substance P and the Tachykinin Family (Kinin and Tensin Gene Family)
4.4.1.3 CRH-Related Family
4.4.1.4 Oxytocin/Vasopressin Family
4.4.1.5 The Somatostatin Family
4.4.1.6 Glucagon/Secretin Gene Family
4.4.1.7 Cholecystokinin/Gastrin Family
4.4.1.8 F- and Y-Amide Gene Family (NPY)
4.4.1.9 Angiotensin Family
4.4.1.10 Motilin Family (Ghrelin)
4.4.2 Neurotrophic Factors
4.4.3 Nucleotide Transmitters
4.5 Retrograde Messengers
4.5.1 Endogenous Cannabinoids
4.5.2 Gases
References
II: Neuroscience Fields of Special Interest for Psychology
5: Clinical Neuropharmacology
5.1 Classification of Disorders Caused Primarily in the Nervous System
5.2 “Organic” Causes May Generate Psychological/Psychiatric Symptoms
5.3 Pharmacodynamics and Pharmacokinetics
5.4 Naming of Psychiatric Medicaments
5.5 Problems in Pharmacological Treatment of Mental Disorders
5.6 Mood and Related Disorders
5.6.1 Mood Disorders
5.6.1.1 Anxiety Disorders
Benzodiazepines
Other Anxiolytic Pharmacotherapy
5.6.1.2 Monopolar Depression
Antidepressants
Monoamine Oxidase Inhibitors
Tricyclic Antidepressants
Selective Reuptake Inhibitors
“Atypical” Antidepressants
Hallucinogens
Antidepressants and Dependence
St. John’s Wort
Non-pharmacological, Non-psychologic Treatments for MDD
5.6.1.3 Bipolar Disorder
Lithium
Antiepileptic Medication
Antipsychotics
5.6.2 Schizophrenia Spectrum Disorders
5.6.2.1 Antipsychotics
“Typical” Antipsychotics
The Next “Generation” of Antipsychotics: The “Atypicals”
5.6.3 Obsessive-Compulsive and Related Disorders
5.6.3.1 Categorization of Disorders that Include Failure of Impulse Control and Obsession
5.6.3.2 Treatment of OCRD
5.7 Neurodevelopmental Disorders
5.7.1 Attention Deficit/Hyperactivity Disorder
5.7.1.1 Psychostimulants
5.7.1.2 Non-psychostimulant Medication for ADHD
5.7.2 Autistic Spectrum and Other Neurodevelopmental Disorders
5.8 Acquired Disorders
5.8.1 Posttraumatic Stress Disorder
5.8.2 Addictions
5.8.2.1 Alcohol Use Disorder
5.8.2.2 Tobacco Smoking
Pharmacological Help
5.8.2.3 Other Substance Addictions
Opioids
Barbiturates and Benzodiazepines
Psychostimulants
Marijuana
5.9 Neurodegenerative Diseases
5.9.1 Alzheimer’s Disease
5.9.2 Parkinson’s Disease
5.9.3 Other Neurodegenerative Diseases
5.10 Non-degenerative “Neurologic” Diseases
5.10.1 Myasthenia Gravis
5.10.2 Epilepsy
References
6: Inputs, Outputs, and Multisensory Processing
6.1 Input and Output of Information?
6.2 From Stimulus to “Representations”
6.3 “Hierarchy” in the NS
6.4 Hearing and Seeing
6.4.1 The “Rule” of Increasing Complexity in Visual and Auditory Pathways and the “Grandmother Cell”
6.4.2 “Top-Down” Regulation Is Found in Most Stations of Sensory Pathways
6.5 Other Exteroceptive Senses
6.5.1 Taste and Olfaction
6.5.2 External Mechanosensitivity
6.5.3 Sense of Temperature
6.6 Gravity Detection and Sense of Balance
6.7 Nociception/Pain
6.8 Interoception
6.9 Movement by Striate Muscles and Proprioception
6.9.1 Sensory-Motor System
6.9.2 Inputs and outputs of Sensory-Motor Systems Are Closely Linked
6.10 Multisensory Perception of a Multimodal World
6.10.1 Advantages and Problems of Multisensory Perception
6.10.2 Multisensory Illusions
6.10.3 Principles of Multisensory Perception
6.10.4 The Neural Correlates of Multisensory Perception
6.10.5 Bridging the Levels of Psychophysical and Neural Analyses
6.10.6 Multisensory Perception in Mental Disorders
References
7: Neuroplasticity in Humans
7.1 Introduction
7.2 Characteristics of Neuroplasticity
7.2.1 Differences between Developmental and Adult Plasticity
7.2.2 Drivers of Neuroplasticity
7.2.3 Time Scales of Plastic Changes
7.2.4 Region-Specificity of Neuroplasticity
7.2.5 Relation between Brain Changes and Altered Behavior
7.2.6 Cortical Maps and Beyond – Brain Variables Affected by Neuroplasticity
7.2.7 Milestones of Experimental Neuroplasticity Research in Animal Models
7.2.8 Neuroplasticity as a Novel Discipline
7.3 Neuroplasticity in Humans
7.3.1 Impact of Modified Use and Practice
7.3.2 Perceptual Learning
7.3.3 Neuroplasticity Evoked by Peripheral or Central Stimulation
7.3.4 Plastic and Perceptual Changes without Physical Stimulation
7.3.5 Rapid, Switch-Like Plasticity
7.3.6 General Performance-Promoting Conditions
7.3.7 Predicting Learning Outcome
7.3.8 Neuroplasticity in the Elderly
7.3.9 Maladaptive Neuroplasticity
7.3.10 Perspectives and Potential of Neuroplasticity
References
8: Mathematical Modeling in Neuroscience
8.1 Mathematical Modeling
8.1.1 What Is a Mathematical Model and Why Is It Useful?
8.1.2 Types of Mathematical Models
8.1.3 Elements of a Mathematical Model
8.1.4 Is a More Detailed Model Better?
8.2 Models of Neurons
8.2.1 The Equivalent Circuit of the Membrane
8.2.2 Simplified Neurons: Integrate-and-Fire Models
8.2.3 Conductance-Based Models: Detailed Simulation of Ionic Currents
8.2.4 The Hodgkin and Huxley Model
8.2.5 Beyond Hodgkin and Huxley
8.3 Models of Networks
8.3.1 Modeling Synaptic Connections
8.3.2 Network Topology
8.4 Large-Scale Models: Neural Masses
8.4.1 Wilson-Cowan Model
8.4.2 Jansen and Rit Model
References
Literature for Further Study
9: Subjective Experience and Its Neural Basis
9.1 Introduction
9.2 Internal Contents
9.2.1 Internal Contents Can Be Represented With or Without Conscious Experience
9.2.2 Hierarchical Processing
9.2.3 Exceptions to Strict Hierarchical Structure
9.2.4 Large-Scale Neuronal Networks
9.3 Emotions and Their Neural Basis
9.3.1 Affective Response Generation and Neural Networks
9.3.2 Affective Response Representation
9.3.3 Conscious Accessibility
9.3.4 Open Questions
9.4 Global Brain States
9.4.1 Moods Are Linked to Neuromodulators
9.4.2 Clinical Relevance
9.4.3 Sleep
9.4.4 Hypnosis
9.5 Conclusion
References
10: Tools of Neuroscience
10.1 Introduction
10.2 Methods Used Frequently in Neuroscience Other than Electrophysiology or Imaging
10.2.1 Lesioning
10.2.2 Pharmacology
10.2.3 Immunologic Tools
10.2.4 Genetic Tools
10.3 Electrophysiological Recording
10.3.1 Electroencephalography (EEG)
10.3.2 Field Potential Recording
10.3.3 Single-Cell Extracellular Recording
10.3.4 Intracellular Microelectrode Recording
10.3.5 Patch Clamp
10.4 Electric, Magnetic, and Optogenetic Stimulation
10.4.1 Electric Stimulation Using Small Electrodes Attached or Inside Neural Tissues
10.4.2 Transcranial Magnetic and Current Stimulation
10.4.3 Optogenetic Stimulation
10.5 Brain Imaging
10.5.1 The Concept of Image
10.5.2 X-Ray Images
10.5.3 X-Rays and the Brain
10.5.4 Computerized Tomography (CT)
10.6 Nuclear Medicine Imaging
10.6.1 Single Photon Emission Computed Tomography
10.6.2 Positron Emission Tomography
10.7 Magnetic Resonance Imaging
10.7.1 General Considerations About Nuclear Spin
10.7.2 Magnetic Moment of Protons and Magnetic Field Interactions
10.7.3 Radio Frequency Pulses and Their Interactions with Protons Producing Magnetic Resonance
10.7.4 RF Pulses and Imaging
10.7.5 Spin Echo: T1, T2, and Proton Density Images
10.7.6 Inversion Recovery (IR) Sequences
10.7.7 Diffusion-Weighted Imaging
10.7.8 Functional MRI
10.7.9 Parallel MRI and Ultrafast MRI
References
Index

Citation preview

Marc L. Zeise Editor

Neuroscience for Psychologists An Introduction

Neuroscience for Psychologists

Marc L. Zeise Editor

Neuroscience for Psychologists An Introduction

Editor

Marc L. Zeise School of Psychology, Faculty of Humanities University of Santiago de Chile Santiago, RM - Santiago, Chile

ISBN 978-3-030-47644-1    ISBN 978-3-030-47645-8 (eBook) https://doi.org/10.1007/978-3-030-47645-8 © Springer Nature Switzerland AG 2021 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

V

This book is dedicated to my mother, Dr. Erika Zeise.

Preface Do you know that nature has invented digitalization and what it is good for? What does the word “drug” mean? Such and similar questions I ask in class to stimulate interest for neuroscience. It typically works with the second question, but only sometimes with the first one. To arouse motivation is certainly a crucial ingredient for a teacher´s success in a learning process and texts used to teach should also be motivating coinciding with the particular interest of students. When I started lecturing about the basics of neuroscience at the School of Psychology, University of Santiago de Chile, nearly 15 years ago, I found that existing textbooks that introduce the field were not very motivating for my students. This is in spite of the fact that there are excellent texts written by outstanding scientists providing pregraduate and graduate students with a wealth of up-to-date information about the nervous system, well written and well presented, systematic and quite complete, but destined for and written by people of the biomedical sciences. Psychology students are not easy to convince that they have to learn about transduction mechanisms or enzymes involved in the synthesis of neuroactive substances. On the other hand, questions like the above about digitalization and the concept of “drug” need to be discussed when psychology students are to learn about neuroscience in a way that will serve them in their professional activity. They need to comprehend concepts of neuroscience relevant for their future, but not so much details of biological mechanisms. For example, traditionally, psychology students would learn about GABA receptors sometimes without having a clear notion of what a receptor is, often confusing cellular and molecular receptors. The situation can be described by the German saying “seeing the trees, but not the forest.” I started to write notes for use in my classes, mainly about electrical and chemical signals in the nervous system. Then I added short texts about transmitters and clinical neuropharmacology. Talking to various people in Social Science and Humanities, but also from Informatics and colleagues from Physics, I realized that there was a need for an “introduction to Neuroscience for psychologists and other ignorants,” “ignorants” meaning the crowd who is not familiar with biomedical terms and facts. The last phrase of that working title, of course, had to be abandoned, while the idea behind was maintained. I received support as intramural project for a text on neurophysiology and neuropharmacology from the academic vice rectory of my university, the University of Santiago de Chile. The resulting text while useful was very incomplete. Fortunately, I was given a suggestion by my colleague Jaime Barrientos putting me in contact with Bruno Fiuza, the representative of Springer International for South America, who, after checking with his colleagues, recommended to write a textbook Neuroscience for Psychologists – An Introduction intending to cover all fields of interest for psychologists. This, of course, was a big challenge. I knew I had to look for help from colleagues. I looked in the literature and contacted my own, very limited circle of colleagues who might be willing to contribute to the project. I was lucky to receive collaboration from two young, very active scientists: Ryan Smith, now working at the Laureate Institute for Brain Research, Tulsa, OK, USA, and Tim Rohe of the Department of

VII Preface

Psychiatry and Psychotherapy at the University of Tübingen, Germany. Two more Chilean scientists belonging to this category who joined the project are Patricio Orio, professor at the Interdisciplinary Center of Neuroscience of the University of Valparaiso in Chile, and Pablo Fredes, a physicist of my university with very original application-oriented research and experience in explaining methods of brain imaging to medical professionals. I also had the privilege to find two collaborators who are of my generation, Hubert Dinse, director and founder of the Neural Plasticity Laboratory, Department of Neuroinformatics, at the Ruhr University Bochum, Germany, and Ulrich Raff of the Department of Physics at the University of Santiago de Chile. Last but not least, Bernardo Morales, a colleague from the Biology Department of my university rendered crucial help in writing 7 Chap. 4 “The Transmitters.” Only with the help of all these colleagues the present work could be realized. The idea was to join several traits in one book: It should be readable for people without knowledge in natural sciences and try to explain or even to define all not self-evident concepts. Further, this book attempts to focus on issues that are of special interest for psychologists, but it also tries to avoid treating subjects in detail that are covered in regular courses for psychology students. In this context, cognitive neuroscience is not covered at all, and, in the chapter about methods, behavioral tests are left out. Finally, as the most difficult goal, the present text attempts to catalyze active investigative thinking and foster a critical posture that appreciates the amazing work done, but is also aware of the huge challenge and big problems ahead for neuroscience. I started 7 Chap. 2 with the four interactions of physics, the most elementary facts of chemistry, and an extremely short run through biology before describing and trying to explain electric signaling in the nervous system. There are two chapters to understand neuropharmacology, one about the basics of neuropharmacology and another about transmitters. Thus, 7 Chaps. 2, 3, and 4 form the first part of this book laying the foundations for 7 Chap. 5, Clinical Neuropharmacology, but are also important for the entire second part. 7 Chapter 6 deals with the inputs and outputs of the nervous system and is strongly biased to a field that is not so much dealt with in neuroscience texts, i.e., multisensory perception. 7 Chapters 7 and 9 are about neural plasticity and neural correlates of subjective experience being of particular interest to psychologists. 7 Chapter 8 is quite demanding dealing with mathematical modeling and is thought to be a bridge to computational neuroscience. Finally, 7 Chap. 10 tries to explain techniques used especially in neuroscience, i.e., mainly electrophysiology and brain imaging. I hope that the present text makes neuroscience not only better known but also more attractive for psychologists as well as for students and professionals of other non-biomedical fields and be a contribution to linking neuroscience better to psychological and social issues of today.  















Marc L. Zeise

Santiago, Chile

Acknowledgments The project of a textbook of neuroscience for non-biomedical readers has been supported foremost by my university, the University of Santiago, helping me financially in the framework of a program that seeks to improve teaching and teaching materials (“Innovación Docente”). I am further indebted to my Alma Mater for letting me dedicate part of my working time to the present work for more than 2 years. Drs. Rudolf A. Deisz, Robert Duncan Oades, and Anja Gabriele Teschemacher gave valuable advice concerning the content as well as the English style. Further, I am grateful to my young colleagues, the physicist Pablo Fredes and the psychologist Ricardo Morales, both from my university, for important conversations on epistemic, psychological, and physics-related issues. The artists Olivia Guasch and Rafael Guendelman have done an excellent job providing a large part of the illustrations. Last but not least, I owe great thanks to my “guide” at Springer Nature, Bruno Fiuza, who helped much more than one could expect, having the patience of a good doctor resolving problems that for me were totally new.

IX

Contents 1

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Marc L. Zeise

I Basics 2

Electrical Signals in the Nervous System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 Marc L. Zeise

3

Basics of Neuropharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49 Marc L. Zeise

4

The Transmitters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69 Marc L. Zeise and Bernardo Morales

II

Neuroscience Fields of Special Interest for Psychology

5

Clinical Neuropharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103 Marc L. Zeise

6

Inputs, Outputs, and Multisensory Processing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153 Tim Rohe and Marc L. Zeise

7

Neuroplasticity in Humans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193 Hubert R. Dinse

8

Mathematical Modeling in Neuroscience . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231 Patricio Orio

9

Subjective Experience and Its Neural Basis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253 Ryan Smith

10

Tools of Neuroscience . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285 Pablo Fredes and Ulrich Raff



Supplementary Information



Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 313

Contributors Hubert  R.  Dinse, PhD  Berufsgenossenschaftliches Universitätsklinikum, Bergmannsheil GmbH, Ruhr-University Bochum, Bochum, Germany Neural Plasticity Lab, Department of Neurology, Institute for Neuroinformatics, ­Ruhr-­University Bochum, Bochum, Germany [email protected]

Pablo Fredes, PhD  School of Medicine, Universidad de Los Andes, Chile, Santiago, Chile Department of Physics, Universidad de Santiago de Chile, Santiago, Chile [email protected]

Bernardo Morales, PhD  Laboratory of Neuroscience, Department of Biology, Faculty of ­ hemistry and Biology, University of Santiago de Chile, Santiago, Chile C [email protected]

Patricio Orio, PhD  Centro Interdisciplinario de Neurociencia de Valparaíso, Universidad de ­ alparaíso, Valparaíso, Chile V [email protected] Ulrich Raff, PhD  Department of Physics, Universidad de Santiago de Chile, Santiago, Chile [email protected]

Tim  Rohe, PhD  Department of Psychology, Friedrich-Alexander University ErlangenNürnberg, Erlangen, Germany [email protected] Ryan Smith, PhD  Laureate Institute for Brain Research, Tulsa, OK, USA [email protected]

Marc L. Zeise, PhD  School of Psychology, Faculty of Humanities, University of Santiago de Chile, Santiago, Chile [email protected]

1

Introduction Marc L. Zeise Contents 1.1

What Is “Psychology”? – 2

1.2

Science and Psychology – 3

1.2.1 1.2.2 1.2.3 1.2.4

 efinitions and Characterizations – 3 D “ Truth” and “Reality” – 4 The Scientific Process – 5 Psychology as Science and Profession – 6

1.3

Neuroscience and Psychology – 7

1.3.1 1.3.2

T heoretical Considerations – 7 Practical Considerations – 7

References – 8

© Springer Nature Switzerland AG 2021 M. L. Zeise (ed.), Neuroscience for Psychologists, https://doi.org/10.1007/978-3-030-47645-8_1

1

2

1

M. L. Zeise

1.1  What Is “Psychology”?

Psychology is one of the academic disciplines and, at the same time, a profession. Academic disciplines usually have a nuclear or primary area and surrounding fields that are necessary or complementary in order to fully realize meaningful work. For example, biology is about living systems. It investigates and manages them. However, without knowledge in chemistry, physics, in some cases even psychology, and other areas, a biologist does not get very far. Now, if biology is about bios (βιοσ = life), psychology is about psyche (ψυχη  =  soul). The psychologist is a soul investigator and a soul manager. While life or, at least living systems, can be defined relatively easily (see 7 1.2), the meaning of “soul” is not immediately clear. We suggest that it is the inner world that everybody or almost everybody knows and differentiates very well from the “outer world.” In order to clarify what “inner world” means, let us consider the following: Some psychotic symptoms (hallucinations) are characterized by a disability of the person affected to distinguish between perceptions that have their origin in the “real” outside world or are created “within.” Patients affected may hear voices no microphone can record or are convinced that they are being persecuted by the CIA while there is really no secret service agent interested in them. Sure, we all sometimes “hear” voices, music, or other things that have no physical correlate in the “outer” world. But we generally are fully aware or, at least, can test successfully about the origin of our perception. This suggests that it is generally accepted, that a normal person should be able to differentiate between an “inner” and an “outer” world. In fact, we are permanently struggling to keep this separation functioning. When it falls apart, we speak of psychotic states, if it is overcome, some speak of a certain spiritual state (Wilber 2000).  

We suggest that “Psychology” means scientific study and systematic work about and with this individual “Inner World.” We all live this dimension of our existence. Phenomena like perceptions, feelings, thoughts, or dreams are part of it (see also 7 Chap. 9). Studying the “individual Inner World,” we find it inseparably connected to a “collective Inner World”: Being social entities we have the ability to put ourselves in the shoes of others (“Theory of Mind”) sharing emotional experiences, ideas, concepts, etc., creating that “Collective Inner World.” However, all this has material correlates that we may identify as our bodies and, particularly our nervous systems, while our societies produce their own collective “bodies” consisting of cities, roads, computers, etc. Interestingly, in Spanish language, there is not just one “to be” but rather two modes of existence: “Ser” and “Estar” (= to be and to be in the state of) often distinguishing between “objective facts” in the “outer” world and the “subjective” experience of “inner” states. As an example, when I feel hungry, a lot can be said about biological states and processes correlated to this feeling, but the feeling itself is hard to explain. Subjective experience is supposedly dependent on consciousness, a phenomenon declared to be the “hard problem” of neuroscience (Chalmers 1997). Taken together, in order to investigate and work with the individual “Inner World” (“I”), the psychologist must also take into account both, the social context of the individual (the dimension of “we”) and the findings and tools of natural sciences that investigate the world of “objects,” most of all the neurosciences (the dimension of “It”). All of us are “amateur psychologists” and want to learn about the inner states of other people. To do this, we naturally rely on the observation of their behavior.  

3 Introduction

That observation is also the main source of knowledge in psychology, together with an increasing number of tools that mainly the various areas of neuroscience provide, creating data from and about the nervous and other corporal systems. Sometimes, psychology is reduced to human ethology, that is, the study of behavior, which is definitely a narrowing of its objectives, lest we name all phenomena of the “inner world” as “behavior.” There are various characterizations of behavior. But, in general, human behavior includes all actions or even suppression of actions that are potentially and directly relevant in social contexts. So, digestion is a biological process that is usually not counted as behavior. However, a hearty burp is, since it can be observed and be relevant in a social context. Or, my brilliant ideas how to change the world for the better are not themselves considered as behavior, but the communication of these ideas in Facebook certainly is. It may be disputed whether the study of behavior is itself a primary goal in psychology or rather a means to study the subjective realm. What is not disputed is that psychology is intimately linked to the study of behavior. Nor is there much discussion about whether psychologists should know neuroscience and diverse social sciences. A more delicate point is the introspection as a legitimate source of knowledge in psychology. We believe that a zombie would be a lousy psychologist because he would not even know what it is all about. So, the experience of “ourselves” is probably necessary in order to be a psychologist, but it is hotly debated whether systematic scientific study is possible utilizing introspection. Historically, the intent to base scientific psychology on introspection alone has failed miserably. On the other hand, a psychology student has to be trained to get to know and manage its “Inner World” to become a good professional. This issue will not be followed any further because it is out of the scope of this text.

1

1.2  Science and Psychology 1.2.1  Definitions

and Characterizations

When we consider the short paragraph above, we may want to rigorously define the concepts used. We believe that if we want to meet the mission of this book, that is, try to teach neuroscience to psychologists and other professionals interested in the field, we should try to construct our explanations on as solid a ground as possible. Ideally, every concept used will be explained sufficiently and beyond doubt. We think that this is impossible. So, let us tackle the impossible: First, we may intend to define “characterizations”: We call “characterization” the listing of one or more properties that distinguish the item to be characterized from others. Definition, then, would be a characterization or a set of characterizations that does not leave room for any exception. For example, if we say that an animal is a multicellular living organism equipped with a nervous system, we are facing a characterization that comes pretty close to a definition.1 Let us, then, look at another definition: A circle is the set of points equidistant to another point in two dimensions. In this case, it is as though we arbitrarily would “create” a definition. But this is not so. The circle, as defined in mathematics, is an abstraction of forms we perceive in nature and culture, like a halo around sun or moon, or the circle of people around a speaker. This example teaches us that a definition should be as close as possible to daily experience and common use of words, at least in

1 Indeed, this leaves out the unicellular organisms where, to our opinion, the distinction animal vs. plant does not make much sense and it also leaves out organisms like sponges and placozoa that are on the brink between uni- and multicellular organization.

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a metaphorical sense (see, e.g., the concept of neuroplasticity; 7 Chap. 7). Also, like in mathematics, we strive for short, “elegant” definitions in a few words or symbols rather than descriptions that take several pages. Further, the word(s) chosen should be ­meaning the same thing throughout the various sciences and fields of knowledge, for example, machine learning should be compatible to learning in humans. What is a definition good for? For one thing, while ambiguities are an important element in jokes or in poetry, it is necessary to avoid them in science (see the next paragraph) and to order and label clearly the phenomena investigated in scientific research. Many discussions lead to no fruitful end, because the matter we are discussing lacks clear definition. Take the word “intelligence” as an example. It sounds quite scientific but lacks generally agreed definition.2 Finally, in science there is a constant need for new definitions since we are collecting new data and developing new concepts and theories. The more general a term, the more difficult is it to find a useful definition. By the way, propagandists like general terms precisely because they may transmit their propaganda more easily and avoid being clear. We are all for “life” and against “terror,” is n’t it? But do I reject drinking wine because its fabrication means sacrificing billions of living yeast cells? And should we illegalize terror movies? To define a living organism or a terroristic act, however, seems more feasible, because those concepts are more specific. Likewise, it is easier to characterize, if not to define, the scientific process of establishing “truth,” than to pretend to define “science” as such.

1.2.2  “ Truth” and “Reality”



2 Recently, the term “intelligence” has experienced a true inflation: People speak about emotional, social, spatial, and verbal intelligence. Finally it becomes to mean any ability that is not exactly a physical one. This does not mean that there are no reliable tests measuring mental abilities yielding reproducible results. The problem is to decide which test is the real intelligence test.

We would like to introduce the scientific process as “establishing truth”; we also could speak of the scientific way of finding facts or true relations. The distinction between “true and false” is a basic concept in human existence and society. The search for truth, besides its daily practical value (like “does a vehicle approach from the right?”), is one of the dimensions in human existence. We will not, in this text, try a definition of this concept, but offer a rather vague characterization, namely that we accept as “true” any information (see 7 2.1.4) or concept that is in line with our experiences and reasoning. But, as we saw for a mathematical structure like the circle, true or false may be seen as an abstraction of everyday distinctions, in the perception of objects (“is that black shape over there a tree or just a shadow?”) as well as in the social sphere (is this guy really aggressive or just a bit histrionic?). If a statement is true, we may say that it is in line with “reality.” Reality, then, would be the universe of true data and relations. Now, it is possible that something is “somewhat true” or partly true, in a way true, etc. This happens particularly in the social sphere where multi-vision is necessary to describe a situation completely. We think, however, that the exact definition of “reality” is beyond the scope of this text. In order to decide whether a statement is true or false, it is generally necessary to agree about the limits of this statement, that is, in what context that statement is supposed to be valid. For example, to say “this substance is toxic” requires specifications about the dose, in what type of organism it is toxic etc. Thus, a drug may be toxic for humans, but not for some other organisms. Curiously, in everyday use we consider physical things as more “real” than concepts, subjective experience, or social structures. The “unchanging,” objective, material world appears as a die-hard illusion we love to cling to (Varela et al. 1991). Consequently,  

5 Introduction

natural sciences are dubbed as “hard sciences” or even just as “sciences” implying that scientific endeavors are more serious if they deal with issues of the “outer” world. However, there is no reason to look at social sciences, psychology, etc., as being inferior to natural sciences even though it is often more difficult to comply with the essential requirements of science when dealing with social or subjective phenomena. 1.2.3  The Scientific Process

Now, we shall try to characterize the scientific way of finding facts or true relations. In the scientific process, we need the following: 55 A question or a hypothesis that makes scientific sense 55 A method to answer the question or decide about the hypothesis 55 Gather and evaluate results 55 Interpret and publish the results Of course, it is not accidental that scientific publications are frequently structured according to the steps outlined above (Introduction, Methods, Results, Discussion). All of these have to be approved by part of the scientific community that shares expertise in the area in question. As you would probably agree, the former characterization has got more the quality of a recipe than a definition. How do we know, for example, whether a question “makes scientific sense?” Its elements certainly must be well defined, the problem has to have scientific relevance, and must be logically coherent, typically cannot be an exact copy of former work already resolved successfully, etc. It is possible to say much more about it, but for this text we have to repeat, whether a question or hypothesis (like any other step in the scientific process) makes sense or not depends on the judgment of the part of the scientific community that works in the corresponding field. This judgment and that community may change in the course of time.

1

Another problem is that in deciding whether a work is scientifically acceptable or not, criteria outside of science (like social relevance, economic feasibility, among others) come into play. While the above statements are incomplete and perhaps not very satisfying, it is possible to say something about what is not or not necessarily part of the scientific process: 55 Whether a social action can be regarded as scientific, does not depend on the object of the search. You may do valid research on dreams, sea-urchins, or likelihood, as long as the object can be defined and this definition is being accepted by your fellow scientists. 55 Repetition (reproduction) of experiments may be useful instruments of scientific endeavor, but they are not necessary prerequisites. Just think of astronomy, social sciences, or clinical studies. However, scientific results should be reproducible and if this is not exactly possible, as in areas like the former ones, they have to be in accordance with data found previously in the field. As Kuhn (1970) and others have shown, science is embedded in society and, therefore, certain paradigms (methodological instruments in a broad sense) appear in an economic, social/cultural context. Appearance of a new paradigm may revolutionize areas of science. Certain areas may become “fashionable” or important for the society. But, what about theories, scientific explanations, models, and meta-analysis? Is this not essential in science? Yes and no. In a first phase of investigation, science is typically descriptive. However, advanced stages cannot do without the elements mentioned above. Let us take an historic example: Epilepsy is a disease of the central nervous system (CNS) that is marked by synchronous activity of many cerebral nerve cells at a time, leading to the symptom of epileptic attacks. This disease has been described in antique times. We can read detailed descrip-

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tions of that illness, often interpreted as Holy Disease, because it was believed that higher powers revealed themselves through the patient when suffering his fits. The nineteenth and early twentieth century saw important advances in systematizing and diagnosing the disease as well as first systematic pharmacotherapy (bromide, later barbiturates). When synaptic inhibition was discovered, epilepsy was interpreted as a failure of central inhibition, a view that still has important value. Thanks to new ­techniques like molecular genetics of ion channels and membrane transporters or recording from excised human brain tissue, among others, today we count with experimentally testable models of mechanisms that generate epilepsy (e.g., Gigout et al. 2016). 1.2.4  Psychology as Science

and Profession

Taking the example of epilepsy that is mostly a medical problem, we can see that the way of science asking for “what is,” is intimately linked to problem solving, asking “how to do.” Psychology, like medicine, is a science, but not only this; it is also lore of how to resolve problems. There are academic areas more explicitly oriented to pure science like biology, physics, or mathematics, whereas others like engineering are mainly interested in resolving tasks (the “how to do” question). Thus, it is important to keep in mind that psychology is a science, but it is more than that: Helping to resolve individual and social problems, it becomes a social tool. Again like medicine, psychology intends to build its actions on scientific grounds, but more often than not it is oriented in helping to heal individuals, improve social relations, etc., moving in terrains that are explored incompletely by science. In this context, it should be mentioned that the psychologist frequently has to act “intuitively.” The psychologist, like other professionals, relies consciously or subconsciously upon her or

his individual and collective experience, a mode of action that may be considered as pre-scientific a bit like artisan work or cooking. This is completely legitimate as long as there is not enough time or no scientific way to resolve the problem and the psychologist is aware of acting without (complete) scientific backing. Further, the psychologist when working with people has to take into account and act as a human being in all the dimensions of human endeavor: scientific (“true and false”), ethical (“good and bad”), esthetical (“beautiful and ugly”) and, don’t forget, humorous (funny and boring). However, as a scientist and a “soul engineer,” he is an expert (hopefully); while in the other areas he is typically just a compassionate, helpful, and astute person. Fortunately, the ethic aspect is also being taught more and more to psychology students, making the psychologist also an expert in applied ethics to a certain extent. It should be mentioned that there are opinions that another dimension of human existence, the spiritual one, is being of importance for the acting of a psychologist. This issue is beyond the reach of this text and will not be followed further (however, see Wilber 2000). Science, especially natural science, has been considered as a way to investigate a given world that surrounds us. Nowadays, in the postmodern era, it is being emphasized that we are constructing in a collective effort our world that we share (Potter 1996). As classical mechanics can be considered as being a special case of quantum mechanics, in many cases we may proceed in the scientific endeavor as if there were an “objective” unchanging world around us. In most problems of natural science, this distortion has little effect on the way we investigate or the “true” results we gain. On the other hand, in social science we must consciously adopt a multiperspective and interactive view. But keep in mind, that at least since Heisenberg (1979) we know that everything that we scrutinize scientifically will not remain completely unchanged by the very act of investigating it.

7 Introduction

1.3  Neuroscience and Psychology 1.3.1  Theoretical Considerations

Neuroscience, the theme of this book, is part of biology and sciences of communication that are, in turn, part of the sciences of nature or mathematics/logics. What then, is the role of these sciences when studying/ practicing psychology? We may divide this question into a theoretical part dealing with the relation between those disciplines and a more practical one concerned with the impact that the findings in neuroscience have on the activity of psychologists as professionals and, further, we may also ask for the impact that psychology has on neuroscience. Before jumping into discussions about the “mind-body-problem” or other evergreen debates, we may want to deal with ideas that are quite common but incorrect and/or false: Sometimes, we read about the “biological bases of human behavior.” We suggest that this is a wrong metaphor. First, as mentioned in the first paragraph, we think that it is awkward to consider all psychological phenomena as “behavior” (as the concept of “biological bases of human behavior” implies). Further, talking about “biological bases of human behavior” might imply that only behavior has to do with objects that biology is interested in (like neuronal signaling), while mental images, dreams, emotions, etc., are not. This interpretation would be not just awkward but simply false: We do not know of “psychic” phenomena that are not associated to biological correlates. Second, biological events like the activity of your brain when you sleep is not the basis but rather the biological aspect, the “It” aspect of your dreaming. Suppose you are sleeping in a neuroscience lab that is doing research on dreaming. Your experience as a dreamer is one thing and the recordings from your brain are another. But we may state that they are just two aspects of

1

the same thing; if the person who does the recording can stimulate adequate centers of your brain your dream will change. Also, if your dream experience changes, it may be noted in (possibly) subtle changes in your cerebral activity. To say your experience is the “real” thing or the neuronal activity is more “real” or that one is the “base” of the other does not seem to be a fruitful discussion. We suggest that it is more adequate to say there is a subjective experience and that there are biological “correlates” or that there are biological processes that manifest themselves as subjective experiences.

1.3.2  Practical Considerations

There are several practical reasons why psychology students should study neurosciences. Among these we would like to mention the following: 1. The psychiatric and neurological aspects of psychological disorders are hard to comprehend without a thorough knowledge of neuroscience. A clinical psychologist who has to collaborate with professionals of the biomedical fields will not be able to follow their discourse without training in biology, particularly neuroscience. This is true also for psychologists working in the fields of education and/or with children or adolescents and those in the social/organizational area, even though to a lesser extent. 2. Assisting people who are in trouble psychologically frequently implies the use of drugs. Even in countries where psychologists are not allowed to prescribe medicaments themselves, they should have good knowledge about indications, types, and collateral effects that may interfere with psychological problems. 3. The abuse and/or the involuntary exposure to neuroactive substances are problems that affect millions of persons. Psychologists must know about the

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effects that neuroactive substances exert on the nervous system, and related problems such as, for example, the physiological side of addiction. 4. More and more diagnostic tools are being introduced that shed important light on cause and course of many disorders and diseases. A short chapter in this book is dedicated to these new instruments. 5. Neuroscience and medical engineering play important roles in therapeutic approaches like the “Neurofeedback” that is helpful in disorders like the attention deficit/hyperactivity syndrome (ADHS) or epilepsy. 6. Psychology and psychotherapy more and more relies on “evidence-­ based” therapies meaning that the results of diverse therapeutic approaches are systematically and quantitatively evaluated. For this, tools of neuroscience are often necessary and/or useful. 7. Last but not least we believe that psychology has a lot to tell neuroscience: As mentioned above, science must be concerned with relevant problems since the society is paying for it. Psychology has to direct biological research, particularly neuroscience to direct their efforts

to relevant problems (Solms and Turnbull 2002). For example, only recently “official science” (and philosophy) has detected conscience as something that exists and is worth investigating. In this task, among others, psychologists have always played an important role.

References Chalmers DJ (1997) The conscious mind. Oxford University Press, Oxford Gigout S, Deisz RA, Dehnicke C, Turak B, Devaux B, Pumain R, Louvel J (2016) Role of gap junctions on synchronization in human neocortical networks. Brain Res 1637:14–21. https://doi. org/10.1016/j.brainres.2016.02.005 Heisenberg W (1979) Philosophical problems of quantum physics. Ox Bow Press, Woodbridge; ISBN 9780918024152 Kuhn TS (1970) The structure of scientific revolutions. University of Chicago Press, Chicago Potter J (1996) Representing reality: discourse, rhetoric and social construction. Sage Publications, London Solms M, Turnbull O (2002) The brain and the inner world. An introduction to the neuroscience of subjective experience. Other Press, New York Varela F, Thompson E, Rosch E (1991) The embodied mind. The MIT Press, Cambridge, London Wilber K (2000) Integral psychology. Shambhala Publications Inc., Boston

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Basics Contents Chapter 2 Electrical Signals in the Nervous System – 11 Marc L. Zeise Chapter 3 Basics of Neuropharmacology – 49 Marc L. Zeise Chapter 4 The Transmitters – 69 Marc L. Zeise and Bernardo Morales

I

11

Electrical Signals in the Nervous System Marc L. Zeise Contents 2.1

 rom Physics to Signals: Some Basics F for the Exploration of Nervous Systems – 13

2.1.1 2.1.2 2.1.3 2.1.4 2.1.5 2.1.6

T he Four Interactions and the Atom – 13 Living Systems – 15 Function – 17 Information and Signals – 18 Detour: What Does “Meaning” Mean? – 20 Electrical Signals Are Useful – 21

2.2

 ow Do Electrical Signals Originate in  H Biological Cells? – 21

2.2.1

T he Basic Parameters of Electricity: Electric Charge, Current, Voltage, and Resistance – 21 Diffusion and the Second Law of Thermodynamics – 23 Ions and the Biological Membrane – 25 Ion Channels: Properties and Classification – 25 Passive Flow Versus Active Transport – 27 The Generation of Cellular Electrical Signals – 27 Electrical Signaling Is Achieved by Closing or Opening Ion Channels – 29 Detour: Capacitance – Why Are Biological Electrical Signals So Slow (Compared to Those in Technical Devices)? – 33

2.2.2 2.2.3 2.2.4 2.2.5 2.2.6 2.2.7 2.2.8

2.3

 eurons and Other Cells Found in the  N Nervous System – 34

2.4

Neurons and Synapses – 35

© Springer Nature Switzerland AG 2021 M. L. Zeise (ed.), Neuroscience for Psychologists, https://doi.org/10.1007/978-3-030-47645-8_2

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2.5

Electrical Signals in Neurons – 36

2.5.1

 eurons Generate Essentially Two Types of  N Electrical Signals: Postsynaptic and Action Signals – 36 “Passive” Spread of Electrical Signals in Neuronal Processes – 37 The Action Signal: Threshold, Explosion, and Feedback – 38 Sodium Channel Inactivation Generates a Refractory Period for Action Signal Generation – 40 How Do Action Signals “Travel” Along the Axon? – 40 Action Signals Are the Form in Which Information Is Conveyed over “Long” Distances in the  Nervous System – 41 The Chemical Synapse: Transduction of Action Signals into Postsynaptic Signals – 42 The Integration of Postsynaptic Signals in the Neuron – 44

2.5.2 2.5.3 2.5.4 2.5.5 2.5.6

2.5.7 2.5.8

2.6

“ Thinking” Implies Energy Consumption: Transporters of Ions in the CNS – 46 References – 47

13 Electrical Signals in the Nervous System

2.1

 rom Physics to Signals: Some F Basics for the Exploration of Nervous Systems

Describing and investigating the non-living universe is essentially considering the distribution of energy in space and time. This implies that this distribution is different from a totally disordered, structure-less chaos. Energy and structure are basic concepts that almost defy definition. Let us try it anyway: Energy is everything that can be assigned an equivalent of work (movement along a certain trajectory of an amount of something like mass or electrical charge in a field of corresponding force). Energy can take different forms and has several equivalent units like Joule, Watt × hour or electron volt, among others (see 7 Box 2.1).  

2

Matter would be anything that can be attributed a mass. On the other hand, there are several other forms of energy besides matter. A photon, for example, carries energy, but does not have a (resting) mass. In biology, and therefore in neuroscience, matter and energy are different and separate. Processes where mass is converted to other forms of energy (or vice versa) are beyond the realm of biology. 2.1.1

 he Four Interactions T and the Atom

As you may remember from high school, an atom, the smallest material unit that can be attributed chemical properties, consists of positively charged protons and neutrons without charge forming the small nucleus while, in certain orbits, negatively charged electrons are zooming around it (. Fig.  2.1). Electrical charge is a basic property of matter (no definition here). In our text, we will deal only with the three  

Box 2.1: Energy Measures The international unit of energy is the Joule (J). It is defined as 1 Coulomb × Volt (CV) or Watt  ×  second (Ws); or as Newton × meter (Nm). This roughly corresponds to the energy necessary for lifting a 100 gram mass in the earth’s gravity field by one meter. Other widely used energy measures are the calorie (0.239 J; energy that heats one gram of water by one degree Kelvin) and the electron volt (the energy to move an electron by one volt (1 J is 6.24 × 1018 eV).

We characterize structure in this context as a distribution of energy that can be generally described. As examples we may think of the form of a galaxy or the distribution of masses and charges in an atom. In physics and chemistry, it is called negative entropy. A particular form of energy, as Einstein has taught us (Einstein 1935), is matter.

..      Fig. 2.1  Model of the “common” carbon atom (isotope 12C) according to the ideas in the beginning of the twentieth century. The nucleus consists of positively charged protons and neutrons without charge. Around it negatively charged electrons, equal in number to the protons, circle in distinct orbits

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particles mentioned above. The model of . Fig.  2.1 is called the model of Bohr according to the Danish physicist Niels Bohr (Bohr 1913). Did you ever wonder how the atomic nucleus is held together given the fact that it consists of positively charged particles (the protons) extremely close to each other, while we were told (correctly) in high school that equally charged electric particles repel each other and, the more so, the closer they are to each other? How come that the atomic nucleus does not explode but rather remains stable? Few of us have told the high school teacher: Stop, what you tell us cannot be true. That nucleus must explode. For physicists, however, as soon as in 1908 the existence of an atomic nucleus was discovered, it

was immediately clear that a new force must exist that “glues” the nucleus together. For its ability to overcome the electromagnetic force it has been called “The Strong Force.” So, there is electric or, better, electromagnetic interaction, the “Strong” interaction and also gravity as we all know. In order to explain phenomena like the so-called beta decay (Konya and Nagy 2012), another interaction had to be introduced: the so-­ called weak force. According to the state of the art of physics today, these are the only four ways (“forces”) in which energy/matter can interact (see . Fig. 2.2): 1. Gravitational 2. Electromagnetic 3. “Strong” 4. “Weak”

..      Fig. 2.2  The four interactions. As far as physicists can tell, there are only four principal ways in which matter does interact. Only two of them, gravity and electromagnetism affect biological processes. While

gravity is important, it is virtually constant on the earth surface and therefore does not influence living systems differentially



2



2

15 Electrical Signals in the Nervous System

Fortunately for us, the weak and strong interactions do not play any role in biology since their action scale does not extend beyond the radius of the nucleus of an atom (1.6– 15 × 10−15 m). In fact, the “weak” force is, at 10−18 m equal to the strength of electromagnetic interaction. (For this, the weak and the electromagnetic interaction are sometimes lumped together as “electroweak” force.) Gravity, of course, does influence biological systems, but it plays a minor role in understanding biological processes. Biological processes, by and large, rely on chemical processes, and they, in turn, involve exclusively electromagnetic interactions. Hearing about just one interaction that counts in biology one may ask: And mechanical forces? Temperature? Radiation of various sorts? Are they not kinds of energetic interactions? Indeed, energy comes in various forms, but the interactions in mechanics, those that involve temperature or non-­ nuclear radiation are all of the electromagnetic type, because it is just the outer shells of electrons of atoms or molecules that interact. Biological organisms have means to detect changes in energy in the forms mentioned above, plus substances in their different forms, so the form of (electromagnetic) energy is quite relevant in biology. All we have to care about are the interactions of electrons and of these merely the outer layer where the number allowed is not yet reached (when an atom has the full number of electrons in its most peripheral orbit, it forms a noble gas, an element that hardly ever makes up molecules with other elements and, therefore, is biologically of little relevance). In . Fig. 2.1, the star of biology, the element carbon, is shown in a classical view having four electrons in its outer orbit forming chemical bonds involving four other electrons of other atoms completing that number to eight (the noble gas configuration). Thus, carbon always has four chemical bonds linking it to other elements like hydrogen, oxygen, and/or several others (for information on chemical bonds see 7 3.1).  



The electric charges of an atom determine its chemical properties. Accordingly, the quantity of positive elementary charges (identical with the number of protons) gives number and name to the chemical elements. The simplest and smallest element is hydrogen with one proton, and the number goes up to 100 and a bit beyond (see . Table 2.1; the periodic system of elements).  

2.1.2

Living Systems

Throughout natural sciences and beyond, we learn about systems. What then, is a system? We may define it as a certain number of two or more distinguishable items called elements that interact with each other relatively regularly. To be a system, it must be clear which elements are in it and which are not. A particular element, however, may belong to more than one system.1 The hypophysis or pituitary gland, for instance, we regard as part of the nervous system, while, at the same time, it also is part of the endocrine system. Open systems receive and emit energy. Living systems, in particular, exchange energy in the form of substances and in other ways with their surroundings (. Fig. 2.3). A system, of course, can be element of another. For example, an ant is a living system. Many ants together may form the metasystem colony of ants displaying “emerging” features (Huxley and Huxley 1947) not observed in the single individual. On our planet living systems appeared about 4 billion years ago and may be defined as self-organizing systems. If we leave it like this, it seems that all biological organisms and more complex systems are self-­ organizing. As an  

1

The word “system” is also used meaning a scheme to categorize or put in order certain separables. An example would be the taxonomic systems in biology that order species according to their apparent and genetic similarity.

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..      Table 2.1  The periodic system of chemical elements. The elements that are important in biology are found in the upper part, that is, they are generally the lighter elements. Red: Elements that make up quantitatively important parts of our solid body. Blue: Elements found dissolved as ions in watery parts of the body; calcium is found in both roles (ion and forming solid compounds). Green: “Trace elements” necessary for survival, but forming less than 0.001% of our total body weight. Yellow: Necessary and sometimes found in large quantities in microorganisms or plants, while in mammals they are absent or their importance is discussed. From: 7 https://en.­wikipedia.­org/wiki/Periodic table; modified

2



Group 1

2

Alkali metals

3

4

5

6

7

8

9

10

11

12

13

14

Alkaline earth metals

15

16

Pnictogens

17

18

Chalco- Halogens Noble gens gases

Period Hydro1

Helium 2 He

gen 1 H

2

Lithium Beryllium 3 4 Li Be

3

Sodium 11 Na

4

5

6

7

Potassium 19 K

Boron 5 B

Magnesium 12 Mg Calcium 20 Ca

Scan- Titanium dium 21 22 Sc Ti

Rubid- Strontium Yttrium ium 37 38 39 Rb Sr Y Caesium

Barium

55 Cs

56 Ba

Francium 87 Fr

Radium 88 Ra

* Lanthanides

** Actinides

*

Zirconium 40 Zr

Chrom- Manga- Iron ium nese 25 26 24 Cr Mn Fe

73 Ta

Tungsten 74 W

Rhenium 75 Re

Ruther- Dubnium SeaBohrfordium borgium ium 104 105 106 107 Rf Db Sg Bh

LanCerium thanum 57 58 La Ce Actin- Thorium ium 89 90 Ac Th

Alumin- Silicon Phosium phorus 13 14 15 Al Si P

Sulfur

Gallium Germa- Arsenic nium 33 31 32 As Ga Ge

Selenium 34 Se Tellurium 52 Te Polonium 84 Po

Cobalt

Nickel

Copper

Zinc

27 Co

28 Ni

29 Cu

30 Zn

Palladium 46 Pd

Silver

Cadmium 48 Cd

Indium

Tin

49 In

50 Sn

Antimony 51 Sb

Mercury 80 Hg

Thallium

Lead

Bismuth

81 Tl

82 Pb

83 Bi

Niobium Molyb- Tech- Ruthe- Rhodenum netium nium dium 41 42 43 44 45 Nb Mo Tc Ru Rh

Hafnium Tantalum 72 Hf

**

Vanadium 23 V

Os- Iridium Platinum mium 76 77 78 Os Ir Pt

47 Ag Gold 79 Au

Has- Meit- Darm- Roent- Copersium nerium stadtium genium nicium 108 109 110 111 112 Hs Mt Ds Rg Cn

PraseoNeo- Prome- Sama- Europ- Gadolindymium dymium thium rium ium ium 59 60 61 62 63 64 Pr Nd Pm Sm Eu Gd

Ununtrium 113 Uut

16 S

Chlorine Argon 17 Cl

18 Ar

Bromine Krypton 35 36 Br Kr Iodine

Xenon

53 I

54 Xe

Astatine Radon 85 At

86 Rn

Flerov- Unun- LiverUnun- Ununium pentium morium septium octium 114 115 116 117 118 Fl Uup Lv Uus Uuo

Ter- Dyspro- Holmium Erbium Thulium Ytterbium sium bium 65 66 67 68 69 70 Tb Dy Ho Er Tm Yb

Protac- Uranium Neptu- Pluto- Ameri- Curium Berkel- Califor- Einsteitinium nium nium cium ium nium nium 91 92 93 94 95 96 97 98 99 Pa U Np Pu Am Cm Bk Cf Es

example we may think of the colony of ants mentioned above. Even the State of Chile is a self-organizing (even though it may not always function perfectly) and, hence, would be a living system. An interesting example of a living system more complex than an individual organism is the biosphere, also called “Gaia” (after the Greek goddess of earth). However, the attribute “living” is usually restricted to biological systems. In this context, it should be mentioned that viruses lack important parts for self-organization to subsist and proliferate, and, therefore, are not considered as living

Carbon Nitrogen Oxygen Fluorine Neon 6 7 8 9 10 C N O F Ne

Lutetium 71 Lu

Fer- Mende- Nobel- Lawrenmium levium ium cium 100 101 102 103 Fm Md No Lr

s­ ystems. They can, however, take part in forming living systems when joining other elements or systems. The simplest living systems therefore are prokaryotic cells.2

2 This means that the cell does not have a nucleus and lacks the cellular organs known of cells in higher developed organisms. For much more than 2 billion years, these were the only living systems on earth. Cells, however, that possess well-distinguishable organelles such as a nucleus or mitochondria are called eukaryotes.

17 Electrical Signals in the Nervous System

..      Fig. 2.3  Scheme of a living system. In general, there must be elements interacting and the system’s borders or extension must be defined. Open systems interchange energy in the form of matter or otherwise with its surrounding. Energy and/or substances entering or leaving may carry information. Information cannot interact directly; rather, it must be coded-­decoded (see also 7 Chap. 6)  

Self-organization and controlled interaction with its environment are necessary and have to be maintained for living systems to stay intact. To describe and investigate living systems, it becomes necessary to introduce at least two more basic concepts beyond energy and structure: function and information. 2.1.3

Function

When investigating living organisms3, we can correlate certain components like organs, genes, or enzymes to processes that are of importance for survival or reproduction. Thus, we may attribute a “function” to those components. For example, the kidneys can be associated to cleaning the blood from substances that, when they accumulate, will lead to serious damage or death. In this context, it is interesting to note that, in some books or articles we read about the

3

By and large, biological living systems are cells or are composed of cells. Particularly, nervous systems are composed of cells. The special cells found in nervous systems are dealt with briefly in 7 2.3.  

2

“functioning” of the nervous system. Now, while “function” implies the question “what is it (the item considered) good for?,” the verb “to function” refers to how a certain function is being realized. Taking again the kidney as example, we may state that this organ realizes its function by filtering the blood producing a primary urine out of which useful substances are then recovered by means of active transport systems, while other substances are actively secreted into the primary urine. In the case of the brain, however, we cannot describe completely “how the brain functions,” that is, how it realizes its functions, because we are unable to describe these “functions” completely. Certainly, several sub-functions are very well known  – such as the participation of the nervous system in maintaining the temperature of the body constant. But what do we understand as essential “function” of the brain? To make a human mind possible? The human “mind,” however, does not have a generally accepted definition in the scientific community (Solms and Turnbull 2002). The full description of what the brain “produces” or the function it serves is still very far from being clear. The main reason for this is that the generation of subjective, “conscious” experience is still a mystery (Chalmers 1996). We suggest, therefore, that a question like “How does the brain ­(nervous system) function?” lacks scientific validity, because we can only ask how a function is realized, when we can describe that function in a way that meets scientific criteria. Asking for the function of a particular substance or a structure, however, is very common in the biomedical sciences. It is also absolutely legitimate. For example, when a protein is found, we immediately ask for its function in the intra- and/or intercellular context. Therefore, even before knowing completely the function (and therefore the functioning) of the brain, we may and we should describe processes and explain “sub”-functions of it.

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2.1.4

Information and Signals

The function of the nervous system can be defined in a more general way: It is a system found in animals (may be human) that receives, processes, generates, and transports a big part of information that reaches, is being generated, stored, processed, or leaves our bodies. The central nervous system (consisting of brain, brain stem, and medulla of the spinal cord) is the central regulator and processor for the rest of the body that can be considered as “periphery.” That is not to say that information is absent in tissues or organ systems outside the CNS. But the nervous system’s only task is just that: to deal with information. Now, what does “information” mean? Information may be seen as a process or as a certain kind of “stuff.” Informing yourself or being informed by another person about the menu in the cafeteria today is such a process, while considering the information amount of that message refers rather to information as “stuff.” Information, as something that can be sent and received and is quantifiable, using some kind of energy as a vehicle, can be most shortly defined as transmissible structure.4 The physical bearer of information in the latter sense is called a memory (“memory” has various meanings, too; in this case we use the word as in informatics). As “stuff,” information can be quantified. Its measure is called bit (derived from “binary unit”) which means the quantity of information con-

4 Often, the term “information” is used in a wider sense meaning the whole content of structure or order of the item considered. In this context, it is identical to negative entropy (Piccinini and Scarantino, 2011). However, this would mean that any kind of structure would be information and we would still have to look for a term describing coded, transmissible structure.

tained in a decision about one yes-or-no question where each alternative has the same (50%) probability. The bit, however, is not the elementary “quantum” of information. Since the information content of a signal is inversely related to its probability to occur, an event in a binary choice that has, let us say, p  =  0.9 probability carries less than one bit of information. Let us now consider the process of “informing.” As a process, information is the transmission of transmissible structure (=information as “stuff”) from a sender to a receiver by means of signals. . Figure 2.4 is a copy of the famous scheme presented by Weaver and Shannon (1963) depicting the essential constituents of information transmission. We prefer to speak of information (as “stuff ”) only if there is a complete “Shannon process” involved. Thus, interactions between pieces of matter such as the radiation of a star hitting earth does not constitute information, even though it falls right into the telescope of an astronomer. The astronomer, however, may generate information on the base of the observation of that radiation. In general, living systems have the capability to generate information that can be stored, processed, sent, received, and destroyed constituting a memory. Information is “mediumindependent,” that is, although it needs matter/energy as a vehicle, it is different from matter/energy and, thus can be generated “out of nothing” or destroyed without leaving anything behind. The biosphere is full of information-­ bearing signals from molecular interaction to human language. In the behavior of ­animals, the emission of signals is particularly obvious (. Fig. 2.5). A signal can be ­characterized as a modulation of one (or several) physical parameter(s) in time and/ or space that may carry and transmit information.  



19 Electrical Signals in the Nervous System

Information source

Transmitter

Transmission

Message Encoding Signal

Receiver

2 Destination

Received Decoding Message signal Noise source

..      Fig. 2.4  Essential elements of an information channel. From Weaver and Shannon (1963). (Modified; source: Wanderingstan at English Wikipedia) ..      Fig. 2.5 A peacock perched and emitting a (visual) signal

The existence of a signal does not necessarily mean that information is transmitted, but just that there is potential transmission of information. Only think of a shipwrecked who desperately emits signal after signal without being answered. What do we need in order to send a signal that is successfully “understood” by the receiver(s)? We need: 55 A physical carrier of the message Almost any form of energy, modulated in time and/or space may serve

as such a carrier. In biology, for example, electromagnetic radiation (visible light  +  infrared and ultraviolet), mechanical movement, certain types of substances or voltage are being used, among others. 55 A sender and a receiver A structure that is able to emit/receive signals. This can be a cell, a cell substructure, an organism, but also big organizations such as a federal institution or an international company.

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2

..      Fig. 2.6  The signal “blue” is not part of the pool of signals in the traffic light code. It does not fit into the codification that must be arranged beforehand. Hence “blue” does not carry information in this c­ ontext

55 A codification A signal is worthless, like a blue traffic light (. Fig.  2.6), if it is not using the code previously agreed with by sender and receiver. That agreement can be explicit, as in human society, or implicit by coevolution, as is the typical case in biology. Codes may be more or less efficient and more or less clear or secure, and they may be digital or analogous. We will readdress this issue below when dealing with the types of signals found in the nervous system (see 7 2.3).  



2.1.5

Detour: What Does “Meaning” Mean?

In socially shared contexts, we can identify meanings or common associations that are

invoked typically by the exchange of words, but also by other signals. Whereas information is received, processed, and sent by and from biological, artificial, or more complex systems, it takes a society to develop context-­ bound understandings establishing and assigning meaning to signals.5 As describing the physical, life-less world concepts like information or function simply do not “make sense,” because there is nothing we may attribute a “function” to, “meaning” is devoid of meaning when we deal with merely biological phenomena  – it implies a socially/culturally generated “world” where individuals or groups of individuals create a space of cultural interchange.6 There is a lot of confusion produced when information and signal processing is equaled to (socially) meaningful interchange. We may read phrases like the brain “thinks” or “learns,” and our nervous system seeks things (in this context, we would have to deal with the concept of “consciousness”). We may take as an example for an information handling device your PC that sends a document to your printer. The “stuff ” sent is structure encoded, which means information. There is no matter transferred to the printer. However, neither your computer nor your printer “knows” what this information is about. Equally, to talk about meaningful actions carried out by the brain does not make sense. The information handling device nervous system becomes meaningful only in a social context. This is not to say that your body does not perform functionally correct actions like keeping itself at the right temperature and reacting adequately to challenges of various sorts. But, a bit like information and function are

5 In non-human “societies,” such as an animal group or an ecosystem, meaning is present in a rather rudimentary form. For example, the cry of a bird may mean “danger” for other species. 6 “Meaning” is also called non-natural semantic information (Piccinini and Scarantino, 2011).

2

21 Electrical Signals in the Nervous System

phenomena that appear with the advent of self-­ organizing structures, that is, organisms, s­ignals may carry meaning only in social/cultural contexts. 2.1.6

Electrical Signals Are Useful

In technical information processing devices such as computers, electrical signals are used almost exclusively. In biological systems, we also find electrical signals quite frequently. In fact, there is no living organism without electrical signaling. Why is this? Why not use air pressure, color, or caloric signals? Probably for three reasons: 1. Electrical signals are potentially fast. 2. They are easy to digitalize. 3. Every functioning biological cell is an electrical battery, that is, a device that stores electrical energy. So there is already the signal parameter, voltage, which can be modulated.

2.2

 ow Do Electrical Signals H Originate in Biological Cells?

In order to understand how the electrical phenomena in living systems originate, we will first consider the various electrical parameters and then describe how the electrical signaling is brought about, in cells in general and cells of the nervous system in particular. 2.2.1

 he Basic Parameters T of Electricity: Electric Charge, Current, Voltage, and Resistance

As was mentioned before, biology does not divide matter more than to the level of atoms and their “classical” constituents: protons, neutrons, and electrons (. Fig.  2.1). Protons whose quantity determines the number and identity of each chemical element (. Table  2.1) are positively charged, while electrons bear a negative charge of exactly the same quantity. Neutrons, as you will not be surprised to learn, are electrically neutral. Electrical current means a flow (i.e., a movement that has a certain direction) of electrical charge and is measured in electrical charge per second, a bit like the flow of a water course may be measured in liters per second. Electrical charge is measured by the number of elementary charges (1 electron or 1 proton carries 1 elementary charge). A very high number of elementary charges (6.242  ×  1018) makes the unit of electrical charge, the Coulomb (Cb; named after Charles-Augustin de Coulomb who first described mathematically the force between electrical charges). Electrical current then is measured in Coulombs (Cb) per second. 1 Coulomb per second is 1 Ampere (A; after André-Marie Ampère, another distinguished Frenchman, who was the founder of electromagnetism as scientific area). 1 Ampere  



Great, so we are sending our messages around the body at the speed of light? Unfortunately, while in technical devices that velocity is almost reached, electrical signals in living organism travel much, much slower7 (the exception is electrical coupling via gap junctions: see 7 4.1). Still, they are the fastest biological signals that exist inside the body. By the way, nervous systems probably developed for need of speed. Multicellular organisms that do not have them are usually referred to as plants and typically do not move around and, thus, can afford to be a bit slowly reacting. We will follow the theme of bioelectricity in the following paragraph.  

7 There are exchanges of electromagnetic signals between animals, such as electric fish that, just as other electromagnetic waves travel with almost the speed of light.

22

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defines a current flow not atypical for household use. For example, in an electric heater will flow a current of several A and through a LED light bulb about a tenth to a hundredth of an A.  Now, what makes the electrical current flow? It is another most important parameter of e­ lectricity, voltage. Voltage (owing its name to Alessandro Giuseppe Antonio Anastasio Volta; 1745– 1827; for the invention of the electrical battery, he was appointed count by emperor Napoleon) is a force that we humans do not have a way of experiencing directly. Therefore, we refer to the widely used metaphor of water in a field of gravity in order to make things more tangible: On our earth all matter is attracted by the earth’s great mass. If we have a reservoir of water that contains a certain known volume and a device called turbine at a lower level, we would be able to convert the energy that the water above releases when flowing down to the lower level, into electrical energy. As any engineer in hydroelectricity could explain to you and what also seems the most plausible solution, the maximal amount of energy that can be  – theoretically – converted into electricity is determined by the mass of water available and the difference of altitude between your reservoir and the level where your electrical plant is being installed. Now, the energy per time, also called power that can be generated by your electric plant will depend on the flow of water and its force. The force depends directly on the difference in altitude, and the flow (=liters per second) will depend on the tubing or resistance against this flow. The wider your tubes, the more water will flow and the more power you will get. The situation in an electrical circuit is quite similar. There is a field of electric force, meaning that to every point in this field you can assign a certain potential (comparable to a certain altitude). Voltage (V) would be analogous to difference in alti-

tude, that is, potential difference. A connection between two points of different potential would initiate a current that depends on the voltage as well as on the resistance of that connection. In fact, it depends proportionally on these two parameters. In other words, doubling the voltage doubles the current and reducing the resistance by a factor of two also doubles the current. That relation in mathematical terms can be written as: Current (I) = voltage (U)/resistance (R); I = U/R or, more commonly, U = R × I; Ohm’s law; (after Georg Simon Ohm, a German physicist). The reverse of resistance is conductance (symbol g; 1/R), meaning the facility by which a current flows. Thus, a more tangible form of Ohm’s law is U g = I. This expresses the fact that the easier your tubing or conductor allows the current to flow, the more flow will actually occur. Now, different from mass in the gravity metaphor, there are two kinds of electrical charge, positive and negative. As you probably know, positive charge is driven toward the negative pole of a battery (an electric battery is a device that generates a relatively constant voltage over a certain time) and negative charge toward the positive pole. Moreover, electrically charged particles will attract each other having opposite polarity and repel each other in case of equal polarity. That force of attraction or repulsion grows when those charges get closer to each other. It does so by the third dimension, so that reducing the distance by half, the force of attraction or repulsion will grow by eight. In a living cell a small voltage is measured between the interior and the exterior, the interior frequently being between −40 and −85  mV (millivolts; 1  mV  =  0.001  V) more negative than the exterior. While this voltage exists in all biological cells, nerve

2

23 Electrical Signals in the Nervous System

cells are specialized in producing, processing, transporting, and transmitting electrical signals that consist in modifications of that voltage. We can also record a potential difference between the inside and outside of certain cellular substructures such as the mitochondria. Nevertheless, in this chapter we will restrict ourselves to the description and explanation of voltage changes between the inside and the outside of cells. In order to explain how that voltage and the signals deriving from its modulation are generated, we shall use the terms of electricity introduced above and, additionally, we must get to know a few facts about the cell membrane and a particular phenomenon in gases and liquids called diffusion. Let us begin with the latter concept: 2.2.2

Diffusion and the Second Law of Thermodynamics

All matter is in a constant random movement; its particles (atoms, molecules, and aggregates of them) “shiver” more or less rapidly. The average velocity of this movement is linearly correlated to temperature. Depending on its temperature, matter is either solid, liquid, gaseous, or plasma (the last state is not important in biology, because it occurs only at very high temperatures or applying high voltages; the sun or the gas in fluorescent lamps are in that state). Particles of liquids and gases can move (almost) freely, whereas in solids their movement is restrained. A substance dissolved in a liquid such as a molecule of sugar in water, for instance, also moves randomly around. This random movement of particles in gases or liquids causes a phenomenon called diffusion. Diffusion produces a m ­ ixing of substances or an equilibration of concentrations as a function of time and temperature. A lump of

sugar, for example, once dissolved in your cup of coffee, will be distributed after a while in the whole volume of the cup. The process of diffusion can be considered as a consequence of the second law of thermodynamics implying that every process in an energetically closed system will end up with less structure or order than was the case at its beginning. In order to reverse the situation, (free) energy is required. Biological systems create structures ever more complex mainly thanks to the constant flow of energy from the sun that makes life possible. The other property of diffusion that is worth to mention is that its action gets very slow at larger distances. While diffusion is fast at molecular distances, it is really slow at a macroscopic scale. Obviously, diffusion is faster at higher temperatures as compared to lower ones. Think of diffusion as the force that mixes substances. Imagine you are the manager of a museum (. Fig. 2.7). You have two halls for exhibition. If you let the visitors enter hall number 1 (. Fig. 2.7a) and, later, open the doors to hall number 2, the people will typically flow from hall 1 to hall 2 (. Fig.  2.7b) until in either hall we have a similar concentration of humans (number per room; in diffusion and, generally in sciences, it would be number per volume). Note that there are persons crossing from hall 2 to hall 1 and vice versa. Equilibrium, without net flow, means that, on the average, an equal number of items moves in either direction. If you want to get back to the former distribution, you need a special effort, like putting up a buffet in the left hall (. Fig. 2.7c). Similarly, in order to concentrate a substance against the tendency of diffusion, a certain amount of energy is necessary, depending on concentrations at the beginning and the end, the respective volumes as well as on temperature.  







24

M. L. Zeise

a

2

b

c

..      Fig. 2.7  a The hall to the right is closed; visitors can only move around in the left hall. b After opening the door, people “flow” from the left hall to the

right until about the same number are in either place. c “Reconcentrating” requires a special effort

25 Electrical Signals in the Nervous System

2.2.3

Ions and the Biological Membrane

As we mentioned earlier, the biological membrane is the other component that – together with the diffusion of ions – makes bioelectricity possible. It is an incredibly thin double layer of fatlike (lipid) molecules. We will consider the biological membrane in more detail in 7 Chap. 3. What is important in the present context is the fact that biological membranes are barriers for water and, ­therefore, to the free flow of ions dissolved in it. Remember that ions are the only carriers of electrical charge in the cell, and thus, membranes create separating compartments not only of different chemical constitution, but they also separate spaces that are at different electric potentials. In this membrane, many different proteins (see 7 Chap. 3) are integrated. Some of these proteins or, more exactly, protein assemblies that “float” in the biological membrane are ion channels. Ion channels are like little holes in the membrane that are permeable only for (certain) small ions and can be in an open or closed state. That means, they may allow or hinder ionic flow from one side of the membrane to the other. In this sense, the biological cellular membrane is not a separator only that insulates the interior from the exterior of a cell, but it is also the organ that allows modulating the membrane resistance in a dynamic way. Thus, the electric separation is variable, in other words, the membrane resistance is dynamic thanks to the ionic channels. Let us then, look a bit more closely at these important structures, their properties, and classification.  



2.2.4

I on Channels: Properties and Classification

2.2.4.1

I on Channels Can Be Open or Closed

All living cells are equipped with ionic channels, that is, membrane pores that render the membrane more or less permeable,

2

more or less specifically, for one or more types of ions. Very few of these, called leakage channels, are just holes in the membrane and do not participate in electrical signaling. The overwhelming majority of the channels, however, have at least one open and one closed state. That means they let or do not let flow ions from one side of the membrane to the other. When an ion channel opens, we speak of activation, when it closes because the stimulus ceases to be there or reverses, it is called deactivation. Additionally, in many, but not all channels inactivation is observed. That means, a channel closes spontaneously, just as a function of time, even though the adequate stimulus may still be present. Biophysicists have shown that the mechanism of closure in deactivation is different from the one underlying inactivation (Hille 2001). The time course of opening and closing and their conductance (i.e., how many ions may pass in a certain time) differ widely among the various ion channels. In the vast majority of cases, ion channels open (or close) responding to a certain physical parameter, that is, an interaction with a certain type of energy. Ion channels are specific in this sense. For example, an ionic channel may responding most sensitively to mechanic energy. This kind of ionic channel we will find in mechanosensitive cells. That does not mean that the channel does not react at all to other stimulus qualities like, let us say, temperature. It means, however, that the mechanosensitive channel responds much more easily to mechanic stimulation as compared to any other. There are various other types of energy that generate electrical signals like chemical or thermal, among others. As we will discuss in 7 Chap. 6, ion channels are our windows to the “outer world” as well as sensors of our bodily states, being able to convert different kinds of stimuli into electrical signals that can be processed by the nervous system.  

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In the nervous system, most ionic channels respond specifically to the following: (a) Voltage (typically a change toward more positive values) (b) Substances (also called ligands, because they form a union with the channel for a short time) 2.2.4.2

I onic Channels Are Specific for Certain Ions

Ionic channels further differ by the type of ion(s) they let pass. For example, there are channels that are almost exclusively permeable for sodium ions. Others let pass more than one ion with relative ease. But they are never equally permeable for all biologically relevant ions. Things are complicated by the fact that there are whole families of channels specific for one type of ions. Thus, in neurons more than 20 different types of channels have been described as potassium channels (7 Box 2.2).  

Box 2.2: Evolutionary History of  Ion Channels and the Nervous System It is not easy to pin down the beginning of nervous systems being intimately linked to the evolution of what we know as “animals,” symmetric multicellular organisms (“metazoans”) as mentioned in the introduction. While most proteins of synapses (see 7 Chap. 3) are already found in sponges and other simple non-­ symmetric organisms, “fast” sodium ion channels providing velocity to the nervous system are first seen in medusa-like animals (“Cnidaria”) and then found in all known following animal groups from worms to humans. There is an evolution of ion channels giving rise to ion channel families such as voltage-dependent cation channels (Senatore et al. 2016).  

Ion channels are the tools that biological cells use to produce electrical signals. As was said above, ion channels are critical for receiving signals from the outside reacting specifically to diverse energy forms (outside the body or outside of the cell considered), for creating and processing information in the nervous system and as well as for the output of the nervous system. This “output” consists mostly, but not exclusively, in movements of the whole or parts of the organism constituting behavior. Ion channels can be blocked or their properties be modified by certain sub­ stances. Ion channels can be blocked in a specific manner. For example, calcium channels are blocked by magnesium (and other doubly positive charged ions = divalent cations) that enters the channel but cannot pass through. On the other hand, this same cation does not influence channels for monovalent ions (ions with one elementary charge). Further, many substances block or influence ion channels in an even more specific manner interacting only with one and no other type of channel. The pharmacological manipulation of ion channels has been and is crucial in neurophysiology in order to investigate ion channel properties and their functions. Thus, if neuroscientists want to refer to a specific channel they may say “the voltage-­ gated sodium channel that can be blocked by Tetrodotoxin.” Tetrodotoxin is the poison of the puffer fish blocking the very sodium ion channels essential in generating signals (action signals; see 7 2.5.3) from neurons to other cells. Ion channels are further referred to by their activation characteristics. There are, for instance, low voltage and high voltage calcium channels indicating that these channels open at relatively low or rather high voltages.  

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27 Electrical Signals in the Nervous System

2.2.4.3

I on Channels in the Nervous System

As mentioned earlier, in the central nervous system we find mostly channels gated by voltage or by ligands. Some of the former generate action signals (for historical reasons called action “potentials,” even though they are not just potentials, but a characteristic change of voltage in time), the signals that carry information from the neuronal body (soma) to other cells, while the latter  – activated by ligands – are mainly involved in the reception of signals at chemical synapses (see 7 Chap. 3). Today, there is, as in every classification of proteins or protein complexes, a genetic classification that uses similarity in amino acid sequences in order to establish a classification system. Classification using genetic criteria gets very close to the one established by more conventional criteria.  

2.2.5

 assive Flow Versus Active P Transport

In all living systems, there are passive and active transports going on in a controlled manner (see . Fig.  2.3). The passage of ions through ionic channels are passive transports, more appropriately called flows, that occur whenever there is a possibility, like water flowing downward if there is no obstacle to it. Active transports, on the other hand, need energy that the biological cell has to muster in order to get the stuff from one place to the other against a so-called gradient (a ratio of concentration or voltage between the two places that is different from 1). From one place to the other, that mostly means, on the cellular level, to get the substance from one side of a membrane to the other. Like a factory, the cell is separated in various compartments by membranes, but perhaps the most important division is

the cellular membrane that makes up the border between the cell and the rest of the world. 2.2.6

 he Generation of Cellular T Electrical Signals

In all living cells active transports include ions, being atoms or molecules that have unequal numbers of protons and electrons. For example, sodium in the water milieu of the cell exists totally in its ion form Na+, meaning that the number of electrons is inferior to the one of protons by exactly one, making the whole particle positively charged with one elementary charge. This ion will be attracted by negative voltage or negative charges, but repelled by positive voltage or charge. There is another force, however, that moves ions: diffusion. As ions involved in cellular electricity are small, they are also strongly influenced by thermal motion or, in other words, diffusion. Thus, ions will flow: 55 From spaces of high concentration toward those of low concentration and they will also move 55 In an electrical field according to the potential difference, that is, the voltage



2.2.6.1

The equilibrium voltage for a certain ion

In all biological cells, there is disequilibrium between inside and outside. This disequilibrium refers to substances, that is, we find certain molecules more concentrated inside than outside or vice versa. Further it concerns voltage, but also other parameters such as acidity (pH value; see 7 3.2) or levels of structuralization (inside a cell there is more “order” as compared to the extracellular space). As ions are concerned, the important ones in this context (the ones that contribute to the generation of electrical signals) are listed in . Table  2.1. As you can  



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see, potassium is more concentrated inside than outside. Cell membranes at rest (without any signals arriving) are mainly permeable to potassium. Voltage is changing as the different ion “batteries” gain or lose impact due to opening or closing specific ion channels. Now, just like performing an imaginary experiment let us suppose for a moment that the only ions able to pass the membrane were potassium ions. In this case, diffusion of these ions would take place from the inside to the outside. However, as potassium ions leave the cell taking with them positive charge, the cell will become more and more negative, attracting positive ions. The cell would exert a negative electrical force, in other words, a voltage. Before the concentration changes substantially, the net flow caused by diffusion will decrease and eventually stop due to the electric force and equilibrium will be established. Without a net flow, the number of potassium ions leaving the cell because of

diffusion being equal to the number that enters the cell due to voltage. The electric force necessary to just keep the ions from leaving the cell will be equal to the diffusion force. Therefore, we may label that electrical force or voltage the equilibrium voltage (in the physiological literature referred to as equilibrium potential). More precisely, it would be the equilibrium voltage for potassium. The force of diffusion determining this voltage will depend on the concentration gradient, or, the greater the difference between inside and outside concentrations, the more electrical force will be needed to keep the ions inside. As you can see in . Table 2.2, any concentration ratio can be associated to a certain voltage by applying the so-called Nernst equation (7 Box 2.3). Note that the equilibrium voltage does not change proportionally to concentration differences nor their ratio, but rather with the logarithm of that ratio.  



..      Table 2.2  Ions relevant for bioelectricity. The logarithm of the gradient (i.e., the quotient) of the concentrations inside and outside the cell together with the temperature and the charge for each ion determine a certain electric force (equilibrium voltage; last column). As ion channels specific for a certain ion open or close, the corresponding voltage gains more or less influence on the overall membrane voltage. As a result, the total voltage inside/outside will get closer to (in the case of opening) or further (when closing) from that specific equilibrium voltage. Values given are approximate for central neurons, but vary considerably. Qualitatively similar concentrations can be found in cells of all higher animals. Note that the internal concentration of free calcium is extremely low.a This has to do with the double role of calcium as an ion involved in signal generation as well as an intracellular messenger (see 7 Chap. 3)  

Ion

External concentration (millimolar)

Internal concentration (millimolar)

Gradient: [ion]ext∕[ion]int

Equilibrium voltage (mV)

K+

4.5

155

0.029

−94.6

Na+

145

12

12.1

+66.6

Cl–

140

7

20

−80.1

Ca2+

1.5

0.0001!

15000

+129

aIn

physical chemistry the term “activity” is used, meaning the concentration of ions that are “free to move.” In biological cells, most of calcium ions are enclosed in proteins and cannot contribute to the equilibrium potential of that ion

29 Electrical Signals in the Nervous System

2

Box 2.3: The Nernst Equation As explained in the text, a concentration gradient of an ion X generates a voltage (E). This is an electrical force that depends on this gradient, the temperature (T), and the number of charges/polarity (z) RT E ( ionX ) = ln [ionX ] o / [ionX ] i zF ( Nernst equation )

(

)

R and F are physical constants (universal gas constant and Faraday’s constant). R describes the energy (work) necessary to concentrate a mole of gas from infinite dilution to a concen-

We obviously also must care for the polarity and the number of charges (1 or 2) that the ion in question is carrying. As we mentioned above, diffusion is a direct manifestation of temperature, so this parameter has to be considered as well. However, as we are mainly interested in warm-blooded creatures like humans, temperature can be considered as constant in most applications. 2.2.6.2

Membrane voltage as result of contributions from various equilibrium potentials

Now, if we do the same mental experiment for the other three ions, namely, calcium, sodium, and chloride, we also would get to a certain equilibrium voltage depending on the concentration gradient between inside and outside (see . Table 2.2). Thus, the cell has four batteries, that is, sources of voltage: a sodium, a calcium, a potassium, and a chloride battery. As any battery, each one of these, given the diverse concentration gradients, maintained almost constant by means of active ion transport (see 2.6), has got its individual electric force or voltage, called equilibrium potential (=equilibrium voltage; see . Table  2.2), The concentration gradients and, hence, the voltage values of the diverse batteries vary  



tration that induces the rise of temperature by 1 degree Kelvin. F is the electric charge of 1 mole of elementary charges. [ionX]o is the concentration of the ion X outside the cell and [IonX]i the concentration of the ion X inside the cell. As we can see from the equation, the voltage produced is directly proportional to the temperature and to the logarithm of the concentration gradient. At 37° Celsius (310° Kelvin) RT/F is 26.73 mV. In the case of the ion sodium (z  =  1) and the gradient 145  mM/12  mM  approximately equal to  12, the Nernst equation yields +67 mV.

depending on the type of cell and the species, but still are qualitatively similar. The actual voltage that you would measure experimentally between the inside and outside of the cell will depend on which battery contributes how much. That contribution is varied by changing how easily specific ions can get from one side to the other. The cell varies that conductance or permeability by opening or closing ion channels. In this way, voltage is modulated and electric signals are produced. The equation that describes this in mathematical terms is called Goldman-­Hodgkin-­Huxley equation (7 Box 2.4). It allows calculating the actual voltage between inside and outside of a cell based on the Nernst diffusion voltage and the relative permeabilities for the various ions involved.  

2.2.7

 lectrical Signaling Is E Achieved by Closing or Opening Ion Channels

In order to explain how the modulation of the cellular voltage is brought about and, in this way, electric signals are generated, we will refer to a water metaphor again. A tank full of water is connected to a basin some

30

M. L. Zeise

a

2

b

..      Fig. 2.8  Manometer metaphor. Opening and closing of ion channels are symbolized by regulating valves. a Only the upper valve is open; pressure is determined by the altitude difference in the upper con-

tainer. b When the lower valve opens, suction will occur determined by the positioning of the lower valve. Pressure may turn into suction. For further explanation, see text

meters above (. Fig. 2.8). A tube of a certain length is attached to the tank producing suction. Inflow as well as outflow can be regulated by valves. In . Fig.  2.8a, the inflow valve is somewhat open, the outflow is blocked. In this situation, the maximal ­pressure will be monitored at the manometer. When, as shown in . Fig. 2.8b, the outflow valve is opened allowing more outflow than inflow, a negative pressure or suction

will be measured. The situation in the upper panel can be compared to a situation where the only ion channels open are of a positive ion concentrated more at the outside, such as sodium, voltage will be determined only by the sodium concentration gradient. When potassium channels (conductances) are opened allowing a stronger flow of potassium than sodium channels, “suction” or a negative force will prevail.







31 Electrical Signals in the Nervous System

Box 2.4: The  Goldman-HodgkinHuxley Equation The actual voltage between inside and outside of a cell depends on the electric force in volts that each ion contributes via its concentration gradient weighted by their respective permeabilities: EM = RT/F(PK[K]o+PNa[Na]o+PCl[Cl]o +PCa[Ca]o)/(PK[K]i+PNa[Na]i+PCl [Cl]i+PCa[Ca]i) Permeability for an ion S (PS) allows a certain transmembrane flux (in moles per area and time) at a given concentration difference. The other symbols are identical with the ones used in 7 Box 2.3.  

Indeed, the action signal in neurons (see below) is generated by “playing” with the sodium and the potassium battery opening and closing sodium and potassium channels (. Table 2.3). . Figure  2.9 represents an electric scheme of the biological membrane. It is relatively easy to implement this circuit and see what happens when the ion conductances, proportional to the number of ion channels open, are varied. The batteries and the resistors are transversal to the membrane, because the voltage exists between inside and outside and the variable resistors called ionic channels are built into the cellular membrane. The scheme shown in . Fig.  2.9 contains also a capacitance (see 7 2.2.8). It is easy to see that, when three of the batteries are disconnected shutting off their respective resistors (no channel open = resistance is infinite and conductance zero), the voltage measured must be the one of the battery left. If, for example, the only one open were the one for potassium, the equilibrium voltage (“potential”) for potassium would  



2

..      Table 2.3  Illustration of how the phenomenon of threshold is produced. 1st column: A cell is brought (by incoming signals or artificially in an experimental situation) to a certain voltage. 2nd column: The induced voltage opens a certain percentage of sodium channels. 3rd column: The voltage achieved by opening the sodium channels indicated in column 2. Every voltage increase opens more sodium channels in a non-lineal manner. At threshold (−47 mV), the imposed voltage is exactly sufficient to open sufficient sodium channels to maintain that voltage. Any slight voltage increase will now induce a self-sustaining process depolarizing the cell. The following files indicate the self-sustaining process taking place. Numbers are fictitious and illustrate the process qualitatively only Membrane voltage imposed (mV)

Percentage of sodium channels open

Membrane voltage induced (mV)

−70

1

−70

−65

1.5

−69

−60

2.5

−67

−55

4.5

−63

−50

8.5

−55

−47

12.5

−47 = threshold for the triggering of an action signal

−45

16.5

−39

−39

31

−10





be measured and EM would be around −90  millivolts. Now, if the resistance, that is, the channels, for, let us say, sodium opened a tiny bit, the voltage across the membrane will come a bit closer to the voltage of the sodium battery, so that the voltage would become more positive. If either resistance is equal, we would expect the voltage to be exactly half way between

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2

..      Fig. 2.9  Electrical scheme of the membrane. By regulating the conductances (gx; proportional to the number of ionic channels open) for the various ions, the voltage between inside and outside (EM) is modified. While, under physiological conditions, Na+ and Ca++ will flow into the cell, potassium normally leaves it. Chloride may flow in either direction, since the

membrane voltage can be positive or negative to the chloride equilibrium voltage (=the voltage of the chloride battery). Time course of voltage changes are strongly influenced by the membrane capacitance (CM) that, in turn, mainly varies proportional to the membrane area. This is why small neurons are “faster” than larger ones

the two extremes (in the case of a neuron that would be a few millivolts below zero). The structures that function as specific variable resistors are the ion channels of a certain kind that, as we have mentioned before, are tiny pores connecting the inside and the outside of the cell and specifically open/close for certain types of ions. They

are practically the only structure giving rise to electrical signals (see 7 Box 2.5). Thus, they are of an immense importance producing signals responding to stimulation from the exterior, producing signals for the processing of signals inside the nervous system and conveying signals to other body tissues.  

Box 2.5: A Common Misunderstanding In many texts, we find descriptions of electrical signal generation like this: Sodium channels open, sodium ions enter the cell rendering it more positive. For example, citing a neuropsychology text: “So many sodium ions get in that, for a very short time, the difference between the outside and inside of the cell is actually reversed: The inside is positive and the outside negative.” While such a description is not wrong, it may lead to wrong conclusions. First, it makes you think that the cell is being filled up with

sodium ions, a bit as in an electrostatic experiment. But it is the force exerted by the higher sodium concentration outside that will be “felt” as soon as the channels open rather than the flow of ions or changes in concentrations that cause the voltage change. It further lets you think that the flow = the current is the important part of the signal instead of voltage. Finally, it makes you believe that concentrations change substantially when there is an electrical signal. That may be the case in very restricted places such

2

33 Electrical Signals in the Nervous System

as the synaptic spine, but in general, particularly as the action signal is concerned, concentration changes play a minimal role as causes for the time course of electrical signals in biological systems. In fact, when Hodgkin and Huxley (1949), who were the first to correctly explain the generation of the action signal, did their classical experi-

+ Electric force

V



Conducting medium/water containing salts +++++++++++++++++++++++++++++++++++++++++++++ Insulating medium/cell membrane ----------------------------------------------------------------------------------Conducting medium/water containing salts

..      Fig. 2.10  Capacitance. The thinner the insulating layer, the higher is the capacitance. As a biological membrane is only about 4  nm thick, the cellular

2.2.8

Detour: Capacitance – Why Are Biological Electrical Signals So Slow (Compared to Those in Technical Devices)?

When we discussed fundamental electrical parameters, a physicist, electric engineer, or professional in electric communication will probably have wondered why an important electric parameter has been left out: capacitance. Capacitance is the ability of electrical circuits to store electrical charge at either side of a (usually) thin non-conducting layer. The biological membrane is such a structure and thus electrical signals in biological cells are strongly influenced by this parameter (. Fig. 2.10). The capacitance is directly proportional to the area and inversely proportional to the thickness of the membrane. Since biological membranes have a thickness of molecular dimensions (approximately 4  nm), the  

ments with the squid giant axon, they could show that even when the pumping mechanism was blocked, still hundreds of action signals could be evoked until the mechanism eventually failed. They did not consider concentration changes in their modeling of action signals getting to a very precise time course of the “spike.”

capacitance is relatively high resulting in a time constant (see . Fig. 2.11) of several milliseconds  

capacitance of them is relatively high. When looking at . Fig. 2.11, we see that as voltage is applied to a capacitor, electrical charge accumulates at both sides of the membrane. The higher the voltage, the more charge will be put on either side; the relation is proportional. Depending on the properties of the capacitor and given a certain voltage, the amount of charge that a capacitor will accumulate differs mainly with two parameters: 1. The area of the membrane 2. Its thickness  

In a cell that is being recorded from with a microelectrode, we can apply a known voltage and release it, measuring the time course of that charge and discharge. The time course is best described mathematically by an exponential function (I = U/R e−t/RC) being very common to a number of natural processes such as the radiation from a radioactive material or the initial growth of cells in culture. As usual, the exponent, in this case RC, is a characteristic of the process considered (see also 7 8.2.1).  

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2

..      Fig. 2.11  Charge and discharge of a capacitor (may be a cellular membrane). When a current is applied to a capacitor, voltage will not change immediately to a value corresponding to that current, but a certain time will elapse to charge or discharge the capacitor. The time constant τ is the time that passes until 1/e of the total charge is put to the capacitor. Ii = induced transmembranal current (proportional to the ions that flow through ion channels); IC capacitive current charging/discharging the membrane. ΔVM/IM is the so-called input resistance; the input resistance gives an indirect and inverse measure of the total amount of channels open

In the case of a capacitance, it is called time constant (τ) giving the time it takes to discharge the capacitor to 1/e of its original charge.8 Suppose, you charged a capacitor with ten volts and connect both sides, a capacitive current will flow for a certain time, namely RC to get to 10/e V (approx. 3.68 V). The measure for capacitance is Farad (F) and is defined as 1Cb/V. That means that a capacitor of 1 F will store a charge of 1 Cb when you apply a voltage of one V. Now, in our cell we may measure a time constant of 5 ms (milliseconds) and the resistance has been calculated as being 20 MΩ (applying Ohm’s law, see 7 2.2.1). In this case, the membrane capacitance is C  =  τ/R  =  5  ms/20  ×  106 Ω = 0.25 nF. This value is not very exact due to the impossibility to measure the resistance of the cell with precision. However, the capacitance by area is pretty constant in biology  

8

“e” is the base of natural logarithms; it is the limit of (1 + 1/n)n.(n: a natural number; 1,2...).

and amounts to 1 μF/cm2. Physiologists know that large cells such as pyramidal neurons cannot produce signals as fast as smaller cells such as inhibitory interneurons. This is due to the cellular membrane covering a much greater area in the former ones and therefore having a relatively large capacitance. Thus, the large pyramidal neurons, at most, produce signals at a frequency of not much more than 1 kHz. Small neurons, however, may “fire” at frequencies of up to 10 kHz. This is a far cry from what technical devices are able to do: Your computer will be about a million times more rapid producing signals as fast as various GHz. You may think of it in this way: Biological cells in order to produce electrical signals, that is, to change voltage must charge or discharge their relatively huge capacitance, while technical signal generators have very small capacitance so their voltage can change much more rapidly. It is fair to say that the properties of a capacitance depend also on the material that constitutes the separating membrane between the two conductors. Since the biological membranes for our contexts are not changing their capacitance, we will not consider this item further. However, measurements of capacitance have been important in eluci­dating the liberation of transmitters during synaptic transmission (Neher and Marty 1982; see 7 Chap. 4 for the definition of transmitter and exocytosis). This is mainly, because membrane area, and thus, capacitance changes when exocytosis takes place.  

2.3

 eurons and Other Cells N Found in the Nervous System

The nervous system (NS) is quite special  – about 30% of our genome codes for it. Types of cells that are found exclusively in the NS are called neurons and glial cells. The overwhelming part of neurons (there are about 100 billions of them) has a unique outgrowth or process called axon that enables them to contact and send signals to far away cells.

35 Electrical Signals in the Nervous System

The signals sent via the axon are quite special for having a digital-like character (see below). Now, as often in life, there are some rare exceptions such as horizontal or bipolar cells in the retina of the eye that neither have axons nor produce those special signals (they do not need to for they do not have to convey messages to far away parts). However, just as all other neurons, they transmit their messages by the special contacts called (chemical) synapses, a structure characteristic for neurons that is dealt with below in more detail. Whereas neurons are anatomically and biochemically relatively similar to each other, glial cells have not much more in common than being specific for the NS and not being neurons. Glial cells, about as numerous as neurons, are somehow the bastard kids of neuroscience as they were thought to have nothing to do with information processing. However, it is quite clear by now that at least the astroglia, a kind of cell that bridges the blood vessels onto nerve cells and covers synapses, but lacks axons, is intimately involved in signaling and signal processing. The problem is that we are quite ignorant about what their role in information processing really is. Some investigators have speculated that they are crucial in producing the phenomenon of consciousness (Pereira and Furlan 2010). Other types of glia, the oligodendrocytes in the brain and Schwann cells in the peripheral NS, form wrapping sheaths around axons enabling them to convey their signals faster. Even these are probably involved in modifying signals. Finally, microglia is a kind of cells that, while being special for the NS, does not originate from the ectoderm but is derived from mesodermal9 bone marrow just like the

9 In embryology, at an early stage, we differentiate between three layers: ectoderm, mesoderm, and endoderm. The external sheath called ectoderm contains precursors of the NS, while the endoderm will form interior parts such as the gastrointestinal and organs related to it. The mesoderm forms muscles and bones, among others.

2

cells found in the blood. Microglial cells are part of the immune system and differ biochemically and functionally from all other types of cells found in the NS. There are also cells/tissues that are more or less similar to others found elsewhere in the body such as blood vessels or epithelial cells and the cells forming the meninges that cover and protect the central nervous system. 2.4

Neurons and Synapses

In order to understand well the following paragraphs, we must recall that neurons consist of a cell body like (almost) any other biological cell and various processes called neurites. The processes that receive signals from other neurons forming the postsynaptic part of chemical synapses are called dendrites (called after their tree-like appearance; (Greek δενδρον (dendron)  =  tree), and the processes that carry signals toward other cells are called axons. They form another tree-like structure where they contact other cells, the so-called axon terminal (. Fig.  2.16). The ramifications of the latter structure end in swellings that are called “boutons” (knobs in French for their appearance) attached to other cells forming a synapse. A word about the concept of synapse: Early morphological studies saw a thickening of membranes where processes of one neuron met those of another. Interpreting these thickenings correctly as contact zones, they were christened “synapse” meaning something like “touch together” in ancient Greek. Only on one side, circular structures were identified that later were called synaptic vesicles containing the transmitter(s). Today when we are talking of “synapse” often we include the “presynaptic” and “postsynaptic” zones close to the thickenings of membranes. Neuroscience literature also refers to “synapse” meaning the “chemical,” classical synapse and not the “electrical” synapse discovered later (see below).  

36

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M. L. Zeise

The structure of contact is called synapse and consists of the boutons that are forming the presynaptic part of the synapse, while the membrane part of the other cell in contact to the former cell is named postsynaptic part of the synapse. It must be mentioned that this description is valid only for the chemical synapse where a substance released transmits information from the neuron to the other cell. The other type of specialized contacts, the electrical synapse is a plasma bridge or junction enabling cells to directly interchange electrical and chemical signals (see 7 4.1). The name “electrical synapse” is unfortunate, not only because neutral molecules such as chemical messengers pass through, but also because the word synapse implies that these contacts are special for nervous systems, as is the case for the chemical synapse. However, plasma bridges that allow for electric and chemical coupling are found in many animal and plant tissues as well as between unicellular organisms.  

information from skeletal muscle back to the medulla up to 400 km/hr. or 10 cm/ms approximately; thinner axons and, especially unmyelinated ones, are up to a hundred times slower.) 2.5.1

Neurons Generate Essentially Two Types of Electrical Signals: Postsynaptic and Action Signals

Only in the second half of the last century, intracellular recording became possible (see 7 10.3.4). When recording the voltage between the inside and the outside from the soma of a functional neuron in a living animal (. Fig. 2.12), a continuous, apparently irregular change of voltage is observed that, as the voltage rises beyond a certain value, triggers rapid “spike-like” signals “riding” on the underlying voltage changes (. Fig.  2.12b). While the former voltage variations come in different size and duration and can be positive or negative-going, neuronal action signals, are pretty uniform or stereotyped. The two types of signals differ in this and various other aspects: 1. While action signals are less frequently observed in dendrites, in axons they are virtually the only electrical signals. In contrast, postsynaptic signals are most prominent in dendrites, but typically absent in axons. 2. As was said above, action signals are more or less one like another, whereas postsynaptic signals vary strongly in amplitude, polarity, and duration. 3. Action signals appear when the interior of the cell is depolarized beyond a certain value called the threshold. Postsynaptic signals do not display this property. 4. Action signals are generated by voltagegated channels, whereas postsynaptic signals owe their origin to ligand-gated channels (see below and 7 Chap. 3).  





2.5

Electrical Signals in Neurons

For a long time, nobody knew about the signals from neurons or other cells since neither cells, neurons, electricity, or electrical signals were known. Bioelectricity was discovered at the end of the eighteenth century when Luigi Galvani from Bologna described the “excitability” of frog muscles showing that electric stimulation of the nerves can trigger muscle contraction (Galvani 1791). First measurements were undertaken in nerves, that is, bundles of axons (the structures of neurons that convey signals to other cells; see below). It was known that peripheral nerves would carry signals from the central nervous system to executive organs such as muscles or glands. The signals measured from nerves were called “nerve impulses” and were shown to travel at relatively high speed. (Aα axons send sensory



37 Electrical Signals in the Nervous System

a

b

c

d

2

..      Fig. 2.12 Neocortical neurons are constantly “bombarded” with synaptic inputs. a Extracellular recording in an awake cat. b–d Intracellular recording from the same animal under ketamine-xylazine anesthesia. b, c Synaptic bombardment causes a large variability of membrane voltage and a permanent generation of action signals. c A hyperpolarizing current is injected that “drowns” in the synaptic noise, but becomes visible when lots of sweeps are averaged. d When neuronal out-

put is silenced with a substance that blocks action signal generating sodium channels (“TTX”), and thus blocks synaptic inputs, membrane voltage becomes “quiet” and the same hyperpolarizing current as in c is responded by a far greater voltage change indicating an increase in membrane resistance (remember that postsynaptic activity depends on opening of ionic membrane channels thus reducing membrane resistance). (Reproduced from: Destexhe and Paré 1999, with permission)

Any student in informatics considering properties 2 and 3 of the two types of signals will tell you that the former signals are digital – the all-or-nothing type action signals  – and the latter analogue – the rather smoothly changing postsynaptic signals. We shall get back to this important difference as we discuss the function of these two types of signals, namely, traveling without distortion or detriment over large distances (action signal; digital) versus integrating signals from different parts (postsynaptic signals; analogue). It should be mentioned in this context that what we call here postsynaptic signals is not necessarily identical to the signals generated at the postsynaptic membrane (see below). Rather, we mean all electrical signals that can be recorded in a neuron except action signals.. These originate at the post-

synaptic sites, but, a bit like waves in the ocean, as they travel along the dendrites they can augment or reduce each other; they also may be boosted or reduced (inhibited) by certain mechanisms that we will discuss later. Now, how do electrical cellular signals “travel” from one place to the other? 2.5.2

“Passive” Spread of Electrical Signals in Neuronal Processes

The processes of neurons, axons, and dendrites alike, are “leaky” cables. Unlike technical cables such as the copper cables used in the house, where the inner resistance is very low and the resistance to the surrounding practically infinite, neuronal processes have

38

M. L. Zeise

λ = rM / rl .

2

..      Fig. 2.13  Illustration of the space or length constant: When a current is injected into the “leaky” cable, it will generate a voltage change that decays as function of the length constant

always a finite resistance to the extracellular surrounding and their inner resistance, although being much lower than the transmembrane resistance, exceeds by far the one of a cable as used in technical applications. Let us consider a part of a neuronal process in a physiological solution where we record the voltage along its length (. Fig. 2.13). When we depolarize artificially by current injection at one point, we observe at the neighboring electrodes a similar signal, however smaller; the more distant the electrode is from the point of current injection, the smaller. We can observe a dilution of the signal as a function of distance obeying an exponential equation somewhat as the voltage of a capacitance, when being charged or discharged, decays in an exponential way as function of time. And again a bit like in the case of the capacitance (. Fig. 2.11), a constant can be defined that gives the distance at which the original voltage has decayed to 1/e. This constant is called length constant or space constant λ and can be defined in any electrical cable (except that in a technical cable the length constant is much larger). This constant depends on the specific resistance within or longitudinal resistance (rl) and the resistance of the membrane (rM).

Thus, we can see that the higher the membrane resistance and the lower the longitudinal resistance of a neuronal process, the better will be the propagation of the electrical signal. Evolution has tried both in order to optimize propagation: It has lowered longitudinal resistance by thickening axons (not so effective, because resistance decreases with the transverse area of the cable) and increasing the resistance between inside and outside which is more effective. The former is illustrated by the squid giant axon, the thickest axon known, allowing the pioneers of neurophysiology to unravel the generation of the action signal; the latter, by the myelinated axon, an invention of the vertebrates, wrapping the axon with isolating myelin sheets. 2.5.3

 he Action Signal: T Threshold, Explosion, and Feedback





There are processes that need that (a) certain parameter(s) exceed(s) a critical value, called threshold. Thus, a certain temperature must be reached before combustion starts. Or a balloon will burst when a certain pressure is being surpassed. However, there is an important difference between the two examples: When the material of the balloon finally gives way, the process ends, whereas combustion is a self-sustained process. The temperature that the process generates, maintains or expands the very process of combustion. Such a configuration is called positive feedback. It is observed frequently in catastrophic or destructive events such as explosions. In the action signal, the process feeding itself is the depolarization or “positivization” of the cell compared to the exterior which opens voltage-gated sodium channels that, on their part, foster depolarization. According to Hille (2001), a biological membrane is “excitable” if and only if such an electric positive feedback loop exists, that

39 Electrical Signals in the Nervous System

2

mV 50

Relative Na+ conductance 0 Relative K+ conductance -50

0

1

2

3

ms

..      Fig. 2.14  The action signal (potential) as generated by changes in sodium and potassium conductance. It is triggered at a threshold voltage (−50  mV approx.) giving rise to an explosion-like voltage

change caused by a rapid increase and decrease in the number of open sodium channels (Na+ conductance) followed by a slower increase and decrease in open potassium channels (K+ conductance)

is, that there is a sufficient density of voltagegated sodium or calcium channels to establish an “explosive” process. Why not chloride or potassium channels? This will be immediately clear when looking at . Table 2.2 that shows that the equilibrium voltage for chloride and potassium is negative, whereas the one for sodium and calcium is positive. So, in order to create a relatively large signal that is fast and of an all-or-nothing character, voltage-gated sodium and/or calcium channels are necessary and are actually found in neurons as well as in other excitable cells such as muscle, receptor, or gland cells. Considering the process of action signal generation closer, we will try to explain also the phenomenon of action signal threshold: As the neuron, more exactly, the voltage between inside and outside, in the region close to or at the soma is getting more positive, normally by incoming synaptic signals, or artificially (. Fig.  2.14), voltage-sensitive sodium channels open

rapidly. However, a small depolarization will not open a sufficient number of sodium channels to depolarize (rendering more positive) the membrane voltage further, and as soon as the induced voltage change terminates (see . Table  2.3), the voltage returns to its former value. As the induced voltage becomes more positive, a point will be reached where a sufficient number of sodium channels open to depolarize the cell beyond the induced value; this depolarization will open more channels depolarizing the cell further, resulting in the positive feedback mechanism described above (. Fig.  2.14). This process of depolarization by positive feedback observed in neurons is the fastest voltage change in biological organisms. The process rapidly comes to an end as the number of open sodium channels are nearing its maximum available. Moreover, there are two other processes that take care of an end of the depolarizing phase leading









40

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to a rapid repolarization (although a bit slower than the depolarization): 55 The inactivation of sodium channels 55 The activation of potassium channels As mentioned at the beginning of this paragraph, some channels close spontaneously, the probability to find them open decreases with time, even though the stimulus for opening remains present. Sodium channels involved in action signal generation stay open for a rather short time before becoming inactivated. Further, potassium channels open with depolarization, but do so more slowly than their sodium counterparts. In other words, in the depolarization phase few additional potassium channels open, while about half a millisecond later they react and reach their maximum toward the end of the repolarization phase. In . Fig.  2.14, membrane voltage and sodium and potassium conductances are displayed. The latter are proportional to the respective number of channels open. As Hodgkin and Huxley (1952) in their pioneering papers around 1950 have shown, the trajectory of the action signal can be explained completely by the opening and closing properties of the sodium and potassium channels involved. We may say in a simplified ­manner: Sodium channels are fast in opening and closing, while potassium channels are a bit slower in either respect  – resulting in the action signal (see also 7 8.2.4).  



2.5.4

Sodium Channel Inactivation Generates a Refractory Period for Action Signal Generation

When inactivated, sodium channels (of the type involved in action signal generation) do not react to voltage changes but need to be “des-inactivated,” in order to react by open-

ing to a new depolarization. This “des-­ inactivation,” just as the inactivation occurs spontaneously, but takes a bit more time than the inactivation, thus creating an insensitive interval called refractory period. In this way, the action signal, as it is propagated down the axon, leaves a “non-­ excitable” segment behind it assuring that the signal does not travel the wrong way.

2.5.5

 ow Do Action Signals H “Travel” Along the Axon?

Now, as action signals are nothing substantial, rather they are a change of voltage in time, the propagation of that signal is comparable to a wave that travels along a rope. Once an action signal is triggered, we have passive propagation as described in 7 1.2.2 causing a depolarization along the axon. We will, depending on λ, depolarize more or less extended neighboring parts beyond the threshold, too, and that will result in a “wave” of action signals that extends from the location of the original stimulation in either direction. The action signal thus travels along the axon. But, wait a minute; the origin of the action signal under normal conditions is not in the middle of the axon as it may be in an experiment, but rather in the soma of a neuron from where it is propagated down the axon. Why does the action signal not “travel” in the other direction toward the dendritic tree? The reason is that neurons normally are not very “excitable” in the dendritic parts close to the soma. In other words, the density of voltage-gated sodium or calcium channels is not sufficient to trigger the self-sustained process of action signal generation. Thus, the action signal generated at the origin of the axon (“axon hillock”) can be propagated only in direction of the axon terminal. A false (“retrograde”) propagation under physiological conditions is also impossible due to the refractory period (see 7 2.5.4) ensuring that  



41 Electrical Signals in the Nervous System

only axon segments “downward” are excitable. The specific resistance in the cytosol10 is quite uniform and constant throughout the animal kingdom. Thus, the longitudinal resistance (called rl in the equation for the length constant in see 7 2.5.2) changes only with the transversal area of the axon. However, the rM part is very variable. For one thing, opening and closing ion channels in the membrane will have a strong effect on transmembrane resistance, and also, vertebrates (animals with a chord as central part of their body) “invented” in the course of evolution an efficient way to accelerate action signal propagation and, with it, reactions and movements: As mentioned in 2.3, many axons of vertebrate neurons are wrapped by some kind of glial cells (oligodendroglia or Schwann cells) leaving exposed only the so-called nodes of Ranvier (nodes, because the axons get a bit thicker there, like a node in a grass stalk). Myelin makes the membrane “thicker” resulting in reduced capacitance reducing the time constant of the myelinated segments. Further, the signal leaps from node to node because large parts of the axon have an almost infinite resistance between inside and outside resulting in a very large length constant. This results in a stark enhancement of the signal propagation velocity reaching in mammals about 100 m/sec (360 km/h) or more. How does a signal that is stereotyped carry information? Since it cannot be the trajectory of the individual unitary signal, it is rather the frequency. Frequency is number of repeated events per time and is measured in number per second, x−sec called Hertz (Hz). The higher the frequency of action signals arriving at the presynaptic part of the chemical synapse, the more transmitter per time will be liberated and reach the postsynaptic receptors and, with it, the target cell.  

10 “Cytosol” is a somewhat old-fashioned expression for the viscous electrolyte inside the cell.

2.5.6

2

 ction Signals Are the Form A in Which Information Is Conveyed over “Long” Distances in the Nervous System

As we mentioned before, action signals have a digital character. They are found, most of all, in axons where they travel from the soma toward the axon terminals inside the central nervous system. They also transmit information from peripheral receptor cells toward the CNS or from the medulla or the brain stem via the cranial nerves to muscles, glands, or other effectors. The axons are means for information transport and apparently not much change or processing of signals is performed in them. Thus, the messages that neurons send should be well conserved in its passage from the cell body all the way to the synapse. Indeed, a peripheral nerve, an axon bundle that carries message to or from parts of the body to the central nervous system, is quite well protected against distortions from mechanical or other sources. This is so, because there are protective sheets of cells around it. However, most of all, information transport in axons of the nervous system is robust thanks to the digital codification in action signals. What is the virtue of a digital codification in conveying information? The cartoon of . Fig.  2.15 shows the obvious advantage in information protection of a digital  =  all or none codification as compared to a graded or analogous signal: It provides more safety that the original message really “gets there” without distortion or “misunderstanding.” Even a small interfering signal will change an analogous signal permanently. A digital message, however, “resists” disturbances up to a relatively high level.  

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2

..      Fig. 2.15  The advantage of digital coding in the axon. The black wedges symbolize recording electrodes, the fine traces the recorded signals. If a perturbation occurs such as mechanical damage, the signal

 he Chemical Synapse: T Transduction of Action Signals into Postsynaptic Signals

will be recovered completely, as long as the remaining signal is sufficient to reach threshold for triggering an action signal downstream

the local intracellular calcium concentration or, more exactly, calcium activity (see footnote in . Table  2.2). In this way, the new information carrier is a substance, namely, the ion calcium. That process is a transduction not only from one carrier All devices, artificial or biological, that pro- (electrical signal) to another (concentracess information need to code and decode tion of substance) but also a change in the signals. In biology, this process is called mode of codification from digital to anatransduction. While action signals serve to logue type (from a “yes or no” type to a send messages from the neuron soma over a “more or less” type of codification). As a certain distance to the cells of destination consequence of the calcium concentration (mostly another neuron but also muscle, being enhanced, a chain of events in the gland, blood vessel, or other types of cells), presynaptic part is triggered resulting the electrical signal does not jump directly eventually in the fusion of synaptic vesifrom one cell to the other (except in the so-­ cles with the presynaptic membrane and called electrical synapse; see 7 4.1). the liberation of a transmitter. Transmitters Therefore, it is necessary to change the sig- are messengers, that is, information-carrynal code and carrier. The action signals must ing substances found in neurons (and be transformed into other types of signals to some other cells) that serve to bridge the bridge the gap between cells that are isolated intercellular gap. They are liberated in electrically from each other. This occurs in chemical synapses that realize an importhe chemical synapse. tant part of the communication between In the axon terminal, that is, the “pre- neurons and are of central importance in synaptic” part of the synapse, voltage-sen- neurophysiological and neuropharmacositive calcium channels are situated that logical processes. respond to the depolarization part of the As transmitter is liberated from the preaction signal by opening, thus augmenting synaptic part it diffuses rapidly to the post2.5.7





2

43 Electrical Signals in the Nervous System

synaptic side because the intercellular gap, the so-called synaptic cleft, is very narrow (20  nm approx.). There it will normally attach to structures called postsynaptic receptors (for definition see 7 3.5). In most chemical synapses (those that function with amino acid transmitters, acetylcholine, or nucleotide transmitters (see 7 4.4.3) plus serotonin (but only acting on one type of its numerous receptors; the 5-HT3 receptor), most of these receptors are ion channels sensitive to the kind of transmitter being used in this very synapse (ionotropic receptors). The typical response is an opening of these channels resulting in a voltage change of the postsynaptic cell. Less numerous, but very important, too, are receptors that are not directly linked to ion channels, but activate intracellular messenger molecules, second messengers, that in turn may open ion channels, but also do influence other processes inside the postsynaptic cell (metabotropic receptors; see 7 3.6 #8). Relatively few synapses in the CNS lack ionotropic receptors such as synapses whose principal transmitter is of the monoamine kind (see 7 4.3.6). Postsynaptic ligand-gated ion channels are very different from voltage-gated ones, not only in their mode of activation, but also in their ion specificity, their molecular composition, and their genetic codes. Concentrating on electrical signals, the big difference is that postsynaptic ligand-gated channels are much less ion-specific than the other group. Some only differentiate between anions and cations. Others are mostly permeable for monovalent cations. What kinds of electrical signal will result with such rather unspecific channels? Let us take the example of a (hypothetic) channel that is equally permeable for sodium and potassium ions. Since, at rest, mostly potassium channels are open, the resting membrane voltage is somewhat near to the potassium equilibrium voltage being frequently close to −90 mV. However, the rela 







tively few sodium, chloride, and calcium channels open make the resting voltage a bit more positive, resulting in, say, −75 mV. Now, what happens when channels open that let sodium and potassium ions pass from one side of the cellular membrane to the other? The total of relative membrane permeabilities (Goldman-Hodgkin-Huxley equation; 7 Box 2.4) will change resulting in more influence of the sodium battery shifting the membrane voltage toward the equilibrium voltage for sodium, that is, toward more positive values. If the newly opened channels strongly outnumber the channels open at rest, the voltage will get close to a value between the sodium and potassium equilibrium voltages. Supposing that these amount to −90 (EK+) and +70 mV (ENa+), respectively, the membrane voltage will be around (−90  +  70)/2 = −10  mV. Indeed, in experiments working with postsynaptic channels that open for sodium and potassium, this voltage was measured being a bit more negative than 0 mV. This reversal voltage (“potential”) for a postsynaptic cation-generated signal is identical to the voltage of the combined batteries with a contribution of roughly 50% for either cation. It is plausible that such a voltage shift – from −75 to −10 mV – at the postsynaptic membrane will enhance the possibility to generate an action signal in the postsynaptic cell. ­ Consequently, synapses that are endowed with cationic channels are excitatory, and the signals produced we will call excitatory postsynaptic signals EPSSs (excitatory postsynaptic potentials, EPSPs, in the literature). Other synapses are opening the passage for small anions which means that mainly the chloride battery will come into play with a tendency to pull the membrane voltage toward the chloride equilibrium voltage (about −80  mV; see . Table  2.2). However, since the anion channels mediating the bulk of synaptic inhibition just as the excitatory ion channels is not specific either, the value for the “anion battery”  



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(i.e., the reversal potential for early GABA inhibition11) is rather around −70 mV. If, as in many cortical pyramidal cells, the resting membrane voltage is around −80  mV the membrane voltage would also depolarize, but only by maximally 10  mV.  If the cell were under the influence of excitatory synaptic inputs that tend to depolarize the cell, activation of anion channels would result in an inhibitory (see below) effect since the threshold to generate action signals (at about −45 mV) would not be reached that easily for the anion conductance pushing the membrane voltage toward −70 mV. 2.5.8

The Integration of Postsynaptic Signals in the Neuron

inside the neuron, the presynaptic part of the synapse. There, the depolarization caused through action signals arriving is diminished and consequently the amount of transmitter released. Now, we may define the “task” or function of a neuron as follows: 55 To receive input in the form of postsynaptic signals 55 To integrate them 55 To send the resulting action signals to the terminals where they are converted in quantities of transmitter liberated as output (. Fig. 2.16)  

As usual there are exceptions: Transmitter liberated may not be the only output of a neuron; especially gap junctions (“electrical synapses”) and paracrine liberation of substances (see 7 4.1) are such exceptions. As was mentioned above, the action signals are produced in the soma in a special zone close to the origin of the axon. This part must be depolarized sufficiently, that is, above its threshold requiring a relatively synchronous arrival of EPSSs and a relatively low inhibitory input. A typical neuron in the brain is usually “bombarded” by many synaptic signals at a time – there are thousands of synapses on the dendritic tree and the soma of a neuron. How is the integration of all these inputs being realized? Let us consider a typical neuron (see . Fig. 2.16 left). It displays, in the peripheral part of its dendritic tree, numerous “spines.” These are the postsynaptic parts of excitatory synapses, while inhibitory syn­ apses contact the more proximal dendrite and the soma forming rather “flat” synapses. By passive conduction as well as “boosting,” EPSSs will sum up propagating toward the soma. There is spatial as well as temporal summation: EPSSs arriving in a certain temporal window will add and also neighboring excitatory synapses will “join forces.” Further, in cortical pyramidal neurons as in some other types of neurons, these EPSSs are “boosted” through a similar mechanism  

At this stage, it is time to define excitation and inhibition in the nervous system, at the neuronal level: Excitation is any process that enhances the synaptic output; inhibition is any process that reduces synaptic output. Frequently, but not always, excitation will be accompanied by an increase in number of action signals produced and vice versa for inhibition. The usual way to “excite” a neuron is the arrival of EPSSs that when coming in sufficient numbers and fairly synchronously will trigger the generation of action signals in the part where the soma forms the initial segment of the axon. An important exception from the “rule” that trains of action signals determine the output of the neuron is presynaptic inhibition. This means that a neuron inhibits another not by reducing the number of action signals sent along the axon but rather at the end stage of electrical signal flow

11 GABA acts at ionic channels (type GABAA) directly producing an “early” inhibition or “early” IPSS. It is followed by a “late” component mediated by metabotropic receptors (type GABAB); see 7 4.3.1.  



45 Electrical Signals in the Nervous System

2

..      Fig. 2.16 The neuron as processor of signals. Left: grossly distorted cartoon of a pyramidal neuron; right: signal flow and processing scheme in a pyramidal neuron

as the one that gives rise to the action signal: Voltage-sensitive sodium channels augmenting EPSS amplitudes in a non-linear way. EPSSs generated at synapses more distant to the soma are favored by a lower threshold compared to the ones closer to the soma. Even though this is a similar process as described in the generation of the action signal  – a self-sustaining positive feedback increases the voltage – we cannot speak here of a digital codification because it is not the frequency of unitary signals that carries information but the amplitude. As excitatory signals summated and, boosted or not, are making their way toward the soma “hoping” to trigger numerous action signals, in the more proximal parts of the dendritic tree, inhibitory synapses lurk intercepting the spread of excitation. It is quite logic that inhibitory synapses must be situated between the origin of excitatory signals and the place of action signal generation. Otherwise, inhibition would be

ineffective. As inhibitory synapses get activated, this results not only in a tendency to maintain the membrane voltage at about −70  mV (anions) or potassium (about −90 mV), respectively, but also by decreasing the transmembrane resistance (chloride and potassium channels open) the length constant is strongly reduced impeding the propagation of EPSSs. The length constant of the cable shortens when transmembrane conductance increases. It is as if the dendritic cable would become quite leaky becoming less able to conduct a signal. This effect is called “shunting inhibition” and is probably the more important part of inhibitory synaptic effects. Now, how come that synaptic excitation does not exert shunting inhibition, too? The more peripheral EPSSs should be inhibited by the more proximal EPSSs as they propagate down the dendritic tree. This would happen if it were not for the peculiar shape of the excitatory synapses. The postsynaptic

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part is connected to the dendrite only by a thin stalk, giving the structure a somewhat mushroom-like form. These postsynaptic parts of excitatory synapses are called “spines.” The spine serves to electrically reduce the shunting effect, since the excitatory channels are not directly situated on the dendrite branch but are electrically distant from the dendrite connected only through the spine’s neck. Thus, excitation that is strong enough to travel to the excitable zone of the soma (with or without the help of boosting mechanisms) and is not impaired too much by inhibitory mechanisms will trigger one or more action signals that will propagate from the soma toward the axon terminals leading to liberation of transmitter at the presynaptic parts of chemical synapses. As usual, reality is more complicated than the story told. The “truthful” propagation of action potentials via one only axon does not always happen like this, for there are failures in triggering/propagating action potentials and things are complicated by axon ramifications. Of course, in the CNS, there are higher levels of signal integration involving neuronal networks. The issue will be discussed in 7 Chap. 9 of this text.  

2.6

“ Thinking” Implies Energy Consumption: Transporters of Ions in the CNS

As has been made clear in previous parts of this chapter, we owe the generation of voltage in biological cells, and hence all the electrical signaling to the disequilibrium in ion concentrations. This disequilibrium tends to level off according to the second law of thermodynamics (see 7 2.2.2) and hence needs to be maintained by active transports. Since any electrical signaling implies current flow, in this case flow of ions, down a gradient, every signal means a bit less of concentration gradient. In order to maintain the gra 

dients, active, energy-consuming ion pumps are necessary. The more activity, that is, the more signals are generated, the more effort is necessary to keep concentration gradients constant. Recent research has revealed that, in the brain, it is not so much the generation of action signals, a process that has been optimized quite well in the course of evolution, but rather of synaptic signals, particularly the excitatory ones, that require the bulk of energy (Alle et al. 2009). By the way, the brain imaging techniques “functional magnetic resonance” and positron emission tomography (see 7 10.6.2) take advantage of this fact. They mirror essentially excitatory synaptic activities by measuring the ratio of oxygenized vs. oxygen-free hemoglobin or glucose uptake. Since excitatory and action signal generation is coupled to a flow of sodium and potassium ions, the quantitatively by far most important ion transport mechanism is the one that shoves potassium from the outside to the inside and sodium ions in the opposite direction. It is also the process that consumes a large part of the brain’s energy, an organ that weighs about 2% of the body, but takes almost 20% of the metabolic energy available (Clarke and Sokoloff 1999). There is a very efficient mechanism for the outward transport of sodium and the inward transport of potassium: the ATP-­ dependent sodium-potassium pump. As you might know from biology classes, adenosine-­tri-­phosphate (ATP) is the most important energy-rich compound in higher animals that “fuels” a host of biochemical reactions requiring energy in the cell. Our “pump” is a protein incrusted in the neuronal membrane that enzymatically (see 7 Chap. 3) cleaves the ATP molecule to ADP (adenosine diphosphate) and a phosphate molecule utilizing the chemical energy to transport sodium to the outside and potassium to the inside. Curiously, under normal physiological circumstances, three sodium ions are transported out of the cell, but only two potassium ions get inside.  



47 Electrical Signals in the Nervous System

This, however, makes sense physiologically, because, ­different from potassium, sodium ions are not exclusively used for signal generation, but the energy of their gradient is also used for a lot of active transports such as the active reuptake of transmitters or the transport of the cell fuel glucose. This 3 to 2 ratio of transport Na+ vs. K+ constitutes a constant electric force toward negative values (“electrogenic pump”). It is a protective mechanism: The more the neuron produces signals, the more the pump is active producing a negative electric force pushing the cell away from action potential threshold. Obviously, we also need ion pumps to maintain calcium and chloride gradients. These two are crucial to protect the nervous system for an overcharge of calcium is a very common cause of neuronal death and chloride transport is necessary for a functioning GABA- and glycinergic inhibition. In following chapters, we will get back to the ion transporters, since their malfunction seems to be causal for important pathologies.

References Alle H, Roth A, Geiger JRP (2009) Energy-efficient action potentials in hippocampal mossy fibers. Science 325:1405–1408 Bohr N (1913) On the constitution of atoms and molecules, part I.  Philos Mag 26:1–24. https://doi. org/10.1080/14786441308634955 Chalmers D (1996) The conscious mind: in search of a fundamental theory. Oxford University Press, New York Clarke DD, Sokoloff L (1999) Circulation and energy metabolism of the brain. In: Agranoff BW, Siegel GJ (eds) Basic neurochemistry. molecular, cellular

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and medical aspects, 6th edn. Lippincott-Raven, Philadelphia, pp 637–670 Destexhe A, Paré D (1999) Impact of network activity on the integrative properties of neocortical pyramidal neurons in  vivo. J Neurophysiol 81:1531–1547 Einstein A (1935) Elementary derivation of the equivalence of mass and energy. Am Math Soc Bul 41:223–230 Galvani G (1791) De viribus electricitatis in motu musculari commentarius. Accademia delle Scienze, Bologna; Digital edition: 2000 Hille B (2001) Ionic channels of excitable membranes, 3rd edn. Sinauer Associates, Sunderland, pp 628–631 Hodgkin AL, Huxley AF (1952) A quantitative description of membrane current and its application to conduction and excitation in nerve. J Physiol 117:500–544 Huxley JS, Huxley TH (1947) Evolution and ethics. The Pilot Press, London, p 120 Konya J, Nagy NM (2012) Nuclear and radiochemistry. Elsevier, Amsterdam, pp 74–75. ISBN 978-0-­ 12-391487-3 Neher E, Marty A (1982) Discrete changes of cell membrane capacitance observed under conditions of enhanced secretion in bovine adrenal chromaffin cells. Proc Natl Acad Sci USA 79:6712–6716 Pereira A Jr, Furlan FA (2010) Astrocytes and human cognition: modeling information integration and modulation of neuronal activity. Prog Neurobiol 92:405–420 Piccinini G, Scarantino A (2011) Information processing, computation, and cognition. Journal of Biological Physics 37:1–38 Senatore A, Raiss H, Le P (2016) Physiology and evolution of voltage-gated calcium channels in early diverging animal Phyla: Cnidaria, Placozoa, Porifera and Ctenophora. Front Physiol 7:481. https://doi.org/10.3389/fphys.2016.00481 Solms M, Turnbull O (2002) The brain and the inner world: an introduction to the neuroscience of the subjective experience. The Other Press, New York Weaver W, Shannon CE (1963) The mathematical theory of communication. Univ. of Illinois Press, Chicago. ISBN 0-252-72548-4

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Basics of Neuropharmacology Marc L. Zeise Contents 3.1

The Chemical Bonds – 50

3.1.1

 symmetric Bonds Make for High Solubility in Water; A Symmetric Bonds Tend to Be Soluble in Lipids – 50

3.2

Acids and Bases – 54

3.3

Amino Acids – 55

3.4

Biological Macromolecules – 55

3.4.1 3.4.2

 roteins and Peptides – 56 P DNA and Other Biological Macromolecules – 58

3.5

The Molecular Receptor – 59

3.5.1 3.5.2 3.5.3 3.5.4 3.5.5 3.5.6 3.5.7

 inding and Specificity – 59 B Unspecific Pharmacological Interactions – 60 Specificity – 61 Receptors and Receptor Sites – 61 Ligand Binding and the Concept of Affinity – 61 Studying Binding – 62 Agonism, Antagonism, Partial Agonism, and Inverse Agonism – 63 Efficacy and Potency – 64

3.5.8

3.6

 harmacological Modulation of P Synaptic Transmission – 65 References – 68

© Springer Nature Switzerland AG 2021 M. L. Zeise (ed.), Neuroscience for Psychologists, https://doi.org/10.1007/978-3-030-47645-8_3

3

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First, let us try to describe what pharmacology is about: Pharmacology is the area of science investigating the interactions and effects of substances, applied from the outside, on biological living systems. It does not take into account substances that these systems absorb as part of their normal functioning like foods, water, minerals, oxygen, etc. In a wider sense, pharmacology also considers substances that originate in the living systems themselves such as hormones, transmitters (see 7 Chap. 4), or cytokines.1 Neuropharmacology, and, in particular, clinical neuropharmacology, is of special interest for the psychologist as well as for other professionals. In this chapter, a few of the most elementary facts about the (mainly) biochemical bases of that area are presented. 3.1  The Chemical Bonds

We may start with the chemical elements as the truly indivisible elements of the whole chemical machinery of biological organisms, that is, atoms that are defined by the number of their protons. This number of protons is identical to the number the element is assigned in the periodic system (. Table 2.1). However, since most natural elements consist of diverse isotopes, sharing the number of protons, but varying in the number of neutrons, almost every element presents a mixture of atoms with different masses. As mentioned in 7 Chap. 2, interaction of matter in biology is almost exclusively electromagnetic interaction. Because neutrons do not bear electric charge, the number of neutrons does not influence the chemical properties of atoms. If their number exceeds a critical value, however, the isotope’s nucleus becomes unstable disintegrating and emitting radioactivity. Radioactive isotopes are widely used as tools that enable biochemists

1 Immunoactive cells liberate these peptides that have signal function.

to mark and trace an atom or molecule as it is transported and/or transformed inside the body just in the same way as its lighter brothers, but can be detected and quantified by means of its emission of radiation. Chemical interaction is the interaction of electrons in the outmost orbit of the atom or the molecule. A molecule is a union of two or more atoms that have formed a chemical bond between them. There are two major ways in which molecules, relevant in biology, can be formed: 55 The ionic bond 55 The covalent bond The first is due to the attraction of opposite charges. For example, in common table salt where sodium (Na+) lacks an electron, whereas chloride (Cl−) got an extra one, each ion attracts a partner in a three-­dimensional lattice forming crystals that mirror the molecular formation. The other, covalent type of bond originates when a pair of electrons take up a common trajectory around the newly formed molecule (. Fig. 3.1).

3.1.1  Asymmetric Bonds Make for

High Solubility in Water; Symmetric Bonds Tend to Be Soluble in Lipids

In fact, the two types of chemical bonds are just the extremes of a continuum: Most chemical bonds are somewhat ionic and somewhat covalent; they are, so to speak, electrically asymmetric covalent bonds. This results in an asymmetric distribution of the “cloud” of the electrons “preferring” one of the two partners or, expressed in a less anthropomorphic way, the probability to find them close to one of the atoms is larger than the probability that they are close to the other. However, “pure” ionic and “pure” covalent bonds are not uncommon, the former exemplified by the bonds inside a salt molecule (crystal) and the other by bonds

3

51 Basics of Neuropharmacology

..      Table 3.1  Periodic table of electronegativity using the Pauling scale. Taken from: 7 chemistry. stackexchange.­com  

1 1 2 3 4 5 6 7

H 2.20 Li 0.98 Na 0.93 K 0.82 Rb 0.82 Cs 0.79 Fr 0.7

2

3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Atomic radius decreases ® Ionization energy increases ® Electronegativity increases He

V 1.63 Nb 1.6 Ta 1.5 Db

Cr 1.66 Mo 2.16 W 2.36 Sg

Mn 1.55 Tc 1.9 Re 1.9 Bh

Fe 1.83 Ru 2.2 Os 2.2 Hs

Co 1.88 Rh 2.28 Ir 2.20 Mt

Ni 1.91 Pd 2.20 Pt 2.28 Ds

Cu 1.90 Ag 1.93 Au 2.54 Rg

Zn 1.65 Cd 1.69 Hg 2.00 Cn

B 2.04 Al 1.61 Ga 1.81 In 1.78 Tl 1.62 Uut

La Ce Pr Nd 1.1 1.12 1.13 1.14 Actinides Ac Th Pa U 1.1 1.3 1.5 1.38

Pm 1.13 Np 1.36

Sm 1.17 Pu 1.28

Eu 1.2 Am 1.13

Gd 1.2 Cm 1.28

Tb Dy 1.1 1.22 Bk Cf 1.3 1.3

Ho 1.23 Es 1.3

Er 1.24 Fm 1.3

Lanthanides

Be 1.57 Mg 1.31 Ca Sc 1.00 1.36 Sr Y 0.95 1.22 Ba 0.89 Ra 0.9

Ti 1.54 Zr 1.33 Hf 1.3 Rf

C 2.55 Si 1.90 Ge 2.01 Sn 1.96 Pb 2.33 Uuq

N 3.04 P 2.19 As 2.18 Sb 2.05 Bi 2.02 Uup

O 3.44 S 2.58 Se 2.55 Te 2.1 Po 2.0 Uuh

Tm 1.25 Md 1.3

Yb Lu 1.1 1.27 No Lr 1.3 1.3

F Ne 3.98 Cl Ar 3.16 Br Kr 2.96 3.00 I Xe 2.66 2.60 At Rn 2.2 2.2 Uus Uuo

..      Fig. 3.1  Two types of chemical bonds: covalent (in this case: N–N) and ionic (between fluorine and lithium). The lines symbolize electron distributions

between equal partners such as the bond between two carbon atoms, an absolutely symmetric covalent bond. The covalent bond is expressed in chemical formulae by a hyphen between the atoms making up the bond. This hyphen also sym-

bolizes the involvement of two electrons. According to the number of electrons available in the peripheral orbit of an atom (usually to complete the number eight in the configuration) an atom can have one, two, three, four, five, or six bonds with neigh-

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boring atoms. The most frequent atoms in organic compounds, carbon and hydrogen virtually always have four and one bond, respectively. “Organic” chemistry is essentially the chemistry of organic substances, that is, molecules that contain the elements carbon and hydrogen. Oxygen and sulfur form two bonds, whereas nitrogen and phosphorus three or five. In some instances, four instead of two electrons constitute a bond. This results in a stronger double bond, although not exactly twice as strong as a single bond (see below how the strength of a chemical bond is defined). In contrast to the single bond, atoms are then unable to rotate giving rise to the phenomenon of the so-­called cis-trans isomers (isomers are compounds with the same atoms, but with different configuration). As usual, there are exceptions. Not all chemical bonds are ionic or covalent (or a mixture of both). Thus, in metals we find electrons that cannot be assigned to particular atoms but are sort of floating around, a property that makes metals electric conductors. However, in biology pure metals are quite rare. Thus, in biochemical processes, all we have to heed is covalent bonds that are more or less electrically asymmetric or completely symmetric. What then produces electrical asymmetry? The stronger the difference in electronegativity between the partner atoms, the more asymmetric is the bond between them. Electronegativity reflects the attraction an atom exerts on electrons when engaged in a covalent bond and is a chemical property of every element (. Table 3.1). The more to the right at the table – the more electronegative; further, electronegativity decreases with increasing atom radius. This is because every atom is energetically in a lower state if it can complete its outer electron orbit, for example oxygen having six electrons in its outer shell “tries” to complete it to eight. Electrical asymmetry of a covalent bond is causal for another sort of bond, the so-­ called hydrogen bond, more than 10 times

weaker than a typical covalent bond and of immense importance in biochemistry. The most common example of a hydrogen bond is the one between water molecules. Their covalent hydrogen-oxygen bonds are strongly asymmetric – resulting in hydrogen bonds between water molecules (. Fig. 3.2a). The fact that water has a relatively high boiling temperature and a relatively high melting point is caused by the high number of hydrogen bonds resisting free movement of water molecules. Hydrogen bonds are also found between water molecules and electrically asymmetric chemical groups or between these (. Fig. 3.2b).

a

b

..      Fig. 3.2  Hydrogen bond between water molecules a and between the nucleotide bases cytosine (C) and guanine (G) b

53 Basics of Neuropharmacology

In order to estimate the electric asymmetry of a covalent bond between two atoms, one simply has to calculate the difference of the two corresponding values of electronegativity. In a trivial, but important case this asymmetry is zero, namely, for the bond between identical partners as the one forming H2 (H–H) or between two carbon atoms. Now, in biochemistry, there is a limited number of partners for covalent bonds constituting the overwhelming majority of biomolecules. Those are firstly: C–C, C〓C, C–H, CN, C–O, C〓O, C–S, C–P. Further, the bonds between atoms without C, such as O–H, N–H, S–H, P–H, N–O, P–O, S–O, among others. The two first, C–C and C–H are the bonds most frequently found in biochemical molecules and, at the same time, they are the least asymmetric ones (with the smallest difference of electronegativities): 0 for C–C and C〓C and 0.3 for C–H. What is all the fuss about electric (a)symmetry good for? One reason we mentioned before is that it causes the very numerous hydrogen bonds. Further, in biochemistry, a most important property of molecules is the degree of electric asymmetry. It determines which cellular compartment the compound will favor, inside attached to some membrane or rather in the aqueous environment inside or outside the cell (the cytosol or the extracellular space), what type of other molecules it “likes” to associate with, and its solubility in water, among others. For the latter property, “asymmetric” compounds are also dubbed hydrophilic (“water-­liking”), while their “symmetric” counterparts are called “lipophilic” (“fat-liking”). There is a rather crude and simplistic, but effective method for estimating how asymmetric or hydrophilic a biochemical molecule will be: Add up all the bonds of C–C and C–H, and calculate the ratio between the sum of all bonds found within the molecule under consideration together and the sum of its C–C and C–H bonds: Sum (X-Y)/Sum (C–C, C–H). The higher the value, the more

3

hydrophilic is your molecule. The lowest possible value is 1 where C and H are the only atoms of the compound (e.g., methane CH4). In the case of the important sugar glucose with six C–O vs. 11 carbon bonds – C–C or C–H (yielding a value of 17/11 = 1.55) is highly soluble in water, whereas cholesterol displaying just one single C–O bond of a total of 70 or so C–C and C–H bonds (71/70 = 1.014) is almost insoluble in water. The stability or strength of a bond corresponds to the energy it costs to tear it apart. Whereas hydrogen bonds are separated using quite a small amount of energy, covalent bonds require a much higher level of energy for destruction. So the C–C bond represents the energy of 348 kJ/mol, the C–N bond 308 and the O–H bond 366 kJ/ mol (see 7 Box 2.1 “Energy Measures” in 7 Chap. 2 for information about J). As ­mentioned above, hydrogen bonds are less than 10 times as strong representing only 5–30 kJ/mol. This is why hydrogen bonds are handy means of gluing molecules together that later can be easily taken apart again. Instead of constructing solid substances, like bones or muscles, life often needs quite fleeting contacts between molecules in order to transmit or process chemical messages or when it comes to catalytic (“enzymatic”) control of chemical reactions or when reading genetic codes is required. In the most important interaction in pharmacology, the one between receptor and ligand, hydrogen bonds always play a role. Besides hydrogen bonds, there are other molecular interactions that help bringing together molecules in such a “provisional” manner as required in receptor-ligand interaction. These are as follows: 55 Attractions between electrically charged groups 55 Van der Waals forces  



Both types of forces, like the hydrogen bond, are weaker than covalent bonds. While the former type is plausible for the attraction of oppositely charged groups, the van der

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Waals forces are less obvious. There are four of them. To explain their mechanisms is beyond the scope of this text. In short, electric multipoles and electrostatic and inductive forces determine an energy minimum for a certain distance between atoms and molecules (Parsegian 2005). In addition to their importance for the ligand-­receptor interaction, these weak forces also play an important part when considering the properties and the conformation of macromolecules (see 7 3.3). 3.2  Acids and Bases

Since, as mentioned above, the interaction of charged groups is important for biochemical interactions, it is decisive if a biomolecule is electrically charged or not. It influences the shape of the biomolecule and hence its function as well as its ability to interact with other substances. In the watery medium where biological processes take place, a factor named acidity or basicity is important in that respect. Consequently, we shall define acids and bases in water: Acids are substances that increase the concentration of H3O+ ions, and bases are substances that diminish it. We may have said the concentration of protons, H+, which is not wrong as writing and chemical formulae are concerned. However, a “solitary” proton (H+) does not exist given the conditions we find at the earth’s crust. Protons immediately get associated with another molecule, in biological systems mostly uniting with a water molecule forming an H3O+ ion. The counterpart of an acid is a base which increases the concentration of OH− ions, thus decreasing the concentration of H3O+ (this is, because one OH− and one H3O+ yield two molecules of water). The cases of hydrochloric acid, HCl and sodium hydroxide, NaOH, are quite clear, because upon dissociation in water they immediately add H+ and OH−, respectively (HCl → H+ + Cl−; NaOH

→ Na+ + OH−). In biology, important acids are the so-called fatty acids that display the carboxyl group COOH and dissociate into COO− and H+ (–COOH ↔ –COO + H+). In contrast to the “strong” acids or acids/bases, such as HCl or NaOH, organic acids do not dissociate completely in water. Consequently they contribute less H+ or OH− and, therefore are called “weak” acids. Similarly, the important basic amino group –NH2 can bind a proton generating –NH3+ thus lowering H3O+ concentration (–NH2 + H+ ↔ –NH3+), although in physiological conditions again only a fraction of amino groups actually will be charged. Thus, different from NaOH or HCl, organic acids or bases (containing carboxyl or amino groups, respectively) are less effective in lowering or raising pH levels. They are called weak bases or acids. Acidity is measured using the pH scale as negative decimal logarithm of the H3O+ ion activity (see 7 Box 3.1).

Box 3.1: pH Value Pure water to a very small part is found as H3O+ and OH− in such a way that one in every ten million water molecules is dissociated into these ions. The relative concentration2 of these ions is then 10−7 (one ion per 107 neutral water molecules) and is equal for both ions. The pH value is the negative decimal logarithm of the H3O+ concentration being 7 when the aqueous solution is neutral, and 0 if there is just H3O+ ions (cannot be reached practically). Towards the alkaline or basic, there are also 7 logarithmic steps reaching 14 as the highest concentration of OH− ions.

2 To be exact, it should say “activity” instead of “concentration.” The difference is that only freely mobile ions count rather than the total number of them (see also footnote a in Table 2.2).

3

55 Basics of Neuropharmacology

Because acidity/basicity is so important in biological systems, the intracellular pH as well as, in multicellular organisms, the extracellular pH is kept quite constant changing by less than one decimal under normal circumstances (intracellular pH is often around 7.2, while the extracellular is frequently slightly more basic close to 7.35; in medicine, a deviant pH value is an important indicator that something is going wrong). 3.3  Amino Acids

Amino acids (AAs) are the molecules that make up proteins being the most frequent highly structured macromolecules (see below). Moreover, some amino acids are neurotransmitters or precursors of neurotransmitters. They contain at least one acidic and one basic group. As shown in . Fig. 3.3, AAs that form natural proteins always contain the carboxyl group, COOH and the amino group –NH2. Thus, their “obligatory” structure is H2N–CHR– COOH, whereas the “rest” R can vary quite a bit. Biochemists divide the amino acids generally into four groups as indicated in . Fig. 3.4: Polar, non-polar, acidic (“− charge”), and basic (+charge”). Since the latter ones can “lose” or receive a proton, and thus be electrically charged, they are also called ionic amino acids. Amino acids alone will also be able to have their “oblig 



..      Fig. 3.3  General formula of an amino acid as found in proteins; the symbol “R” indicates the ­variable part

atory” groups charged. However, as we will see below, when they are part of a peptide or protein chain, these groups ­cannot assume a charged state any longer (. Fig. 3.5). There are 20 amino acids found in higher vertebrates. In eight of them, their variable part is of lipid (=apolar) character (mainly consisting of C and H; alanine, valine leucine, isoleucine, methionine, phenylalanine, tyrosine, and tryptophan), three have basic (arginine, lysine, and histidine), and two acidic chains (glutamate and aspartate), and four are hydrophilic (serine, threonine, glutamine, and asparagine). Three are not easily classified (glycine, proline, and cysteine), but usually are counted as non-polar. Due to the properties of their integrated amino acids, chains of amino acids (proteins and peptides) may have parts that are lipophilic and tend to be attached to cell membranes, whereas more hydrophilic parts will be found mainly in the cytosol or in the extracellular space.  

3.4  Biological Macromolecules

The existence of biological macromolecules is common wisdom. Proteins, fats, and carbohydrates are discussed in the evergreen debates about diets, among many other issues, and DNA is known as the molecule of biological heritage and is on every man’s mind who is struggling to deny or to get acknowledged for the parenthood of a child. There are essentially three types of big molecules: 55 Giant inorganic molecules like salt crystals, diamond, graphite, and similar macroscopic “molecules.” 55 Synthetic polymers we know as plastics, fibers, and the like. 55 Biological macromolecules can be divided into proteins, polylipids, polycarbohydrates, and nucleic acids. All of them can have structural or energy stor-

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M. L. Zeise

H H H3N+ C

C

H

3

O O–

Glycine (Gly/G)

H H3N+ C

O

C

O–

CH3

Alanine (Ala/A)

H3N+

C

C

CH

H3N+

C

C

CH2

H

O O–

H3N+ C H3C

C

CH

O O–

H3N+ C

C

CH2 S

CH3 CH3

CH3

CH3

C

C

CH2

O–

O O–

H2N+ C H2C

C

CH2

O O–

CH2

Cysteine (Cys/C)

H H3N+ C

C

CH2

CH2

CH2

Isoleucine (IIe/I)

H3

H

O

SH

Valine (Val/V)

CH

Leucine (Leu/L)

O–

H

H N+

CH3 CH3

H H

O

O O–

Proline (Pro/P)

C

CH2

C

C

C

CH2

O O–

H H3N+ C

C

CH

O

CH2

CH2 NH

CH2

C = NH2+ NH2

Arginine (Arg/R)

O

H H3N+ C



O

OH CH3

Serine (Ser/S)

Threonine (Thr/T)

C

O O–

NH

Histidine (His/H) − CHARGE

H C

O O–

O–

OH

CH2

NH+

H H

O–

CH2

POLAR

H3N+

O

CH2

Methionine Tryptophan Phenylalanine (Met/M) (Trp/W) (Phe/F)

H3N+ C

C

CH2

O–

Lysine (Lys/K)

CH2

HN

H3N+ C

H3N+ C

O

NH3+

H H3N+ C

H

OH

Tyrosine (Tyr/Y)

H H3N+ C

C

CH2

O O–

H3N+ C

C

CH2

H

O O–

H H3N+ C

C

CH2

CH2

C

C

C

NH2 O

NH2 O

Asparagine (Asn/N)

Glutamine (Gin/Q)

O–

O

H3N+ C

C

CH2

O–

O O–

CH2 C

O

O–

O

Aspartic Acid Glutamic Acid (Asp/D) (Glu/E)

..      Fig. 3.4  The 20 “common” (=found in eukaryotic organisms; see footnote 2 in 7 Chap. 2) amino acids. They are categorized as polar or nonpolar and whether they can bear an electric charge, positive or negative. As glycine, proline, and cysteine are not eas-

ily classified, they are treated sometimes as a group of “special” amino acids. Some authors also include selenocysteine as 21st amino acid. Taken from: Prephixa Mar 11, 2018; Socratic Q&A; World School IB

age functions. Proteins and nucleic acids are additionally able to store information taking part in the “auto-­organization” (see 7 2.1.2) of the biological system.

acids. There may be hundreds or even thousands of amino acids forming complex macromolecules with diverse functions. When a smaller number of amino acids (100

Adenosine triphosphate, adenosine, and others

Monoamines

Acetylcholine

Dopamine, noradrenaline, adrenaline, serotonin, histamine

Acetylcholine

4.2  Classification

there are numerous “classical” transmitters, but rather that the amounts of these transmitters are various orders of magnitude higher than those of neuropeptides or other transmitters. Neurons typically use a “classical” transmitter as their main synaptic messenger. For the “classical” transmitters, the so-­ called Dale’s principle1 is generally valid stating that one neuron contains and releases only one transmitter. So, if one neuron transmits its signals using glutamate, it does not use, say, serotonin or any other principal transmitter in addition, but only glutamate. (There are a few exceptions: dopamine-­glutamate co-release has been demonstrated, among others.) Therefore, it is possible to classify neurons after the principal transmitter they liberate. A neuron whose principal transmitter is glutamate is called “glutamatergic2,” and one that uses serotonin “serotonergic,” etc. Neuroanatomical projections are often characterized by the main transmitter

For the purpose of this book, we will classify neurotransmitters in two groups: Principal or “classical” transmitters and Co-transmitters (. Table 4.1): The first group is, by far, quantitatively the most important. Not in the sense that

1 The British scientist Sir Henry H.  Dale stated in 1936 that a neuron can be either cholinergic or adrenergic but does never release both transmitters. 2 Derived from the Greek (F)εργον (“vergon”  = work; the “F” is an ancient letter that later got omitted resulting in “εργον”)

bloodstream. Thus, almost all cells will be exposed to a hormone (although only those containing the adequate receptors will respond). In contrast, synaptic transmitter release is extremely local  – confined to a structure smaller than conventional microscopes can detect. A mode in between the synaptic and endocrine way to convey chemical signals from cell to cell is called “paracrine” where a neuron or other cell delivers its chemical message to just a few cells in the vicinity (this is quite common in some monoaminergic neurons and is a major way for the delivery of many neuropeptides (see below). Taking into account the multiple functions of many neurotransmitters and their use by glial and other cells to transmit information, some authors prefer the term “transmitter” instead of “neurotransmitter.”

of Neurotransmitters



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involved, so they are called glutamatergic or serotonergic and so on. However, it should be kept in mind that neurons receive signals always from diverse transmitters, even though they are utilizing only one principal transmitter to send messages. Principal transmitters can be divided in three groups with just a few members: (i) Amino acid transmitters (3) (ii) Monoamines (5) (iii) Acetylcholine (1) Among the principal transmitters, there is also an important quantitative division: While glutamate is the excitatory transmitter in the brain, GABA is the the inhibitory one (in some parts of the brain stem and the medulla replaced by glycine). If you take all neurons in the brain that use these two amino acids as transmitter and compare their number to the rest, that is, neurons that work with other transmitters, you get to a ratio larger than the relation of the number of people who live in the smallest state in the world, the Vatican City (population about a thousand), to the biggest (as for the number of people), China with its more than 1.3 billion inhabitants. In fact, it has been estimated that there are almost 100 billion glutamatergic and GABAergic neurons in the brain,3 whereas all others may account only to no more than 10,000,000. In the case of noradrenaline, in humans only about 20,000 neurons are found in the locus coeruleus (Bracha et al. 2005), which is where almost all noradrenergic neurons of the CNS are found. Yet, these neurons innervate large parts of the cortices, thalamus, hypothalamus, brain stem nuclei, and the cerebellum, among others).

3 There are about 5 times more glutamatergic than GABAergic neurons at least in the neocortex of mice (Sahara et al. 2012).

4.3  Principal or “Classical”

Transmitters

Three of the principal transmitters are amino acids: glutamate, GABA, and glycine (see 7 3.3). The overwhelming majority of neurons in the central nervous system use those as principal transmitters. They can be compared to the accelerator (glutamate) and the brakes (GABA and glycine) of the brain, because glutamatergic neurons always “excite,” whereas GABA- and glycinergic neurons always “inhibit” their target cells. Acting mainly on ionotropic receptors, their action is rapid and locally precise. We may think of them as the “working horses” of the brain.  

4.3.1  Glutamate: the Activator

Glutamate is perhaps the most fascinating transmitter because it stands for the most important property of the brain, its flexibility or, better plasticity, but also for the danger that comes with activation and plasticity as we will see below. (This not to say that GABAergic synapses are not “plastic”, but rather that much more is known about the plsticity at gllutamtergic synapses.) To understand its remarkable functions and how they are realized, let us behold again its chemical properties. Glutamate is one of the two acidic amino acids (see 7 Chap. 3, . Fig. 3.4), of the 20 constituents of common proteins. This means it has got an extra carboxyl group (-COOH). Without this group, the remaining molecule is devoid of all affinity to glutamate receptors (see also following section about GABA). Glutamate is the excitatory transmitter in our brain. This is true in a double sense: First, it is always purely excitatory, at least through its ionotropic receptors. Second, practically all excitatory neurons in the brain are glutamatergic.  



4

73 The Transmitters

Glutamate has been fully recognized only relatively late as neurotransmitter by the scientific community, because it is found in all cells. As glutamate is an amino acid naturally present in all proteins, there is, different from other transmitters, no particular enzyme necessary for its synthesis that could be used as a marker for glutamatergic neurons. This fact has made it difficult to identify glutamatergic neurons. As explained in the former chapter, there are two kinds of postsynaptic receptors acted upon by transmitters: ionotropic and metabotropic receptors. The amino acid transmitters use either class. Glutamate acts on three types of ionotropic and eight different metabotropic receptors. The ionotropic glutamate receptors/ channels are cationic postsynaptic receptors, that is, when they open, the positively charged sodium and potassium ions can pass through the membrane and, to a certain extent, depending on the receptor type, the doubly positive calcium ion. Glutamate ligand-gated receptors/channels are classified according to substances that activate them specifically and are named as follows:

..      Fig. 4.1  Electric stimulation elicits glutamate-­ mediated postsynaptic signal (“potential”) in cortical neuron of the rat motosensory cortex in vitro. At time 0, the stimulus artifact is seen as a fast “spike” followed by a short latency period. The depolarization

55 AMPA (α-amino-3-hydroxy-5-methyl-4-­ isoxazolepropionic acid) receptor 55 Kainate (2-Carboxy-3-carboxymethyl-4-­ isopropenyl-pyrrolidine) receptor and 55 NMDA (N-methyl-D-aspartate) receptor Only glutamate and acetylcholine (see below) receptors bear such romantic and tedious names  – other receptors are classified as 1, 2, 3 or α, β, γ; just as their discoverers would have it. Unfortunately, there is no unified system of receptor nomenclature. In 7 Chap. 3, we discussed that the ionotropic receptor/channel complexes are not very specific as to the ions they let pass. In other words, voltage-gated ion channels are often highly specific for just one ion, ligand-­gated ones differentiate much less. It is mainly just size and polarity that counts for them. Release of glutamate from the presynaptic vesicles, at the postsynaptic part of the synapse, gives rise to the excitatory postsynaptic “potential” (EPSP) as shown in . Fig. 4.1. The bulk of the early depolarizing signal is due to activation of AMPA receptors. Kainate and NMDA receptors are associated with smaller and longer-lasting responses.  



leads to an action signal (“potential”). Return to the resting membrane voltage takes roughly 100 milliseconds. This is due to a depolarizing GABAergic inhibitory component. (Courtesy R. Deisz, with permission)

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M.L.Zeise and B.Morales

Immediately after the onset of the EPSP, an inhibitory postsynaptic “potential” (IPSP) sets in. . Figure 4.1 shows a recording “in vitro,” that is, from a brain slice, devoid of other incoming signals. Due to the lack of incoming postsynaptic signals, a constant resting potential of −72 mV is observed. The synaptic response is depolarizing and contains excitatory and inhibitory components. When the membrane is artificially depolarized, the IPSP components become hyperpolarizing (see . Fig. 4.3). The eight metabotropic glutamate receptors mGLUR1 through mGLUR8 are found at post- and presynaptic locations. Metabotropic receptors activate second messengers (=intracellular message cascades) that end usually in the phosphorylation or dephosphorylation of proteins. As almost all proteins of the cell can be (de) phosphorylated, their effects are multiple. A few of these effects are as follows: They are autoreceptors (see 7 3.6 #7) at the presynaptic site of glutamatergic synapses, they regulate neuron excitability, they are involved in processes of neural plasticity (see below and 7 Chap. 7), in the mechanisms that induce neurodegenerative diseases (Crupi et al. 2019) and, interestingly, modulate social behaviors making them a potential target of substances that might improve many of the psychiatric disorders that involve social isolation (Zoicas and Kornhuber 2019). Further, there is a system of glutamate transporters (four main types), responsible for the reuptake (see . Fig. 3.8, # 9), that ensure a brisk functioning of the signal and also low concentrations of glutamate in the extracellular space. We shall discuss glutamate reuptake at the end of this chapter when their necessity for neuronal health has become clear.  

4









4.3.2  Detour: Glutamate, Synaptic

Plasticity, Learning, and Memory

The psychologist Donald Hebb (1949) launched the hypothesis that the ability of organisms to learn, is mainly due to changes at the synapses of their nervous systems. He also proposed that the mechanism for this follows a bit the saying: Where people walk, paths come into being. In other words, synaptic connections that prove to be useful will be enhanced and survive, others that turn out to be used less will shrink or will be removed. At this point, it seems necessary to define the concepts of (neural) plasticity, learning, and memory. Plasticity means the ability of a system to functionally reorganize itself according to its history. Learning is based on plasticity and normally refers to a new or improved ability. Thus, in machine learning a task is improved on the “experience” or the data produced by trying to resolve the task. Importantly, learning refers to performance of the whole system, in animals referred to as behavior. So, I can learn something, but only will know about it when behaving. Learning in animals is principally based on neuroplasticity,4 but not all plastic changes in the NS result in learning (e.g., forgetting is a plastic change, but will be associated rather to “unlearning” than learning). Learning entails memory, that is, a capacity to store and retrieve information. Both, learning and processes associated to memory are based on changes in properties of neural networks. The underlying neuroplasticity, in turn, is based on changes

4 Other tissues or organ systems are also plastic (e.g., your heart is trained by exercise).

75 The Transmitters

4

same time. So, for example, in order to get your printer printing, an AND-gate waits until all necessary conditions are fulfilled that may include that the printer is switched on and configured and you strike the correct key at your keyboard. While there are various kinds of LTP and mechanisms for their generation, an important and perhaps the best-understood form of LTP is the one that involves the NMDA glutamate receptor. The NMDA glutamate receptor has been the first molecular ANDgate described in neuroscience. In the 1980s and 1990s, the glutamatergic NMDA ionotropic receptor has been identified as being crucial for and directly involved in hippocampal LTP, at least in the CA1 region when stimulated by a tract named Schaffer collateral that originates in the CA3 region. In general, ligand-gated receptors are activated simply by the presence of the agonist. However, for an activation of the NMDA receptor, two conditions have to be met: The presence of an agonist (normally glutamate) AND a depolarization of the postsynaptic part of the synapse. Only in this case, the NMDA receptor/channel opens giving rise to a number of events that eventually result in LTP. LTD is induced, when depolarization and presence of glutamate are not coinciding and/or when a low frequency (around 1 Hz) stimulation is applied. Now, how come that the NMDA receptor is sensitive to depolarization? It has been shown that the ion magnesium, present in the extracellular space at a concentration comparable to the one of calcium (somewhat above 1 millimolar), blocks the relatively wide opening of the NMDA receptor channel. It does so in a voltagezz The NMDA Receptor as an AND-Gate dependent manner, because at negative All learning processes, except very simple intracellular voltages, such as the resting ones, such as habituation and sensitiza- membrane voltage, the twice positively tion, need association. Association, in turn, charged (divalent) magnesium ion is pulled relies on the existence of (a) so-called AND-­ to the inside blocking the entering of ions gate(s). In informatics “AND-gate” means a even when the internal channel gate is open. switch that turns an event on if and only if Now, like the other ionotropic glutamate two or more conditions are fulfilled at the receptors, the NMDA receptor channel is

at synaptic and cellular levels; we speak of synaptic and cellular plasticity. At the cellular level, changes in ion channels or ion pumps, for example, influence neuronal excitability that lead to modified signal processing in neuronal networks. However, our knowledge about these mechanisms and their role in neuronal plasticity, let alone their contribution to learning, is limited. Synaptic plasticity, on the other hand, has been studied broadly and we know that it is intimately linked to learning in many, if not all, cases. Most of what we know about synaptic plasticity has been achieved by studying processes at the glutamatergic synapse. It is, as we have mentioned, the most frequent synapse in the brain and the one associated to communication between distant brain areas. The monoamine neuromodulators (see . Table 4.1) and acetylcholine, but also many neuropeptides and nucleotide messengers among others, have been shown to play a role in synaptic plasticity at this synapse. The functional change at the synapse during plastic processes is principally its efficacy. Synaptic efficacy means the quantitative relation between the input at the presynaptic side compared to the postsynaptic output or response. If, after a certain manipulation affecting a synapse, a given input at the presynaptic side results in an increased postsynaptic response, we talk about synaptic potentiation; if the postsynaptic signal is decreased, it is called postsynaptic depression. If that potentiation or “depression” lasts more than about 20 minutes, it is called “long-term potentiation” (LTP) or “longterm depression” (LTD).  

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4

..      Fig. 4.2  Mechanism of long-term potentiation (LTP). In a glutamatergic synapse, high frequency stimulation (HFS) triggers a chain of events that eventually render the synapse more effective (a presynaptic

stimulus leads to a larger response than before HFS). Further explanation, see text. (Scheme by Bernardo Morales)

permeable for sodium and potassium, but unlike the others, to a large degree it is also permeable for the ion calcium. This is due to the larger diameter of its pore. As the postsynaptic part gets more positive due to incoming excitatory signals, probability increases for magnesium to dissociate from the channel mouth and allow cationic ion flow through the NMDA receptor channel. That flow includes calcium that is not only an ion involved in electric signaling, but is also an intracellular messenger. The increase of calcium activity at the postsynaptic site triggers a chain of events involving well-known second messengers, among them being a kinase (Calcium/calmodulindependent protein kinase II (CaMKII)), an

enzyme capable of attaching phosphate to other molecules, particularly proteins). This leads to phosphorylation of AMPA receptors rendering them more effective. Moreover, other retracted, non-­functional AMPA receptors are drawn to the synaptic surface increasing synaptic efficacy even more (see . Fig. 4.2). In this way, the NMDA receptor acts as an AND-gate that only opens if and when two conditions are fulfilled and its activation leads to a chain of events that change synaptic efficacy. If NMDA receptors are blocked, pharmacologically or otherwise, the performance in diverse learning tests is seriously impaired. Thus, the involvement of NMDA receptors in learning has been shown beyond doubt.  

4

77 The Transmitters

Obviously, psychology is interested in neuroplasticity and its mechanisms, particularly neuroplasticity in humans (see 7 Chap. 7) for the reason that it is the basis for learning and the processes associated to memory.5  

4.3.3  Glutamate as a Killer

The title of this section certainly sounds sensationalist, but it is not an exaggeration that perhaps most human deaths are linked to the main excitatory transmitter in the brain. If, for any reason, the oxygen or energy supply to the brain or parts of it is interrupted, glutamate is causally involved in the processes that kill brain cells. They die much more rapidly than other cells or other tissue in this situation. So, if your heart fails due to an infarction or you suffer a stroke that affects a major part of your brain, in a matter of minutes affected brain cells will undergo severe damage. Since cardiovascular failure is still the most important cause of death, at least in Western societies, it is not an exaggeration to blame glutamate as a killer. This phenomenon called excitotoxicity also plays an important role in degenerative processes like those taking place in the brain of Alzheimer patients, quantitatively by far the quantitatively most important disease associated with the aging brain. When glucose and/or oxygen is lacking, the ionic pumps that normally maintain cellular voltage generally well below the threshold of triggering action signals start to fail, so that sodium and calcium will accumulate inside and potassium loss due to outflow will not be replaced. This leads to depolarization getting the neurons closer to their firing threshold, and an abnormal number of action signals will be generated producing more sodium inflow and potassium

5 Contrary to a widespread confusion, “memory” itself is not a process, but rather is defined by processes (such as storing and retrieving data).

outflow. Moreover, depolarization and the excess of activity liberate more glutamate than normal. The NMDA receptor has been identified to be a crucial link in the events that finally lead to neuronal death as depolarization together with the presence of glutamate opening NMDA receptors/channels. More than 30 years ago, it has been shown that calcium influx through NMDA receptors/channels are causal for neuronal death (Choi 1987). The process involving glutamate release, calcium influx, and depolarization is potentiating itself leading rapidly to a catastrophic outcome (see 7 2.5.3 about positive feedback). Further, glutamate reuptake, as well as other transport mechanisms in general, depending frequently on the sodium gradient, will be compromised generating a further lack of vital substances. It has been shown that, in rats, brain injuries after lesions were reduced, after administration of a blocker of NMDA receptors (Yi et al. 2019). Activation of glutamate receptors with agonists such as kainate or ibotenate alone can damage nervous tissue. In fact, excitatory substances are being used to make lesions in certain brain areas in order to investigate the function of those areas. In contrast to lesions made by other methods (e.g., mechanically or heat-induced damage), nerve fibers passing through the target area in ibotenate or kainate lesions remain intact. This is because axons are practically devoid of glutamate receptors.  

4.3.4  Glutamate Uptake

When glutamate is applied to the brain by means of a micropipette, it has an excitatory effect on surrounding neurons, but much less so than the abovementioned agonists, even though the affinity of glutamate is usually higher to its receptors than that of other GLU receptor agonists. The reason for this lies in a most efficient uptake system that does not transport agonists such as kainate or ibote-

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nate, but is rather specific for glutamate, even though aspartate is also a substrate for glutamate transporters. As explained in 7 3.6. #9, transmitter reuptake serves to terminate the synaptic signal as well as to re-capture and in this way “recycle” the transmitter. In the case of glutamate, a functioning reuptake is crucial also to avoid excitotoxic effects. A further important protective mechanism is that the main glutamate uptake is into glial cells where glutamate is converted into glutamine, an amino acid with no affinity to glutamate receptors. As glutamatergic neurons require supply of their transmitter, glial cells liberate glutamine that is taken up and reconverted into glutamate by the neuron. In this way, the extracellular concentrations of glutamate are kept sufficiently low to avoid excitotoxic effects. Pre- and postsynaptic parts of glutamate synapses are closely surrounded by astroglia making the uptake quite brisk, ending glutamate effects within a millisecond. This can be shown by blocking glutamate transport that leads to strong prolongation of the postsynaptic response. Glutamate reuptake depends on the sodium gradient and is quite different from vesicular transport. Three glial and one neuronal glutamate transporters have been identified so far, while a fifth one has been found in the retina. Failure of glutamate transport has been implicated in neuronal death in neurodegenerative diseases. It has also been suggested that hyperactive glutamate transport may be a causal factor in schizophrenia (Bauer et al. 2008).  

4

4.3.5  GABA and Glycine: Putting on

brakes; slow down and relax

Synaptic action of GABA and glycine is always inhibitory; in other words, their action tends to reduce the output of a neuron. Different from glutamatergic contacts that are found mainly far from the neuronal soma, synapses that use GABA or glycine

do not form spines ending at more proximal dendrites (see . Fig.  2.16), or even on the soma. Further, in the case of presynaptic inhibition, GABA is liberated at presynaptic parts (see 7 3.6 #7 and . Fig. 3.8). GABA acts only on two types of receptors, one ionotropic and the other metabotropic, named GABAA and GABAB. (There is a subtype of the GABAA receptor that was previously named GABAC. This ionotropic receptor is composed exclusively by a subunit called ρ.) Glycine also acts at either type of receptor, even though we know little more about the metabotropic one than it is G-protein-coupled like all other metabotropic receptors.  





4.3.5.1  The Ionotropic Receptor

GABAA

The GABAA ionophor is formed by five proteins (“subunits”). Like all ionotropic receptors/channels, these subunits are arranged in a circle forming a hole or pore in the membrane. Since there are numerous different subunit types, GABAA receptors are not always completely identical and neither are their electrophysiological or pharmacological properties. However, the most common GABA channel in the mammalian CNS contains subunits named alpha, beta, and gamma. Being the “counterpart” of the glutamate ionotropic receptors, the GABAA receptor opens an anionic rather than a cationic conductance. As most of free extracellular anions are chloride ions, these are the ions that flow mainly through that channel. However, it has been shown that the equilibrium voltage for the inhibitory postsynaptic potential (IPSP) caused by the activation of the GABAA receptor is not exactly the same as the one for chloride (equilibrium voltage for chloride (ECl) is about −85 mV in the mammalian neocortex, whereas the inhibitory synaptic component ascribed to GABAA receptor activation reverses its polarity about 10 mV more positive). This is because, to a small extent, HCO3− ions are also passing (Kaila et al. 1993). The receptor GABAA contains two binding sites for GABA as well as various allo-

79 The Transmitters

steric (see 7 3.5.7) ones, not identical to the place where the principal, natural ligand, GABA, binds to its receptor. Together with the channel opening, these are exposed to the action of exogenous natural and synthetic ligands. Further, intracellular sites are targets for modulation that influence the functioning of this important receptor. Finally, some substances such as ethanol and, perhaps steroids are supposed to act through the cellular membrane. The GABAA receptor is important in clinical pharmacotherapy, because it is a target for numerous substances used in psychiatry and medicine in general, such as in anxiolytic and anticonvulsive therapy, as well as, in general, to lower agitation and tension (physiological and subjective). In this respect, there is a main difference to glutamate receptors that are hardly ever directly involved in mechanisms of therapeutically used drugs. All target sites of the GABAA receptor used therapeutically are so-called allosteric (7 3.5.7) sites, that is, they do not interact directly with GABA-binding sites. There are at least four of them. The GABAA site itself or the channel pore is blocked by various convulsive substances. From the intracellular side, just as in many other protein complexes, kinases and phosphatases, as terminating parts of intracellular second messenger systems, may attach or remove phosphate at the ionophor modulating the functioning of this protein complex. Of the substances acting at the GABAA receptor, the ones used most in medicine are the benzodiazepines. Consequently, perhaps the allosteric site best known and of most importance in psychopharmacology is the benzodiazepine site. (Sometimes we read about a benzodiazepine receptor. However, in this text we prefer to restrict the term “receptor” to macromolecules or macromolecular complexes as characterized in 7 3.5.4). Benzodiazepines do not activate, that is, open the GABAA ion channel by them 





4

selves, but rather augment the action of GABA. They do so by increasing the probability of channel openings and by raising the affinity of GABA to its receptor. Since GABA is the inhibitory transmitter in the brain, benzodiazepines act in almost all parts causing anxiolytic, relaxant, anticonvulsant, and sleep-inducing effects. The inverse agonists beta-carbolines, on the other hand, further anxiety. No endogenous ligands of the benzodiazepine site have been described so far. However, several exogenous natural sources of such ligands have been identified such as potatoes, milk as well as several plants used in herbal medicine such as Valeriana or St. John’s wort. Benzodiazepines are used widely in medicine also as acute measure to prepare surgical interventions or in emergencies to interrupt states of overexcitation or sustained convulsions. (see also 7 5.10.2). About 30 years ago it was shown that not only exogenous substances, but also various steroid hormones and some of their metabolites are agonists or antagonists at the GABAA receptor. Steroid hormones are produced in the cortex of the adrenal gland, and by the sexual glands, their common precursor being cholesterol. Steroids have their own receptors,6 but they also bind to and act at the GABAA receptor augmenting or diminishing GABAergic inhibition. Just as the benzodiazepines steroids are non-­ competitive agonists or antagonists, that is, they bind at sites different from the site where the principal ligand, GABA, gets attached. Another allosteric binding site at the GABAA receptor is the barbiturate site that used to be of great pharmacologic relevance, having sedative and anticonvulsant effects when activated. However, through

6 Steroid receptors are situated in the cell plasma, rather than inserted in the cellular membrane. When activated they bind to nuclear DNA and interfere with gene expression.

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the advent of benzodiazepines, barbiturates have been largely replaced as anxiolytics and anticonvulsants. This is because barbiturates have a relatively narrow therapeutic window,7 are potentially lethal, and are of a considerable addictive potency. In general, substances that diminish GABA potency can lead to severe situations of anxiety, agitation, or convulsions when they are discontinued rapidly. Therefore, their excessive and prolonged use may cause physiological dependence. Taken together, augmenting the efficacy of GABA by means of benzodiazepines can be extremely valuable as a short- or medium-­ term measure. Long-term use, however, has to be well-founded and monitored. 4.3.5.2  The Metabotropic Receptor

GABAB

Just like all known transmitters, GABA acts on metabotropic receptors. In this case, we know of only one type, namely, GABAB. Remember that the action of these receptors is indirect, that is, the biological effect is separate from the protein structure that receives the ligand (=transmitter). As most metabotropic receptors, GABAB acts through a G-protein (see 7 Chap. 3) that, in this case, is coupled to a cyclic AMP-producing enzyme. (Cyclic AMP (adenosine monophosphate)) is perhaps the most common second messenger.) Its effect is inhibitory, the activity of the enzyme, called adenylate cyclase, is reduced. This, in turn, opens potassium channels and closes calcium channels, both effects tending to hyperpolarize the neuron shifting its voltage away from the threshold to elicit an action signal. In closing calcium channels, it may also have a protective effect against excessive influx of calcium that can damage the cell  

7 Therapeutic window is the range of doses used clinically that have a therapeutic effect without too many undesired collateral effects.

as described in (See 7 4.3.3) about glutamate. When we apply GABA to a cortical neuron, be it artificially through a capillary next to that cell, or physiologically by stimulating GABAergic axons that terminate on the neuron we are recording from, a biphasic response is typically observed (. Fig. 4.3). Both components are overlapping in time and the first one has a reversal voltage (“potential”) of about −70 mV, whereas the slower one hyperpolarizes the cell beyond −80  mV.  As shown in . Fig.  4.3, the late, slow component caused by GABAB receptor activation is sensitive to perfusion of the cell by a whole-cell patch clamp configuration that interferes with second messenger systems. Either inhibitory synaptic component can also be abolished when selective GABAA or GABAB receptor blockers are being applied. In . Fig.  4.4, recordings from two human cortical neurons are presented, one normal and the other from resected epileptic tissue: One displays a normal GABAB receptor-­ dependent response, whereas in the other, this component is virtually absent. Thus, it seems that GABAB receptors are essential to maintain the cortex from entering into states of abnormal firing of action signals. Different from GABAA receptors, GABAB receptors are also found presynaptically where they fulfill the function of autoreceptors (see 7 3.6 #7), that is, they reduce the liberation of GABA when this transmitter is abundant in the synaptic cleft – just as in other chemical synapses. The reduction of liberation through autoreceptors, in the case of GABA leads to an interesting phenomenon: the so-called frequency dependency of inhibition. When a GABAergic synapse is stimulated at frequencies above 0.5 Hz, that is, every 2 seconds, IPSPs are being reduced, and the higher that frequency, the more so (Deisz and Prince 1989). It has been shown that this effect is important in the induction  









81 The Transmitters

a

4

1 nA

b

c

20 mV 150 ms ..      Fig. 4.3  Postsynaptic inhibition recorded in rat neocortical neurons comparing different recording techniques. Synaptic stimulation (arrowheads) evokes an IPSP that interrupts a train of action potentials triggered by depolarizing current injection. Triangle: time of stimulation Diamond; IPSPearly arrow: IPSPlate current injection a 1.2  nA (in b) and 0.9  nA (in c),

respectively. b Recordings performed with high-­ resistance sharp microelectrode impalement; action potentials triggered by current injection of 1.2 nA and c with whole-cell clamp configuration (action potentials are truncated. Note the absence of a late hyperpolarizing IPSP component in c). (Reproduced from: Teschemacher et al. (1995); with permission)

of long-term potentiation (LTP) where a depolarization is reached in the postsynaptic part sufficient for NMDA receptors to become activated (see above). Among the many functions that GABAergic inhibition fulfills, it is worth mentioning that the maturing of GABA receptors seems to explain the temporal window for some plastic changes that occur during development such as the fixation and specialization of receptive fields in primary cortical visual neurons. This critical period marks the time window during development when major plastic changes of the receptive field are possible (Jiang et al. 2005).

4.3.5.3  Glycine

It has been known since ancient times that seeds from certain trees in Asia and Africa would cause painful death to humans and other vertebrates together with violent convulsions. The cause for this is that the glycine ionotropic receptor-channel complex is competitively blocked by an alkaloid called strychnine. Glycine, the smallest amino acid (see formula in . Fig. 3.4) is an inhibitory transmitter present only in the brain stem and the spinal cord. Its mechanism, similar to the one for GABAA receptors, is to open anionic channels. While strychnine has become famous (and infamous) in medi 

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such receptors have been described only in the retina; later there appeared also a report about their presence in chromaffin cells. It should be kept in mind that glycine just as glutamate is one of the amino acids found in eukaryotic organisms and, as such, part of the proteins and peptides found everywhere in the body.

a

4 10 mV 16 V

100 ms

b

4.3.6  Monoamine Transmitters:

The Modulators

Monoamines, are small molecules derived from the amino acids tyrosine (adrenaline, noradrenaline, dopamine), tryptophan (serotonin), or histidine (histamine). The synthesis is taking place in the presynaptic part and involves a decarboxylation (taking away the COO− group). This is all it takes to produce histamine. However, the other monoamines additionally need one or two steps of hydroxylation (adding an OH group; see . Fig. 4.5) for their synthesis. As was explained before, neurons working with amino acid transmitters vastly outnumber neurons working with other “classical” transmitters (monoamines and acetylcholine). However, monoaminergic neurons project to many, in the case of noradrenaline and serotonin, almost all parts of the CNS.  They are also called “widely projecting transmitters” (together with acteylcholine and orexine; Nestler et al. 2015). Thus, virtually no central neuron is devoid of monoamine receptors. Monoaminergic neurons are mostly found outside of the telencephalon, including neo- and archecortices and basal ganglia. Many of them project their axons from the brain stem to the “higher parts” of the brain, while descending pathways are glutamatergic or GABAergic. It has been proposed (Jiang et  al. 2005) that monoamines together with acetylcholine have a kind of “priming” function, modulating functionally neurons or groups of neu 

10 mV 100 ms 20 V ..      Fig. 4.4  Recordings from human cortical neurons. a Normal neuron from a resection of a tumor patient. Superimposed traces of membrane potential changes (resting Em − 77.1 mV) during current injections (from top to bottom +0.3 to −0.5  nA) and orthodromic stimulation (16 V). Note the pronounced IPSPB about 170 ms poststimulus. b Neuron from a patient suffering from temporal lobe epilepsy with Ammon’s horn sclerosis. Superimposed traces of membrane potential changes; resting EM − 72.3 mV obtained by injecting currents of incremental amplitudes (from top to bottom +0.3  nA to −0.5  nA). (From: Teichgräber et  al. 2009; with permission. ©2009 International League Against Epilepsy)

cine and literature, no therapeutically used substance interacts specifically with glycine receptors. Much less do we know yet about metabotropic glycine receptors. In 2008,

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..      Fig. 4.5  Synthesis of monoamine transmitters. Two, one, or zero steps of hydroxylation precede a step of decarboxylation depriving an amino acid of its

acid character yielding the monoamine ready to be accumulated in synaptic vesicles

rons, frequently preparing them for plastic changes (“metaplastic” effects; Abraham and Bear 1996). Interestingly, many of the medicaments used in psychiatry influence monoaminergic systems, in one or the other way. This is true for almost all antidepressant drugs used against monopolar depression and many antipsychotics, but also for psychostimulants such as the ones used in patients suffering from attention deficit/ hyperactivity disorder (see 7 Chap. 5).

would expect that adding the syllable “nor” signifies something added to the substance adrenaline, but again, to make life not so easy for students, it is exactly the opposite: adding “nor” means less (a methyl (CH3) group less; . Fig. 4.5). Adrenaline, produced and released as a hormone by the adrenal glands, acts as an activator preparing the body for action, while its “cousin” noradrenaline (NA) does the same in the sympathetic part of the autonomic nervous system (ANS). Either substance may figure as transmitter or hormone or, as a paracrine messenger (see 7 4.1). Importantly, both substances act at the same receptors. Therefore, we just speak of “adrenergic” receptors or adrenoceptors. As with all monoamine transmitter receptors (only exception: 5-HT3 receptor; see below), they are of the metabotropic type and include three major subtypes: α1, α2, and β. Activation of α2 and β receptors



4.3.6.1  Adrenaline/Noradrenaline

(Epinephrine/ Norepinephrine): Activation and Plasticity

Adrenaline, derived from Latin, means “next to the kidney.” To make things a little more complicated, the corresponding word taken from ancient Greek, epinephrine, is also used, meaning exactly the same. Now we





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has opposite effects augmenting or reducing adenylate cyclase activity, respectively. α1 receptors are coupled to another second messenger system (inositol triphosphate and diacylglycerol). As the ANS influences all bodily organs including the skin and all kinds of glands, these receptors are of great importance in medicine. What is more, the ANS (together with the immune system) is an important relay for so-called psychosomatic effects, such as stress-/anxiety-induced symptoms (see also 7 Chap. 5). Almost all noradrenergic neurons of the CNS are found in or next to the “locus coeruleus”, a slightly bluish8 nucleus in the mesencephalon. There are only a few thousands of them “providing” with noradrenaline through their projections all major parts of the brain. In order to do this, they possess numerous “varicosities,” that is, axon thickenings where NA is released without a proper postsynaptic part. Even though there are vesicles in these varicosities, no postsynaptic specialization is found opposite to these vesicular agglomerations implicating a paracrine way of transmission (see 7 4.1). NA is not the only transmitter released from varicosities. Varicosities have been observed that liberate glutamate or other transmitters. In this way, the number of neurons that are modulated by noradrenaline is vastly increased as compared to neurons that are only connected synaptically. It has been shown decades ago that NA can induce LTP without special synaptic stimulation (Stanton and Sarvey 1987). Thus, it can directly increase synaptic efficacy, that is, it produces plastic change. On the other hand, NA is “metaplastic,” that is, it makes neurons more responsive for plastic changes as has been demonstrated in hippocampal and other neurons (Hansen and Manahan-Vaughan 2015. An important fraction of antidepressants reduces the  



8

“coeruleus (Latin) means “heavenly blue.”

reuptake of NA either alone or together with other monoaminergic transmitters. A relatively new remedy against the attention deficit/hyperactivity disorder (ADHD) also reduces NA reuptake (atomoxetine; see 7 5.7.1).  

4.3.6.2  Dopamine: Madness,

Pleasure and “Free Will”

Dopamine (DA) has been known as a precursor of NA and adrenaline since the middle of the last century, but has been shown to be a transmitter in its own right only in the 1960s. As depicted in . Fig. 4.5, tyrosine is hydroxylated to dihydroxyphenylalanine (DOPA) that is converted through decarboxylation into the transmitter DA (the synthesis can also start from phenylalanine changing it into tyrosine by hydroxylation). Different from NA, histamine, and serotonin, dopaminergic neurons do not project to all parts of the neocortex, but mainly to the frontal lobe. As has been demonstrated in the famous historical case of Phineas Gage (Damasio et  al. 1994) whose frontal lobe was destroyed by an accident, the frontal lobe is crucial in the control of our behavior. Phineas Gage who, before the accident, was a responsible and orderly person changed into a man unable to control himself. Likewise, attention and consciousness (among other functions) have been linked to the frontal lobe and its modulation via dopaminergic neurons. Substances, such as psychostimulants that increase dopamine levels in the frontal cortex, can improve attention and diminish impulsivity. In this context, there was a discussion about the “Free Will” being the possibility, thanks to dopamine, to restrain yourself from doing (bad) things. Indeed, the impulsivity of children and adolescents can be reduced using psychostimulant therapy, probably by increasing dopamine levels in the frontal/prefrontal neocortex. The “Free Will” discussion broke out when data were presented showing that  

85 The Transmitters

recordable brain activity foretells that a certain action will be executed even before the subjects had consciousness of this imminent action (“Bereitschaftspotential”; Libet 1985). That seemed to indicate that our actions are predetermined “by the brain.” To avoid the dilemma, some liberty freaks propose random processes or quantum leaps (supposedly occurring in your brain) as if random processes or quantum mechanics would make you more “free” avoiding a pure “mechanical” functioning of your brain. Other “Free Will” defenders responded that our control constituting freedom is to suppress an action (thanks to the action of dopamine) even though it had been “decided” already by “your brain.” To any system, there are constraints: A knee joint is not “free” to rotate (Ouch!) and you probably will not be able or “free” to talk to a person from Papua New Guinea in his native language. In social, economic, or political contexts, constraints or the absence = “freedom” of them are defined in laws and other rules. However, a bit as we discussed concerning “Life” in the Introduction, a concept of liberty or Free Will “as such” is not helpful in the scientific endeavor. It is just something we seem to observe subjectively as we – more or less – are conscious of our processes of decision. Thus, it may be unnecessary trying to invoke neuroscience to explain a phenomenon that is ill defined. Apart from decision-making, dopamine is very important in the mechanism of antipsychotics that act blocking dopaminergic postsynaptic receptors in the frontal/prefrontal neocortex reducing psychotic symptoms. Modern antipsychotics or neuroleptics also act on other transmitter systems, but none is devoid of dopaminergic actions. Thus, dopamine is firmly associated to “madness” or psychosis. Patients who suffer from psychotic symptoms are having experiences that do not have equivalents in the “real” physical or social world. Antipsychotics then are a class of medicaments that reduce those symptoms (see also 7 5.6.2).  

4

The most prominent dopaminergic projection to the frontal lobe comes from a nucleus containing dopaminergic neurons called the ventral tegmental area (VTA), part of the mesencephalon. This nucleus is central in the so-called “Reward” or “Seeking” system (Panksepp 2011) and hence intimately linked to mechanisms that “drive” our behavior as well as influence our inner states. This mesencephalic area and areas connected to it, particularly the nucleus accumbens, are central for motivation, “impulses” and, therefore, the acquisition of addictions and the behaviors linked to addictions. Clinically very important is also the nigrostriatal projection that is failing for lack of functional dopaminergic neurons of the substantia nigra in the case of the Parkinson disease, the second most frequent neurodegenerative disease. Like all other classical transmitters (with the exception of acetylcholine; see 7 4.3.7), dopamine is being taken up by a high-affinity uptake system which assures a brisk termination for the synaptic transmission and reuse of the transmitter. Now, as has been mentioned before, the majority of substances used in psychopharmacology exert their effects via monoaminergic systems. Out of these, most psychoactive molecules used in pharmacotherapy act through modulating reuptake mechanisms. Thus, antidepressants are mostly inhibitors of monoamine uptake, in a more or less specific manner. P ­ sychostimulants, used in the therapy of the attention deficit/hyperactivity disorder (ADHD), but used also for recreative purposes, mainly in the form of amphetamines or cocaine, act reducing monoamine transport, particularly of dopamine and NA, at the cellular membrane and/or at synaptic vesicles. Now, while there are very specific ligands for several postsynaptic dopamine receptors, strictly specific dopamine uptake inhibitors are unknown. Further, as for the other transmitters, there is an active transport into vesicles that is even less specific. Thus, “vesicular mono-

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amine transporters” (VMAT) do not differentiate much between catecholamines.9 4.3.6.3  Serotonin: Feeling Great or

Suffering?

4

When you are physically hurt and blood vessels are cut, an essential mechanism to survive is to curtail blood loss. This is achieved by blood clotting and constriction of blood vessels. When blood platelets initiate the chain of biochemical events leading to coagulation, they liberate serotonin that activates smooth muscles resulting in vasoconstriction. It is this function that gave serotonin its name. The bulk of the serotonin content in the human body, however, is found in the so-called chromaffin cells of the gut where it also activates smooth muscles – this time of the intestine. Serotonin may make you suffer since diarrhea is often caused by plant products or microbes containing or liberating serotonin (e.g., Entamoeba histolytica). Serotonin, just as the other monoamine transmitters, is derived from an amino acid: tryptophan. While the monoamines of the catechol type contain the common benzene ring, tryptophan and, hence, serotonin contain an indole ring (see . Fig. 4.5) two condensed ring systems of which one has a nitrogen atom. Synthesis is analogous: First, tryptophan is endowed with an OH group, and then the carboxyl group is taken away (see . Fig.  4.5). Thus, serotonin, chemically spoken, is 5-hydroxy-tryptamin, in short 5-HT, an acronym widely used in the literature. Serotonin receptors, therefore, are named 5-HT receptors. Obviously, we will be concerned with serotonin’s role as a neurotransmitter. As a widely projecting neurotransmitter, serotonin is delivered via projections that spread  



9 Dopamine, noradrenaline, and adrenaline are called catecholamines, because chemically they can be considered as derived from catechol (a benzene ring with two OH-groups attached in position “ortho” = next to each other.

to virtually all SNC regions, including the medulla of the spinal cord. The serotonergic neurons are found in the brain stem, in the so-called Raphe nuclei. In the brain, serotonin is also involved in the regulation of the tonus in blood vessels. The common cause of headache and feeling sick called migraine has to do with an abnormal dilatation of brain arteries especially in the posterior neocortex. Certain serotonin receptor agonists called triptans are, at present, the most widely used medication against this debilitating condition. Possibly, serotonin is involved as both, neurotransmitter and vasoconstricting agent in the etiology (=causation) of migraine. Unfortunately, the exact mechanism of its generation is unknown. Curiously, serotonin levels as reflected by the concentration of its metabolite 5-hydroxy indole acetic acid in the urine is directly linked to our well-being. Thus, serotonin levels in people who have committed suicide have been shown to be significantly lower than those of normal controls. The former had even lower levels in the case that they killed themselves in a violent way rather than in a more “silent” manner (Forsman et  al. 2019). Even in daily life, relatively high serotonin levels are correlated with feeling well, being free of pain, and having slept well. In psychopharmacology serotonin  – via its uptake or one or several of its numerous post- or presynaptic receptor types – is perhaps the most prominent transmitter. It is involved in the action mechanism of most antidepressants. Further, almost all antipsychotics (“neuroleptics”) of the newer generation (“atypical” ones) act on 5-HT receptors, frequently on presynaptic ones. Further, some psychostimulants such as MDMA (“extasy”; +3,4-methylenedioxy-­m ethamphetamine) influence monoamine uptake including the serotonin transporters. There is also an anxiolytic drug, buspirone, which works mainly through its action on 5-HT1A receptors. Further, the effects of various hallucinogenic drugs are (partly) mediated by serotonergic receptors (5-TH2A). Those hal-

87 The Transmitters

lucinogens are partial agonists (7 3.5.7). Perhaps the most cited ones are lysergic acid diethylamide (LSD), mescaline, and psilocybin.  

4.3.6.4  Histamine: Staying Awake

and Alert

Histamine is derived from histidine by decarboxylation in just one enzymatic step (. Fig.  4.5). Most of histamine is found outside of the CNS fulfilling gastrointestinal, immune, cardiovascular, and reproductive functions. Particularly the intestine contains great amounts of the transmitter where it is excitatory, but also the so-called mast cells contain and secrete histamine. The latter ones are part of the immune system and, in the case of inflammation, invade the CNS. Histamine has been the Cinderella among the brain monoamines, because it was detected as a neurotransmitter somewhat late and is not involved in the generation or therapy of any of the major mood-related disorders. However, there are histaminergic projections to almost all parts of the brain. Similar to the case of noradrenaline, histaminergic neurons are found virtually in one single nucleus, the tubero-mammillary nucleus (Haas et al. 2008). In one more way, the histaminergic system is akin to the noradrenergic one: much of histamine is not released in conventional synapses, but rather from containing vesicles in varicosities, that secrete histamine into the extracellular space but lacking a postsynaptic counterpart. Thus, histamine reaches far more cells than if there were only typical synapses involved (paracrine mode of transmission; see 7 4.1). As histamine reaches next to all subcortical regions, its function should be important in a general way. In fact, it has been found that the transmitter apparently makes the brain “stay awake.” It is the transmitter that has the strongest diurnal variability: During sleep, histaminergic neurons are practically silent and histamine levels consequently very low. Histamine has also been implicated in attention, but in the sense of being  



4

or staying attentive in a general way rather than “pay attention” to something special (a function that has been attributed more to the prefrontal and parietal cortices). In pharmacotherapy, histamine receptor antagonists are being used to lower anxiety. They are considered less effective than the commonly used benzodiazepines (see 7 5.6.1.1), but do not cause dependence and therefore are more appropriate for long-­term usage. Perhaps even better known are histamine receptor antagonists for alleviating symptoms of allergic reactions. These pharmacological therapeutic applications have to do with the role of histamine as a regulator of diverse vegetative functions. Histamine is pivotal in inflammatory reactions at the biological level as well as at the corresponding subjective level (itching and pain, among others).  

4.3.7  Acetylcholine: Mediating

Behavior, Regulating Body Organs, and Modulating Functions in the Brain

Acetylcholine is a special neurotransmitter in more than one way: First, chemically it has no similarity with the other principal transmitters that either are amino acids or are derived from amino acids. It has got a more apolar moiety, choline, a substance found as part of cellular membranes (as phosphatidylcholine). However, due to a positively charged nitrogen atom (. Fig.  4.6) and the acetate part, acetylcholine is well soluble in water. Second, whereas reuptake into glial cells and neurons typically ends the transmitter signal, acetylcholine must be broken apart into choline and  

..      Fig. 4.6  Chemical formula of acetylcholine

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acetate by acetylcholinesterases, enzymes that are among the most effective ones we know (about 1000 acetylcholine molecules cleaved per second). One product, choline, is taken up by a high-affinity transport system just as the transmitters we have been describing above. Acetate, on the other hand, is a substrate for many biochemical reactions (see biochemistry texts “acetyl CoA”). Thus, it will swiftly disappear, reused again to build acetylcholine or for other purposes. Acetylcholine is the most important transmitter in the peripheral nervous system: 55 It conveys the neural commands to skeletal muscles. 55 It is the only transmitter in the parasympathetic part of the autonomic nervous system (ANS) and, together with noradrenaline, also acts in its sympathetic branch. In this way, acetylcholine mediates most of our behavior, since movements of voluntary muscles and ANS-mediated physiological reactions (blushing, liberation of odors, sweating, secretion of tears, etc.) are our behavioral “outputs.” Like amino acid and nucleotide transmitters (see 7 4.4.3), acetylcholine acts on metabotropic and ionotropic receptors. The latter are found in the peripheral nervous system: The fast, highly localized transmission via ionotropic receptors is realized in skeletal muscle since speed is essential in neuromuscular transmission. Further, they are found in the ANS (see below). In the brain nicotinic recptors are also found in many parts, such as the thalamus, frontal and parietal cortices, hippocampus, cerebellum, aomg others. These receptors/channels are called nicotinic receptors after nicotine, the active ingredient of tobacco (see also 7 5.8.2). Just like other members of the ionotropic receptor channel family, there is some variety due to unequal subunits, in this case called alpha1 through alpha9 and beta1 through beta4. The receptors at the muscular junction consist purely of alpha1 and beta1 subunits.  



The metabotropic receptors are named muscarinic receptors after the beautiful fairy tale mushroom Amanita muscaria (fly agaric) containing muscarine, an agonist at the metabotropic receptors classified M1 through M5. In the ANS muscarinic as well as nicotinic receptors are found: Whereas the “first” (preganglionic) neuron in the sympathetic as well as in the parasympathetic part acts on nicotinic receptors, muscarinic receptors abound in diverse organs, which means that the second parasympathetic neuron activates these metabotropic receptors. Thus, acetylcholine in the ANS mediates the regulation of body organs and, thus, many “psychosomatic/emotional” responses (see 7 Chap. 9). In the brain, cholinergic neurons, like monoaminergic ones, are clustered in just a few nuclei projecting to almost every part of the CNS.  Different from monoaminergic nuclei of the brain stem, cholinergic ones are found in the neocortex, mainly in the basal forebrain. From there cholinergic neurons project to most parts of the cortices, where nicotinic as well as muscarinic receptors are found. Further, there are two cholinergic nuclei in the brain stem (mesopontine nuclei) projecting mainly to other brain stem parts including the cerebellum. As, tragically, becomes manifest in the great number of Alzheimer patients where cholinergic neurons are among the first to degenerate and die, acetylcholine is involved in several higher functions such as acquisition of memory contents, spatial and social orientation, or repair and adaptive mechanisms. This transmitter seems to prime or prepare neurons for certain tasks modulating their plasticity (Picciotto et al. 2012).  

4.4  Co-transmitters

Co-transmitters can be found in synaptic vesicles just like principal transmitters. The difference is that co-transmitters are in much less quantities in the presynaptic part as compared to the principals. Typically, there

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are more than one type of co-transmitters in the presynaptic bouton. There are two types of co-transmitters: neuropeptides and nucleotides. 4.4.1  Neuropeptides: From

Digestion to Bliss

The term “neuropeptides,” also called “neuroactive peptides” refers to peptides with signaling functions found in the nervous system. Frequently, however, neuropeptides are also found in various other parts of the body. They function as messenger molecules in the gastrointestinal tract as well as in other organs and tissues. Often, signaling or regulatory peptides, as they are also called, play the function of hormones and/ or are only for a small part released at typical synaptic sites, but rather their liberation has paracrine character (see 7 4.1). Neuropeptides are qualitatively different from the “classical” transmitters in various aspects: 1. They are peptides ranging from 5 up to more than 100 amino acids. Thus, they have at least three times the molecular mass compared to the “principal” transmitters. 2. If stored in vesicles, these are frequently different from the common “clear” ones and can be found in practically any part of a neuron (so-called electron-­ dense core vesicles – being less numerous than the clear type). 3. They are formed from larger precursors synthesized in ribosomes of the soma and/or the proximal dendrite. 4. There are no high-affinity transport systems for neuropeptides; so there is no rapid synaptic reuptake as in “classical” transmitters. 5. Concentrations of neuropeptides, in general are two orders of magnitude or more below those of “classical” transmitters.  

Property 5 makes it obvious that neuropeptide receptors have to be of the metabo-

tropic type. Electric signals by opening ion channels directly would be too small to have important effects. The intracellular messenger chains, however, can amplify the signal sufficiently to make up for the small number of transmitter molecules liberated. Neuropeptides are typically associated with a classical transmitter, such as somatostatin with GABA or substance P with serotonin. Some authors therefore refer to them as co-transmitters. However, there are other non-classical transmitters as well, such as some nucleotides (see 7 4.4.3). Due to the absence of efficient reuptake, neuropeptides may diffuse over large distances being eventually degraded by peptidases. Further, many neuropeptides act also as hormones. They are also frequently linked to the immune system. Immunoactive cells express receptors for neuropeptides, and neuropeptides are released from cells of the immune system. Taken together, a neuroactive peptide may act as transmitter, hormone, and/or cytokine.10 Frequently, peptide functions are much better known in peripheral parts such as the digestive tract, whereas their functions in the brain remain obscure or knowledge is still very limited. In pharmacotherapy, neuropeptide receptors still play a marginal role as targets. However, opioid receptors are important for the management of pain, and some agonists can be helpful in substitute therapy for opioid addicts. Recently, the neuropeptide ­oxytocin is being tested in humans suffering from disorders of the autistic spectrum. There are promising preclinical and clinical studies under way with agonists and antagonists that may soon push forward neuropeptides and their receptors to the forefront of the treatment of important psychiatric and mental disorders.  

10 The term “cytokines” refers to signaling peptides released mainly by immunoactive cells.

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There is another characteristic for neuropeptides: Neurons that use one and the same neuropeptide are usually not as strictly clustered as is the case for monoaminergic or cholinergic ones; so to make a map of neurons that transmit a specific neuropeptide is not always easy. However, peptidergic receptors of the same kind are frequently clustered in distinctive areas. As neuropeptides are derived from larger precursors, they can be grouped in a rather natural way as families. There are about 23 such families and about ten orphan neuropeptides. Those numbers are uncertain because, different from the principal transmitters whose number is well-known, we still witness the discovery of new neuropeptides. It would be beyond the reach of this text to describe all of the more than 100 neuropeptides. We will therefore restrict ourselves to present some of the more prominent ones whose role in the brain is more or less established. 4.4.1.1  The Opioid Family

The opioid family of neuropeptides are perhaps known best because almost everybody has heard about heroine or morphine. While neither is a neuropeptide, these substances are agonists at opioid receptors. The history of opioids is typical for several groups of psychoactive drugs derived from plants and having a tradition intimately linked to diverse cultures for thousands of years. First, a plant product is being used for pushing the mind state to an extraordinary level often linked to religious or other ceremonies. In this case, from a poppy plant, opium is being extracted and ingested in order to get into a state of bliss and forgetfulness. Second, already in modern times, (an) active ingredient(s) is (are) isolated. In our case, the most important active ingredient of opium, morphine, has been isolated in the early nineteenth century and was quite a successful sale in the pharmacy shop of a Mr. Merck in the town of Darmstadt, Germany. Its name is derived from the ancient Greek god of sleep

(Μορϕευσ; Morfeus) for its strong sleep-­ inducing potential. Third, many decades later, only in the 1970s, the term “endorphin” was coined indicating the existence of endogenous “morphine-like factors” (Iversen et al. 2009). Still later, as a fourth step, receptors were identified, that is, high-­affinity sites for opioid agonists and antagonists. Finally, and shortly after, the first “endorphins”, that is, the first “natural” agonists were isolated. In our case, two almost identical pentapeptides (peptides with 5 amino acids) were shown to be effective via opioid receptors. They differ only in the C-terminal amino acid being methionine in one case and leucine in the other, named consequently Met5 and Leu5-enkephalin. Similar stories can be told of other psychoactive plant products, such as marijuana, hallucinogenic mushrooms, or tobacco. Opioid peptides are divided into four families, each one associated to one type of receptor11: 55 Enkephalins encoded by the pro-­ enkephalin gene interacting with δ-receptors. 55 Endorphins (in the narrower sense; the term “endorphins” sometimes refers to all endogenous opioid peptides) encoded by the pro-opiomelanocortin gene and interacting with μ-receptors. 55 Dynorphins encoded by the prodynorphin gene interacting with κ-receptors. 55 Nociceptin encoded by the nociceptin gene interacting with the nociceptin receptor. Agonists and antagonists, endogenous and exogenous, natural as well as artificial ligands at these receptors are of great pharmacological and clinical interest. ­ Opioid peptide receptors are found in the brain, the spinal cord and, in the case of μ-receptors, also in the intestinal tract. 11 Firmly established since 2013 and recognized by IUPHAR (International Union of Basic and Clinical Pharmacology).

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All of the opioid receptors are involved in some way in pain perception or processing, usually alleviating it. There are situations where the typical reaction to pain, namely, trying to avoid it, is counterproductive making opioids important biological agents for survival and reproduction. This is true for life-threatening situations or extraordinary efforts to be completed such as mountainclimbing or child-birth. It has been shown that in these and similar situations opioid peptides are being released. Agonists at opioid receptors are still the most important pain killers. However, the traditional ones such as morphine are good only for the treatment of acute pain, while chronic pains are better influenced through κ and/or nociceptin receptor activation (Mika et al. 2011) that also has anti-­inflammatory action. Interestingly, immunoactive cells liberate agonists for these receptors and express them. Thus, opioid peptides like several other neuropeptides, form a “bridge” between immune and nervous systems. Extraordinary situations as those mentioned above, also trigger feelings of euphoria and well-being. This capacity of opioid receptor agonists is the entrance door to addiction. However, maintenance of the drug-taking habit is assured by the effect of withdrawal symptoms that are, in the case of opioids, especially terrible (see 7 5.8.2). Opioids are among the oldest and most addictive recreational drugs, highly addictive and lethal when overdosed. However, opioid receptors bear an important potential as to treat pain, particularly chronic pain states. Moreover, they are linked to the most fulfilling and blissful moments in our lives.  

4.4.1.2  Substance P and the

Tachykinin Family (Kinin and Tensin Gene Family)

Another peptide group with numerous members and several subfamilies called the kinin and tensin family includes quite prominent members such as substance P, angiotensin,

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and peptides probably involved in vesicular transmitter storage, the granins. If natural release of opioids is associated with pain relief and euphoria, substance P, at least in part, is their counterpart. It has been linked to pain perception being released from primary sensory cells that convey nociceptive signals in the dorsal horn of the medulla. Therefore, in popular terms it has also been coined “substance pain.” It is also involved in other uncomfortable states and functions such as stress and anxiety, nausea, and vomiting. Substance P belongs to a neuropeptide subfamily derived from the two pre-pro-­ tachykinins. “Tachykinin” means “rapid mover” because these peptides are able to induce rapid intestinal contractions. There are three types of receptors named NK1, NK2, and NK3. Neurokinin A and B, neuropeptides of the tachykinin family, bind to the two latter receptors, while substance P activates NK1. The effect is mostly excitatory, and these peptides are frequently associated with glutamate. The receptors NK1 that bind substance P are also found in structures linked to emotions such as the periaqueductal gray, amygdala, hypothalamus, and, in humans, substance P is associated with ascending pathways of the serotoninergic raphe nuclei. Neurokinin A is found in secretory cells of the hypothalamic-­pituitary-­ adrenal (HPA) axis. That means it is linked to the most important stress response. It is, as we have seen before in the case of opioids, linked to the immune system, because it seems to induce the migration of T-cells12 toward lesions and/or inflamed tissue. In preclinical studies, tachykinin ­receptor antagonists yielded promising results as anxiolytic and/or antidepressive treatment. However, as of 2020 none of these has made it to the market yet; except one used as an antiemetic (substance used against nausea and vomiting).

12 T-cells are part of the immune system.

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The granin subfamily contains secretogranins and chromogranins. The latter ones and secretory granule neuroendocrine protein-­1 (SGNE1) are almost omnipresent in the brain as well as in endocrine tissue. It has been suggested that chromogranins A and B are crucial in the regulation of the formation of dense core vesicles (vesicles containing neuropeptides), a function that would explain their ubiquitous appearance in the nervous and endocrine systems. 4.4.1.3  CRH-Related Family

Having mentioned the HPA axis, the importance of CRH, short for corticotropin-­releasing hormone (also called cortico-tropin-releasing factor; CRF), should be stressed. This substance is released from the (paraventricular nucleus of) the hypothalamus and induces the release of corticotropin or adrenocorticotropic hormone (ACTH) from the pituitary gland. ACTH stimulates adrenal cells to release glucocorticoids such as cortisol. As activation of the HPA axis is a hallmark of the stress response and chronic stress is an inducer of many psychosomatic ailments and psychic disorders, CRH and its receptors are in the focus of many studies that aim to find causal factors and/or treatments implicated in those medical or psychiatric problems. In fact, a CRF1 antagonist, pexacerfont, has made it to clinical studies testing its possible anti-anxiety properties. CRH is also released from the placenta playing a role in the regulation of child-birth. In the CRH family, we find five more “pre-pro” polypeptides that give rise to various peptides with names such as urotensin I, sauvagine, urocortin II, and urocortin III. Those peptides are present in metazoans since ancient times, CRH being the most “derived” or the most varied one of the family (Lovejoy et al. 2009).

4.4.1.4  Oxytocin/Vasopressin

Family

The activating effect of CRH on ACTH release is greatly enhanced by vasopressin. In . Fig. 3.6, the chemical structure of oxytocin is presented, identical to the one of vasopressin except that the third and the eighth amino acid are different (phenylalanine instead of isoleucine and arginine instead of leucine). Both peptides, like CRH, are produced in the supraoptic and paraventricular nuclei of the hypothalamus influencing the pituitary gland. Vasopressin is also called antidiuretic hormone (ADH), because in the kidney it foments water reabsorption. Oxytocin, as a peripherally acting hormone, initiates parturition. In spite of these quite different peripheral functions, both peptides seem to be similar as for their central synthesis and effects. Either peptide is being produced in magnocellular neurons of the hypothalamus being stored in the hypophysis. Either hormone seems to be important in pair-bonding, friendship, and love, but also in “social memory” and “social intelligence.” This is not due to activation of the same receptors for either act on its “own” type of receptors (AVRP vs. OXT), even though the second messenger systems activated overlap significantly (activation of phospholipase C by proteins Gq). It has been suggested that persons suffering from autism have a genetic deletion in a gene coding for an oxytocin receptor. Further, some studies suggest that autism symptoms can be alleviated with oxytocin administered nasally. Curiously, oxytocin appears to be the more “female” hormone activating maternal behavior, such as breast feeding, whereas vasopressin seems to be more important for bonding in males. At least, this has been demonstrated in the monogamous prairie vole (Wang et al. 2013).  

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The anxiolytic buspirone, an alternative to benzodiazepine treatment, because of its lack of addictive potency, acts at serotonin receptors of the 5-HT1A type, the same that activates oxytocin release. 4.4.1.5  The Somatostatin Family

Somatostatin is another extremely versatile neuropeptide because it influences the release of numerous other hormones. It comes in three forms: SS28, SS14, and SS12. SS 12 consists of the first 12 amino acids, SS 14, of the last 14 of SS28. Somatostatin was first described as the agent that limits growth hormone release and got its name after it. Today, we know that it acts at numerous sites and is involved in many regulation processes. Its receptors (sst1 through sst 5) have been found from the central nervous system to the pancreas and gut, and in the pituitary, kidney, thyroid, lung, and immune cells (Lahlou et al. 2004). Like most of peptide receptors, they are G-protein coupled acting on at least a dozen different enzymes, mostly kinases and phosphatases (enzymes that add or remove a phosphate moiety to or from a protein). In this way, somatostatin inhibits gastrointestinal motility, secretion, and absorption and reduces the liberation and/or action of diverse hormones such as the growth and thyroid hormones, insulin, and glucagon, among others. In the CNS, somatostatin lowers the excitability of neurons augmenting the so-called M-current that is generated by an opening of potassium channels tending to make the neuron’s interior more negative and thus rendering it less excitable. In fact, agonists of somatostatin receptors have been proposed as antiepileptic therapeutics (Qiu et  al. 2008). In a similar way, namely completing a role in inhibition, somatostatin is frequently found associated with the main inhibitory transmitter GABA.  For example, in the brain, somatostatin is found in inhibitory neurons of the hippocampus particularly sensitive to amyloid beta, the main component of Alzheimer plaques (Villette et al. 2012).

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A close “relative” of somatostatin, cortistatin, derived from the same “pre-pro”peptide, seems to reduce neuronal activity and has been found in GABAergic cells, too. 4.4.1.6  Glucagon/Secretin Gene

Family

There are seven different genes coding for seven “pre-pro”-peptides forming what is perhaps the largest among the peptide “families.” From the more than 20 different peptides originating from those precursors, we shall present only one of them: the vasoactive intestinal peptide (VIP). VIP is found in many parts of the gastrointestinal system stimulating motility and the secretion of water and ions into the lumen of the tract. In the brain, it is associated with the suprachiasmatic nucleus, the important pacemaker structure of the hypothalamus. VIP has been proposed to be crucial for the creation of rhythms in this structure (Harmar 2003). Importantly, in the hypothalamus and in the anterior pituitary, VIP promotes the liberation of various peptides such as prolactin, growth hormone, ACTH, and vasopressin and inhibiting the release of somatostatin. Thus, VIP is sort of counteracting somatostatin whose action is inhibitory for a couple of peptides. 4.4.1.7  Cholecystokinin/Gastrin

Family

This small family with its prominent member cholecystokinin (CCK) that, in spite of its name (“gall bladder mover”), is by no means restricted to the guts. Rather, CCK and its receptors (CCK1 and CCK2) are found in most parts of the telencephalon, in the thalamus, the olfactory bulb, the amygdala, the nucleus accumbens, and the ventrotegmental area, among others. This peptide has been implicated in attention and memory-­related processes, but also in anxiety and depression-like states (Del Boca et al. 2012). Thus, when CCK was knockeddown by local injection of an RNA blocking the mcck gene (coding for CCK) in the

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basolateral amygdala of mice, the animals appeared more “daring,” In tests that measure depression-­like behavior (“forced swim test”), signals of “giving-up” were shown significantly later than in control animals. Taken together, CCK is involved in various important emotional states and cognitive capacities. The family also includes the peptides derived from the gastrin gene that stimulate gastric acid and enzyme production as well as gastric motility, but have little presence in the nervous system.

4.4.1.9  Angiotensin Family

Above, a neuropeptide family was presented by the name of “Kinin and tensin gene family.” Angiotensin is a member of a family from a different gene, located at a different chromosome and having little homology with the tachykinins, but has been categorized as belonging to a family of “Tensins and kinins.” Angiotensin, like several other neuropeptides, comes in various lengths, so there is angiotensin I through IV. Angiotensin has been studied for over 80 years by now and is of enormous clinical 4.4.1.8  F- and Y-Amide Gene Family importance because of its involvement in the (NPY) regulation of blood pressure and, together This family contains numerous peptides with other hormones (such as rennin and whose most prominent member in neurosci- aldosterone) in water/mineral homeostasis. ence is neuropeptide Y (NPY). It has been As hypertension is a very common ailment, isolated 30 years ago and was found mainly angiotensin receptor antagonists and inhibiin the arcuate and paraventricular nuclei of tors of the cleaving enzyme (angiotensin the hypothalamus. NPY was shown later to converting enzyme; ACE) are being used to be an important inducer and/or regulator of normalize it. the HPA axis (see 7 4.4.1.3). It stimulates However, the peptide’s role in the brain the release of CRH and therefore is inti- is also eminent. Clinically, ACE and angiomately linked to the stress response. In this tensin receptors in the brain (AT1 through context, elevated levels of NPY have been AT4) are or have been suggested as (potenshown to be correlated to increased resil- tial) targets in numerous clinical applicaience or stress resistance protecting against tions: post-traumatic stress disorder. Blockade of AT1 receptors blunts the NPY causes increase of food intake in stress response. experimental animals. The role of NPY in Memory is improved in Alzheimer’s disthe regulation of eating and its pathologies ease by diverse AT receptor blockers (AT4 is complex since the activation of two types agonists, however, seem to improve memof NPY receptors (Y1 and Y5) stimulates ory). feeding, whereas activation of type Y2 and Cerebral protection can be achieved by Y4 seems to reduce it. improving cerebral blood flow with AT The effect on the stress response and receptor agonists. on feeding may be linked, for it has been Reduction of depressive symptoms was demonstrated that stress-induced feeding is reported after application of ACE inhibimediated by NPY (Kuo et al. 2007). tors. ACE also reduced ethanol consumpAnother relevant peptide of this family is tion in rats. neuropeptide FF (NPFF). It is found in the AngII seems to lower, whereas AngIV dorsal spinal cord and in dorsal root gan- was found to increase seizure threshold in glia modulating nociception and the opiate-­ mice. induced analgesia (7 4.4.1.1) potentiating or In Parkinson’s disease, angiotensin recepreducing the effect of opiate receptor activa- tor blockers seem to protect dopaminergic tion (Cline and Mathews 2008). neurons.  



95 The Transmitters

4.4.1.10  Motilin Family (Ghrelin)

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The peculiar spelling of ghrelin has to do with “growth hormone-related,” because the peptide induces GH release. Whereas at least three peptides curtail appetite (peptide YY, leptin, and insulin); ghrelin is the appetite-­ inducing hormone and its level changes with the degree of satiety during the day. Like other regulatory peptides found in the periphery, ghrelin is involved in “higher functions” of the brain such as in learning and memory-related processes. Intrahippocampal injection of ghrelin revealed that ghrelin was influencing memory-related processes, in particular the consolidation of memory.

cesses, that is, against their programmed self-destruction. Further, BDNF has been implicated in a number of psychiatric disorders. Thus, the level of BDNF in monopolar depression is abnormally low and rises with antidepressant pharmacologic or other treatment (if successful), such as sleep deprivation or electroconvulsive therapy. The brain-derived neurotrophic factor (BDNF) or its precursor is released upon raised neuronal activity including seizures and seems to have an activating influence on glutamatergic (=excitatory) and to reduce GABAergic (inhibitory) transmission. BDNF levels are indicative for major depression (see 7 5.6.1.2).

4.4.2  Neurotrophic Factors

4.4.3  Nucleotide Transmitters

Neurotrophic factors are not considered as transmitters, but as neuroactive peptides/ proteins forming families sharing about up to 50% of their amino acid sequence. There are three groups: neurotrophins, the ciliary neurotrophic factor (CNTF) family, and glial cell line-derived neurotrophic factor (GDNF) family. Just like the (other) neuropeptides, they are derived from larger precursor proteins and are partly released from synaptic dense core vesicles (Frotscher and Misgeld 1989). However, they are special in a number of ways: 55 They are much larger molecules than the neuropeptides we have dealt with up to now, so they are usually referred to as proteins (12–14 kDalton corresponding to about 250 amino acids). 55 They are regulating and protecting neurons and neuronal growth. 55 Most of them are involved in regulating neural plasticity.

As we have seen in 7 Chap. 3, structure-­ bearing macromolecules in biology are proteins and nucleic acids. All the transmitters, we have spoken about before, are amino acids (glutamate, GABA, and glycine) derived from amino acids (the monoamines), or are chains of amino acids (neuropeptides) and thus akin to proteins – with the remarkable exception of acetylcholine whose molecular structure is related to the chemistry of lipids. Nucleotid transmitters, however, are molecules found in nucleic acids. Just as proteins and their elements serve various functions in organisms, DNA, RNA, and their elements are important in various roles. Perhaps best known is DNA as “library” or data bank for hereditary information and RNA associated to the realization of that information. One nucleotide, adenosyl-triphosphate (ATP) plays a central role in the chemical factory of the cell as energy currency or “fuel,” driving reactions that do not take place spontaneously. Therefore, ATP and its di- and monophosphate (ADP and AMP) as well as adenosine are found literally everywhere.

BDNF, perhaps the most prominent one, protects neurons against apoptotic pro-





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Further, nucleotides are crucially involved in second messenger signaling chains (see . Table 3.2) as parts of G (guanidyl) proteins or as cyclic adenosyl monophosphate (see texts of biochemistry). ATP, just like glutamate, is not only found everywhere in the nervous system, but also in millimolar concentrations, mainly due to its function as an energy store. The role of nucleotides as neuronal transmitters has been studied in earnest only since the 1980s, although as early as 1972 Burnstock and colleagues proposed a transmitter role for ATP in the autonomic nervous system (Burnstock et  al. 2011). Later, specific receptors have been characterized and cloned. Interestingly, nucleotide transmitters, like amino acid transmitters and acetylcholine act on both, ionotropic and metabotropic receptors. The corresponding groups of receptors are named P2X (P2X1 through P2X7) and P2Y (P2Y1,2,4,6 and P211–14; . Fig. 4.7; Khakh and North 2006). However, the molecular structure of P2X receptors/channels is quite different from those gated by amino acid transmitters and acetylcholine being trimers (consisting of three protein subunits) rather than pentamers (consisting of five protein subunits). On the other hand, the metabotropic nucleotide receptors resemble the great majority of others in that they cross the cellular membrane seven times and are coupled to G-proteins. ATP seems to be the only nucleotide acting on ionotropic receptors (. Fig. 4.7). As  

4





..      Fig. 4.7 Purinergic receptors and their ligands. Diagram of the two types of nucleotide receptors (P2), the one for cyclic AMP (CAR) and for adenosine (A; also called P1)

depicted in that illustration, some pyrimidines or their phosphorylated compounds (such as uridyl diphosphate) also bind to and activate purinergic receptors even though to a much lesser extent than the purines or purine-­derived molecules. As for the biological functions of nucleotide transmitters, it is difficult to name any that are not influenced by purinergic transmission (Boué-Grabot et  al. 2020 and the articles in the issue of the journal volume mentioned in this reference). We have evidence for the involvement of purinergic receptors at least in the following: 55 Regulation of sleep/awake rhythms 55 Food intake 55 Locomotor activity 55 Learning and memory 55 Mood and motivation Purinergic receptors also play a role in numerous pathologies from trauma, ischemia and stroke, neurodegenerative diseases, psychiatric affective disorders such as depression and anxiety to neurological problems including epilepsy, migraine, and neuropathic pain. Attention, as well as cognitive impairment, also has been linked to purinergic regulation. Not surprisingly, there are a lot of pharmacotherapeutic promises that agonists and antagonists at purinergic receptors hold. One of the many preclinical findings is as follows: The psychotic symptoms induced by NMDA receptor antagonists (such as ket-

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amine or phencyclidine) are all ameliorated by A1/A2A receptor agonists. Curiously, the main effect of caffeine is probably an antagonism at A1/A2A receptors. Further it has been postulated that purinergic signaling is essential for the communication between the diverse cell types in the brain for these receptors have been found to be very dense in astro-, oligodendroglia, and microglia. Thus, co-released ATP in normal synaptic transmission binds to postsynaptic, but also to astroglial purinergic receptors since glial processes are part of the synaptic complex. On the other hand, all glial cells release ATP that binds to neural P2 receptors. Even epithelial cells of the brain blood vessels react to ATP, a mechanism that has been related to migraine. Taken together nucleotides and their derivatives are ubiquitous, they take part in numerous, if not all main nervous system functions, they are involved in many pathologies, and therapeutically their future seems promising. 4.5  Retrograde Messengers

Even though as neurotransmitters we understand substances that are found in synaptic vesicles at the presynaptic site of the synapse, it is adequate to mention in this chapter a class of messenger molecules that are liberated at the postsynaptic part and from there influence the presynaptic site, that is, whose direction is opposite to the typical signal flow from pre- to post- and therefore are called retrograde messengers. As was discussed in the beginning of this chapter (7 4.1), an important difference between the so-called “electric” synapses or gap junctions and the chemical synapse is that the former allows symmetric signaling, that is, information flow is principally possible in both directions and no pre-or postsynaptic side exists. In contrast, chemical synapses display synaptic vesicles at the presynaptic side that the postsynaptic part is lack-

ing. Thus, quite a long time neuroscientists believed that there is no information flow from the post- to the presynaptic part of the chemical synapse (this is called retrograde, whereas anterograde indicates the “normal” direction of signal flow). However, in the 1990s, it became clear that substances liberated from the postsynaptic side can influence synaptic transmission. This feedback mechanism was investigated and found to be important in long-term potentiation and depression. Changes in synaptic efficacy, shown to underlie at least some forms of synaptic plasticity involved in associative learning, have been explained above by a merely postsynaptic mechanism, namely, the activation of intracellular messenger chains by postsynaptic calcium inflow. However, frequently there are presynaptic mechanisms involved that have been mostly attributed to retrograde messengers (Citri and Malenka 2008). Several transmitters that have been dealt with before can also act as retrograde messengers such as dopamine, dynorphin, glutamate, GABA, or neurotrophic factors. However, a few retrograde messengers seemingly are not to be found in synaptic vesicles. Among these “pure” retrograde messengers, the best known are two groups of substances: 55 Substances binding to cannabinoid receptors (eicosanoids such as anandamide) 55 Gases (NO, CO) The former two are interacting in LTP or LTD induction in that the enzyme nitric oxide is activated by agonist binding at CB1 receptors (see below).



4.5.1  Endogenous Cannabinoids

The use of marijuana is probably much older than the written history of mankind. Its pharmacological history follows, by and large, the pattern described in 7 4.4.1.1 for opioids. First, in 1964, the active ingredient,  

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named Δ9-Tetrahydrocannabinol (THC), was isolated. Then, receptors, called CB1 and CB2 were identified and cloned. They are akin to most metabotropic receptors being linked to a G-protein. CB1 is almost omnipresent in the brain, but can also be found in other tissues, whereas CB2 receptors are less numerous and restricted to the brain stem, being more important in the immune and hemopoietic13 systems. The CB1 receptors are common at the presynaptic part of glutamatergic synapses where their activation reduces the release of glutamate. As glutamate is excitatory, the overall tranquilizing effect of marijuana is readily explained. But, how come that there are so few people who kill themselves with marijuana? After all, glutamate is virtually the only excitatory transmitter at cortical neurons and plays a very important role in other brain parts. The reason is that THC is a partial agonist (see 7 3.5.7) at the CB1 receptor. In other words, THC never blocks glutamate release completely but rather reduces it by maximally 50%. Marijuana is a relatively “soft” drug with little addictive potency and not very toxic. However, heavy and sustained use is probably damaging the brain, particularly for young users where marijuana may increase the risk for schizophrenia (see 7 5.8.2). However, since the “war against drugs” is not successful and the risks for adult users are comparably small, the Netherlands have regulated the consumption many years ago without increase of consumption, but almost eliminating crime associated to the use or sale of this drug. Several US states have been following course recently. Endogenous cannabinoids all have been found to be related chemically to arachidonic acid, a well-known second mes 



13 “Hemopoietic” means “blood-making” and refers to tissue inside the bones.

senger. The substance and its derivatives are highly lipophilic, consist of 20 carbon atoms, and are therefore dubbed eicosanoids (εικοσι = twenty in Greek). From arachidonic acid, important paracrine and autocrine messenger molecules are derived such as the prostaglandins and leukotrienes. The latter are also thought to be agonists at CB receptors. Another eicosanoid with the romantic name anandamide (taken from a Sanskrit word for bliss) has surely been identified as important endogenous cannabinoid, together with other eicosanoids. 4.5.2  Gases

It may sound strange that gases are present in the body (we are not talking here about the gastrointestinal tract) and that they are messenger molecules. In fact, CO (carbon monoxide) and NO (nitrogen monoxide; nitric oxide) are the smallest molecules found in living systems that fulfill signaling functions. CB receptors and NO production are linked, for CB receptor agonists increase NO synthesis by activating the enzyme nitric oxide synthase via G-proteindependent second messengers. NO and cannabinoids have been shown to modulate synaptic efficacy expressed as LTP and LTD.  As CB receptors are presynaptic, cannabinoids and NO are involved in presynaptic mechanisms causing LTP or LTD (see 7 4.3.2). In this case, the cannabinoid would be the true retrograde messenger carrying the signal to the presynaptic site. However, NO is also a retrograde messenger in its own right. CO has been shown to function as retrograde messenger in the enteric nervous system as well as in the brain (e.g., in the olfactory bulb). However, it seems to play a minor role in the brain as a mediator of synaptic plasticity as compared to NO.  

99 The Transmitters

References Abraham WC, Bear MF (1996) Metaplasticity: the plasticity of synaptic plasticity. Trends Neurosci 19:126–130 Bauer D, Gupta D, Harotunian V, Meador-Woodruff JH, McCullumsmith RE (2008) Abnormal expression of glutamate transporter and transporter interacting molecules in prefrontal cortex in elderly patients with schizophrenia. Schizophr Res 104:108–120. https://doi.org/10.1016/j. schres.2008.06.012 Boué-Grabot E, Blum D, Ceruti S (2020) Editorial: purinergic signaling in health and disease. Front Cell Neurosci 14:15. https://doi.org/10.3389/ fncel.2020.00015 Bracha HS, Garcia-Rill E, Mrak RE, Skinner R (2005) Postmortem locus coeruleus neuron count in three American veterans with probable or possible war-related PTSD.  J Neuropsychiatry Clin Neurosci 17:503–509 Burnstock G, Krügel U, Abbracchio MP, Illes P (2011) Purinergic signalling: from normal behaviour to pathological brain function. Prog Neurobiol 95:229–274. https://doi.org/10.1016/j. pneurobio.2011.08.006 Choi DW (1987) Ionic dependence of glutamate neurotoxicity. J Neurosci 7:369–379 Citri A, Malenka RC (2008) Synaptic plasticity: multiple forms, functions, and mechanisms. Neuropsychopharmacology 33:18–41 Cline MA, Mathews DS (2008) Anoretic effects of neuropeptide FF are mediated via central mu and kappa subtypes of opioid receptors and receptor ligands. Gen Comp Endocrinol 159:125–129. https://doi.org/10.1016/j.ygcen.2008.09.001 Crupi R, Impellizzeri D, Cuzzocrea S (2019) Role of metabotropic glutamate receptors in neurological disorders. Front Mol Neurosci 08. https://doi. org/10.3389/fnmol.2019.00020 Damasio H, Grabowski T, Frank R, Galaburda AM, Damasio AR (1994) The return of Phineas gage: clues about the brain from the skull of a famous patient. Science, New Series 264:1102–1105 Deisz RA, Prince DA (1989) Frequency-dependent depression of inhibition in Guinea-pig neocortex in vitro by GABAB receptor feed-back on GABA release. J Physiol 412:513–541 Del Boca C, Lutz PE, Le Merrer J, Koebel P, Kieffer BL (2012) Cholecystokinin knock-down in the basolateral amygdala has anxiolytic and antidepressant-­like effects in mice. Neuroscience 218:185–195. https://doi.org/10.1016/j.neuroscience.2012.05.022 Forsman J, Masterman T, Ahlner J, Isacsson G, Hedström AK (2019) Selective serotonin re-­ uptake inhibitors and the risk of violent suicide: a nation-

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wide postmortem study. Eur J Clin Pharmacol 75:393–400. https://doi.org/10.1007/s00228-0182586-2 Frotscher M, Misgeld U (1989) Characterization of input synapses on intracellularly stained neurons in hippocampal slices: an HRP/EM study. Exp Brain Res 75:327–334 Hansen N, Manahan-Vaughan D (2015) Locus Coeruleus stimulation facilitates long-term depression in the dentate gyrus that requires activation of β-adrenergic receptors. Cereb Cortex 25:1889– 1896 Harmar AJ (2003) An essential role for peptidergic signalling in the control of circadian rhythms in the suprachiasmatic nuclei. J Neuroendocrinol:335–338 Haas HL, Sergeeva OA, Selbach O. (2008) Histamine in the nervous system. Physiol Rev. 88(3):1183–1241. https://doi.org/10.1152/physrev.00043.2007 Hebb DO (1949) The organization of behavior. Wiley and Sons, New York Iversen L, Iversen S, Floyd E, Bloom FE, Roth RH (2009) Introduction to neuropsychopharmacology. Oxford University Press, Oxford, UK Jiang B, Huang ZJ, Morales B, Kirkwood A (2005) Maturation of GABAergic transmission and the timing of plasticity in visual cortex. Brain Res Brain Res Rev 50:126–133 Kaila K, Voipio J, Paalasmaa P, Pasternack M, Deisz RA (1993) The role of bicarbonate in GABAA receptor-mediated IPSPs of rat neocortical neurones. J Physiol 464:273–289 Khakh BS, North RA (2006) P2X receptors as cell-­ surface ATP sensors in health and disease. Nature 442:527–532 Kuo LE, Kitlinska JB, Tilan JU, Li L, Baker SB, Johnson MD, Lee EW, Burnett MS, Fricke ST, Kvetnansky R, Herzog H, Zukowska Z (2007) Neuropeptide Y acts directly in the periphery on fat tissue and mediates stress-induced obesity and metabolic syndrome. Nat Med 13:803–811 Lahlou H, Guillermet J, Hortala M, Vernejoul F, Pyronnet S, Bousquet C, Susini C (2004) Molecular signaling of somatostatin receptors. Ann N Y Acad Sci 1014:121–131 Libet B (1985) Unconscious cerebral initiative and the role of conscious will in voluntary action. Behav Brain Sci 8:529–566. https://doi.org/10.1017/ s0140525x00044903 Lovejoy DA, Rotzinger S, Barsyte‐Lovejoy D (2009) Evolution of Complementary Peptide Systems: Teneurin C‐terminal‐associated Peptides and Corticotropin-releasing Factor Superfamilies. Trends in Comparative Endocrinology and Neurobiology 1163:215–220 https://doi.org/10.1111/ j.1749-6632.2008.03629.x

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Mika J, Obara I, Przewlocka B (2011) The role of nociception and dynorphin in chronic pain: implications of neuro-glial interaction. Neuropeptides 45:247–261. https://doi.org/10.1016/j. npep.2011.03.002 Nestler EJ, Hyman SE, Malenka RC, Holtzmann DM (2015) Molecular neuropharmacology: a foundation for clinical neuroscience, 3rd edn. McGraw Hill, Columbus. ISBN 0071827706, 9780071827706 Panksepp J (2011) Cross-species affective neuroscience decoding of the primal affective experiences of humans and related animals. PLoS ONE 6(9):e21236. https://doi.org/10.1371/journal.pone.0021236 Picciotto MR, Higley MJ, Mineur YS (2012) Acetylcholine as a neuromodulator: cholinergic signaling shapes nervous system function and behavior. Neuron 76:116–129 Qiu C, Zeyda T, Johnson B, Hochgeschwender U, de Lecea L, Tallent MK (2008) Somatostatin receptor subtype 4 couples to the M-current to regulate seizures. J Neurosci 28:3567–3576. https://doi. org/10.1523/JNEUROSCI.4679-07.2008 Sahara S, Yanagawa Y, O’Leary DDM, Stevens CF (2012) The fraction of cortical GABAergic neurons is constant from near the start of cortical neurogenesis to adulthood. J Neurosci 32:4755–4761. https:// doi.org/10.1523/JNEUROSCI.6412-11.2012 Shannon CE, Weaver W (1949). A Mathematical Theory of Communication. University of Illinois Press. ISBN 0-252-72548-4 Stanton PK, Sarvey JM (1987) Norepinephrine regulates long-term potentiation of both the popula-

tion spike and dendritic EPSP in hippocampal dentate gyrus. Brain Res Bull 18:115–119 Teichgräber LA, Lehmann TN, Meencke HJ, Weiss T, Nitsch R, Deisz RA (2009) Impaired function of GABA(B) receptors in tissues from pharmacoresistant epilepsy patients. Epilepsia 50:1697–1716. https://doi.org/10.1111/j.1528-1167.2009.02094.x Teschemacher A, Zeise ML, Holsboer F, Zieglgänsberger W (1995) The neuroactive steroid 5a-Tetrahydrodeoxycorticosterone increases GABAergic postsynaptic inhibition in rat neocortical neurons in vitro. J Neuroendocrinol 7:233–240 Villette V, Poindessous-Jazat F, Bellessort B, Roullot E, Peterschmitt Y, Epelbaum J, Stéphan A, Dutar P (2012) A new neuronal target for β-amyloid peptide in the rat hippocampus. Neurobiol Aging 33:1126. e1–1126.e14. https://doi.org/10.1016/j.neurobiolaging.2011.11.024 Wang H, Duclot F, Liu Y, Wang Z, Kabbaj M (2013) Histone deacetylase inhibitors facilitate partner preference formation in female prairie voles. Nat Neurosci 16:919–924 Yi NX et al (2019) MK-801 attenuates lesion expansion following acute brain injury in rats: a meta-­ analysis. Neural Regen Res 14:1919–1931. https:// doi.org/10.4103/1673-5374.259619 Zoicas I, Kornhuber J (2019) The role of metabotropic glutamate receptors in social behavior in rodents. Int J Mol Sci 2019(20):1412. https://doi. org/10.3389/fnmol.2019.00020

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Neuroscience Fields of Special Interest for Psychology Contents Chapter 5

Clinical Neuropharmacology – 103 Marc L. Zeise

Chapter 6 Inputs, Outputs, and Multisensory Processing – 153 Tim Rohe and Marc L. Zeise

 

Chapter 7 Neuroplasticity in Humans – 193 Hubert R. Dinse Chapter 8 Mathematical Modeling in Neuroscience – 231 Patricio Orio Chapter 9

Subjective Experience and Its Neural Basis – 253 Ryan Smith

Chapter 10 Tools of Neuroscience – 285 Pablo Fredes and Ulrich Raff

II

103

Clinical Neuropharmacology Marc L. Zeise Contents 5.1

 lassification of Disorders Caused Primarily C in the Nervous System – 106

5.2

“ Organic” Causes May Generate Psychological/ Psychiatric Symptoms – 109

5.3

Pharmacodynamics and Pharmacokinetics – 109

5.4

Naming of Psychiatric Medicaments – 112

5.5

Problems in Pharmacological Treatment of Mental Disorders – 113

5.6

Mood and Related Disorders – 114

5.6.1 5.6.2 5.6.3

 ood Disorders – 114 M Schizophrenia Spectrum Disorders – 127 Obsessive-Compulsive and Related Disorders – 131

5.7

Neurodevelopmental Disorders – 132

5.7.1 5.7.2

 ttention Deficit/Hyperactivity Disorder – 132 A Autistic Spectrum and Other Neurodevelopmental Disorders – 136

5.8

Acquired Disorders – 137

5.8.1 5.8.2

 osttraumatic Stress Disorder – 137 P Addictions – 138

© Springer Nature Switzerland AG 2021 M. L. Zeise (ed.), Neuroscience for Psychologists, https://doi.org/10.1007/978-3-030-47645-8_5

5

5.9

Neurodegenerative Diseases – 144

5.9.1 5.9.2 5.9.3

 lzheimer’s Disease – 145 A Parkinson’s Disease – 146 Other Neurodegenerative Diseases – 146

5.10

Non-degenerative “Neurologic” Diseases – 147

5.10.1 5.10.2

 yasthenia Gravis – 147 M Epilepsy – 148

References – 149

105 Clinical Neuropharmacology

Clinical neuropharmacology, by and large, is the academic area of knowledge and skills about how to help people who suffer from mental or neurological disorders through administration of neuroactive substances. But, what is a disorder? We suppose something is in disorder when it is not functioning correctly. Sigmund Freud supposedly stated that we are functioning adults when we are fully able to enjoy life, love and work.1 Indeed, when we mistake our husband or wife for a hat,2 when, out of inexplicable fright, we do not dare to leave our house, or when we are unable to treat our child with love, enjoying a fulfilling life and coping with our social roles will be seriously impaired, and dysfunctions appear obvious. But, in many cases, it can be very difficult to draw the line between something as mental “disorder” - rather than a personal crisis, a purely medical problem or a result of “normal” aging. Also, as societies change, the ideas of how a person has to “function” right are varying, too. Perhaps the best known examples for this are the socalled “paraphilic” disorders. The ideas of what “normal” sexuality is vary widely in time and between cultures. What is considered abnormal sexual behavior has been and still is, in many societies, punished severely. Today, in liberal societies, to consider a behavioral pattern as “paraphilic” disorder, is accepted only if it is “accompanied by distress causing impairment in the individual or present a harm, or risk of harm, to others” (Lyngzeidetson 2014). “Dysfunction”, in the context above, relates to individual/subjective, and/ or social “functions”. Now, what about dysfunctions at the biological level? The answer is that we do not fully understand the mechanisms that generate psychiatric disorders as yet. Consequently, in no case

1 Even though that saying is proverbial, at least in the German-speaking countries, I was unable to find a written source for it. 2 See the “classic” book by Oliver Sacks (Sacks 1998)

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of psychiatric disorder, we can pinpoint what biological dysfunction(s) is/are at its basis. As it is really problematic to assign and define specific functions to the nervous system or parts of it, biological dysfunction in this context is also ill defined. Moreover, manifestations of mental or psychological problems are practically always gradual. In other words, there is a big “zone of uncertainty” between “normal” and pathological. For example, it is often difficult to determine if a sadness you suffer for a while should be categorized as “normal” or rather should be seen as sign of a mild depression. So, while we need to construct a border between pathologic and normal state, it is not always an easy task. Fortunately, there is an increasing body of biological knowledge and diagnostic tools to help identify and monitor mental disorders, for example, in neurodegenerative diseases. By the way, it is for that reason we speak of neurodegenerative disease rather than simply disorder, because that class of “disorders” can be associated to “objective” abnormalities, i.e., changes at the biological level. An ever larger body of evidence about biological correlates for mental disorders is being accumulated in the fields of anatomy, physiology, biochemistry, among others. Further, genetic factors have been identified that correlate with elevated risks to suffer from the respective disorder. However, this knowledge does not yet allow a complete, causal understanding. Exceptions exist for some neurologic disorders (but by far not for all) that are pretty well understood mechanistically. The genuinely psychiatric disorders, at best, allow for biological markers to help diagnosis and monitor interventions. Biological markers are any parameters measurable with methods of natural sciences that are closely correlated to the syndrome/disorder specified by other means such as neuropsychological tests and/or questionnaires. To give one example, it has been found that the amount of brain-derived neurotrophic fac-

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tor (BDNF; see 7 4.4.2) in the CNS of patients is reduced in monopolar or major depressive disorder. It also has been found that levels of BDNF return to normal with successful treatment (Lee and Kim 2010). Thus, BDNF levels can be used as monitors of development/improvement of that ­mental disorder.  

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5.1

Classification of Disorders Caused Primarily in the Nervous System

You don’t have to be crazy… Typically, a person sees a psychiatrist because (s)he is suffering. Thus, speaking of psychological/psychiatric symptoms we refer firstly to personal experience, to phenomena of the “Inner World” as characterized in the introduction. As the person’s subjective problems are not directly observable by people apart from the patient, the therapist must rely on his observation and report of the patient, on observation of other patient behaviors, on reports of people close to her/ him and/or information from other medical or psychologic professionals. In most cases, if a grave mental or neurological disorder is present, there will be little uncertainty about that there is something wrong. The problem is rather how to evaluate the symptoms or syndromes presented and assign them to an underlying pathology. To achieve this, systems have been created that allow for such a categorization intending to help diagnostics and the understanding between professionals (Phillips et  al. 2010). “Symptom” then refers to an existing system of disorders; it has to be always “symptom” of some diagnosable problem. In fact, all classification systems that deal with or include mental disorders describe a bundle of symptoms to define a disorder. An important part of the training of a psy-

chiatrist or a clinical psychologist consists in learning how to recognize and categorize symptoms for the diverse disorders. The various existing schemes mainly organize according to type, gravity, duration frequency, and/or co-appearance of symptoms. Further, categorization is sometimes based on possible causes, such as intoxications. Thus, diagnostic criteria are created that allow classification which, in turn, will determine treatments. For this book, we have intended to give an abridged view over all frequent and damaging disorders that are caused primarily by problems of the nervous system (. Table  5.1). Several types of disorders mentioned in categorization systems such as the Diagnostic and Statistical Manual of Mental Disorders (DSM) of the American Psychiatric Association have been left out for the sake of simplicity and for other reasons (see below). We do include neurologic disorders mainly because epilepsy is frequent and requires pharmacologic treatment and this type of problems may be of interest for the psychologist. . Table  5.1 in an extremely condensed way presents names and symptoms as well as treatments. Further columns indicate the existence of manifest changes in the nervous system, the age at which first symptoms typically appear, and prevalence (“epidemiologic importance”). The column gender ratio requires special attention. There is an important ignorance as to the causes for gender bias ranging from different variability, different manifestation thresholds for genes to social/cultural causes. Supposedly, in major, i.e. monopolar depression (MDD), anxieties, and eating disorders, social/cultural factors produce a big part of gender imbalance, whereas in other disorders, genetic factors or even biased sampling procedures and/or diagnostic criteria may be more decisive (the latter factors generating just appearance, but not real sex/gender differences; Hartung and Lefler 2019).  



Supposedly caused mainly by non-genetic factors; “badly programmed” (?) One or more “negative” emotional systems dysfunctionally activated

Personality disorders

Developmental disorders

Neurodegenerative diseases

SNC development abnormal or delayed

Diverse therapies to alleviate symptoms/ distress Treatment of secondary disorders Specific therapies such as “Sensory Integration” being developed / implemented, biofeedback

Psychotherapy

Disorders with psychotic Symptoms

Perceptions that do not have physical or social correlates; emotional and cognitive impoverishment Progressing with age without the possibility of halting or reversing the process

Psychotherapy such as cognitive behavior therapy

Behavioral and other psycho-therapies MDD: ECTc, body exercises, light

Diverse psychotherapies

Non-­pharmacological treatment

Obsessive/ compulsive Thoughts/urges leading and related + eating to repeated actions; disorders; suppression causes anxiety

Mood disorders

Characteristics

Type of Disorder

Subtle

Subtle

Subtle

Un-known

Manifest changes in the NS

Treatments to Gross alleviate and/or delay symptoms; treatment of secondary disorders ADHD: Subtle psycho-stimulants and others; other disorders without specific medication

Antipsychotics, antiepileptics

Antidepressants, antipsychotics

Anxiolytics, antidepressants, mood stabilizers, antiepileptics

No specific pharmacological treatmentb

Pharmacological treatment

..      Table 5.1  Disorders caused primarily by problems of the nervous system

ADHD 1/3; Autisms 1/4 Rett syndrome ♀ only

1/1

Anxieties: 2/1 Monopolar depression: 1.5/1 Bipolar disorder:1/1 Eating disorders: 3/1; TOC: 1/1; “typical” OCs for ♀ and ♂ Schizophrenia: 1/1

? Estimation extremely difficult

Epidemiologic importancea

Childhood

Senior age

107

(continued)

High

Very high

Adolescence High

(childhood)d High adolescence, early adulthood

Adolescence Very high

Incidence gender First ratio symptoms ♀/♂ typically appear in ? Adulthood (?)

Clinical Neuropharmacology

5

Induced by bio-graphical factors or incidents, though vulnerability influenced genetically

Abnormalities/lesions in the Central or Peripheral NS

Acquired pervasive disorders

Other Neurological disorders

Physical therapies, surgical interventions; psychotherapy for secondary problems

Psychotherapies, frequently in groups

Non-­pharmacological treatment

Anxiolytics, antipsychotics to alleviate symptoms and/or help to “confront” Epilepsy: Anti-convulsant pharmacotherapy others: no specific pharmacotherapy

Pharmacological treatment

bException:

In general no age bias

Incidence gender First ratio symptoms ♀/♂ typically appear in Addictions: Addictions: 1/1.5; trauma or adolescence stress-related:?

Subtle to In general no gross; gender bias frequently well defined

Subtle

Manifest changes in the NS

or “Very High”: Probability to be affected at least once in life higher than 1% or higher than 10%, respectively Borderline Personality Disorder considered as requiring medication (often similar to bipolar disorders) cElectro-Convulsive Therapy dSome problems of obsessive/compulsive type can occur already in childhood such as Tourette’s syndrome

a“High”

Characteristics

5

Type of Disorder

..      Table 5.1 (continued)

High

High

Epidemiologic importancea

108 M. L. Zeise

109 Clinical Neuropharmacology

5.2

“ Organic” Causes May Generate Psychological/ Psychiatric Symptoms

Thorough medical examination is necessary. Let’s imagine that a patient presents himself to a psychiatrist suffering from and presenting symptoms of depression (see below) as described in the DSM. After having stated the diverse symptoms, the doctor will meticulously search for causes called “organic” or non-psychiatric scrutinizing the patient’s medical history and ordering diverse medical exams and/or probably examine the patient himself. This is necessary because medical problems generated outside the central nervous system can cause psychiatric disorders. Our depressed patient may suffer from pancreatic cancer. This cancer is known to be often accompanied by depression. In fact, symptoms of depression occur much more frequently for pancreatic as compared to gastric or cancer of the colon. In many cases, the psychiatric symptoms precede “somatic” ones. In such a case, would the psychiatrist treat the patient just with antidepressant medication, (s)he might be responsible for a premature death of the person due to failure of an adequate and timely treatment of the primary medical cause, the cancer. On the other hand, this does by no means imply that a patient suffering from psychiatric symptoms should be denied treatment addressing its (secondary) psychological or psychiatric problems. An antidepressant treatment would be indicated reducing the patient’s suffering and possibly even influencing positively its primary medical problem (Mayr and Schmid 2010). It is not at all rare that (a) medical problem(s) cause psychiatric symptoms, particularly when endocrine and/or immune systems are involved. Taken together, the psychiatrist tries to get as detailed as possible an account of his patient’s medical state, but also information about possible medication and possible intake of other neuroactive substances. The

5

DSM considers undesired side effects of medications and effects of substances taken independent of medical prescriptions. Thus, it is very adequate that the psychiatrist has got to have studied medicine. It is also very much justified, because many mental disorders are causing or are accompanied by bodily/physiological ailments. Furthermore, “purely medical” problems generate distress in many cases leading to mental/psychiatric symptoms and/or precipitate a formerly hidden or “sub-threshold” mental/psychiatric disorder. Obviously, for the psychologist, keeping in mind the influence of possible non-­ psychological causes before commencing and during interventions is equally important. In this context, he should be collaborating with all specialists who have been and/or are being consulted by his client and, if necessary, propose to his client (further) psychiatric and, possibly, other professional help. 5.3

Pharmacodynamics and Pharmacokinetics

What happens between taking the pill and appearance/disappearance of its effects? In 7 Chap. 3, we tried to explain the basic mechanisms of interaction between neuroactive substances and their receptors considering the ionotropic and metabotropic ways of producing biological effects. Pharmacodynamics starts from that interaction describing the relationship between drug concentration at the receptor site and the resulting effect(s) in a quantitative way taking into account time courses and potency (see 7 3.5.8). It is mostly the way of intracellular or “second” messenger pathways that determine pharmacodynamics. For if the receptor is a ligand-gated ion channel, i.e. ionotropic mechanism of action, the way from ligand binding to opening or closing the channel is extremely direct and fast. Onset times involved are  



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in the order of milliseconds or below and, duration of action is also typically no more than a few milliseconds due to the action of efficient reuptake mechanisms (see 7 3.6, #9). Only relatively few molecules used in pharmacotherapy act directly on ionotropic receptors. Most important among these are the benzodiazepines that act directly at the benzodiazepine site of the ionotropic receptor GABAA (see 7 4.3.5.1 and below). In the case of local anesthetics (see 7 3.6, #2), the occupation of the site is also the biological effect because it causes the blockade of the axonal sodium channel. Thus, pharmacodynamics mostly deals with the ligand–receptor (site) interaction and metabotropic, i.e. intracellular messenger mechanisms. These may include “third messenger” (see 7 3.5.3) action, the activation of messengers that bind to nucleic acids modulating gene expression usually being the case when long-lasting effects are involved. In 7 3.5.5, affinity was explained as probability to find a ligand bound to a certain receptor site. Concentration/effect relation is given by the EC50, i.e., the concentration that, at the receptor site, induces a half-maximal effect. If there are several effects, such as the desired and collateral effects, more than one EC50 can be determined. Pharmacokinetics tries to unravel what happens to a certain amount of substance administered on its way from its entrance into the body to its receptor sites and all the way down to its elimination from the body. In theory, we would like to know concentrations and their time course at the receptor site. However, it is seldom possible to measure inside the brain. The closest we normally get is the cerebrospinal fluid. Nuclear tracing can achieve even better results. However, the clinical routine only measures concentrations in the blood serum and in the urine. Because mainly of the blood–brain barrier (see 7 Box 5.1), the latter measurements do not give a true picture of pharmacokinetics of neuroactive substances.  



5







As practical memo for the processes that determine pharmacokinetics, the term ADME (absorption, distribution, metabolism, and elimination) has been introduced. While their meaning seems obvious, details, as usual, are quite complicated: When a medication is taken orally, in order to have an effect, it must be absorbed by the digestive tract. Absorption is the part of the digestion that transfers substances from intestine to blood. Before absorption, substances are exposed to digestive enzymes. Thus, “A” implies not only absorption itself, but also possible changes of pharmacologically relevant compounds by enzymatic “attack” or pH changes in the gastro-­ intestinal tract. Now, absorption is difficult to measure directly. Instead, pharmacologists and medical doctors deal with bioavailability comparing blood serum concentrations after administering a certain drug orally with the concentrations following intravenous application (. Fig.  5.1). This parameter is expressed as percentage of the amount of substance that reaches systemic blood circulation after oral ingestion. Graphically, it can be shown as the ratio of  



..      Fig. 5.1  “Areas under curve” for oral and intravenous (iv) administration

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111 Clinical Neuropharmacology

two “areas under curve”, the integral of the concentration from the moment of intake to infinity or, in practice, the time when there is no measurable amount of the substance left in the serum (. Fig. 5.1). The time course of the concentration after iv-administration is simplified, for it does not instantly produce maximal concentration and the decay is seldom exponential, but rather follows a two-phase decline as in . Fig.  5.2 or an even more complex pattern. In . Fig. 5.1, there is no much difference between the two “areas under curve”. However, in most cases in neuropharmacology, there are clear differences. For example, the anxiolytic clonazepam (Rivotril®, a benzodiazepine; see below) has a bioavailability of about 90%, another anxiolytic, buspirone, only 4%. In the latter case, this low value is not because of poor absorption or destruction by digestive enzymes but rather by hepatic metabolism. In other words, bioavailability is not only a function of possible chemical changes before absorption plus absorption itself, but also of the so-called “first-pass metabolism” due to the fact that all substances absorbed from the digestive tract will have to go via a blood vessel called  





“Vena portae” through the liver before they reach the systemic bloodstream. The next factor, D for distribution, describes the process of distribution through the cardio-vascular system and the entering of the substance in question into the diverse corporal liquids and tissues. There are large differences as to where substances “preferably” get. Perhaps the most important factor in this context is solubility in water vs. in more apolar medium (“hydrophilic” or “lipophilic” caused by electrical symmetry or asymmetry; see 7 3.1.1). That factor determines whether a substance can enter cells crossing cellular membranes and thus whether it will be distributed mostly in the extracellular space or also inside the cells. Further, whether the substance “prefers” lipid-rich tissue and cellular compartments or rather aqueous ones. Particularly important for kinetics of neuroactive substances is the fact that lipophilic molecules normally will cross the blood–brain barrier (BBB; see 7 Box 5.1) at higher rates than hydrophilic ones. Indeed, many substances used in neuropharmacology are quite lipophilic (apolar), such as tricyclic antidepressant drugs or many antipsychotics (see below). However, there are other factors influencing the passage into the brain like active transports that may allow certain hydrophilic compounds to enter the CNS. Further, in some parts, the BBB is less tight as in the so-called “circumventricular” organs (for example, the neural part of the hypophysis). Special cells equipped with tight junctions (see 7 Box  5.1) protect the rest of the brain from these areas. If and when the BBB is damaged, as in some neurodegenerative diseases or by toxins, severe neurological sequels result. M stands for metabolism or metabolization. Metabolization, in this context, means just a chemical change. This may, and typically does, inactivate the substance considered, but can also lead to new compounds that are pharmacologically active. So, in the case of bupropion, an “atypical” antide 





..      Fig. 5.2  Two compartment model of concentration diminution in blood plasma after a single intravenous injection. “IV bolus”: Intravenous administration of neuroactive substance

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pressant, there are three active metabolites formed from the parent substance (Dhillon et  al. 2008) rendering pharmacokinetics (and pharmacodynamics) really complex. For a great part, metabolization is realized by the liver. As mentioned above, orally ingested substances have to pass through it before entering the general, “systemic” blood circulation (“first pass metabolism”). After this, our drug or other pharmacologically active substance may pass through the liver again via the systemic bloodstream. Not only in the liver but also in other parts of the body inside or outside of cells, metabolizing enzymes can be found. E is for excretion and mainly determined by renal function. The metabolizing activity, mostly of the liver, is crucial for elimination as it “prepares” the way for successful elimination by the kidneys. Typically, the bulk of a substance or its metabolites are eliminated through the urine. Thus, by measuring concentrations in the urine, elimination can be monitored well in most cases. In order to adjust doses, the so-called “halflife” is important: it means the time that elapses from serum concentration at the onset of elimination phase to half of that concentration. As for medical pharmacotherapy, quantitative pharmacokinetics are important for reaching a therapeutic level of concentration at the site of the receptors without getting into concentrations that produce undesired collateral effects, and hopefully maintain a steady level during the whole period of therapy. Mathematical models have been created in order to describe and predict those concentrations. Here we will restrict ourselves to one of the easiest cases where blood plasma concentrations can be described by a “twocompartment” model. After the administration of a single dose, a substance will appear in the blood plasma creating a peak soon after administration that is followed by two exponential decays, a faster one caused by distribution in the body and the other by metabolization-excretion (. Fig.  5.2). For  

example, the pharmacokinetics of the classic anxiolytic benzodiazepine (see 7 5.6.1.1) diazepam, i.e. valium can be described in such a way (Eatman et al. 1977).  

Box 5.1 The blood-brain barrier (BBB) impedes the diffusion exchange of substances between the brain and the brain capillaries. It also selects molecules and ions through active transport and fulfills metabolic functions. From inside to the outside (of the capillary), it consists of: 55 Endothelial cells 55 Pericytes 55 Astroglial processes The endothelial cells in the brain are held together with so-called “tight junctions” that hinder the flow between the cells resulting in transports and flows mainly through the interior of these cells. The best-known physiological function of the BBB is to keep the brain clear of toxins, infectious organisms such as viruses or bacteria, and some messenger molecules and eliminate noxious substances from the brain. However, the term “barrier” is somewhat misleading, because besides barring against the inflow of substances its constituents also facilitate the flow or transport of vital molecules such as water, glucose, and amino acids into the brain.

5.4

Naming of Psychiatric Medicaments

Antidepressants are not always used against depression Substances applied in psychiatry are frequently labeled by the type of problems for which they are mostly used. There are antidepressants, anxiolytics, antipsychotics, and so forth. However, this does not mean that these

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113 Clinical Neuropharmacology

substances are used exclusively for the problems implied by their names. Particularly, antidepressants are administered to patients with diverse disorders, such as obsessivecompulsive disorder, narcolepsy (attacks of muscle weakness and sleeping), panic attacks, and many more. On the other hand, in the case of bipolar disorder that comes with depressive episodes almost impossible to differentiate from those of the major or monopolar depressive disorder (MDD), antidepressants are seldom prescribed (at least as monotherapy). Instead, anticonvulsants are frequently used in patients with bipolar depression, substances that originally had been developed for the treatment of epilepsy. Therefore, while we will use the common labeling for psychiatric medication in this text, one should keep in mind that it is not always totally adequate or precise.

5.5

Problems in Pharmacological Treatment of Mental Disorders

The “art” of the psychiatrist Naturally, as with other medications, pharmacological treatment of mental disorders can induce unwanted effects ranging in severity from feeling uncomfortable all the way to life-threatening. In neuropharmacological treatment, digestive, cardiovascular, respiratory problems, weight gain, or libido reduction are frequent, often caused by anticholinergic effects (acetylcholine is the transmitter that “moves” the parasympathetic autonomic nervous system; see 7 4.3.7). Undesired action in the CNS may lead to headaches, dizziness, blurred vision, sleep problems, concentration deficits, and many more. As we treat the main disorders, we shall briefly mention the important undesired collateral effects of medication used to treat the respective disorder. Interestingly, there may also be positive side effects of pharmacotherapy. Some antidepressants  

have been shown to be neuroprotective (Tizabi 2017), presumably because they are anti-inflammatory and foster the levels of neurotrophic factors (see 7 4.4.2). To balance direct and indirect benefits a medication exerts on the patient, against the burden of tackling with awkward or even dangerous side effects, is often a complicated and demanding task for the psychiatrist. In real life, the economic factor, the burden of the costs of pharmacotherapy, has to be considered, too. Beyond undesired effects, there is another frequent problem, the so-called “non-­ responders”. This refers to people who simply do not display beneficial effects even though treated with substances that are in use for many years and have proven to be helpful in thousands or even millions of cases. Even more patients will be classified “non-sufficient responders” meaning that benefits are below average and do not justify possible undesired effects. This is a huge problem. As an example, in the most frequent mood disorder, MDD, between 20% and 40% of patients are classified as responding suboptimally to medication. Further, many psychopharmaceuticals, such as many antidepressants and antipsychotics, are slow in displaying beneficial effects that may set in one or more weeks after the beginning of pharmacotherapy. However, undesired effects can be felt often right from the start. The reason for this time gap is still largely mysterious. It is, by any means, an indication that the immediate biochemical action is not beneficial per se, but a repetitive action triggers (adaptive) changes that make the difference. Further, an important effect to heed is interaction. This refers to interaction between one or more physiologically active substances taken by the patient in the context of therapy or outside of it (for example, “recreative drugs”). Effects of substances might simply add. For instance, the sedative effect of a benzodiazepine, will considerably be enhanced by the intake of ethyl alcohol  

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at the same time. Other more complicated examples include effects on metabolizing enzymes. Thus, a substance given may raise or lower levels of another medicament by influencing the activity of enzymes that are involved in the chemical changes that the drug undergoes in the body. For instance, the anticonvulsant or antiepileptic drug carbamazepine is known to modulate the action of liver enzymes of the so-called P450 group.3 These enzymes are involved in the metabolism of many substances used in pharmacotherapy. There are many more cases of drug interactions. In conclusion, here is one more reason why the psychiatrist has to evaluate and take into account all medication and/or other intake of physiologically active substances by the patient, and it is one of the reasons why monotherapy, i.e., treatment with one neuroactive substance is often desirable, although not always possible.

5.6

Mood and Related Disorders

In most of the severe mental/psychiatric disorders, medication may help and must be tried. In the following paragraphs important disorders, as listed in . Table 5.1, and some of their pharmacological treatments will be presented. As has been mentioned, this text considers only a restricted number of disorders or disorder groups: first, it concentrates on problems that affect, on average, at least once in lifetime 0.5% or more of the people in highly industrialized countries. Second, it leaves out several disorders that do not  

have specific pharmacological treatment, not even in a palliative4 way. Third, we shall not take into account personality disorders since they lack evidence-based specific pharmacotherapy with the possible exception of the borderline disorder. Even in this case, there is an on-going discussion whether there are adequate substances for long-term treatment (Starcevic and Janca 2018). Before starting to deal with the various mental disorders and their pharmacological treatment, it is important to state that there is no mental disorder that should not be treated by psychological means with or without medication. Only one important CNS-related problem comes to mind that may be treated with medication only, epilepsy. However, epilepsy can be considered as neurological rather than a mental disorder.

5.6.1

Under this label appear the most common and, at the same time, also some of the most severe mental disorders. While many non-­ psychiatric diseases, such as cardiovascular problems or infections, on a world-wide scale are slowly losing importance in the count of “lost years5”, just MDD “is ranked by the WHO as the single largest contributor to global disability (“7.5% of all years lived with disability in 2015”; WHO 2017). According to the same source, MDD is also “the major contributor to suicide deaths”. And the figures are increasing. Anxieties are also very common, causing roughly half the rate of disabilities as compared to MDD. However,

4 3

These enzymes found in all living systems have got a heme moiety that is also at the core of hemoglobin enabling it to carry oxygen. Heme absorbs at 450 nm producing a reddish color. In general, enzymes containing heme are able to transport/ exchange electrons and are involved in oxydation/ reduction processes.

Mood Disorders

“Palliative treatment” means taking measures that do not aim to cure the patient but rather to alleviate distress and pain of the patient and their caregivers. 5 “Lost years” in this context means years in which a person is disabled to fulfill their social roles such as creating sources of maintenance for her/himself and her/his dependents.

115 Clinical Neuropharmacology

the figures for either one cannot be simply added, because there is a high “overlap” or “comorbidity”; in other words, many people who suffer from MDD also display symptoms of anxiety and vice versa. All severe mood disorders require pharmacological treatment and by far the largest amount of remedies prescribed in psychiatry are in this category. 5.6.1.1  Anxiety Disorders

To characterize anxiety disorders seems to be very easy: being afraid too much. However, less apparent but quite important is that many patients are suffering from worrying too much, in this way producing their own fears. Very typical for people with panic disorders and phobias is being worried of how to avoid the next panic attack or the confrontation with the situation or object that may trigger distress. Being afraid always produces activation of the sympathetic part of the autonomic nervous system (ANS; see 7 4.3.7) preparing the body for action by raising heartbeat, muscle tonus, and respiration but dampening digestive and sexual organs, among others. On the other hand, not all ANS activation is correlated to fright. It may be caused by joy or rage or an exploring situation too. The factors and situations that lead to ANS activation are named stress. Long-lasting and “wrongly” evoked stress is intimately linked to depressive and anxiety disorders and via the ANS accounts for many bodily ailments accompanying these mood disorders. Anxiety disorders are the one major group of mood disorders where the ratio of women to men affected is highest: It is roughly at 1.7:1 (McLean et al. 2011). The same source states that (the disorders are) “not only more prevalent but also more disabling in women than in men” because of comorbidities. As most societies today are man-dominated, and women, on the average, are much more at risk, this is not surprising. Given the almost ubiquitous  

5

presence of patriarchal structures, it is difficult to say if and how much biological factors contribute to that strong gender bias. Anxiety disorders can be divided into two categories: those associated with a triggering situation or object and more generalized disorders where no particular trigger can be identified. In the former case, we talk about phobias being the anxiety mainly triggered by one or few situations or objects. Phobias are easily subdivided according to the type of trigger. We all know of objects and situations that can render you uneasy. This may be speaking in front of other people, being enclosed in a narrow space, or confronting a snake or a spider. If this causes an unbearable and lasting feeling of horror or panic rather than just an uncomfortable fright that is, however, manageable, and if the sensing of terror is grossly out of scale considering objective danger, and if this anxiety is impeding life quality for many months or more, we speak about a phobia. Phobias may cause panic attacks, a state of extreme distress with psychiatric as well as bodily symptoms. Now, panic disorder counts as a separate form of anxiety disorder in the DSM-5. This illustrates again the difficulty to categorize, since if the patient suffers from panic attacks in the framework of a phobia, (s)he may be labeled as suffering from panic disorder or specific phobia. The DSM-5 does not speak explicitly of phobias in cases of fright of being separated from a person the patient is attached to, (separation anxiety disorder), anxiety of speaking (“selective mutism”), or anxieties caused by social situations, such as meetings (social anxiety disorder) even though they are linked to more or less specific social situations. Evidently, in the case of a specific phobia conditioning or, rather, de-conditioning, therapy is often implemented. Generalized anxiety is characterized by a constant worrying, a seeking or searching for actual or more or less imaginary dangers. Different from phobias, non-­pharmacological therapy techniques are more difficult to

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choose and more variable. Cognitive behavioral treatment and acceptance and commitment therapy are amongst them. These can be combined with diverse relaxation therapies, such as yoga and the like. Generalized anxiety is frequently combined with other types of anxiety, MDD, and disorders of the obsessive compulsive spectrum. What was said in 7 5.2, namely, that the therapist has to check for not psychiatric causes of the symptoms presented, is particularly true for anxieties. There are numerous factors that can generate anxiety, some of the more important being: 1. Medical, such as Respiratory Endocrine Cardiovascular Metabolic Neurologic 2. Drug-induced by Stimulants/sympathomimetics (amphetamines, cocaine, caffeine ephedrine, adrenaline, etc.) Anticholinergics (benztropine, atropine, scopolamine, etc.) Dopaminergics (amantadine, L-DOPA, etc.) Hallucinogens (lysergic acid diethylamide (LSD), phencyclidine (PCP) etc.) 3. Drug withdrawal (from benzodiazepines, ethyl alcohol, other sedatives, etc.) Obviously, if such a situation is diagnosed, the focus will be in treating the primary cause of anxiety. However, pharmacological anxiolytic treatment may be indicated to relieve the patient’s distress and suffering and help them to cope with their situation. Pharmacological treatment of anxiety disorders relies mainly on two types of substances: benzodiazepines and antidepressants. These two groups of pharmaceuticals are quite different considering their mechanism of action, virtues, as well as their shortcomings and risks.  

5

Benzodiazepines Great for immediate relief and short-term therapy, but may be problematic in the long run. These molecules share the coupling of a diazepine ring with a benzene ring (. Fig. 5.3). As the constant part has only two nitrogen atoms inserted in a ring and, otherwise, consists only of hydrogen and carbon, benzodiazepines are very lipophilic even though substituents (the “R” parts) can be chloride and/or oxygen making them somewhat more water-soluble. The high solubility in lipids has several consequences: 55 Benzodiazepines are dissolved in the blood plasma only to a small extent’ the rest is transported by the lipophilic site of blood proteins. 55 Blood–brain barrier is readily passed, but mainly by the fraction dissolved in serum. 55 The volume of distribution is relatively big; benzodiazepines pass into the cellular compartment. 55 Tend to be accumulated in adipose tissue as well as in the nervous system (myelin sheaths of axons). 55 Access to the fetus in pregnant women.  

All this, together with moderate metabolization rates, make the half-life of most benzodiazepines rather long. Clonazepam (Rivotril®), perhaps the benzodiazepine

..      Fig. 5.3  Benzodiazepine structure. The most common substitute sites are marked Rx

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117 Clinical Neuropharmacology

most prescribed, has a half-life of about 30  hours (1–2.5  days). This is an advantage in therapy, because it helps to maintain serum levels more or less constant taking just two doses per day. As described in 7 4.3.5.1, benzodiazepines bind to the GABAA receptor at the benzodiazepine site. The biological effect is an increase of the open times increasing frequency of opening events plus an increase of affinity of GABA to its site (Bianchi et  al. 2009; not identical with the benzodiazepine site). Thus, pharmacodynamics is almost negligible as compared to pharmacokinetics which is pretty slow (see above). Benzodiazepines are amongst the neuroactive substances whose mechanism of action is best known from the molecular level up to behavior. As GABA receptors are almost ubiquitous in the CNS, benzodiazepines produce a general dampening of activity, lowering tension and anxiety, and inducing sleep. At higher doses, the sedation may lead to a coma-like state. However, unlike other sedative agents, lethal outcome due to respiratory arrest occurs very seldom. Benzodiazepines are partial agonists considering their ability to enhance GABAergic inhibition. But, care must be taken when used together with other sedatives, such as ethyl alcohol. In such cases, even benzodiazepine overdose may be lethal. Together with the rather low risk of voluntary or non-voluntary death, benzodiazepines present low toxicity, i.e., even at high doses there will be usually no major physiological damage. Therefore, patients may, to some extent, medicate themselves as and when they feel they need it. Thus, for all types of anxiety associated with objects or situations as well as for panic attacks, benzodiazepines are great because they can be taken beforehand or when the patient feels that they are going to have a problem. As worrying in anxiety is frequent, and this favors entering into an anxious state or even a panic attack, the sheer knowledge to have a remedy “in case  

of ” can be very comforting and help to not getting into or overcome the crisis. This is possible, because benzodiazepines taken orally, by and large, start to exert their relief effect between 15  minutes and half an hour thanks to their fast absorption and the swift passing of the BBB. Some have an even faster onset of effect such as diazepam (Valium®). Benzodiazepines are the medication of choice against anxiety if help is needed rapidly and the time of therapy with them is short (no more than approximately 4 weeks). Also, as in the cases above, if medication is scattered and taken infrequently only as needed, benzodiazepines can be helpful without causing much of undesired collateral effects. In this context, the fast and reliable effects and low toxicity of benzodiazepines are taken advantage of in medical emergencies, administering benzodiazepines intravenously to interrupt epileptic attacks that do not cede (“status epilepticus”) or eclampsia convulsions (a complication in pregnancy and child-birth that can lead to convulsions and death). Further, victims of an accident or assault may need swift calming, and before surgical intervention, benzodiazepines are also used to relax the patient and lower muscle tonus. In contrast, in generalized anxiety, i.e., a permanent state of worry and fright requiring medication for extended periods, benzodiazepines are prescribed hesitantly and other medication such as antidepressants or buspirone (see below) are preferred. The reason why benzodiazepines are less indicated for prolonged therapy is their potential to cause dependence together with tolerance (see 7 5.8.2). In other words, after long periods, for 2 months or more, of taking benzodiazepines regularly dependence may set in, because to stop or even to reduce doses is difficult for strong anxiety and incontrollable distress and even convulsions may occur. In . Table  5.2, on the dependence scales, benzodiazepines  



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..      Table 5.2  Scale of drugs after their potential harm and abuse (Nutt et al. 2007)

5

Drug

Mean

Pleasure

Psych. dependence

Phys. dependence

Heroin

3.00

3.0

3.0

3.0

Barbiturates

2.01

2.0

2.2

1.8

Benzodiazepines

1.83

1.7

2.1

1.8

Tobacco

2.23

2.3

2.6

1.8

Alcohol

1.93

2.3

1.9

1.6

Cocaine

2.37

3.0

2.8

1.3

Amphetamine

1.67

2.0

1.9

1.1

Cannabis

1.51

1.9

1.7

0.8

Ecstasy

1.13

1.5

1.2

0.7

LSD

1.23

2.2

1.1

0.3

figure right after opioids, barbiturates and tobacco. While almost all psychiatric medication should not be discontinued abruptly, with benzodiazepines special care, i.e., slow “tapering” and closely monitored dose reduction is necessary; the more so, the longer benzodiazepines had been used. It should be mentioned that benzodiazepines are “popular” due to their swift effect, their potential to cause dependence, and their low price. Thus, in most countries, there is a “grey” market. Diverse “benzos” are sometimes sold by people in fairs or market places (physical or virtual) without them being considered or considering ­themselves as “narcos” or drug dealers.

Other Anxiolytic Pharmacotherapy So, what to do if long-term pharmacological treatment is necessary? By far, the substances most used in this case are antidepressants. These, in general, induce less dependence and can be taken for years. They will be dealt with in the next subchapter. Further, there are a few medicines, such as buspirone, that help specifically against generalized anxiety disorder. Quite different from benzodiazepines, buspirone

inhibits specifically 5-HT1A receptors. Now, these receptors are mainly found in the role of autoreceptors (see 7 3.6, #7). Autoreceptors limit the liberation of the main transmitter of a synapse. So, as 5-HT is the transmitter serotonin, inhibiting autoreceptor action means, in this case, augmenting serotonin liberation. Serotonin levels are correlated to well-being, so it makes sense that people feel better taking buspirone. However, unlike benzodiazepines, but like many other substances used in psychiatry, buspirone will not bring relief beginning the first day it is taken, but typically only a week or two after the first dose. So, we must suppose that the action is more indirect as a new equilibrium at serotoninergic synapses is achieved. Further, as was mentioned above, bioavailability is poor, only about 4% reaching systemic blood circulation due to metabolic action of the liver. However, one important metabolite, 1-(2-Pyrimidinyl) piperazine, is also helping to reduce anxiety inhibiting adrenergic receptors of the type α2. Noradrenalin is the final transmitter of the sympathetic ANS acting on corporal organs. So, blocking them will impede the main peripheral effect of anxiety, reducing  

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bodily symptoms and thus reducing anxiety itself. This brings us to another class of anxiolytics, sometimes called “symptomatic”, that lower activation of the sympathetic ANS. They act primarily on the physiological effects or correlates of fear, bringing down accelerated heart rate, blood pressure, trembling, and other “symptoms” of anxiety thus also bringing relief to the “state of being anxious”. These are the so-called “beta blockers”, such as propranolol or atenolol, used in cardiac patients to lower the load on the heart. Used with care, they are quite safe, even though again an abrupt discontinuation is to be avoided for the risk of backlash activation of the sympathetic ANS with all its consequences that may lead, among other problems, to tachycardia (elevated pulse frequency) or even to cardiac arrest. Another way to slow down sympathetic tonus is by administering α2 receptor agonists as these are activating an autoreceptor-­mediated (7 3.6, #7) reduction of noradrenaline release. Substances used to lower blood pressure, such as clonidine, act in this way and for some people are suited to reduce anxiety. Another class of anxiolytics primarily based on physiological action are antihistamines, properly called histamine receptor antagonists or inverse agonists (see 7 3.5.7), that also lower activities involved in the fear response. They do not imply such important risks in case of sudden discontinuation, but often are not so effective.  



5.6.1.2  Monopolar Depression

The great epidemic? Being depressed or sad is a normal state that most of us have experienced and whose duration varies from hours to years. That state is characterized by grief, feeling helpless and/or worthless, abnormal sleep, inner tension or lethargy, low “energy” (everyday tasks appear hard), and incapacity to enjoy anything, sometimes suicidal thoughts and

5

frequently social isolation, among other symptoms. If the psychosocial situation that triggered the depressive state changes for the better and the person is still depressed, then that person is likely to suffer from a monopolar depressive disorder (MDD). Mental disorder category systems, such as the DSM, give quite clear criteria as to differentiate a person as suffering from MDD who needs professional help from another whose depressive state is triggered by an event “justifying” it that will end soon without treatment. Of course, as in all mental disorders, there is a large intermediate zone between healthy people having the blues for a limited time and those who suffer from severe depression. And, in case of doubt, especially when the patient asks for help, no psychiatrist will deny antidepressant medication just because (s)he feels that the patient will eventually get better even without medication. Further, it should be mentioned that a depressive state with all the typical symptoms can be caused by a bipolar disorder and it is very important to exclude it before starting a therapy with antidepressants. We will discuss below how the differentiation can be achieved. Monopolar depression is the most frequent mental/psychiatric disorder worldwide, and its contribution to disability is increasing. However, part of that increase has nothing to do with a real growing number of sufferers, but rather to more patients seeking professional help. As the social stigma of depression is being less severe than it used to be, more people are openly looking for relief. In this context, it should be said that there is a tendency to mistake problems in the context of a normal personal crisis for mental disorder (Horwitz and Wakefield 2007). Now, are there subdivisions of MDD like those we have seen for anxiety disorders? The answer is that it is more difficult to subdivide MDD because we cannot subdivide it by looking at triggering factors. Depressive episodes may be triggered in the same per-

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son once by the loss of a dear person to the patient and next time by a stressing situation at work and a third time there may be no obvious trigger at all. However, there is MDD of the anxious, agitated type, sometimes called melancholic and a rather lethargic type where any movement or decision seems almost impossible, called atypical MDD (Gold and Chrousos 2002). In the article cited, the two types of MDD are described and explained as opposite, abnormal ways to cope with stress. Thus, symptoms present may go in “opposite directions”. For example, while “melancholics” tend to sleep too little and lose weight, “atypicals” usually sleep too much and gain weight. The authors describe the melancholic type as caused by overreaction, the atypical one as too low activation of the HPA axis (hypothalamic-pituitaryadrenal; see 7 4.4.1.3), a central structure for the stress reaction. In the “melancholic” patients, levels of the “stress hormone” cortisol as well as noradrenaline and adrenaline levels are chronically elevated, whereas in the atypical patient these levels are below normal. The overlap between anxiety disorders and MDD is mainly due to the agitated, tense, and anxious state of the “melancholic” type of MDD patients. Thus, in psychiatry practice, once an MDD has been diagnosed, one of the first questions in order to decide about medication will be: is there a clear component of anxiety in the symptoms presented?  

Antidepressants When discussing anxiety disorders, it was mentioned that a major line of anxiolytic pharmacologic treatment is the use of antidepressants. But antidepressants can help to relieve not only anxieties, they are used in a long list of problems, obsessive compulsive and related disorders perhaps being the most frequent, but by far not the only uses of antidepressants outside MDD. Curiously, while there have been vivid discussions about the efficacy of antidepressants putting in doubt their beneficial effects over placebo

(Hieronymus et  al. 2017), this is hardly the case for their other applications. In 7 Chap. 4, when dealing with neurotransmitters, it was stated that monoamines, in spite of their far minor quantity compared to amino acid transmitters, are involved in most psychiatric medications. In fact, virtually all substances for the treatment of MDD as first immediate effect raise extracellular levels of one or more monoamines. The so-called atypical antidepressants (see below) do so, too, but also exert additional effects. How to raise extracellular levels of monoamines close to synapses? We could raise synthesis or liberation of these transmitters, or we could reduce reuptake or degradation/inactivation. Possibly due to their accessibility from the outside, the latter way is used by practically all antidepressants, namely to inhibit the removal or inactivation of extracellular transmitters.  

Monoamine Oxidase Inhibitors First antidepressants and still useful Historically, the first effective type of antidepressants inhibits inactivation by metabolization. These are the monoamine-­ oxidase inhibitors (MAOI). They diminish the rate of monoamine oxidation through the corresponding enzymes. Monoamine transmitters are enzymatically degraded or metabolized by methylation of a hydroxyl group at the benzene ring of dopamine, noradrenaline, or adrenaline, or by replacement of the amino group by an oxygen molecule (with the exception of histamine). The latter process is catalyzed by monoamine-oxidases (there are two types; A and B). These enzymes that are located in mitochondria not only metabolize monoamine transmitters, but also dietary monoamines among many other natural as well as synthetic compounds with accessible amino groups. MAO inhibitors (MAOIs) constitute the first “generation” of antidepressants. They were introduced and commercialized in the

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early 1950s. Tyramine, a monoamine that is contained in many foods, such as cheese, chocolate, processed meats, beer and red wines plus numerous others, induces noradrenaline release and has to be degraded rapidly to avoid substantial increase in blood pressure by sympathetic activation of the cardiovascular system. Thus, if and when MAOs are blocked, ingesting tyramine can precipitate a dangerous and sometimes life-­ threatening hypertensive crisis. While being reasonably effective, there are two important disadvantages to MAOIs: 55 As they are not very specific, a dangerous accumulation of amines, such as tyramine, can occur, leading to cardiovascular problems. 55 MAOIs interfere with numerous substances used in pharmacotherapy. Thus, MAOIs imply a dietary regimen in which many (often perceived as delicious) foods have to be avoided and moved from first choice or primary medication in the treatment of MDD to second choice treatment. However, more selective and more reversible MAOIs have been and are being developed. For example, moclobemide®, among various others, only inhibits one class of MAOs and inhibits reversibly, and in this way, greatly reduces the dietary requirements. Taken together, MAOIs, although less used than other antidepressants, are still of importance, particularly because there are patients who do not respond satisfactorily to other medication (. Fig. 5.4).

5

Tricyclic Antidepressants Effective, but may be dangerous Shortly after the introduction of MAOIs, another, quite different class of antidepressants were introduced, the tricyclics. This class of antidepressants elevates extracellular levels of monoamine transmitters by inhibiting their transport and, thus, their reuptake in an unspecific way. Their chemical hallmark is a system of three coupled (“condensed”) rings whose center consists of seven “corners”: six C atoms and one N atom. Further, there are two benzene rings at the sides (. Fig.  5.5). The beneficial effects of tricyclic antidepressants (TCAs) are supposedly due to their ability to inhibit serotonin and noradrenaline uptake, neither one very specific. However, there are TCAs that inhibit serotonin transport somewhat more than noradrenalin reuptake, while with others it is vice versa. TCAs are classified according to these preferences. Still, TCAs are considered “unspecific” monoamine reuptake inhibitors, because this “preference” quantitatively goes not far beyond a factor of ten, whereas “specificity” in pharmacology implies ratios of affinity by 1000 or more (see 7 3.5.5). Arguably, TCAs are considered as the “strongest” antidepressants. Some investigations imply that in severe cases TCAs should be the primary choice (Boyce and Judd 1999), particularly in the “melancholic” subtype. On the other  





..      Fig. 5.4  Chemical structure of moclobemide, a reversible, MAO-A-specific MAO inhibitor

..      Fig. 5.5  Chemical structure of a tricyclic antidepressant (imipramine)

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hand, TCAs are used much less by now, because of their partly severe undesired side effects. The most common are due to the inhibition of (acetyl)cholinergic muscarinic receptors (7 4.3.7). As the only transmitter in the parasympathetic branch of the autonomous nervous system is acetylcholine, this can lead to problems with digestion, from dry mouth to obstipation and weight gain, but also to problems in the regulation of blood pressure (“orthostatic hypotension”) and cardiac arrhythmias. An important problem for patients that can reduce their so needed self-esteem and/or their capability to enjoy life is that TCAs may induce sedation and sexual dysfunction. There even is evidence that anticholinergic medication may increase the risk of dementia when taken over more than 10 years (Gray et al. 2015). TCA-induced collateral effects can be severe and suicides with overdoses occur. Due to the strong side effects, the “drop-out” rate, i.e., the rate of patients that discontinue medication, is quite high. Further aggravating is the fact that the beneficial effects of TCAs, just as practically all present antidepressants, are only experienced several weeks or even months after the beginning of treatment. Considering all this, TCAs in ambulatory treatment must be prescribed with caution, and usually later “generation” antidepressants are be preferred, whereas in the clinic TCAs are more often used as first choice.  

5

Selective Reuptake Inhibitors The market busters of the last decades This class of antidepressants, “the third generation”, introduced broadly in the 1980s, at present is the most used among the antidepressants, and perhaps together with the benzodiazepines, the most prescribed and sold type of neuroactive substances (Nielsen and Gøtzsche 2011). They are characterized by their relative specific inhibition of serotonin or noradrenaline reuptake.

..      Fig. 5.6  Chemical structure of Fluoxetine (A) and Sertraline (B), two of the most prescribed Specific Serotonin Reuptake Inhibitors

The chemical structure (. Fig. 5.6) is quite different from the one of TCAs, so undesired side effects are different too. Whereas TCAs interact not only with monoamine transporters, but also with several types of transmitter receptors, such as acetylcholine receptors, the affinity of specific uptake inhibitors to these is relatively low, resulting in side effects of lesser gravity. Thus, reports of life-threatening complications by taking prescribed doses or taking overdoses are hard to be found (Nutt et al. 2019). Further, in contrast to TCAs, specific reuptake inhibitors are mostly devoid of side effects that may aggravate depression, such as weight gain, sedation, and loss of sexual libido. Therefore, selective reuptake inhibitors rapidly became very popular. Undesired collateral effects include nausea, digestion problems, insomnia, and dizziness among others. In many patients, these unpleasant side effects are temporary. However, there are problems that are affecting well-being and are partly long-term. Among these are changes in the immune system, reducing levels of inflammatory cytokines. The latter  

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side effect cannot easily be labeled “good” or “bad” as it may imply weakened immune response to infections, but also could be neuroprotective (Tizabi 2017). “Selective serotonin reuptake inhibitors” (SSRIs) are the most prescribed and commercialized antidepressants. In . Fig.  5.6, chemical formulae of two of the best-known SSRIs are shown: fluoxetine (“Prozac®”) and sertraline (“Zoloft®”). On the other hand, substances that are specific for the noradrenaline transporter are few and are not well suited for the treatment of MDD (Cipriani et  al. 2018), but rather for the treatment of attention-­deficit/hyperactivity disorder (ADHD). However, antidepressants that show combined inhibition for both monoamines, Serotonin/Noradrenaline reuptake inhibitors (SNRIs), have been catching up in the 1990s and later with venlafaxine (Effexor®) and others acquiring important sections of the market for antidepressants.  

“Atypical” Antidepressants Most recent, most diverse Atypical antidepressants not only interact with monoamine transporters, but additionally with pre- or postsynaptic transmitter receptors. We shall present two of the ones used most: Bupropion and Nefazodone. Bupropion (“Wellbutrin®”), is a substance mentioned above as being metabolized in the liver to hydroxybupropion and other compounds by up to 96%. It is mainly the latter substances that exert the therapeutic function. Bupropion hardly changes serotonin reuptake, but inhibits noradrenaline as well as dopamine reuptake (the mother substance more than the metabolites). Further, it is a non-­competitive antagonist at nicotinic acetylcholine receptors in the brain. It is for the latter effect that bupropion is perhaps the best-known aid for smokers to get “off the hook”. Chemically it has similarity with amphetamine and can be categorized

as psychostimulant. Therefore bupropion is not advised if there is a history of seizures. Actually, in high doses, it may precipitate convulsions. Another peculiarity, but a positive one, is that it almost never induces sexual dysfunction. On the contrary, it is being used to some success to mend this problem, often as an adjunct to other antidepressants. In general, it is not uncommon that psychiatrists prescribe bupropion when first line antidepressants, such as SSRIs, alone fail to achieve remission. This makes sense, insofar as with the combination a reuptake inhibition of all three important monoamine transmitters can be obtained. Nefazodone, another “atypical”, while having a low but significant affinity to all three monoamine transporters, inhibits some serotonin receptors, and also inhibits alpha type adrenoceptors (7 4.3.6.1). The latter property presumably contributes to its anxiolytic properties making it an effective treatment for panic attacks and other disorders linked to overexcitation and aggression. While side effects are comparable to SSRIs, nefazodone, in rare cases, has been proved heavily hepatotoxic leading to destruction of the liver.  

Hallucinogens On March 5, 2019, the FDA approved esketamine (FDA 2019; should be S-ketamine for being the S-enantiomer6 of ketamine). It has been hailed as “arguably the biggest breakthrough in the field of depression in over 60 years” (Duman 2018). Ketamine has been known for many years as “dissociative anesthetic” meaning that the substance can be used as general anesthetic, but has “dissociative” properties, i.e., that there is a capac6 Enantiomers are isomers (7 2.1) that by having different steric configuration rotate polarized light to the right or the left respectively. Biological structures, such as enzymes or receptors, are sensitive to that difference.  

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ity to induce schizoid or psychotic episodes. However, it is still used, particularly in medical emergencies because ketamine, different from other general anesthetics (7 3.5.2), largely lacks respiratory and cardiac suppression. Ketamine is a non-competitive (7 3.5.2) channel blocker of NMDA type glutamatergic receptors (7 4.3.1). It also has been known for a long time that NMDA receptor blockers, such as phencyclidine (“angel dust”), among others can induce hallucinations. Its antidepressant mechanism of action is not clear, but seems not to rely only on its NMDA receptor blockade. It seems as though some metabolites exert antidepressant effects due to an AMPA receptor rather than an NMDA receptor blockade (Zanos et  al. 2016). It is also strongly discussed that ketamine may work through an action on serotonergic transmission either through its (relatively weak) affinity to the 5-HT transporter or indirectly. This brings us to another type of hallucinogens that work on serotonergic systems, such as lysergic acid diethylamide (LSD), psilocybin or N,N-dimethyltrypamine (DMT). These hallucinogens all have structural resemblance to serotonin and directly interact with serotonin receptors as agonists. At the time being (2020), research is intense as for the antidepressant actions of these substances. At any rate, ketamine and the other hallucinogens display an extraordinary feat that the former antidepressants lack, that is speed of action. As early as 2 hours after application (with a nasal spray as approved by the FDA), patients sense a relief of severe symptoms such as suicidal ideation. In animal experiments, it has been shown that the decrease in synapse numbers induced in a depression model could be reverted in this short time after administration (Zanos et al. 2016). Further, the effect is long-lasting: one single administration can cause betterment  





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for up to 1 week or more. This long-lasting effect would be explicable by changes in the neuronal network rather than only by biochemical effects. At this time (2020), the use of hallucinogens, considering their ability to induce hallucinations, has been approved only for pharmacotherapy-resistant depressive patients. There is hope that, with hallucinogens, antidepressant development that has been stalled for decades will start into a new era.

Antidepressants and Dependence It must be noted here that all antidepressants that fulfill their goal, namely to alleviate the burden of being depressed, imply a certain risk of dependence,7 because stopping to take them can have very unpleasant consequences, such as anxiety, sleep disturbance, or other mental distress. However, since antidepressants lack the immediate reward that lures people into addiction (see 7 5.8.2), they are not considered addictive. In that respect, benzodiazepines are more dangerous, because they induce a better feeling typically within 1 hour or less. At any rate, terminating an antidepressant therapy has to be done by carefully “tapering off ” the doses in order to avoid distress or even relapse into a new depressive episode.  

St. John’s Wort Herbal medicine has fanatic followers and fanatic detractors. As usual, truth is not as easy as yes or no. While some plants have been labeled to help but are without effect (such as the use of mistletoe against cancer; Freuding et  al. 2019), there is a host of herbal medicine whose beneficial and undesired effects are unclear. The problem is that herbal extracts can be produced in very ­ different ways and, in more severe

7 For ketamine and other hallucinogens dependence may not occur.

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cases, they are used alongside with established therapies making a scientific evaluation difficult. Many pharmaceutically used substances have their origins in plants, such as local anesthetics (derivatives of cocaine; Erythroxylum coca), opioids (Papaver somniferum), or aspirine (Salix alba) among others. St. John’s wort (Hypericum perforatum) has been shown to be helpful and active, and antidepressant ingredients have been identified (Apaydin et  al. 2016). It is known to heal psychic pains at least since the middle ages. Around 795, it is mentioned as helpful against “melancholy” (MDD; “Lorscher Arzneibuch”). This application is valid up to now, but supposedly also includes all kinds of anxiety disorders, sleep problems, and others. Side effects are not really dangerous such as an increased dermal photosensitivity. However, there is interaction with several substances used therapeutically for mental disorders and “medical” illnesses. In severe cases of MDD, its effects are usually non-satisfactory.

Non-pharmacological, Non-psychologic Treatments for MDD Physical exercise and relaxation techniques are among the generally advised preventive measures for physical and mental health and well-being. There is clear evidence for this in cardiovascular problems as well as neurodegenerative diseases among other health problems. In anxieties and MDD, as in many other mental health problems, such techniques are also recommended, often as complement to psychologic and pharmacological treatments. However, physical exercise in MDD should be moderate and sustained (Gerber et al. 2016). Moreover, there exist several “physical treatments” that are less commonly used in other disorders: 55 (Repetitive) transcranial magnetic stimulation: By inducing a magnetic field in coils held close to the head, electric

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currents are induced in the brain (see 7 10.4.2). This technique, originally developed as a diagnostic tool in neurology and also used for research, has been approved by the FDA for treatment in MDD, whereas, to date, not for any other disorder (Terranova et al. 2019). 55 Light therapy: A low percentage of MDD cases are strictly dependent on season. These patients, but, sometimes other MDD cases too, may be responding to light therapy. Patients may be substantially relieved being exposed to light, particularly in the light-poor seasons. 55 Electroconvulsive therapy (ECT): Electroshock has gained a dreadful name for having been abused in the past century as an instrument for punishing patients in some psychiatric clinics. However, it is acknowledged that some pharmacoresistant MDD patients respond well to ECT.  Today, the treatment is realized under systemic (full) anesthesia and administering muscle relaxant drugs resulting in strongly reduced pains and distress.  

5.6.1.3  Bipolar Disorder

The artists’ madness? The composer Robert Schumann had episodes of high productivity interrupted by episodes in which he wrote not a single note. The writer Virginia Woolf has been diagnosed and almost certainly died of bipolar disorder (Koutsantoni 2012). Searching on the Internet, you will find a near endless list of artists of all kinds and epochs who suffered of deep depression following episodes of highly creative and productive ones. No other mental problem is known to be linked to creativity as is bipolar disorder. On the contrary, most of mental disorders are disabling in almost any aspect including creative work. Unfortunately, in the majority of cases, manic episodes, while charac-

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terized by abnormal activity and often a feeling of greatness and immense capabilities, do not produce great works, but rather lead to a waste of personal and often family resources as the affected thinks she or he has found the way to make a big fortune or a ground-­breaking discovery. During a manic episode, hardly anybody is asking for professional help, but family and friends are, in order to avoid oncoming disaster. During manic episodes, rational thinking and deciding gets overwhelmed by a drive to restless activity that, for the affected person, appears highly important, efficient, and sensible. Thus, it is not surprising that there are famous artists but much less scientists or successful businesspeople known to be bipolar. Bipolar disorders are diagnosed by the appearance of maniac, often euphoric stages accompanied by little sleep and hectic activity. However, as patients seek help mostly during depression, the psychiatrist has to be careful to search for maniac or, at least strongly active, episodes in their life story to avoid confusion with MDD.  Reason is that the depressive phase is characterized by exactly the same symptoms as those for MDD.  Psychiatric evaluation searches for possible maniac or hypomaniac episodes often including interviews with people who know the patient well, such as family members, friends, or colleagues of working places. If there are pronounced maniac phases, patients are characterized as suffering from bipolar disorder type I; if it is rather just unquiet periods, we speak of type II. The differentiation mentioned above between MDD and bipolar disorder is crucial for a correct pharmacotherapy, since antidepressants do not work well in bipolar patients; they have even been reported to be counterproductive, sometimes aggravating mood swings. However, they are sometimes still used in combination with mood stabilizers (Cascade et al. 2007).

Lithium Lithium is the only chemical element used in neuropharmacology; all others are molecules. It is the third in the periodic system of elements after hydrogen and helium and heads the column of the so-called halogens (“saltformers”). In the same column figure sodium and potassium, the cations involved in producing the action signal and excitatory postsynaptic signals (see 7 2.5). When it was discovered that lithium had the capacity of a mood stabilizer, i.e., that it dampens the mood “oscillations” in bipolar patients, it was thought that its beneficial effect was due to it being an electrolyte or ion. In fact, lithium enters and leaves the cells of the CNS with ease, mainly through sodium channels, but also by the Na+ transport. Therefore, early research focused on lithium’s effects on neuronal electrical properties. In fact, the main energy consumer in the CNS, the ATP-­ dependent Na/K pump is being influenced by lithium, possibly lowering excitability. Later, it was shown that lithium modulates a series of intracellular messenger systems including third messengers that influence gene expression. It has also been shown to modulate monoamine transmission (dopamine, serotonin, and noradrenaline) and to raise levels of BDNF, a polypeptide whose relative lack is a hallmark of MDD. However, in spite of, or perhaps because of the astounding multiplicity of effects, the mechanism(s) of lithium’s beneficial action in bipolar disorder is far from clear.  

Antiepileptic Medication Three substances originally introduced/developed as antiepileptic drugs are frequently used in the treatment of bipolar disorder: Valproate, Carbamazepine, and Lamotrigine. These anticonvulsants are approved by the US Food and Drug Administration for the use against maniac or “mixed” episodes, but not for maintenance in bipolar disorder. However, psychiatrists usually recommend to take them ­continuously.

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Valproate can be understood as dipropyl acetate, a branched short chain fatty acid. It has been discovered in 1962 when being used as solvent for other substances scanned for their antiepileptic activity. For its protective function against seizures, but also in the treatment of bipolar disorder, high doses have to be used reaching up to 2.5 grams per day. It displays no high affinity to any receptor or other protein structure. Consequently, diverse actions/mechanisms are reported, such as increase of GABAergic inhibition, modulation of various second messenger systems, influence on transcription of various genes as well as on biosynthesis of steroid sexual hormones or sodium ion channels involved in action signal generation. In this way, valproate must be considered as a rather unspecific substance modulating diverse regulating systems possibly by interfering with membrane–protein interaction. While the undesired immediate side effects are usually not very dangerous, valproate is known to be teratogenic (inducing malformations in the fetus) and should be avoided in pregnancy. Also it may be hepatotoxic, i.e. producing damage to the liver. Therefore, valproate blood serum levels and liver function indicators in the blood must be monitored. Carbamazepine is also an anticonvulsant known and used for decades and has been marketed already in the early 1960s. Chemically, it has got similarity to tricyclic antidepressants for having the same “tricyclic” ring system. In fact, it has been shown to increase extracellular monoamine concentration, at least for serotonin. Further, it presumably lowers neuronal excitability and repetitive “firing” by being a weak blocker of action signal generating sodium channels prolonging the inactivation phase. Adverse effects include drowsiness and nausea. An infrequent side effect, special for carbamazepine and potentially dangerous, is a reduction of blood cell production in the bone marrow. So, blood exams are necessary. As mentioned above, carbamazepine is notorious for interacting with the metabolism of

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many other drugs and therefore combined therapy has to be well balanced and substance levels monitored. The third substance in this group, lamotrigine, has been commercialized only in the 1990s. It has been approved in the United States for treatment of bipolar I and II disorder. Like carbamazepine, it acts on sodium channels involved in action signal generation but has little effect on monoamine transmission. Collateral effects are mainly related to the CNS, such as dizziness, loss of balance or coordination, and double vision. Different from other anticonvulsants, there can be unpleasant and even dangerous effects on the skin, like skin rashes that may, in rare cases, develop to more serious skin-related syndromes according to the manufacturer (Glaxo-Smith-Kline). As the substance is considerably “younger”, prices are higher than for the more established anticonvulsants. High doses paradoxically can lead to convulsions, possibly because GABAergic mechanisms are affected leading to disinhibition.

Antipsychotics This class of medication will be dealt with in more detail in 7 5.6.2. In bipolar disorders, antipsychotics are being used principally to lower intensity of manic episodes. However, over the last 15 years or so, evidence has accumulated that for the s­o-called maintenance phase, when there are no clear symptoms present of either depression or mania, to prevent relapse the use of monotherapy or adjunctive therapy with ­ antipsychotics appears more and more justified.  

5.6.2

Schizophrenia Spectrum Disorders

Classical “madness” Schizophrenia is characterized by the appearance of psychotic episodes. Psychosis is a state, not a disorder or illness. Perhaps the best-known symptoms are hallucina-

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tions and delusions: hallucinating, you may perceive sensory perceptions that have no physical equivalent like hearing voices that no microphone can record. On the other hand, the concept delusion is used when you live non-real social relations, sometimes with non-real entities, such as beings from outer space. For example, you may be convinced that you are persecuted by agents of an intelligence service, whereas no such persecution is taking place. It is fair to say that all of us have sometimes sensations or phantasies without direct relation to the external world. The point is that, in such a case, you will have a conscience of the lack of reality, whereas the psychotic person is convinced that it is all real and just the rest of the world is insensitive or crazy. Further, to diagnose schizophrenia, the DSM-5 requires the presence of at least two of the following symptoms: 55 Hallucinations 55 Delusions 55 Disorganized speech 55 Disorganized or catatonic behavior 55 Negative symptoms At least one of those symptoms have to be of the first three. The third and fourth of these symptoms indicate a disorganized mind where coherent thinking is difficult and so is behavior including speech. The person may be unable to follow a sentence to a logical end and/ or to perform even everyday activities to a successful end. Catatonia is an extreme manifestation of this, rendering the person into a “statue” without movement or uttering a sound. However, catatonia may be seen in other disorders too, such as MDD. “Negative symptoms” are more difficult to describe. The name “negative” is used because, whereas the other symptoms are deviations or experiences that a “normal” person would not feel, these symptoms are a lack of capacity or richness of the “inner world” natural for “normal” people. “Negative symptoms” imply an emotional

“flattening”, a lack of interest, enthusiasm, and creativity or/and an “inner indolence”. In the former versions of the DSM, various types of schizophrenia were differentiated depending on what type(s) of symptoms were more or less manifest. DSM-5 has abandoned this categorization, because too many cases would be “in between” often showing several or even all of the symptoms. While schizophrenia is by far less common than anxieties or depressions, it is not a rare disorder. The lifetime prevalence8 worldwide has been estimated to 0.4% (Saha et al. 2005). The same publication states that there are no significant gender differences in prevalence. Psychotic episodes have to be present for schizophrenia to be diagnosed, but psychosis is by no means limited to schizophrenia. Psychosis can occur in bipolar disorder as well as a consequence of brain lesions or neurodegenerative diseases. Further there are a number of substances that can induce psychotic states, such as alcohols or hallucinogenic drugs, among others. As mentioned before, MDD and anxiety disorders have a strong “overlap”, i.e., many patients suffer symptoms of both types. A similar combination is schizoaffective disorder, where symptoms of schizophrenia and MDD or bipolar disorder are found. Finally, the DSM-5 lists “delusional disorders” under schizophrenia spectrum, problems that are characterized by delusions that go together with sometimes “bizarre” actions related to obsessive/compulsive disorders (see below). 5.6.2.1  Antipsychotics

Putting an end to “mad-houses”? The history of treatment or abusive treatment in mental hospitals that schizophrenics and other people considered “mad” had to suffer is probably the most sinister chap-

8 The proportion of individuals in the population who have ever manifested a disorder, who are alive on a given day.

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ter of psychiatry. Patients were often fettered, incarcerated, and tortured. Now, this is not to say that the majority of psychiatric doctors did not work very hard to alleviate the ordeal of their patients trying to reduce measures of force (see, for example, the lifelong work of Alois Alzheimer; Maurer and Maurer 2002). But only the introduction of antipsychotics put an end to the necessity to physically constrain patients with severe psychotic disorders. However, with some justification, especially when the older (“typical”) antipsychotics are considered, it was criticized as “chemical restraining”.

“ Typical” Antipsychotics Chlorpromazine is the name of the first antipsychotic that really reduced the severity and frequency of psychotic episodes. It was synthesized in France in 1950 and got to be used in psychiatry by the mid-1950s. Chemically, chlorpromazine belongs to a group of antipsychotic substances called phenothiazines that were synthesized modulating that molecule. Surprisingly, while “playing” with these substances, a new class of antidepressants were discovered; the TCAs that share with the phenothiazines the three condensed rings. However, phenothiazine and its derivatives are composed of hexagonal rings where the central ring contains a sulfur atom, whereas in TCAs the central ring has seven “corners” and lacks the element sulfur. The “tail” in both types of substances originates from the nitrogen in the central ring giving the various compounds their specific properties. The other group of “classical antipsychotics” are the butyrophenones meaning a benzene ring with a short “tail” of three carbon atoms whose first has got an oxygen with a double bond attached. To achieve antipsychotic properties, the “tail” is greatly prolonged with two additional rings while at the benzene end a fluor atom is attached (. Fig. 5.7). The potency of haloperidol is almost a hundred times higher than the one of chlorpromazine: the average clinical dose for haloperidol is 5–10  mg/day, whereas chlor 

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..      Fig. 5.7  Chemical formula of haloperidol, a “typical” neuroleptic or antipsychotic

promazine requires 300–600 mg/day. As for the mechanism of action, all typical antipsychotics are inhibitors of postsynaptic dopamine type 2 receptors with a relative high affinity compared to other receptors. This led to the so-called dopamine hypothesis for the generation of schizophrenia: all antipsychotics act on dopamine receptors. Decades ago it was shown that people who suffer from schizophrenia are particularly sensitive to amphetamine, a psychostimulant (see 7 5.7.1.1) known to raise extracellular dopamine levels. More recent research has produced evidence that the ventral hippocampus that is hyperactive in schizophrenics influences activity of dopaminergic cells (Grace 2012). The author suggests that it is not a failure of these cells, but their regulation that is deviant based on reduced GABAergic inhibition in the hippocampus. This sheds light on a general problem in pharmacology and, in particular, neuropharmacology: we are still unable to target specific cell groups in the CNS but have to “flood” the system with the substance producing undesired side effects in structures that are functioning normally. In fact, blockade of dopamine receptors produces characteristic side effects due to a disturbed dopaminergic modulation of basal ganglia (striatum) by the Substantia nigra. This projection is necessary for smooth voluntary movements. Its blockade produces involuntary movements, rigidity, and tremor  

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just as seen in Parkinson patients that suffer from degeneration of the ­Substantia nigra dopaminergic neurons (see 7 4.3.6.2). Further, there is dopaminergic regulation of the hypophysis, the endocrine “mastergland”. Its blockade by antipsychotics, particularly the “typical” ones, leads to a hyperproduction of prolactin, the hormone that stimulates the growth of mammary glands and milk production. There are other side effects too, due to action on other receptor sites and less specific for antipsychotics. Haloperidol and the other butyrophenones in this respect are “cleaner” than chlorpromazine and other phenothiazines, having relatively low affinities to receptors apart from dopamine.  

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The Next “Generation” of Antipsychotics: The “Atypicals” When modern antipsychotics were introduced in the late 1950s and 1960s, there was a great enthusiasm because many inmates of mental institutions improved significantly and a large quantity could be released. However, the ones who remained and received antipsychotics every day for years frequently developed involuntary movements resembling Parkinson’s disease that, in an important fraction of patients, did not cease even when medication was discontinued (“tardive dyskinesia”). Further, even though psychotic agitation was reduced, “negative symptoms”, i.e., the “flattening” of emotions and ideas did not improve much. “Negative” symptoms” are a terrible problem for the affected patient and their quality of life, but less a problem for society, so they were given less attention for a long time. The “new” generation of antipsychotics brought improvement in this respect. They also inhibit D2 receptors, but their beneficial effects do not only, or almost only, depend on D2 receptor blockade, but they act on various dopamine receptors as well as on various others. But, “atypical” antipsychotics have other shortcomings that we will consider below. Nowadays, the cate-

gory “atypical” is put in doubt since there are important differences among them and some have properties that are quite similar to the “typicals”. The first “atypical”, clozapine, was synthetized as early as 1958 and tried for the first time in the 1960s, but after cases of agranulocytosis, i.e., a lethal cease of production of immunoactive cells of the blood, clozapine was withdrawn from the market. Only more than 10 years later it was shown that clozapine is effective in a considerable number of medication-resistant schizophrenics and its use was resumed. In the case of clozapine, the naming “atypical” seems justified, because it almost never produces “extrapyramidal9” or Parkinson-­like symptoms. Prolactin levels are also mostly normal. However, clozapine may produce other severe complications besides the agranulocytosis mentioned above. Myocarditis, i.e. inflammation of the heart muscle and gastrointestinal hypomotility are also very dangerous side effects. Further, there is the “neuroleptic malignant syndrome” (NMS) that can be caused by all antipsychotics, but is seen most when clozapine is administered. The life-threatening complications are infrequent, but warrant that a treatment with clozapine should be very closely monitored, doses should be slowly raised and stationary treatment rather than ambulatory is recommended. At the same time, clozapine is clearly the medication with best success when other antipsychotics have failed. The difference in action and side effects compared to the typical antipsychotics are explicable by the relative high affinity of clozapine to diverse serotonin receptors that also may be the cause for its relative lack of extrapy-

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The “pyramid” is a bundle of axons in the medulla conveying motor signals from the motor cortex. Other networks important for voluntary movements thus are called “extrapyramidal”.

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ramidal side effects (disinhibition of striatal neurons compensating for the block of dopamine receptors). The other atypical antipsychotics  – the most commonly used are quetiapine, ­risperidone, olanzapine, and ziprasidone  – are less likely to produce the dangerous side effects associated to clozapine. Further, ­anticholinergic side effects (see 7 5.5) are milder than with clozapine or absent. These newer antipsychotics have quite different profiles amongst each other considering efficacy and side effects. Some are associated (like clozapine) with weight gain and diabetes “2”10 among other metabolic problems and/or display side effects similar to the “typical” antipsychotics albeit with a lesser severity. In general, they are today the antipsychotics used as first choice outside the clinic and are used in other disorders, such as bipolar disorder, sometimes in combination with other medication.  

5.6.3

Obsessive-Compulsive and Related Disorders

The urge to think permanently about something in a compulsory way and/or feeling to have to do things repetitively without really “wanting it” is an experience we probably have had sometimes in our life, particularly in childhood and adolescence. Usually those urges go away and rational decision-making gets the upper hand. However, many people cannot help to ruminate for hours about issues that appear totally unimportant for most of us and/or act a long time and repetitively in a weird manner. In an obsessive/compulsive disorder, such actions and preoccupations occur daily and are in the way of normal routines, work, and relations to others.

10 Diabetes can be due to low levels of insulin (type 1) or failing insulin receptors (type 2). The second one being much more frequent.

5.6.3.1  Categorization of Disorders

that Include Failure of Impulse Control and Obsession

Changing from DSM IV to DSM V obsessive-­ compulsive disorder (TOC) has been changed from the category of anxieties to a newly created category: “Obsessive-­ Compulsive and Related Disorders” (OCRD). The term “spectrum” after some discussion eventually has not been accepted in the DSM V system (Phillips et al. 2010). It seems justified to unify the disorders that are marked by obsessive thoughts or ideas and compulsory action that, if tried to suppress, cause distress and anxiety. In the present text, as displayed in . Table  5.1, in this category, eating disorders (anorexia, bulimia, and binge-eating disorder) are also included displaying obsessions and delusive ideas similar to other OCRDs. This seems justified since eating disorders fulfill the criteria of obsession and compulsion. Further, in the DSM V body dysmorphic disorder (BDD; obsession with real or ideated bodily flaws) is included in the OCRDs being similar to and showing a big overlap with eating disorders, i.e. many patients at the same time suffer from symptoms of both kinds. There also exists a host of similar disorders labeled impulse control disorders, of which some have been integrated into the OCRDs, such as trichotillomania (the urge to pull out one’s own hair) or skin picking disorder. Now, addicts also have an impulse to do something that is hard to suppress and are mentally occupied with their search for drugs or behavior satisfying their impulses. However, since DSM and other categorizing systems are for the clinician, only the addictions to behaviors, such as gambling, have been put in the group of impulse control disorders, but drug addiction was separated, even though the neural substrates for both types of addictions are very similar (see 7 5.8.2).  



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5.6.3.2  Treatment of OCRD

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Since OCRDs, a bit like object- or situation-­ related anxiety disorders, are linked to habitual, repetitive situations and actions, cognitive behavioral therapy, sometimes together with other psychotherapies, is applied to help the patient regain the control over dysfunctional behaviors and mental obsessions. Pharmacological treatment of “classic” OCD uses mostly antidepressants. SSRIs are frequently helpful, but also TCAs, such as clomipramine. Successful remission requires typically higher doses as compared to MDD medication. Patients suffering from other disorders of the OCRD group usually do not respond so well to antidepressant medication. Sometimes antipsychotics are useful given alone or together with antidepressants. As for prevalence, estimations are difficult because of the problems described in categorization. However, for the OCD alone a lifetime prevalence of 2.3% has been published (only USA; Ruscio et  al. 2010). In total, OCRD prevalence is considerably higher. Given the overall frequency of OCRDs, a clinical psychologist or psychiatrist will have to deal with these disorders helping to find out the best therapy, or, frequently, the best combination of therapies. In severe cases, pharmacological treatment will be often among them. 5.7

Neurodevelopmental Disorders

Developmental disorders are defined as being manifest and identifiable in childhood. Now, almost all disorders can appear before adolescence. But only problems that in the majority of patients can be diagnosed already in childhood are considered as developmental disorders.

5.7.1

Attention Deficit/ Hyperactivity Disorder

Attention deficit/hyperactivity disorder (ADHD) is definitely the most frequent, the best known, and most discussed of the developmental disorders. It is the developmental disorders with the highest prevalence by far. In the United States, the National Institute of Mental Health (NIMH 2017a) gives a life time prevalence for the year 2011 of 11%. The same source indicates an increase between 2003 and 2011 from 7.8% to 11%, i.e., 5% of total incidence every year. Other studies report even higher percentages (e.g., 15.5%; Rowland et al. 2015). Now, these figures are based on DSM IV criteria. Since DSM-5 has lowered the requirements (onset of problems at 12  years instead of 7 and impairment no longer necessary) the measured prevalence will raise further. The rate of boys vs. girls from 2003 through 2011 is slightly decreasing from 2.5 to 2.25 (NIMH 2017a). Separate figures for adolescents (13–18) and children (6–12) are difficult to come by, but the vast majority of children maintain ADHD problems in adolescence. ADHD prevalence in adulthood is even less established than for childhood/adolescence. Not so far ago the disorder was not even recognized for adults. Thus, in Sweden in only 4 years, between 2007 and 2011, the apparent ADHD prevalence in adults has more than doubled (Polyzoi et  al. 2018). For “higher-income countries”, a percentage of 4.2% ADHD in adults has been given (Fayyad et  al. 2007). Taken together, the prevalence of ADHD is difficult to assess. It is on the rise, and differences between gender and between age groups are diminishing. ADHD has been described and illustrated as early as 1840 by the German psychiatrist Heinrich Hoffmann (. Fig. 5.8). ADHD diagnostic criteria are lack of attention and/or impulsivity-hyperactivity (7 Box 5.2).  



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..      Fig. 5.8  Hyperactive child as depicted in the children’s book Struwwelpeter (“shaggy Peter”) by psychiatrist Heinrich Hoffmann

Box 5.2  Diagnostic criteria for ADHD Attention Often fails to give close attention to details or makes careless mistakes in schoolwork, work, or other activities. Often has difficulty sustaining attention in tasks or play activities. Often does not seem to listen when spoken to directly. Often does not follow through on instructions and fails to finish school work, chores, or duties in the workplace (not due to oppositional behavior or failure to understand instructions). Often has difficulty organizing tasks and activities. Often avoids, dislikes, or is reluctant to engage in tasks that require sustained mental effort (such as schoolwork or homework). Often loses things necessary for tasks or activities (e.g., toys, school assignments, pencils, books, or tools). Is often easily distracted by extraneous stimuli.

Is often forgetful in daily activities. Hyperactivity/Impulsivity Often fidgets with hands or feet or squirms in seat. Often leaves seat in classroom or in other situations in which remaining seated is expected. Often runs about or climbs excessively in situations in which it is inappropriate (in adolescents or adults, may be limited to subjective feelings of restlessness). Often has difficulty playing or engaging in leisure activities quietly. Is often “on the go” or often acts as if “driven by a motor”. Often talks excessively. Often blurts out answers before questions have been completed. Often has difficulty awaiting turn. Often interrupts or intrudes on others (e.g., butts into conversations or games).

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At least 6 symptoms for each category (Attention, Hyperactivity-Impulsivity) must be present for at least 6 months and at least some of them must appear before age 12. Further, they must be present in more than one “setting”, such as in school, at home, or at the workplace. And, as with other diagnostics, they must not be better explained by other disorders (DSM V in this context took out Autism Spectrum Disorder; see below). All criteria are based on observation of behavior. In contrast, diagnostics of other disorders, such as MDD, is mainly diagnosed by subjective experience and biological criteria (e.g., depressed mood; weight gain or loss). The reason is that ADHD, for a long time, has been considered a problem of children only and biological criteria or markers (see introduction to this chapter) have not been firmly established. In developmental disorders, and particularly in ADHD, age is a decisive factor. Most children at age about 4 years are more or less “hyperactive” and “impulsive” and have short time-spans of attention. If not, there is reason to worry. Gaining selfcontrol is an important part of development with its biological individual-psychological and social-­cultural aspects. For example, if a child “often leaves seat in the classroom or in other situations in which remaining seated is expected”, it may be “detected” as suffering from ADHD. But, at what age in which situation and for how long can we expect a child to remain seated? 5.7.1.1  Psychostimulants

The word “psychostimulants” is somewhat misleading as if their effects would consist in a sort of mental stimulation only. Instead, these substances, also called sympathomimetics, i.e., activators of the sympathetic part of the ANS, increase corporal activity and energy consumption. In fact, amphetamine, the first psychostimulant synthetized, has been marketed for helping to lose weight. In 1937, Bradley (1937) reported that ­ children who received Benzedrine

(a trademark for a racemic11 mixture of amphetamine) “improved” their behavior. He already noted that the treatment did not bring a permanent change, but the beneficial effects ceded as soon as the treatment was discontinued. Further, there was an apparently inexplicable divergence of effects: some children became more subdued conforming to what they were told to do. Others were stimulated as would be expected from a “psychostimulant”. Bradley was also strictly against a one-sided pharmacologic treatment. “His observation that pharmacological solutions should always be provided in a supportive environment and within an established doctor-­patient relationship is one that appears particularly appealing in our modern context.” (Strohl 2011). In a way, Bradley anticipated the modern debate about the use and role of pharmacological treatment and its embedment into an integral approach on therapy of ADHD. Psychostimulants act on transporters of monoamine transmitters just like most antidepressants. So, why do substances with such a similar mechanism of action do have so different effects and uses? One answer is that antidepressants almost always act on serotonergic mechanisms (among others) and not much on dopaminergic ones, whereas psychostimulants affect mainly dopamine and noradrenaline uptake. There are two psychostimulants that seem to be most efficient in “normalizing” ADHD symptoms: amphetamine and methylphenidate. Now, amphetamine, besides just blocking reuptake, inverts the reuptake and also affects the H+-dependent pump whose task is to concentrate transmitter in vesicles (7 3.6; #4) literally “draining” catecholaminergic, i.e. noradrenaline and dopamine containing) neurons of their transmitters. This makes overdoses of amphetamine dangerous. Amphetamine also has an addictive poten 

11 “Racemic” indicates a mixture of the two stereoisomers levo- and dextroamphetamine.

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..      Fig. 5.9  Chemical structure of methylphenidate (A), amphetamine (B), and dopamine (C)

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practically the only psychostimulants used in ADHD therapy. The confusing multitude of marketed medications is due to slow liberation formulations, mixture or pure stereoisomers (dextroamphetamine, etc.), minimal chemical change (lisdextro-amphetamine, methamphetamine) or just added savors or modified consistency to make “pills” more attractive for children. Numerous experiments in non-human and human animals have shown that MPH as well as amphetamine can improve “cognitive” performance, such as working memory, attention and inhibitory control, among others, at low or medium clinical doses (up to approx. 1 mg/Kg) acting preferentially in the prefrontal cortex (Spencer et  al. 2015). However, at higher doses, these and other psychostimulants impede cognitive performance. MPH, like other psychostimulants, is metaplastic increasing long-term-potentiation (see 7 4.3.2) at glutamatergic synapses via adrenergic and dopaminergic receptors, an effect that persists for more than 2 weeks after ending repetitive administration of MPH (1 mg/kg; Burgos et al. 2015).  

tial (see 7 5.8.2), even though at therapeutic doses usually no addiction is induced. This is an important reason why the substance that is being used by far most in ADHD treatment is methylphenidate (MPH; . Fig. 5.9). It is easy to see that MPH has a part similar to dopamine and another quite different one, whereas amphetamine’s size and structure is much closer to the one of dopamine. In contrast to amphetamine, the lack of OH groups and an additional methyl (CH3) group makes MPH much less water soluble as compared to dopamine and noradrenaline/ adrenaline. MPH does not enter into the presynaptic parts of neurons being no substrate for transport, probably due to its larger size. Thus, different from amphetamine, it does not interfere much with vesicular transport. The review of Faraone et al. (2015) compares amphetamine and MPH and tries to give orientation and advice for the clinician. By and large, amphetamine-based medication is estimated to be “somewhat more efficient”, whereas side effects and overdose risk of methylphenidate, on the whole, appear less problematic. MPH and amphetamine are  



5.7.1.2  Non-psychostimulant

Medication for ADHD

Atomoxetine is a non-stimulant inhibitor of noradrenaline reuptake. Apparently, it does not work on transporters in the ANS.  Instead, it has been shown to raise dopamine levels in the prefrontal cortex, as supposedly in this brain area dopamine reuptake is mainly realized through noradrenaline transporters (Sauer et  al. 2005). Atomoxetine has low affinities to almost all receptors in the brain with the remarkable exception of the NMDA receptor (see 7 4.3.1) whose genetic expression also seems to be affected (Udvardi et  al. 2013). The addictive potential is even lower than the one for MPH and so is overdose toxicity. However, its efficacy for symptom relief is being judged somewhat lower as compared to MPH (Ghuman and Hutchison 2014). Further, for being a substance that has only  

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been marketed relatively recently (approval in the United States in 2002) and its patent has expired only in 2017, atomoxetine is still quite expensive and has not everywhere found its way to public health services. Thus, first selection in ADHD treatment still is psychostimulants. Agonists of adrenergic (α2) receptors are used as second selection in ADHD treatment, particularly two: guanfacine and clonidine. Both have originally been introduced for lowering blood pressure decreasing sympathetic activity, supposedly because of acting on presynaptic noradrenergic autoreceptors (7 3.6, #7). Only in 2009, guanfacine has been approved by the FDA for the treatment of ADHD. When psychostimulants are not well tolerated, these substances can offer a viable alternative. Either substance should be used in “extended release” or “modified release” formula. As they are “antistimulants”, lowering sympathetic activity, particularly blood pressure, care must be taken to avoid cardiovascular complications and abrupt termination can produce heart failure and anxiety. Practically all disorders can appear combined with others; with ADHD this is quite notorious as in far more than half of the cases it appears with one or more “co-­morbidities” (Reale et al. 2017). Thus, some speak of defiant-oppositional ADHD or anxious or depressive ADHD. Pharmacological treatment has to be adjusted accordingly.  

5.7.2

 utistic Spectrum and Other A Neurodevelopmental Disorders

Beyond ADHD, the DSM-5 lists six other types of developmental disorders: 55 Intellectual disabilities 55 Communication disorders 55 Autism spectrum disorder (ASD) 55 Specific learning disorder

55 Motor disorders 55 Tic disorders Impulse control and conduct disorders are not categorized as neurodevelopmental disorders in DSM-5 even though they are manifest very frequently in childhood, often together with one or more of the above mentioned ones, particularly ADHD. Different from ADHD, none of these disorders has a very specific pharmacologic treatment. The various forms of ASD have in common that the patient does not communicate well with his social surrounding, seems to be rather “locked-in” and tends to act and react in a bizarre and often repetitive manner. ASD is sometimes treated with substances that help to approach and sympathize with other people. For example, the psychostimulant “ecstasy” (3,4-­Methylenedioxyme thamphetamine; MDMA) lowers inhibition to engage in social contacst, hence its popularity as a party drug. Another promising substance is the peptide hormone oxytocin that fosters “caring”, confidence in others, and bonding (see 7 4.4.1.4). However, these treatments are not adequate for patients with language or other serious c­ ognitive disabilities; they are still in an experimental phase and studies have been hampered by the social ban on “drugs”. While autism spectrum is not as frequent as ADHD, it is estimated that more than 1% of children suffer from some type of autism, being much more frequent in males than in females (Baio et  al. 2018). ASD typically does not “go away”, but mostly is a life-long disorder, even though many affected learn how to cope with it. Tic disorders are characterized by “chronic, unexpected, quick impromptu non-­ fluid behaviors and/or vocalizations” (Lyngzeidetson 2014). In most cases, they are not treated pharmacologically; only in very severe cases antipsychotics or other tranquilizers are tried to reduce involuntary movements and/or vocalizations. Different from ASD, tics often go away by themselves.  

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Their prevalence is comparable to that of ASD. As for most other developmental disorders there is little that neuropharmacology can contribute for the time being (2020).

5.8

Acquired Disorders

Biographical episodes are essential for the development of these disorders. In the case of posttraumatic stress disorder (PTSD), there is a high probability that, without a traumatizing event or sequence of events, the disorder would not have developed. Addictions are also acquired, even though the process may have started in the intrauterine phase of life when a pregnant woman is ingesting substances with addictive potential. While biographical events, by definition, are not directly genetically determined, vulnerability to either disorder type has a strong genetic component. 5.8.1

Posttraumatic Stress Disorder

In line with such a genetic predisposition, according to Skelton and co-workers (Skelton et al. 2012), more than 30% of the variance associated with PTSD is related to a heritable component. Further, it seems that earlier traumatic events increase the probability for the disorder to develop. In the DSM 4, PTSD appears under the rubric of anxiety disorders. However, PTSD symptoms do not completely coincide with those known for anxieties. Therapies also are different. Therefore, the 5th DSM version views PTSD as a separate disorder. Symptoms are: Re-experiencing, avoidance, negative alterations in cognition/mood, and alterations in arousal and reactivity are important symptoms that indicate PTSD. Psychotherapy consists mainly in guiding the patient to confront the traumatic memories a bit as in phobias, but techniques

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have to take into account individual, social, and cultural particularities. While there is no specific pharmacological treatment, pharmacotherapy is often used to help the patient to “stand” the invasion and/or confrontation of those re-experiencing memories. Various antidepressants (mostly SSRIs; see above) and anxiolytics are used, but sometimes antipsychotics are necessary in order to ban the “demons” of the trauma from invading the mind of the patient unexpectedly. According to the National Institute of Mental Health (NIMH) between 2001 and 2003 3.6% of adults in the United States suffered from PTSD (1.8% males and 5.2% females). Lifetime prevalence for adolescents has been estimated as 5.0%, being female victims also much more frequent (8.0%) than males (2.3%; NIMH 2017b). As for world prevalence, figures depend heavily on government’s willingness to cooperate, recognize problems, and do something about it (reported prevalence in China 0.3% vs. New Zealand 6.1%; Kessler and Ustun 2008). However, divergent diagnostic criteria are also an important source of insecurity. The strong bias in vulnerability for PTSD toward women, however, can be taken for sure with the exception of combatrelated PTSD where, for obvious reasons, more men are affected. The DSM-5 lists some other disorders under the category “Trauma- and stress-­ related disorders”. These are acute stress disorder and adjustment disorders that present similar symptoms to PTSD, but are not lasting more than 6 months after the stressing factors have been removed. Therapies are not different from PTSD treatment. Further there are two disorders only observed in childhood that are opposite to each other: One is reactive attachment disorder meaning that the child does not react positively to consolation and/or caring behaviors from adults. On the other hand, a disorder is mentioned that consists in reduced or absent inhibition to contact strange adults.

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5.8.2

Addictions

Addiction, as the World Health Organization has determined, means a loss of control about the craving behavior that compels an animal (including humans) to seek and take a substance or realize a certain pattern of behavior. Acquisition of addiction is considered a learning process (see also 7 Chap. 7). As with virtually all relevant medical or psychiatric problems there is a genetic disposition; some people are more prone to acquire addiction than others. While not easy to quantify, the contribution of genetic factors to the risk of getting addicted is roughly 50%, clearly below the percentage for most neurodegenerative diseases, such as Alzheimer’s or Parkinson’s disease, but probably similar to the one associated to schizophrenia or MDD. Drug addiction often comes together with physical dependence, i.e., withdrawal causes major physical problems involving activation of the sympathetic ANS resulting in tachycardia, sweating, digestion problems, and the like. These symptoms are extremely unpleasant, but usually not very harmful. However, the withdrawal from sedative drugs such as ethyl alcohol, barbiturates or, in rare cases, benzodiazepines can be life-­threatening, leading to convulsions or delirium. In either case, anxiety, craving, and severe restlessness among other psychic problems are common. Physical as well as psychic withdrawal symptoms constitute essentially the addictive potency of a drug. That potency varies greatly among the different groups of recreational drugs. There is no doubt that the sedative drugs as mentioned above, all opioid drugs, nicotine as well as some psychostimulants, particularly cocaine and amphetamine and some amphetamine derivatives, are highly addictive. Other psychostimulants, however, such as ecstasy or methylphenidate (“Ritalin”) are much less addictive. The same is true for cannabis, and even more so for several hallucinogens such as LSD or psilocybin. Interestingly, the two “legal” drugs, alcohol  

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and tobacco, take places 4 and 5 in a scale of addiction that takes into account psychological and physical dependence of the 20 most common recreational drugs (. Table  5.2; Nutt et al. 2007). Dependence is certainly the mechanism that maintains addiction. However, in order to start addictive habits in the first place, a certain reward or pleasure or relief from some ailment is necessary. The former implies activation of the dopaminergic reward circuit that has been briefly described in 7 4.3.6.2. Depending on the drug and the time of abuse, pleasure may become completely absent after a while and the only drive that keeps moving the poor addict is to avoid the agony of withdrawal. Development of tolerance is often found aggravating the effects of addiction: dosing of several addictive drugs, particularly opioids as well as cocaine and amphetamine and its derivatives, have to be increased over time to achieve the same rewarding/withdrawal avoiding effect. Thus, ever increasing quantities of neuroactive substances produce more toxic side effects and make withdrawal more difficult. We have already given a short introduction to addictive processes (see 7 4.4.1). In the present chapter, we have put together addictions with PTSD as “acquired disorders”. Both are acquired, but the “learning process” in addictions is usually different from the one found in PTSD.  Whereas PTSD is often induced by a single event, “one trial addiction” is infrequent. The addiction typically develops by repetitive behaviors mostly associated to a certain social setting. The alcoholic has got his friends and his rituals and the gambler and the opioid junky as well. To count as addiction, the behavior has to be linked, at least in the beginning, to a reward, a feeling of pleasure or satisfaction. Addiction develops when that behavior becomes compulsive, turns into “craving”, and is repeated even though the person affected is aware of negative consequences for themself and/or  





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people close to them. In the case of addiction to a substance, physiological dependence is almost always necessary to become “hooked”. Being addicted to a certain behavior renders high probability to become addicted to others. Hence multiple addictions or changing addictions are not infrequent. Addictions to substance use have been also associated to co-morbidities with other mental disorders, such as MDD or ADHD pointing to common genetic risk factors (Volkow and Muenke 2012). There has been and there is ongoing research as to the mechanisms of addiction. For quite a time it has been known that, for addiction acquisition to develop there will be changes at least in three brain areas: the midbrain ventrotegmental area (VTA), the nucleus accumbens, part of basal ganglia, and the prefrontal cortex. As was discussed in 7 4.3.6.2, the majority of VTA neurons are dopaminergic and project to the aforementioned brain parts modulating what has been called “seeking behavior” or “motivation”. Dopamine modulation implies plastic changes eventually leading to a loss of control over addictive behaviors. It has been shown that these plastic changes can become permanent through the recruitment of tertiary messengers (Carlezon et al. 1998). Berridge et  al. (2009) demonstrated that this “reward system” is divided in a “pleasure” and a “desire” part. Thus, “wanting” and “liking” is not identical and sometimes get separated. In fact, addicted persons may crave for ingesting a substance or other behaviors without feeling pleasure anymore when they reach their goal. Further, addiction can lead to the activation of stress responses that establish an “anti-­ reward” system and precipitates in the irritability and anxiety related to withdrawal. Koob (2017) has called that “the dark side of addiction”. Diagnostics appear comparatively simple, because of the behavior criterion making differentiation between diverse addictions easy. However, there is usually a big prob 

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lem with denial. As addictions are seen as personal, often moral failure, many patients tend to not admit their being affected by a mental disorder and therefore negate their problem. That denial refers to themselves, their social groups and consequently also to the patient’s doctor or therapist. As addictions are diagnosed principally using questionnaires or interviews, an addiction may go successfully hidden. Typically, mental disorders cannot be cured, but people can, with the help of pharmaco- and other therapies, gain or regain a fulfilling life. Addictions seem to be different, because it is often possible to finish the habit. However, the brain seems to have permanently changed when the addiction was acquired. For example, an alcoholic who has stopped drinking may recover from the damage to their health and social relations caused by their habit, but the reaction to alcohol stays different from that of a “normal” person. This is why ex-alcoholics must not expose themselves even to a minor quantity of ethanol, lest they risk relapse. In that respect, the disorder, just as in the case of other mental problems, can be successfully managed, but it seldom will disappear. Pharmacotherapy is used to mitigate the physiological and psychological problems associated to stopping the habit and further to help maintain the patient “clean” avoiding relapse. Prevalence is known relatively well only for the more frequent substance addictions and for pathologic gambling. 5.8.2.1  Alcohol Use Disorder

(Salud? Santé? Нa здорове?) The social acceptance and even celebration of ethanol containing drinks is deeply embedded in “Western” as well as in many Asian, African, and Latin-American societies. Ethanol is toxic and causal or co-causal for many millions of premature deaths worldwide. Thus, to say “health” to each other when drinking is a euphemism to say the least.

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DSM-5 joined the DSM-4 concepts of Alcohol Abuse and Alcohol Dependence to one category: Alcohol Use Disorder (AUD). It is diagnosed by answers to a questionnaire asking for symptoms similar to diagnosing other mental disorders, such as ADHD or MDD. AUD is further subdivided into mild, moderate, and severe depending on the number of symptoms present. The National Survey on Drug Use and Health (NSDUH 2017) estimated that about 6.1% of all adults in the United States were heavy alcohol users corresponding to severe alcohol use. Gender ratio was almost exactly 2:1 “in favor” of men. As alcoholism among all substance addictions generates the highest rate of violence and accidents in absolute and relative figures, the economic and other social damage is enormous (almost 250 billion US$ in 2010; Sacks et al. 2010). Drinking favors a number of medical pathologies, among them being cancers and cardiovascular diseases. Further, alcohol drinking is highly toxic for the nervous system. It is often related to other mental disorders; the alcoholic tries to “cure” himself from anxieties and/or depression. On the other hand, alcoholism can cause mental disorders, associated mainly to depression, anxieties, and psychotic states. Thus, a vicious circle may be established. Only “about 6.7 percent of adults who had AUD in the past year received treatment” (NSDUH 2015). As mentioned above, affected people try to hide their problems; denial plays probably a greater role as compared to other mental disorders. However, insurance coverage is also a problem in addiction treatment. AUD, just as other mental disorders, requires psychological counseling and therapy. Pharmacotherapy is used to mitigate the physiological and psychological problems associated to stopping the habit and further to help maintain the patient “clean” avoiding relapse. As described in 7 3.5.2, alcohols are unspecific, i.e., without particular high affinity to any receptor. However, there are preferences. Ethanol augments GABAergic

inhibition and reduces NMDA receptormediated activity. Further, monoamine mechanisms directly or indirectly are also involved (Matthews et al. 2014). Chronic alcohol use is related to downregulation of these receptors/ mechanisms resulting in an overshoot when alcohol intake is suddenly stopped. Anxiety, convulsions, hallucinations, together with hyperactivity of the sympathetic ANS, are often consequences of withdrawal. Thus, withdrawal from alcoholism can be extremely painful both at the “corporal” and at the psychological level. It is this agony of withdrawal that keeps the heavy drinker hooked. In severe cases, p ­ harmacotherapy is necessary to protect the patient from serious damage or even death. First choice in treating the alcohol withdrawal syndrome is benzodiazepines for their tranquilizing, anticonvulsant, and anxiolytic effects. In extreme cases, systemic anesthetics or barbiturates are administered. Further, classic anticonvulsants, such as carbamazepine or valproate, and against the sympathetic symptoms, clonidine or beta blockers, are used. This phase of detoxification in moderate to severe cases lasts for about 1 week. While to stop drinking is painful and can be costly, it is often easier than to stay sober practically the rest of life when most of the time no helping doctor or therapist is present and the patient is confronted with her/ his everyday problems. While psychotherapy and specially support groups12 are very important, medication can also be helpful to stay sober. There are three mechanisms how a medication can help in maintenance of abstinence: 55 Produce negative corporal sensation when alcohol is ingested, such as nausea and dysphoria 55 Blocking pleasure associated with alcohol 55 Reduce craving



12 “Alcoholics Anonymous” has been pioneering in lay group support work for addicts and ex-addicts.

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All three mechanisms are being used aiming to maintain the patient “clean”. For example, disulfiram produces bad feelings immediately after and even while ingesting alcohol. The second mechanism implies opioid receptor blockers, such as naltrexone. Finally, acamprosate that interacts with NMDA receptors (Zeise et  al. 1993) helps reduce the yearning and, when successful, represents the best pharmacological strategy to stay free from alcohol. 5.8.2.2  Tobacco Smoking

The other substance addiction that generates huge damage is tobacco smoking. While in the case of alcohol by far the most economic damage is caused through work place productivity reduction, tobacco smoking is the one most damaging habit for health, worldwide. In “Western” countries (including Latin America, excluding Eastern Europe), tobacco smoking is declining mainly due to cultural changes; it is not “cool” anymore to smoke cigarettes; but also through politics that forbid smoking in public places, reduce commercials, and raise taxes on tobacco products. Thus, in Germany, between 2001 and 2015 smoking among 12 to 17-year-old teens fell dramatically from 27.5% to 7.8% (Kuntz et  al. 2018). However, cigarette sales have increased in Asia and Africa. In China, for example, about 300 million persons smoke; absolute numbers are rising, but percentage (25%) is more or less constant (201213). The heavy death toll of tobacco smoking is due to the combination of 55 The high addictive potential of nicotine 55 The damaging effect of combustion products The first stage of addiction, being drawn into the habit, can be explained since nicotine is directly activating dopaminergic neurons of the ventral tegmental area (VTA; see 7 4.3.6.2), the nucleus believed to be at the  

13 7 https://ourworldindata.org/smoking  

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base of the reward system. The other main factor of addiction, withdrawal symptoms, mainly due to problems related to the ANS, is quite strong as well, although never lifethreatening as in severe cases of alcohol dependence. Whereas nicotine by raising blood pressure and producing vasoconstriction bears heightened risks for cardiovascular complications, the damage inflicted by combustion products in the smoke is far greater. Carbon monoxide directly lowers oxygen supply. Numerous compounds that originate during (particularly incomplete) combustion are cancerogenic. Smoke ingredients favor the formation of plaques on coronary and other arteries; blood clogging is favored among other cardiovascular damage. Smoke ingredients thus greatly increase the risk for heart as well as for brain stroke, damage the respiratory system, and cause lung and other cancers.

Pharmacological Help There is no protective substance that helps against the more than 200 toxins in tobacco smoke. The only practicable way of protection is to quit. While, different from AUD, “cold turkey” for some people works, more often than not, regular smokers are not successful to stop for good except with the help of pharmacotherapy and/or psychological support. In order to help “weaning” and to avoid aversive feelings caused by withdrawal, there are several possibilities of smoke-free nicotine administration. Replacement therapy is realized by nicotine patches, gums, lozenges, or inhalers. However, there are also other pharmacological strategies. The “atypical” antidepressant bupropion reduces craving and also helps in the numerous cases where smoking is a way to fight depressive mood (Picciotto et  al. 2002). Further, a nicotine receptor agonist acting mostly on a special subtype (α4β2), varenicline, reduces craving supposedly by imitating certain actions of nicotine on reward mechanisms. Side effects are practically always slight.

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Both, tobacco and alcohol are “legal” in most countries even though their negative impact on health and, in the case of alcohol, also on mental health and social interaction exceeds by far the one caused by any other addictive substance. 5.8.2.3  Other Substance Addictions

Opioids

According to . Table 5.2, a list of prototypical neuroactive substances, the most addictive substance, measured as physiological dependence, is heroin followed by barbiturates and benzodiazepines. Heroin, like other opioid receptor agonists, induces well-­ being and euphoria together with analgesic and sleepinducing effects. In many countries, but particularly in the United States, opioids have been and still are prescribed as “pain killers” to patients with strong and/or chronic pain. As much as a quarter of these patients become addicted. Addiction to opioids is a severe disorder, since overdose can be lethal, tolerance requires ever increasing dosage and it is almost impossible to liberate oneself from it without professional help. In 2017, more than two-thirds of drug overdose deaths in the United States were due to opioids representing almost 48,000 cases (NIDA 2018). Unfortunately, doctors who have prescribed opioids are not obliged to assist weaning from opioids if and when the patient becomes addicted. Thus, when patients are not able anymore to receive the drugs by prescription they turn to heroin or even to synthetic opioids such as fentanyl, being much more potent than heroin. In fact, in about half of opiate overdose deaths, fentanyl has been discovered (NIDA 2018). The increase and the rise of increase are troubling and also the change from prescribed opioids to illicitly manufactured ones (1990 through 2017: sixfold increase; 2016–2017: illicitly manufactured fentanyl raises by 47%; CDC 2018). Moreover, there are continuously appearing new synthetic opioids, some of them even more potent than fentanyl.  

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As mentioned in 7 4.4.1.1, opioid addiction is related to high tolerance so that there is a strong tendency to take higher and higher doses. As in the case of nicotine addiction, treatment consists primarily in administering replacement drugs. However, to change from one opioid to another does not reduce health hazard as much as does the change from smoking to smoke-free nicotine administration. In some countries, patients with an opioid addiction receive a dose of opioid for free that is administered under supervision. This avoids infection by contaminated needles and reduces potential crime committed by the addict in order to pay for his/her next dose. This obviously does not free from addiction. However, importantly, in centers or doctor’s offices where opioid addicts are given their doses of replacement opioids, diverse therapeutic measures can be offered that may help to become clean. As withdrawal from opioid addiction, perhaps together with ethyl alcohol addiction, compared to other substance addictions causes the severest distress, reaching sometimes suicidal ideations, an immediate stop is almost impossible. Instead, a “detoxification” period that may last for several months or more is often necessary, at least in an outpatient setting. Two opioids are used most in replacement therapy: methadone and buprenorphine. Both have less euphoric/hedonic effects as compared to heroine. Thus, the patient is first weaned of the “psychological addiction” rather than the physiological one. Further, there seems to be less of tolerance effects as compared to most illicit opioids. Methadone implies more hazards as a respiratory depressant, and mortality by overdose is more frequent than in the “newer” substitute buprenorphine. This is presumably because buprenorphine, different from methadone, is a partial agonist (7 3.5.7) at the opioid type μ receptor, the one that mediates respiratory suppression, the principal hazard of overdose. In the course of a withdrawal management,  



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medication is aimed to alleviate withdrawal symptoms, such as benzodiazepines for insomnia and anxiety and substances like clonidine that relieve autonomic NS symptoms such as diarrhea, cramps, nausea, abnormal body temperature, etc.

Barbiturates and Benzodiazepines Barbiturates today are almost not prescribed anymore, because they are dangerous and have a high addictive potential. Although, there still are addicts to barbiturates. Withdrawal symptoms can be severe and withdrawal management should be realized in a clinic or specialized institution. Benzodiazepines arguably are the group of neuroactive medication used the most worldwide. As prescription growth rates are rising sharply, their use is too, at least in the United States (Agarwal and Landon 2019). There are several worrying aspects here: first, benzodiazepine-related mortality has risen sevenfold between 1999 and 2016 from 0.6 per 100,000 to 4.4. Second, even though benzodiazepines are not recommended for long-term treatment, they are prescribed frequently for many months and years and, third, sometimes combined with opioid pain killers: “The co-prescribing rate of benzodiazepines with opioids quadrupled from 0.5% (95%CI, 0.3%–0.7%) in 2003 to 2.0% (95% CI, 1.4%–2.7%) in 2015” (Agarwal and Landon 2019). Of course, medical prescription is not the only source for the benzodiazepine flood. Characteristically, these drugs are sold in public, for example, in popular markets or in the Internet alongside with herbal preparations and other popular medical formulations. As this kind of sale is tolerated by authorities, it has been called “Grey Market”. Health risks seem negligible and crime associated is marginal. Thus, the danger of benzodiazepine addiction is not very much on the screen neither in the media nor in the medical community. Withdrawal management consists simply in tapering the dose calculated in diazepam (valium) equivalents during about 1 week.

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Normally, this can be done in an outpatient setting, except when the patient had been taking more than 50  mg a day or there is multiple dependence or other complications, such as risk of seizures.

Psychostimulants The type of neuroactive substances that follows the benzodiazepines in addiction potential are the so-called psychostimulants with cocaine as natural “mother” substance and amphetamine and its derivatives as most important synthetic compounds. These are also called “sympathomimetics”, since they activate the sympathetic branch of the ANS.  Quite different from benzodiazepines and opioids, at present there is little influence of prescribed medication on the prevalence of psychostimulant addiction. This has been different 100 and still 50 years ago, when amphetamines were prescribed as appetite reducers. As sympathetic activation goes together with parasympathetic depression, the digestive functions are deactivated, reducing appetite. The main effect of psychostimulants is at monoamine transporters reducing reuptake and, thus, increasing extracellular levels of dopamine and noradrenaline at central as well as peripheral sites. This can augment attention and vigilance and create a “clearer” mind. It also creates the feeling of high energy as it activates the sympathetic ANS.  Cocaine additionally has a local anesthetic effect. Most local anesthetics are derived from cocaine. Prevalence of psychostimulant addiction is high, particularly in Europe. Life time prevalence (not for addiction, but for use) is 18 (3.5%) million for cocaine, 14.7 (2.9%) million for MDMA (“extasy”) and 12.4 (2.4%) for amphetamines (EMCDDA 2019). Figures for North America are similar but not so much on the rise as compared to opioid or benzodiazepine use. Overdose deaths by psychostimulants are second after opioids, even though by a large distance. The addictive potential of psychostimulants differs widely. It depends on the type

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and the way they are administered. Orally taken methylphenidate (“Ritalin®”) rarely leads to addiction, whereas cocaine taken through the respiratory airways as “crack” is highly addictive. Speed is important for the addictive potential. When methylphenidate is “snorted” the way cocaine is usually ingested, it can lead to addiction. Withdrawal and withdrawal management is not as difficult as in addiction to alcohol or opioids, for there are less severe corporal symptoms. However, strong craving may last for many months. As psychostimulants are directly affecting reward circuits and there is a tolerance effect, it may take a long while to rebuild normal pleasure for the “normal” joys of life, such as food, sex, and/or corporal exercise. There are no specific substances recommended to reduce withdrawal symptoms or craving. Rather, anxiolytics and/or antidepressants are used.

tries is still illegal, mixture with other substances and other fraudulent manipulations by dealers are frequent, leading sometimes to involuntary ingestion of addictive or other dangerous substances. Taken together, while marihuana should not be illegal, it must be controlled to protect the youth and monitor purity and content. For example, in the Netherlands where marijuana use is tolerated and controlled since 1976, crime associated to marijuana is almost inexistent and dealers cannot mix addictive drugs into marijuana, because they have lost most part of the marijuana market. On the other hand, marijuana may alleviate effects of substances used in the therapy of cancers. In some patients its anxiolytic effects can be useful. However, in the “fight for legalization” sometimes the therapeutic potential of marijuana is exaggerated.

Marijuana

5.9

Does marijuana (hemp) cause addiction? There is no or almost no physiological dependence due to marijuana use. Hence, there is seldom loss of control that is a defining characteristic of addiction. But, is it dangerous? To smoke marijuana is just as bad for health as any other inhalation of combustion gases. Further, users of marijuana are at higher risk to develop psychotic disorders, particularly children and adolescents (Di Forti et al. 2019). In this context, the increase during the last 20  years or so in content of the principal active ingredient, Δ9-tetrahydro-cannabinol (THC), has increased the risk of psychotic episodes. As explained in 7 4.5.1, THC reduces the liberation of glutamate by being a partial agonist at CB1 receptors. Even under laboratory conditions, glutamate release is reduced maximally by about 40%. Therefore, it is virtually impossible to kill oneself with marijuana. Thus, compared to the health toll and social costs caused by tobacco smoking and drinking ethanol, cannabis causes little damage. But, as marijuana in most coun 

Neurodegenerative Diseases

This group of problems is special in that there are, different from other disorders, gross degenerative changes in the CNS. Further, it is the group of nervous system problems that is most correlated to (old) age. Neuronal death is inexorably progressing until the patient’s death often caused fully or in part by the neurodegenerative disease (ND). There are at least 30 different ones. Most of them are caused by endogenous factors only, others imply viruses (such as dementia induced by AIDS), or prions14 (such as Bovine spongiform encephalopathy), others have an autoimmune origin like multiple sclerosis. Their causes are mostly unclear. For example, the most frequent of NDs, Alzheimer’s disease, in spite of many billions invested for research did not find the exact mechanisms that are at the beginning of the disease causing the various damaging processes observed in brains afflicted by

14 Prions are infectious protein fragments.

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AD. The most frequent NDs are Alzheimer’s disease (AD) and Parkinson’s disease (PD). Whereas disorders such as depressions, psychotic states, epilepsy, addictions or obsessions are known and described in millennial documents, historically, NDs have received much less attention. Alzheimer delivered his famous first systematic description in a meeting in 1906. And Parkinson published his description on “shaking palsy” in 1817. Only in the second half of the last century together with the dramatic increase of life expectancy in more and more countries, neurodegenerative diseases have become a major concern. There is no group of NS problems growing as fast as NDs. AD cases, for example, grow exponentially, doubling more or less every 25 years. As mostly elderly people are affected, the social burden is caused not so much by taking out the affected person of socially productive activities, but rather their caretakers and institutions offering the corresponding service. By now, the global cost of dementias is well over US$ 1 trillion, much more than 1% of the global GDP (World Alzheimer Report 2019). 5.9.1

Alzheimer’s Disease

In a stark contrast to this fast increasing social cost is the scarcity of therapy, particularly pharmacotherapy. In the case of Alzheimer’s disease that makes up about half of the cases of ND patients and about two-thirds of those that include dementia, only two types of medications have been approved: 55 Inhibitors of acetylcholinesterase 55 NMDA receptor blockers. To explain the mode of action of these substances, one has to know that several important NDs start with the degeneration of a certain type of neurons, in the case of AD cholinergic neocortical neurons, i.e., those whose principal transmitter is acetylcholine. In the CNS that transmitter is involved in

important cognitive functions. The corresponding cholinergic neurons are found in the basal forebrain. As axonal transport is hampered in AD, there are ever decreasing amounts of ACh available at the presynaptic endings leading to failure of functions such as the construction and storage of new memory. Acetylcholinesterase blockers can delay somewhat that failure. The NMDA receptor, as has been explained in 7 4.3.1, can kill neurons by an excessive inflow of calcium ions. This mechanism is, at least partly also at work when neurons die in the brain of an AD patient. A substance called memantine that is a relatively “mild” inhibitor of NMDA receptors is sometimes able to slow down the dying of neurons. Both methods buy a bit of time slowing the symptoms of the destructive processes without influencing it much. The failure to find medication that really slows down, stops, or even reverts the progress of the disease has led to the conclusion that, at a stage when symptoms appear, irreversible damage has already been done and biological switches are moved in the direction of doom. The astounding capacity of the brain to compensate for losses hides the destructive processes for years. Thus, increasingly strong research efforts are taken to diagnose AD as early as possible. Using Positron Emission Tomography (see 7 Chap. 10) and biochemical analysis of cerebrospinal fluid allows the detection of amyloid β (Aβ) long before clinical symptoms appear. Further, genetic risk factors can be detected anytime. At an early stage, medication that impedes Aβ formation or destroys Aβ by immunological means may be helpful even though it is inefficient at later stages. Clinical trials are underway in patients of high genetic risk to develop AD. Non-pharmacological preventive measures have been found to be essentially bodily and mental exercises together with other “good life style”, such as good nutrition, avoidance of alcohol and tobacco smoke, sufficient and good quality sleep, among others.  



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5.9.2

Parkinson’s Disease

The next ND, as prevalence goes, is Parkinson’s disease (PD). As in AD, almost all affected are older than 60 years and incidence is growing even when aging of population is considered (Dorsey and Elbaz 2018). Different from AD, there is a clearly higher prevalence for men than for women (by a factor of 1.4; Dorsey and Elbaz 2018). Lifetime risk is estimated roughly as 5%. Just as in AD, there is primarily one group of neurons affected, the dopaminergic neurons of the substantia nigra in the midbrain. Similar as for cholinergic neurons in AD, up to 90% of dopaminergic neurons in that midbrain nucleus have to be destroyed for symptoms to become manifest. These neurons project to the striatum and are essential for smooth goal-directed movements. Thus, the first sign of PD are stiffness, often with a forward bowing posture and/or involuntary movements, mainly tremor. Cognitive functions may be affected too, but if so, mostly at later stages. In an advanced stage hallucinations and delusions occur. Compared to AD, PD does not imply such a massive death of neurons, is not destroying the personality so utterly and there are much better means to alleviate symptoms. Still, advanced stages mean total dependence on help of others and frequently psychotic symptoms. A causal therapy, in the case of PD that would mean stopping the substantia nigra neurons from dying does not yet exist. Thus, pharmacotherapy relies mostly on reestablishing dopamine receptor activation by augmenting dopamine levels or by administering dopamine receptor agonists. As dopamine does not pass the BBB, the precursor of dopamine L-DOPA (Levodopa; see . Fig. 4.5) is used. The effect is spectacular, almost instantaneous; patients all of a sudden are free of symptoms. L-DOPA is rapidly transformed into dopamine by decarboxylation. However, with levodopa given alone, there are side  

effects such as nausea caused by the excess of dopamine in the body and, as dopamine hardly passes the BBB, dopamine levels in the brain stay relatively low. This is usually countered by combining levodopa with an inhibitor of DOPA decarboxylase, such as carbidopa, so that the bulk of L-DOPA is transported unchanged into the brain where it is then transformed into dopamine. In this way, patients can almost be free of symptoms, at least for some time. Chronic treatment unfortunately leads to a wearing off effect and to so-called on-off oscillations among other problems. On-off oscillations are sudden phases of immobility and/ or tremors often together with distress or depression of the patient that end as abrupt as they appear. Non-pharmacological treatments include electric “deep brain stimulation” and physical exercises. 5.9.3

Other Neurodegenerative Diseases

Fortunately, the many other NDs are clearly less frequent; best known are perhaps the Disease of Huntington and amyotrophic lateral sclerosis (ALS). Both affect primarily the ability to move. In ALS, motoneurons are being destroyed, those in the cortex as well as the ones in the medulla of the spinal cord. Thus, voluntary movements are hampered, but so are reflexes and automatic movements such as swallowing or breathing. Progression is faster than in most other NDs. People have a life expectancy of roughly 3 years after first diagnosis and die frequently from breathing problems. Medication is almost completely palliative, alleviating physiological and psychological ailments. One substance by the name of Riluzole prolongs life on the average by 2–3 months . Mental capabilities stay often, but not always, intact, as impressively demonstrated by the case of world-renown cosmologist Stephen Hawking.

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Huntington’s disease is one of the rare almost completely hereditary diseases. In affected people a gene named HTT that naturally has a trinucleotide repeat region (cytosine-adenine-guanine coding for glutamine) with normally up to 27 repeats has 36 or more repeats rendering the protein Huntingtin less functional impeding a correct folding. There is a rigid correlation between number of repeats and probability of outbreak and severity of the disease. Huntingtin is found in all cells of the body, particularly in the brain and is involved in a large number of functions, some of them being neuroprotective. It has not been possible to identify which function is responsible for neuron death, may be it is a combination of failures related to the cellular Huntingtin tasks. Given the multiple roles of Huntingtin the symptoms of HD are manifold, including motor system failure leading to uncontrollable movements and, like in ALS, to problems in reflexive and automatic movements. As the disease progresses, more and more cognitive functions are affected ultimately leading to dementia. Medication is purely symptomatic, mainly by suppression of the hyperkinetic syndrome. Genetic approaches, such as gene silencing, will probably be more auspicious. The disease could be completely or almost completely extinguished if gene bearers would refrain from having biological offspring. In fact, a growing number of institutions offer counselling together with genetic analysis. There is a group of NDs that arise as a response of the immune system attacking structures important for NS functioning. The most frequent is multiple sclerosis. It is caused by an autoimmune damage of the axonal myelin sheaths produced by oligodendroglia leading to less reliable propagation of action signals in central axons. It is usually counted amongst the NDs even though it does not directly damage neurons, but rather obstructs in a degenerative way normal communication in the NS. As higher

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cognitive functions regularly rely on the cooperation of distant parts of the brain, multiple sclerosis leads to mental problems as well as difficulties in sensory and motor functions. Symptoms start typically with the latter ones. As a disease involving the immune system, inflammatory processes are always seen in patients suffering from multiple sclerosis. These processes attack the BBB and consequently lead to the entering of noxious substances and even T-cells producing further strain on neurons and an abnormal proliferation of astroglia. It should be mentioned that there are NDs associated to infections, such as AIDS-­ related dementia or transmissible spongiform encephalopathies (such as the “mad cow disease” or bovine spongiform encephalopathy). 5.10 

Non-degenerative “Neurologic” Diseases

A general problem in neurology is the existence of thousands of syndromes that affect only a relatively small number of patients each, but summed up, occur in millions of patients worldwide often lacking even an adequate diagnosis, let alone an effective therapy. While this tragic fact must be kept in mind, for obvious reasons, a textbook for psychologists cannot consider it. In this book, we shall deal with only two of the most frequent ones: Myasthenia gravis and epilepsy. 5.10.1 

Myasthenia Gravis

In spite of being a disease affecting the NS and sometimes developing toward complete helplessness, Myasthenia gravis is not considered a neurodegenerative disease because it usually does not include death of neurons but rather affects the nicotinic receptors at the neuromuscular junction. This leads to failures of the neuromuscular transmis-

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sion. Neuronal nicotinic receptors are not affected as they are composed of completely different subunits (α2–α9; β2–β3) compared to the ones in the neuromuscular junction (α1, β1, δ, γ, ε). The disease includes an unusually large fraction of persons without family history (>95%), so-called “sporadic” cases. However, in Myasthenia gravis patients, problems with the immune system are more frequent than in the general population. In this way genetic factors are perhaps more important than the figure above would indicate. There are important gender differences: more women suffer from MG than men. This is because women are at risk from early adulthood on, males are mostly affected at an age above 60 (Carr et al. 2010). Different from NDs the “muscle weakness” has efficacious medication even though there is no clear causal treatment. As has been explained for AD, acetylcholinesterase inhibitors can compensate, at least in milder forms, for the failing nicotinic transmission. Another way of controlling the disease, particularly in more advanced stages, is suppression of immune activities by means of corticoid steroids or other immunosuppressive agents. Unfortunately, all of them, while quite helpful in regaining strength, come with serious side effects. Moreover, immune suppression, obviously, as such involves considerable risk. Further, surgical removal of the thymus gland can bring relief. Finally, antibodies can be removed by a sort of blood filtering or rendered less effective by infusion of immunoglobulins. 5.10.2 

Epilepsy

As shown in . Table 5.3, epilepsy is quite frequent affecting between 0.5% and 1% of the population. It is characterized by epileptic fits that cut conscious experience by a few seconds (“petit mal”) or precipitate convulsions involving a time of uncon 

..      Table 5.3  Number of persons affected by important neurologic diseases around 2016 Neurodegenerative and other neurologic diseases Rough estimates of global frequencya Alzheimer’s disease

150,000,000

Epilepsy

40,000,000

Parkinson’s disease

25,000,000

Myasthenia gravis

7,500,000

Huntington’s disease

3,800,000

Amyotrophic lateral sclerosis

3,700,000

Multiple sclerosis

2,000,000

Sources: Dorsey and Elbaz (2018); Wikipedia aFrequency, in this context, is the total number of cases at a specific time worldwide

sciousness for many minutes up to a few hours. Epileptic fits are simply states that indicate an unbalance between excitation and inhibition caused by brain lesions or other damage to the brain as for example in advanced alcoholism. On the cellular level, epileptic fits are caused by synchronized spiking activity that spreads from one focus and rapidly involves the whole cortex (neo- paleo- and archecortex). Epilepsy means that the seizures are not due to an actual abnormality such as a poisoning alcohol withdrawal or ion unbalance, but rather to a permanent cause. The focus from where the convulsive activity starts may be caused by a brain tumor, a trauma or a lesion produced by a stroke. In most cases the focus is localized in the hippocampus or in the adjacent ­temporal lobe. However, there are cases where a fixed focus is not identifiable. Epilepsy is about the only primary NS disorder that can be treated with medication only without psychological help. The latter, however, may be necessary if there are other comorbid problems or because of

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problems with social relations and discrimination induced by the “special state” of the affected. Up to now, epilepsy patients are seen as “strange” or “slightly mad”. In Nazi Germany sufferers from epilepsy were even murdered. As mentioned in the introduction, bromide, introduced in the nineteenth century, was not only the first effective antiepileptic substance introduced but about the first substance used successfully in a disorder primarily affecting the NS. Several anticonvulsants today such as valproate, lamotrigine, and carbamazepine among others allow about 70% of patients to live without or almost without seizures. For acute intervention, i.e., to stop an ongoing epileptic fit, benzodiazepines are the medication of choice. The action mechanism for benzodiazepines has been explained in 7 4.3.5.1. Other anticonvulsants may also increase GABAergic inhibition, but there are also other sites of action such as the tetrodotoxin-­ sensitive sodium channel whose opening causes the depolarizing phase of the action signal (see 7 2.5.3). Some types of human epilepsy seem to be caused by insufficient chloride extrusion from neurons rendering inhibition depending on GABAA receptors ineffective or even counterproductive (when the IPSP becomes depolarizing even at membrane potentials of −60 or −50  mV; Deisz et  al. 2011). Patients resistant to medication can often be helped by neurosurgery removing “epileptic tissue” in the hippocampus and/ or the temporal lobe. “Biofeedback” is also used. In this therapy, EEG recordings are performed and the person is conditioned to avoid a constellation that is indicative for a possible attack. There are hundreds of neurologic disorders more, but fortunately, all of them are much less frequent than epilepsy, even though the total number of cases is considerable. As to my knowledge, in none of these rare disorders there is a specific pharmacotherapy.  



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References Agarwal SD, Landon BE (2019) Patterns in outpatient benzodiazepine prescribing in the United States. JAMA Netw Open 2:e187399. https://doi. org/10.1001/jamanetworkopen.2018.7399 Apaydin EA, Maher AR, Shanman R, Booth MS, Miles JNV, Sorbero ME, Hempel S (2016) A systematic review of St. John’s wort for major depressive disorder. Syst Rev 5:148. https://doi. org/10.1186/s13643-016-0325-2 Baio J, Wiggins L, Christensen DL et al (2018) Prevalence of autism spectrum disorder among children aged 8 years — autism and developmental disabilities monitoring network, 11 sites, United States, 2014. MMWR Surveill Summ 67(No. SS-6):1–23. https://doi.org/10.15585/mmwr.ss6706a1 Berridge KC, Robinson TE, Aldridge JW (2009) Dissecting components of reward: ‘liking’, ‘wanting’, and learning. Curr Opin Pharmacol 9:65–73. https://doi.org/10.1016/j.coph.2008.12.014 Bianchi MT, Botzolakis EJ, Lagrange AH, Macdonald RL. Benzodiazepine modulation of GABA(A) receptor opening frequency depends on activation context: a patch clamp and simulation study. Epilepsy Res 2009;85(2-3):212–220. https://doi.org/ 10.1016/j.eplepsyres.2009.03.007 Boyce P, Judd F (1999) The Place for the Tricyclic Antidepressants in the Treatment of Depression. Australian & New Zealand Journal of Psychiatry 33:323–327. https://doi.org/10.1046/j.1440-1614. 1999.00580.x Bradley C (1937) The behavior of children receiving benzedrine. Am J Psychiatry 94:577–581 Burgos H, Cofré C, Hernández A, Sáez-Briones P, Agurto R, Castillo A, Morales B, Zeise ML (2015) Methylphenidate has long-lasting metaplastic effects in the prefrontal cortex of adolescent rats. Behav Brain Res 291:112–117. https:// doi.org/10.1016/j.bbr.2015.05.009 Carlezon WA Jr, Thome J, Olson VG, et al. Regulation of cocaine reward by CREB. Science. 1998;282(5397):2272–2275. https://doi. org/10.1126/science.282.5397.2272 Carr AS, Cardwell CR, McCarron PO, McConville J. A systematic review of population based epidemiological studies in Myasthenia Gravis. BMC Neurol. 2010;10:46. https://doi.org/10.1186/14712377-10-46 Cascade EF, Reites J, Kalali AH (2007) Antidepressants in bipolar disorder. Psychiatry (Edgmont) 4:56–58 CDC Centers for Disease Control and Prevention (2018) https://www.­cdc.­gov/drugoverdose/data/ fentanyl.­html

150

5

M. L. Zeise

Cipriani A, Furukawa TA, Salanti G, Chaimani A, Atkinson LZ, Ogawa Y, Leucht S, Ruhe HG, Turner EH, Higgins JP, Egger M, Takeshima N, Hayasaka Y, Imai H, Shinohara K, Tajika A, Ioannidis JP, Geddes JR (2018) Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. Lancet 391:1357–1366. https://doi.org/10.1016/S0140-6736(17)32802-7. PMC 5889788. PMID 29477251 Deisz RA, Lehmann T-N, Horn P, Christoph Dehnicke C, Nitsch R (2011) Components of neuronal chloride transport in rat and human neocortex. J Physiol 589(6):1317–1347 Dhillon S, Yang LP, Curran MP (2008) Bupropion: a review of its use in the management of major depressive disorder. Drugs 68:653–689 Di Forti M, Quattrone D, Freeman TP, Tripoli G, Gayer-Anderson C, Quigley H, Rodriguez V, Jongsma HE, Ferraro L, La Cascia C, La Barbera D, Tarricone I, Berardi D, Szöke A, Arango C, Tortelli A, Velthorst E, Bernardo M, Del-Ben CM, Menezes PR, Selten JP, Jones PB, Kirkbride JB, Rutten BP, de Haan L, Sham PC, van Os J, Lewis CM, Lynskey M, Morgan C, Murray RM, EUGEI WP2 Group (2019) The contribution of cannabis use to variation in the incidence of psychotic disorder across Europe (EU-GEI): a multicentre case-control study. Lancet Psychiatry 6:427–436. https://doi.org/10.1016/S2215-­0366(19)30048-3 Dorsey ER, Elbaz A (2018) Global, regional, and national burden of Parkinson’s disease, 1990– 2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol 17:939–953. https://doi.org/10.1016/S1474-­4422(18)30295-3 Duman RS (2018) The dazzling promise of ketamine. Cerebrum. Cer-04-18 Eatman FB, Colburn WA, Boxenbaum HG, Posmanter HN, Weinfeld RE, Ronfeld R, Weissman L, Moore JD, Gibaldi M, Kaplan SA (1977) Pharmacokinetics of diazepam following multiple-dose oral administration to healthy human subjects. J Pharmacokinet Biopharm 5: 481–494 EMCDDA The European Monitoring Centre for Drugs and Drug Addiction (2019) European Drug Report 2019. https://doi.org/10.2810/191370 Faraone S, Asherson P, Banaschewski T, et al. Attention-deficit/hyperactivity disorder. Nat Rev Dis Primers 1, 15020 (2015). https://doi.org/10.1038/ nrdp.2015.20 Fayyad J, De Graaf R, Kessler R, Alonso J, Angermeyer M, Demyttenaere K, De Girolamos G, Haro JM, Karam EG, Lara C, Lépine JP, Ormerl J, Posada-Ville J, Zaslavsky AM, Jin R (2007) Cross-national prevalence and correlates of adult

attention-deficit hyperactivity disorder. Br J Psychiatry 190:402–409 FDA (2019) https://www.­fda.­gov/NewsEvents/Newsroom/PressAnnouncements/ucm632761.­htm Freuding M, Keinki C, Micke O, Buentzel J, Huebner J (2019) Mistletoe in oncological treatment: a systematic review: part 1: survival and safety. J Cancer Res Clin Oncol. https://doi.org/10.1007/ s00432-018-02837-4. [Epub ahead of print] Gerber M, Holsboer-Trachsler E, Pühse U, Brand S (2016) Exercise is medicine for patients with major depressive disorders: but only if the “pill” is taken! Neuropsychiatr Dis Treat 12:1977–1981. https://doi.org/10.2147/NDT.S110656 Ghuman JK, Hutchison SL (2014) Atomoxetine is a second-line medication treatment option for ADHD. Evid Based Ment Health 17:108. https:// doi.org/10.1136/eb-2014-101805 Gold PW, Chrousos JP (2002) Organization of the stress system and its dysregulation in melancholic and atypical depression: high vs low CRH/NE states. Mol Psychiatry 7:254–275 Grace AA (2012) Dopamine system dysregulation by the hippocampus: implications for the pathophysiology and treatment of schizophrenia. Neuropharmacology 62:1342–1348. https://doi. org/10.1016/j.neuropharm.2011.05.011 Gray SL, Anderson ML, Dublin S, Hanlon JT, Hubbard R, Walker R, Yu O, Crane PK, Larson EB (2015) Cumulative use of strong anticholinergics and incident dementia. A prospective cohort study. JAMA Intern Med 175:401–407. https:// doi.org/10.1001/jamainternmed.2014.7663 Hartung CM, Lefler EK (2019) Sex and gender in psychopathology: DSM–5 and beyond. Psychol Bull. Advance online publication. https://doi. org/10.1037/bul0000183 Hieronymus F, Lisinski A, Näslund J, Eriksson E (2017) Multiple possible inaccuracies cast doubt on a recent report suggesting selective serotonin reuptake inhibitors to be toxic and ineffective. Acta Neuropsychiatr:1–7. https://doi.org/10.1017/ neu.2017.23. PMID 28718394 Horwitz AV, Wakefield JC (2007) The loss of sadness: how psychiatry transformed normal sorrow into depressive disorder. Oxford University Press, New York Kessler RC, Ustun TB (eds) (2008) The WHO world mental health surveys: global perspectives on the epidemiology of mental disorders. Cambridge University Press, New York, pp 1–580 Koob GF (2017) The dark side of addiction. J Nerv Ment Dis 205:270–272. https://doi.org/10.1097/ NMD.0000000000000551 Koutsantoni K (2012) Manic depression in literature: the case of Virginia Woolf. Med Humanit 38:7–14 Kuntz B, Waldhauer J, Moor I et  al (2018) Zeitliche Entwicklung von Bildungsunterschieden im

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Rauchverhalten von Jugendlichen in Deutschland. Ergebnisse aus vier bevölkerungsweiten Studien Bundesgesundheitsblatt 61(1):7–19 Lee BH, Kim YK (2010) The roles of BDNF in the pathophysiology of major depression and in antidepressant treatment. Psychiatry Investig 7:231– 235. https://doi.org/10.4306/pi.2010.7.4.231 Lyngzeidetson AE (2014) DSM-5 overview. BarCharts Inc, Boca Raton Matthews BA, Kish SJ, Xu X, Boileau I, Rusjan PM, Wilson AA, DiGiacomo D, Houle S, Meyer JH (2014) Greater monoamine oxidase a binding in alcohol dependence. Biol Psychiatry 75:756–764. https://doi.org/10.1016/j.biopsych.2013.10.010 Maurer K, Maurer U (2002) Alzheimer. Piper publishing, Munich Mayr M, Schmid RM (2010) Pancreatic cancer and depression: myth and truth. BMC Cancer 10:569. https://doi.org/10.1186/1471-2407-10-569 McLean CP, Asnaani A, Litz BT, Hofmann SG (2011) Gender differences in anxiety disorders: prevalence, course of illness, comorbidity and burden of illness. J Psychiatr Res 45:1027–1035 National Institute on Drug Abuse (2018) National Institutes of Health; U.S.  Department of Health and Human Services. https://www.­drugabuse.­gov/ related-topics/trends-statistics/infographics/fentanyl-other-synthetic-opioids-drug-overdose-deaths National Survey on Drug Use and Health (2015) Summary of the effects of the 2015 NSDUH questionnaire redesign: implications for data users [Internet]. Rockville (MD): Substance Abuse and Mental Health Services Administration (US); 2016. Available from: https://www.­ncbi.­nlm.­nih.­ gov/books/NBK524967/ Nielsen M, Gøtzsche P (2011) An analysis of psychotropic drug sales. Increasing sales of selective serotonin reuptake inhibitors are closely related to number of products. Int J Risk Saf Med 23:125– 132. https://doi.org/10.3233/JRS-2011-0526 NIMH (2017a) https://www.­nimh.­nih.­gov/health/ statistics/attention-deficit-hyperactivity-disorderadhd.­shtml NIMH (2017b) https://www.­nimh.­nih.­gov/health/statistics/post-traumatic-stress-disorder-ptsd.­shtml NSDUH (2017) https://www.­samhsa.­gov/data/ report/2017-nsduh-annual-national-report Nutt D, King LA, Saulsbury W, Blakemore C (2007) Development of a rational scale to assess the harm of drugs of potential misuse. Lancet 369:1047–1053. https://doi.org/10.1016/S0140-6736(07)60464-4 Nutt D, Davies S, Wilson S, Bolea-Alamanac B (2019) Chapter 20: Psychotropic drugs. In: Bennett PN, Brown MJ, Mir FA, Sharma P (eds) Clinical pharmacology, 12th edn. Churchill Livingstone/ Elsevier, London. https://doi.org/10.1016/B978-07020-4084-9.00059-8

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Phillips KA et  al (2010) Should an obsessive-­ compulsive spectrum grouping of disorders be included in DSM-V? Depress Anxiety 27:528– 555. https://doi.org/10.1002/da.20705 Picciotto MR, Brunzell DH, Caldarone BJ (2002) Effect of nicotine and nicotinic receptors on anxiety and depression. Neuroreport 13:1097–1106 Polyzoi M, Ahnemark E, Medin E, Ginsberg Y (2018) Estimated prevalence and incidence of diagnosed ADHD and health care utilization in adults in Sweden  – a longitudinal population-based register study. Neuropsychiatr Dis Treat 14:1149–1161 Reale L, Bartoli B, Cartabia M, Zanetti M, Constantino MA, Canevini MP, Termine C, Bonati M (2017) Comorbidity prevalence and treatment outcome in children and adolescents with ADHD.  Eur Child Adolesc Psychiatry 26:1443– 1457. https://doi.org/10.1007/s00787-­017-1005-z Rowland AS, Skipper BJ, Umbach DM, et al. The Prevalence of ADHD in a Population-Based Sample. Journal of Attention Disorders. 2015;19(9):741– 754. https://doi.org/10.1177/1087054713513799 Ruscio AM, Stein DJ, Chiu WT, Kessler RC (2010) The epidemiology of obsessive-compulsive disorder in the National Comorbidity Survey Replication. Mol Psychiatry 15:53–63. https://doi. org/10.1038/mp.2008.94 Sacks O (1998) The man who mistook his wife for a hat. Touchstone, New York Sacks JJ, Gonzales KR, Bouchery EE, Tomedi LE, Brewer AD (2010) National and state costs of excessive alcohol consumption. Am J Prev Med 49:e73–e79 Saha S, Chant D, Welham J, McGrath J (2005) A systematic review of the prevalence of schizophrenia. PLoS Med 2:e141 Sauer JM, Ring BJ, Witcher JW (2005) Clinical pharmacokinetics of atomoxetine. Clin Pharmacokinet 44:571–590. https://doi.org/10.2165/00003088­200544060-00002 Skelton K, Ressler KJ, Norrholm SD, Jovanovic T, Bradley-Davino D (2012) PTSD and gene variants: new pathways and new thinking. Neuropharmacology 62:628–637. https://doi.org/10.1016/j. neuropharm.2011.02.013 Spencer RC, Devilbiss DM, Berridge CW (2015) The cognition-enhancing effects of psychostimulants involve direct action in the prefrontal cortex. Biol Psychiatry 77:940–950. https://doi.org/10.1016/j. biopsych.2014.09.013 Starcevic V, Janca A (2018) Pharmacotherapy of borderline personality disorder: replacing confusion with prudent pragmatism. Curr Opin Psychiatry 31:69–73 Strohl MP (2011) Bradley’s Benzedrine studies on children with behavioral disorders. Yale J Biol Med 84:27–33 Terranova C, Rizzo V, Cacciola A, Chillemi G, Calamuneri A, Milardi D, Quartarone A (2019)

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Is there a future for non-invasive brain stimulation as a therapeutic tool? Front Neurol 9:1146. https://doi.org/10.3389/fneur.2018.01146 Tizabi Y (2017) Duality of antidepressants and neuroprotectants. Neurotox Res 30:1–13. https://doi. org/10.1007/s12640-015-9577-1 Udvardi PT, Föhr KJ, Henes C, Liebau S, Dreyhaupt J, Boeckers TM, Ludolph AG (2013) Atomoxetine affects transcription/translation of the NMDA receptor and the norepinephrine transporter in the rat brain--an in  vivo study. Drug Des Devel Ther 7:1433–1446. https://doi.org/10.2147/DDDT.S50448 Volkow ND, Muenke M (2012) The genetics of addiction. Hum Genet 131:773–777. https://doi. org/10.1007/s00439-012-1173-3 WHO (2017) Depression and other common mental disorders: global health estimates. World Health Organization, Geneva. Licence: CC BY-NC-SA 3.0 IGO

World Alzheimer Report (2019) Alzheimer’s Disease International. Attitudes to dementia. Alzheimer’s Disease International, London Zanos P, Moaddel R, Morris PJ, Georgiou P, Fischell J, Elmer GI, Alkondon M, Yuan P, Pribut HJ, Singh NS, Dossou KS, Fang Y, Huang XP, Mayo CL, Wainer IW, Albuquerque EX, Thompson SM, Thomas CJ, Zarate CA Jr, Gould TD (2016) NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature 533:481– 486. https://doi.org/10.1038/nature17998 Zeise ML, Kasparov S, Capogna M, Zieglgänsberger W (1993) Acamprosate (calciumacetylhomotaurinate) decreases postsynaptic potentials in the rat neocortex; possible involvement of excitatory amino acid receptors. Eur J Pharmacol 231: 47–52

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Inputs, Outputs, and Multisensory Processing Tim Rohe and Marc L. Zeise Contents 6.1

Input and Output of Information? – 155

6.2

From Stimulus to “Representations” – 155

6.3

“Hierarchy” in the NS – 156

6.4

Hearing and Seeing – 158

6.4.1

T he “Rule” of Increasing Complexity in Visual and Auditory Pathways and the “Grandmother Cell” – 160 “ Top-Down” Regulation Is Found in Most Stations of Sensory Pathways – 162

6.4.2

6.5

Other Exteroceptive Senses – 164

6.5.1 6.5.2 6.5.3

T aste and Olfaction – 164 External Mechanosensitivity – 165 Sense of Temperature – 166

6.6

Gravity Detection and Sense of Balance – 166

6.7

Nociception/Pain – 167

6.8

Interoception – 168

6.9

 ovement by Striate Muscles M and Proprioception – 168

6.9.1 6.9.2

S ensory-Motor System – 170 Inputs and outputs of Sensory-Motor Systems Are Closely Linked – 171

© Springer Nature Switzerland AG 2021 M. L. Zeise (ed.), Neuroscience for Psychologists, https://doi.org/10.1007/978-3-030-47645-8_6

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6.10

Multisensory Perception of a Multimodal World – 171

6.10.1 6.10.2 6.10.3 6.10.4 6.10.5

 dvantages and Problems of Multisensory Perception – 172 A Multisensory Illusions – 174 Principles of Multisensory Perception – 176 The Neural Correlates of Multisensory Perception – 182 Bridging the Levels of Psychophysical and Neural Analyses – 186 Multisensory Perception in Mental Disorders – 188

6.10.6

References – 190

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155 Inputs, Outputs, and Multisensory Processing

Humans, like other animals, have sensory structures allowing them to transduce diverse physical stimuli into signals that the nervous system (NS) can process. The signals of the NS may represent external objects and events outside the body, but signals may also represent information derived from bodily sensors. Further, there are signals that are not easily classified as “coming from outside” or arising from the body such as acceleration of the head (vestibular apparatus) or body damage (nociception) that may be caused from “outside” and/ or “inside.” Perception of all “sense qualities” can be generated without the “natural” stimulus. For example, there may be a visual perception without any light getting to your visual receptors, but as an “inner” image, or as consequences of pathological changes on the visual pathway or a punch on your eye. 6.1  Input and Output

of Information?

“A stimulus carries information entering us by means of our senses. That information is sent to our brains, processed there eventually resulting in our behavior.” This is a scheme known as the “Black Box.” It has been discarded scientifically a long time ago, but lives on in numerous popular ideas about the human nervous system. The title of this chapter may indicate such a model, so a short clarification is in order. As was stated in 7 2.1.2., living systems exchange matter, energy, and information with their surroundings. However, while energy and matter can be absorbed/emitted or ingested/secreted directly, information can neither be received nor be emitted directly but needs to be decoded and recoded as was shown for an information channel (. Fig.  2.5). Further, only a small fraction of stimuli carries semantic information. For instance, most stimuli interpreted as “red” are not part of a set of symbols such as the  



red traffic light. At any rate, the nervous system constantly has to “make sense” of the incoming stimuli, i.e., filtering, enhancing, and recognizing patterns such as visual and auditory according to the needs at every moment, putting them into a context and interpreting and foreseeing possible consequences, often to form adequate behaviors. Among those behaviors can be the creation of signals conveying meaningful semantic information. Thus, new information is generated all the time in living systems, particularly in their nervous systems. Insofar, . Fig. 2.3 presented in 7 Chap. 2 indicating simply arrows pointing inward and outward could be misleading as they may imply immediate inflow and outflow of information. We may categorize the inputs to the NS as “exteroception, “propioception,” and “interoception.” Exteroception means generating information about objects/processes outside our bodies, proprioception being the ability to feel/direct our bodies harmoniously and efficiently, and interoception would include inputs that carry signals about body parameters such as blood pressure, pH, or gut filling. Some kinds of inputs are not easily categorized that way like nociception or feeling of balance.  



6.2  From Stimulus

to “Representations”

The first step is always a physical interaction where a certain form of energy, such as light or mechanical force, interacts with a receptive structure. We call stimulus as any energy/substance that interacts with a specific receptive structure of a living system leading to an electric signal (=transduction) in the receptor cell. The receptive structure frequently is an ionic channel that opens when deformed by mechanic force by a ligand or by other interaction (see 7 2.2.4). In the exceptional case of photoreception, it is the whole membrane (consisting mainly of rhodopsin) as a part of the photorecep 

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tor (the outer segment of retinal rods or cones) that gets less permeable when hit by photons. There is also the transduction that takes place by means of metabotropic receptors (see 7 Chap. 3) as in the case of taste and smell. At any rate, the resulting electrical signal in turn is transduced into a chemical one (liberation of transmitters at synapses) and as such transmitted to other cells and processed. The incoming signals are filtered, patterns are detected, certain parameters are enhanced or diminished, and links are generated. There are examples where incoming stimuli trigger a biological response almost immediately as in the case of reflexes or pheromones1. However, in humans practically all socially relevant and most biologically relevant information are generated at several hierarchical levels. We speak about “pathways” for certain sensory qualities indicating certain layers or nuclei of the CNS that step by step “make sense” of the incoming signals. For example, in a simplified way, retina-thalamus-neocortex is such a pathway for the visual system. An image produced by the eye’s optical apparatus generates a signal pattern at the receptor (rods and cones) level that represents that image. “Higher up” at retinal, thalamic, and neocortical levels, more representations are hypothetically produced of that original image. And as we go from “low” to “high” levels, signals are enhanced or diminished, selected and interpreted, associated and transformed in such a way that these representations contain more and more information produced that are suited for evaluation, understanding, prevision of future relevant events, storage in memory, and/or planning of behavior.  

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1 Pheromones are chemical messengers carrying signals from one living system to the other as first described and investigated by Butenandt for airborne messengers enabling communication in some butterflies.

6.3  “Hierarchy” in the NS

In publications that intend to model brain functioning, we frequently read of bottomup or top-down signaling referring to a ­ type of hierarchy. Now, what is the meaning here of “high” or “low” levels? In neuroscience, we consider parts of the CNS as anatomically low and high in the hierarchy along a vertical dimension if a human is in an upright position. This means that the medulla of the spinal cord is lower than the medulla oblongata, lower than the metencephalon, mesencephalon, diencephalon, basal ganglia and cortices. However, in the neocortex, this hierarchy does not apply: The temporal cortex is not “lower” than the parietal cortex, even though in the upright human, it is definitely below the parietal cortex. Another hierarchy is defined in sensory pathways, such as the visual and auditory. In vision, the retina is “below” the thalamus which is “below” the visual cortex, because, by and large, signal transmission is from retina to thalamus and from there to the cortex. Such pathways can be defined for the other exteroceptive senses, too. From the very beginning, i.e., the level of receptors, processing of stimulus-generated signals is influenced from “above”, i.e., “inputs” are not really a “one-way street” but depend on the history and of states of the nervous system “above.” An example is shown in . Fig. 6.1, the sound attenuation reflex. In this case, the top-down adjustment goes all the way to the structures involved in capturing the stimulus. In particular, in the visual and auditory pathways, “top-down” regulation has been found at any level. Part of that regulation from “above” serves to filter “hoped-for” or expected features, a process necessary to produce “attention.” One example is spatial attention: When we expect a certain event in the right visual field, visual neurons encoding the right visual field will fire at a higher baseline level. Higher baseline activity due to attention can be found in neurons low in the visual hierarchy, such  

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..      Fig. 6.1  The sound attenuation reflex. An example of modification of the incoming stimulus “from above”: Auditory information is transmitted from the organ of Corti via the central processes of bipolar sensory neurons to the ipsilateral ventral cochlear nucleus. Subsequent connections are bilateral. Information is then transmitted sequentially to the superior olivary nucleus which in turn projects to the trigemi-

nal motor and facial motor nuclei. The trigeminal motor nucleus projects to the tensor tympani and the facial motor nucleus projects to the stapedius muscle, causing their contraction, thus dampening the auditory input. FN facial nucleus, TMN trigeminal motor nucleus, SON superior olivary nucleus, VCN ventral cochlear nucleus, SG spiral ganglion, OC organ of Corti, OW oval window, T tympanum, S stapes

as in the thalamus, and in neurons in higher regions, such as in the primary visual cortex (O'Connor et al. 2002). There must be a caveat about hierarchies. The brain is not organized in a strictly hierarchical manner. As we go “further up,” we find more and more parallel processing in the brain. In the visual as well as in the motor system, there are parallel pathways already at relatively low levels. Now, the nervous system communicates not only with the world outside but also

with all body parts and body systems. While with “perception” we usually refer to the subjective experience induced by stimuli that originate outside the body, “proprioception” means the reception of signals originating from the sensory-motor and vestibular systems and “interoception” the reception of signals related to parameters sensed in other parts of the body. Our “outputs” are part of our behavior – signals conveyed principally in social contexts, quantitatively most of it in the

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form of spoken or written language. As far as these outputs are meaningful, i.e., as they form socially relevant signals, they obviously depend on the same processes mentioned above such as decoding and interpreting for being received by our fellow humans. zz “Inputs” from the “External World”

6

As was mentioned earlier, all types of perception may be generated exclusively from the “inside” without any external stimulus. However, in the normal functioning, “exteroception” would include all “senses” that developed in evolution for capturing stimuli from the outside. On the other hand, most senses can generate information about my own body or its activities via the “outer” world. I can hear myself speaking or my stomach growling, I can smell my own odors (sometimes). In the case of tactile or temperature stimuli, my subjective experience tells me something not only about the “external” world but also about where my body was touched or warmed up. If the contacted object is, say, a wall, it may tell me something about my posture etc. Exteroceptive senses can be categorized by the physical types of the correspondent stimuli: electromagnetic radiation (visible light), mechanical energy, substances, and temperature. As subjective sensory qualities, traditionally, five “senses” are listed: seeing, hearing, tasting, smelling, and tactile feeling. In spite of the fact that we all can perceive temperature (mainly changes in temperature) consciously, a temperature sense does not appear in the traditions. The “seventh sense” would be our gravity “sense,” whose receptors in the inner ear (see below) respond to the earth’s gravity, but that “sense” as such does hardly generate reportable “feelings” and thus is usually not counted. Detection of gravity is a special case of mechanoreception and, in the context of the vestibular system, serves to maintain balance.

6.4  Hearing and Seeing

Arguably, these two are the most “human” senses. According to the ancient Greeks, we develop along the axes of Good, Fair, and True, where “Fair” is to be understood in its old meaning as beautiful. You may also say that human culture in principle is about justice, arts, and sciences/technology2. It is evident that art is conveyed mainly by hearing and seeing, whereas morals (in a broad sense) and science are intimately linked to language being heard or read. Thus, visual and auditory senses are the ones most associated with human culture. Their pathways (that is the diverse centers or nuclei involved in the specific processing of that sensorial quality) are by and large comparable, whereas chemical, tactile, and temperature senses are organized quite differently. The quantity of data flow in the optical sense is much larger than the one in audition. The optic nerve contains roughly a million axons, whereas the auditory nerve only about 30,000. On the other hand, when listening to spoken language, the auditory channel may convey more semantic information. The two pathways, depicted in . Figs. 6.2 and 6.3, start with sophisticated devices to catch the adequate stimulus: the eye and the external and middle ears. An important difference is that the eye is in constant motion (only in dreamless sleep it is relatively quiet) tracking the object of attention, whereas in humans the ear is almost immobile. Eye movements are intimately correlated to attention for specific aspects of the environment. Thus, eye-tracking devices nowadays are both an important and affordable means for basic and clinical research of attention.  

2 Humor is also a dimension of humanity, but science (even humanities) has never taken it very seriously….

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..      Fig. 6.2  Visual pathway(s). Besides the main visual pathway, retina–thalamus (lateral geniculate bodies)–visual cortex, there is an important optic nerve input to the midbrain superior colliculi (next to thalamus; not shown) that, via the oculomotor nuclei and the oculomotor nerve, helps to maintain the visual

6

image stable even when the object and/or body and head are moving. The latter is achieved by vestibular projection to the superior colliculi. (Reprinted with permission from Springer Nature: Springer; Neuroanatomy for the Neuroscientist; by Stanley Jacobson, Elliott M. Marcus and Stanley Pugsley (Eds); 2018)

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Then follow the receptor layers, quite different in both pathways: the layer of photosensitive receptors (rods and cones) and the cochlea of the inner ear. The cochlea is not only a receptive structure like the rods and cones of the retina, but it is also an amplifier and gain regulator (among others, the cochlear functioning is not yet understood completely (Maoiléidigh and Ricci 2019)). Then we have several layers or nuclei of neural processing. The following are found in the visual pathway (. Fig. 6.2): 55 The various retinal neuronal layers (outer plexiform and inner nuclear layers, and inner plexiform and ganglion cell layers) 55 Thalamus (lateral geniculate nucleus; LGN) 55 Visual cortex (areas V1, V2, and V3)  

The stations of the auditory pathway are as follows (. Fig. 6.3): 55 Cochlear nuclei (dorsal and ventral) 55 Superior olive 55 Inferior colliculus 55 Thalamus (medial geniculate nucleus) 55 Auditory cortex (primary, secondary, and tertiary)  

6.4.1  The “Rule” of Increasing

Complexity in Visual and Auditory Pathways and the “Grandmother Cell”

The technique of single cell recording (7 10.3.3) starting with the 1960s of the past century opened the way to investigate response characteristics of single neurons at the various levels of sensory pathways in order to get clues about how stimulus patterns are detected/preferred, filtered, and finally recognized/interpreted. By definition all neurons in the visual pathway react to visual and all  

in the auditory pathway to auditory stimuli. However, one neuron only responds to a part of the total visual field (its receptive field) or part of the acoustic spectrum, respectively. It was found that single neurons respond optimally to more complex stimuli if they are “higher” in the respective pathway. Thus, peripheral neurons are relatively widely tuned (i.e., they are not very specific), whereas getting “higher up” the units require more and more sophisticated combinations of stimulus parameters in order to respond maximally. For example, a retinal bipolar cell’s receptive field has a simple center-surround organization. Light to the center without light on the surround maximally excites or inhibits the unit. Its response also depends on spectral distribution, but other parameters, such as movement, go undetected. Detection of movement, however, can be found in the next layer, the retinal ganglion cell layer with several other features endowed principally by amacrine cells that are subdivided into 50 (!) subtypes (Kim and Kerschensteiner 2017) producing a large number of diverse properties in the ganglion cell layer. Further up, at the thalamic and cortical levels, optimal activation requires even more complex stimulus patterns. In the auditory pathway, a similar principle of increasing sophistication is at work (Tian et al. 2013). Even though the cells in the auditory pathway all have their receptive fields, i.e., a characteristic frequency that elicits a maximal response, as we ascend in the auditory pathway, other parameters, such as a changing frequency and every time more complex sounds, are required as an optimal stimulus. Does that specialization in the neuron’s response characteristics of ascending pathways go as far as to recognize individual persons or items? This problem, known as the “grandmother cell” hypothesis, would mean that we ultimately have one neuron for every separable object that we know and recognize. It is now generally agreed that this hypothesis is not likely to be true.

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..      Fig. 6.3  Auditory pathways. When comparing the visual and auditory pathways, the last two stations of the auditory pathway resemble the visual pathway, from thalamus (medial geniculate body = MGB) to the cortex. The inferior colliculus, a part of the main auditory pathway, is next to the superior one, a nucleus functioning in the control of eye movement rather than conveying image signals. The more peripheral parts of the auditory

pathway, spiral ganglion, cochlear nuclei, and superior olive, are quite different from the retina being the peripheral part of the visual pathway(s). NC neocortex, AA acoustic area, IC inferior colliculus, MB midbrain, NL nucleus of lateral lemniscus, MO medulla oblongata, VCN ventral cochlear nucleus, CDV Cochlear division of vestibulocochlear nerve, SO superior olivary nuclei, RF reticular formation, SG spiral ganglion

First, such super-specialized cells have not been detected. More importantly, neurons in “higher” cortical areas more distant from the primary regions have become multi-­modal and associative (see 7 6.10). It is believed nowadays that recognitions

(and probably all cognitive functions) are achieved as collective emerging features (e.g., an activation pattern of a group of neurons) rather than as a composition or puzzle of single cell properties (Dehaene and Naccache 2001).



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6.4.2  “ Top-Down” Regulation Is

Found in Most Stations of Sensory Pathways

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In order to model brain functions, neuroscience nowadays bets on “networking” rather than trying to understand them from the single cellular level only. The big problem here is that networks in the brain are dynamic. Brain “hardware” is not “hardwired” but it changes connections and their efficacy depending on use and other factors (see 7 Chap. 7). In visual and auditory pathways, there is filtering and a selection of “important” characteristics. “Important” certainly depends on the actual situation, needs, and expectations. To select or create the ­adequate selection at any time and situation, the stages of auditory and visual pathways must be provided with signals in order to adjust selection. At all stages, we meet efferent (=“top-down”) influence that tunes the selection and the forthcoming features. We know relatively little about how this top-­down tuning works, even though many axons are involved. In the LGN, there is as much as 80% of excitatory synapses of the efferent kind, i.e., the LGN neurons receive massive input from the visual cortex (Usrey and Alitto 2015). However, we can only speculate what this strong topdown influence may be good for. One function is probably to generate part of what in psychology is called expectation/attention. This means that quite specific characteristics of a surround are preferably detected while other may go unnoticed. There are numerous examples for selective perception, for not seeing the “elephant in the room,” but being extremely alert to “meaningful” input, such as the almost inaudible whining of a sick baby for a caretaker. Further, efferents may be necessary to produce the constancy phenomena. This is the well-known perceptive capacity that lets us perceive, say, a strawberry as red, even though it may provide very little reflection  

..      Fig. 6.4  Ponzo illusion. This well-known “railway-­ inspired” size constancy illusion illustrates just one of the various types of perception constancies

of light at around 650  nm (that normally leads to the perception of “red”), because it is illuminated by light of shorter wavelength. This color constancy is just one of various constancies we experience in our visual and auditory perception. Among these there are visual size, intensity, color, shape, and speed constancies. Auditory constancies do not refer to parameters or dimensions. Rather there is an ability to recognize a music instrument or voice under very different acoustic conditions. Constancy phenomena are possible because of comparison with stored properties of objects and contexts that are signaled “top-down.” Many of the surprising perceptive “illusions” in psychology fall into the category of “constancies,” such as the one shown in . Fig. 6.4. Psychologists must learn that the mechanisms that underlie those “illusions” are crucial to orient ourselves and adjust our behaviors. Generally, in order to be successful biologically and socially, we must make sense of the entire situation we are in – often fast. This goes from estimating a distance all the way to understanding the situation of humanity as a whole, and, pathologically, from funny or dangerous errors about our immediate surroundings to hallucinations, paranoia, and false conspiracy theories. Visual and auditory senses, different from other senses, are also involved in the  

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construction of a three-dimensional external world. Binocular vision is crucial for depth perception, even though many other clues are involved in that construction (such as perspective, shadows of reliefs, apparent size, among others). In contrast, sound localization is almost exclusively achieved through processing binaural delay and intensity difference. Tracing visual and auditory pathways “higher above” to multi-modal, associative,

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and interpretative functions, in either pathway there have been defined dorsal and ventral “streams.” First, in the visual system, evidence accumulated that neurons in the parietal lobe were more responsive to orientation/location (“where?”), whereas those of the temporal lobe reacted rather to categories (“what?). Different from the lower layers of visual/auditory pathways, ample evidence from clinical, lesion, electrophysiological and imaging studies is consistent

Via higher-order frontal networks Articulatory network pIFG, PM, anterior insula (left dominant)

Dorsal stream

Spectrotemporal analysis Dorsal STG (bilateral)

Combinatorial network aMTG, aITS (left dominant?)

Ventral stream

Sensorimotor interface Parietal-temporal Spt (left dominant)

Phonological network Mid-post STS (bilateral)

Input from other sensory modalities

Conceptual network Widely distributed

Lexical interface pMTG, pITS (weak left-hemisphere bias)

..      Fig. 6.5  The dual stream model (Hickok and Poeppel, 2000, 2004, 2007) holds that early stages of speech processing occur bilaterally in auditory regions on the dorsal STG (spectrotemporal analysis; green) and STS (phonological access/representation; yellow), and then diverge into two broad streams: a temporal lobe ventral stream supports speech comprehension (lexical access and combinatorial processes; pink) and a strong left dominant dorsal stream supports sensory-motor integration and involves structures at the parietal-temporal junction (Spt) and frontal lobe.

The conceptual network (gray box) is assumed to be widely distributed throughout cortex. IFG inferior frontal gyrus, ITS inferior temporal sulcus, MTG middle temporal gyrus, PM premotor, Spt Sylvian parietal-temporal, STG superior temporal gyrus, STS superior temporal sulcus. (Reprinted by permission from Springer Nature: Nature; Nature Reviews Neuroscience; The cortical organization of speech processing. Gregory Hickok et al.; © 2007 Nature Publishing Group (2007); with permission)

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with the notion of two “higher” pathways. This does not mean that the bifurcation, “what’” and “where,” starts in the neocortex. At least in the visual system, there are thalamic neurons (“parvocellular”) that provide input mainly to the ventral stream, whereas others (“magnocellular”) rather connect (­indirectly) to neurons in the parietal lobe constituting the dorsal stream. The “where” part receives signals from the whole retina, whereas the “what” system only from foveal and parafoveal parts. This has to do with the ventral stream being more closely linked to attention and conscious experience, while the dorsal stream rather generates fast behavioral reactions without much “thinking about.” The ventral visual stream instead is closely linked to ventral stream auditory processing and thus with language and abstract thinking. So, the auditory ventral stream recognizes phonemes making possible word/language recognition. Then, is the auditory dorsal stream to localize sounds? May be in part, but mostly it is necessary to prepare speech, for example when answering a question (Hickok 2012). . Figure  6.5 illustrates that concept. Evidently, with new studies, the “streams” concept has been challenged. In particular, the strict separation of the two streams has been put in doubt. However, in the visual system, it seems to be fairly separated, at least to a certain stage. In the auditory/ speech realm, a strict separation has never been postulated since language understanding and producing must be intertwined. In total, the concept of the “streams” remains valid for both visual and auditory systems (Rauschecker 2018).  

6.5  Other Exteroceptive Senses

As mentioned above, traditionally taste and smell, tactile sense, gravity sense, and temperature sense have been classified as providing us with data that help us to handle our relations to the world outside our bodies.

6.5.1  Taste and Olfaction

The chemical senses identify substances or acidity of substances. Chemical receptors are only reacting to compounds or chemical elements dissolved in a watery medium. The taste sense reacts to substances already dissolved or being dissolved in the mouth, whereas olfactory (nasal) receptors work with a mucous liquid that dissolves volatile substances typically carried by the air. Chemical reception is found in all living systems – we do not know of organisms that do not react specifically to certain substances by means of receptive protein complexes. Taste is associated with only five types of receptors that mediate five qualities: sweet, sour, bitter, salt, and umami. The last one was described at the beginning of last century in Japan, but only many decades later, umami was also recognized in the West. Umami receptors are activated by glutamate and ribonucleotides (such as guanosine monophosphate). It makes sense that this quality is crucial in finding protein- and nucleotide-rich foods. The other four taste qualities also have obvious functions in order to ingest or avoid food. In the so-called taste buds of the tongue, there are several taste receptor cells joined together. These are quite unspecific, i.e., most of them react to various taste qualities. Their axons project to the gustatory nucleus in the medulla oblongata. From there, the next layer is in the thalamus (ventral posterior medial nucleus) and finally the ultimate station is a primary gustatory cortex situated in the insula stretching through the lateral sulcus reaching the parietal cortex surface just above the sylvian gyrus. A bit as in the visual system where three types of cones provide the data to construct a “world of color,” a five-dimensional “savory” world is produced. It can be speculated that the fact that important parts of the gustatory cortex lie in the “insula” has to do with the “feel-good/feel-bad” function of taste. All over the world, tasty food is an instrument to make the other person(s) more

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accessible and more inclined to yield to our own wishes. In line with this, the feeling bad related to drug abstinence in addicts (i.e., craving) goes away when the insula is temporarily paralyzed (Contreras et al. 2007). Olfaction, the second chemical sense for the exterior, uses another receptor principle as compared to audition, vision, and taste: instead of a few receptor types, there are hundreds of them, everyone detecting a different scent “spectrum.” However, this does not mean that these are “grandmother” receptors; they are broadly tuned just like other receptors, each one reacting optimally to a certain constellation of scents rather than to a specific odor only. The olfactory receptors situated in the nasal epithelium connect to cells of the olfactory bulb above them. As in the other sensory pathways, there is top-down regulation that starts right in the olfactory bulb. It is supposed that this means “focusing” on certain odors and filtering of olfactory “noise.” The bulb’s neurons project to the olfactory cortex. It is said that smell is the oldest among the mammalian senses. This opinion comes from the fact that the olfactory cortex is present in primitive vertebrates such as sharks that do not have a neocortex. Further, olfaction is directly connected to the limbic system through the amygdala and the entorhinal cortex, among others. We usually do not reflect or talk much about smells, but it immediately can trigger repulsion or attraction and trigger memories and emotions. 6.5.2  External Mechanosensitivity

Perceiving touch and temperature on the skin tells us about our immediate surroundings. Sensory bipolar neurons whose cell bodies are found in the dorsal root ganglion receive signals from the skin and, in the other direction, send signals to neurons of the dorsal columns, which are nuclei situated at the border between spinal cord and medulla oblongata. The “nerve endings” in the skin can

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be “naked” or, a bit like the outer ear or the optic apparatus of the eye, can be covered by layers of connective tissues that wrap around or cover the free axons of the bipolar sensory neurons (so-called Pacinian or lamellar corpuscles and Meissner corpuscles). This auxiliary apparatus has important consequences for the properties of the whole receptor: the sheath of connective tissue cells provides sensitivity to vibrations (optimal frequency 200–300  Hz in Pacinian and around 50  Hz in the smaller Meissner corpuscles). Further, the shape of the “nerve endings” influences receptive properties. The so-called Ruffini endings are encapsulated, branched, dendritic tree-like structures. These are also important as joint angle detectors of the motor system (see below). Around hair follicles nerve endings are of spiral form and convey also mechanoreception. Thus, there are four different organelles of mechanoreception whose optimal activation depends on frequency, pressure, size, and movement of the object touching that eventually produce sensations such as light touch, heavy pressure, trembling or vibrating, itching or stroking. The pathway after the dorsal root ganglion cell goes to a sensory nucleus at the border between spinal cord and medulla, the dorsal column, and from there either directly via the thalamus to the primary sensory cortex. The somatosensory cortex, together with the motor cortex, provides a map of the body, sometimes called “homunculus.” This is a grotesquely deformed human with huge lips and tongue and hands, but with small trunk and legs. This truthful mapping is the base for much of our body-feeling. We register the contact to the world, particularly the one to our co-humans. Thinking about it, the “somatic” sense does not provide us with signals from a distant external world as seeing and hearing does, but rather from objects touching us giving us a “body-­ feeling” that has a lot to do with our wellor not-so well-being. In line with this is the fact that the secondary somatosensory cortex lies at the ceiling of the lateral sulcus, the

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structure that forms a “cavern” inside the cortex whose inner wall is the insular cortex. Remember that the pathways of tasting and gustatory senses are connected to the insular cortex, too. Thus, it can be speculated that well-being is intimately connected to rather “primitive body-feelings.” As mentioned above, the tactile sense – even though it is a way of orienting ourselves in the immediate surround and, thus, is an “external” sense – at the same time is one of the ways we experience our bodies.

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6.5.3  Sense of Temperature

Temperature, as far as mediated through skin receptors, also tells us about our immediate surroundings and about our body. It is a clearly separate sensation well differentiated from tactile or other inputs. Thermoreceptors, however, are multimodal, i.e., they react to temperature and chemicals. As subjective experience they produce feelings of hot/cold and pain. This is why substances such as capsaicin (active ingredient of “hot” chili peppers) trigger feelings of heat and pain and menthol a feeling of cold. Thermoreceptors belong to a large family of about 30 receptors, the TRP receptors, which are cationic ion channels and were discovered only in the 1990s of the last century. Temperature is being sensed by at least six different channels/receptors that are found in the so-called free nerve endings, i.e., mostly unmyelinated arborizations of the same type of bipolar neurons mentioned above for the tactile sense. Further processing of thermal inputs is realized in parallel to the nociceptive pathway (see below). 6.6  Gravity Detection and Sense

of Balance

In the inner ear, otoliths (“earstones”) are found in the center of the vestibular organ (. Fig.  6.6). They are coupled to a mem 

..      Fig. 6.6  Organs of the inner ear. Utricle and saccule house the otoliths that provide signals about gravity. VG vestibular ganglion, SSC superior semicircular canal, CWA cristae within ampullae, M maculae, S saccule, U utricle, HSC horizontal semicircular canal, CD cochlear duct, PSC posterior semicircular canal

brane that shifts as otoliths move. This happens either by the force of gravity when the head is tilted or by inertia if there is an acceleration. So, this organ provides data about where “down” is relative to the position of the head. But also it detects linear acceleration of the body, be it passively when sitting in a car or actively as you start running or get to a halt. The brain must compute if it is gravity or inertia or both that generate signaling. The membrane we mentioned before is coupled to hair cells almost identical to the ones found in the organ of Corti and in the rest of the vestibular apparatus. This astounding similarity of two senses that are subjectively completely different is easily explained: they have developed from one and the same sensory organ  – the side line of fish. The vestibular organ may be called the organ of balance, and besides the otolith organ in its center consists of three arcs oriented in the three planes x, y, and z. It catches angular accelerations caused by turning the body, the head, or both. From the input of hair cells situated in the “ampullae” at the base of each arc, the movement is calculated for the correct adjustment of eyes, head, limbs, and trunk. There is a ganglion close to the vestibular apparatus containing sensory cells receiving hair cell input and leading signals to the vestibular nucleus in the mid medulla. From there, projections run mainly to parts of

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motor control: the cerebellum to motor neurons in the spinal cord and also via thalamus to the motor cortex in order to keep the head and the rest of the body in balance. Further, through a nucleus in the midbrain (superior colliculus), eye movements constantly adjust the position of the eyes in such a way that a steady image on the retina is maintained. The corresponding vestibulo-­ocular reflex is very fast and avoids disruptions of vision, even though you are running or jumping. We have no conscious access to the vestibular sense. However, if and when something is wrong with it, we feel dizzy or swooning. The vestibular apparatus is quite sensitive to many neuroactive substances. Therefore, dizziness is one of the most frequent undesired side effects in neuropharmacological therapy (see 7 Chap. 5).  

6.7  Nociception/Pain

From a functional point of view, pain is a natural warning and triggers strong avoidance reactions but usually does not tell you much about the external world. It is therefore not counted as a “sense.” Notwithstanding, we have a cortical mapping of the body that lets us identify the place where at the surface or inside of the body something unpleasant is going on. As with other sensations, pain does not necessarily have its cause by activation of the correspondent receptors, but can be produced intrinsically by the brain or parts of the nociceptive pathway. However, the most common cause for the sensation of pain is the activation of nociceptors, i.e., free nerve endings that contain various ion channels sensitive to mechanical force, chemicals, and/or temperature. These are not always specific, but sometimes multimodal. A famous example is the TRPV1 channel being sensitive to the above-mentioned capsaicin (active ingredient of hot spicy peppers) and temperature rising above 43 °C producing the sensation of pain and

“hot.” Whereas injury or lesions produce acute pain, most of these insults burn for a considerable time due to the tissue reactions and chemicals produced as consequence of that reaction. At first the nociceptive nerve endings release an undecapeptide by the name of substance P, member of the tachykinin-­ family of neuropeptides (see 7 4.4.1). Substance P (“pain”) activates cells of the immune system, the so-called mast cells that liberate histamine (see 7 4.3.6.4), a monoamine involved in inflammatory and allergic reactions. Further the injured tissue mobilizes the liberation of prostaglandins3, bradykinin, and potassium4. All these substances contribute to the perception of relatively long-lasting or chronic pain. The pathway is from the dorsal horn of the spinal cord, where substance P is also crucial in the synaptic transmission, then directly to the thalamus and from there to the somatosensory cortex and is common for the sensation of pain as well as of temperature. Pain sensation can be potently modified by neurons of the periaqueductal gray, a structure in the brain stem that is common to all basic emotional systems. Thus, certain strong emotions may enable persons to tolerate pain that normally would be unbearable. Further, endogenous opiates that are particularly concentrated in areas involved in nociceptive reception may reduce the feeling of pain (see 7 4.4.1.1). The analgesic effect of placebos is also mediated by opioid receptors.  





3 Prostaglandins are signaling lipids with para- or autocrine functions. 4 In 7 Chap. 2, the cellular ionic gradient of K+ was discussed and its relatively high intracellular concentration. Any destruction (necrosis) of cells will lead to elevated K+ concentrations in the extracellular fluid.  

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6.8  Interoception

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In order to keep all the parameters relevant for body functioning in an optimal range, we need, just as in all regulatory systems, receptors that sense the relative values of the parameter(s) and their changes. These parameters include temperature, pH, blood pressure, oxygen CO2 and glucose levels, ion concentrations, osmotic/water distributions among others. In all these regulations, the nervous system, in particular the hypothalamus, inhibits, excites, and coordinates the diverse organs via the autonomous nervous and endocrine systems to maintain homeostasis. A special case of organ in this context is the gastrointestinal tract from stomach all the way to the rectum. “Brain in the guts” means that there is a nervous system in two layers (“enteric nervous system”) of the intestines that regulates the peristaltic movements, the blood circulation, and absorption. However, this NS is by no means isolated from the other nervous systems, but receives and sends permanent signals to and from the autonomic nervous system (ANS) as well as endocrine signals mostly in the form of peptides. Interestingly, many of the neuropeptides have been found first in the guts. It goes without saying that we do not have conscious access to these regulations (luckily, without a few exceptions like heart fluttering and stomach cramps), but this does not mean that interoception be without impact on our souls/well-being and even to cognitive processes. Emotions are clearly molded by interoception, as well as all physiological systems of the body are influenced by emotions (see 7 Chap. 9). The hypothalamus, the central regulator of homeostasis, is part of the limbic system and has particular impact on the insular cortex, the hub of “interior feelings.”

6.9  Movement by Striate Muscles

and Proprioception

Muscle contraction is the way how macroscopic bodily movements are achieved. There are two types of muscles: smooth or “involuntary” muscles and striate or skeletal, “voluntary” muscles5. The ANS in principle conveys orders and receives signals from smooth muscles that move parts of the body inside (such as peristaltic movements of the intestines). The striate or voluntary musculature is driven by the motoneurons of the spinal cord’s dorsal horn and motoneurons of diverse nuclei in the brainstem. They make contact to the muscles via spinal or cranial nerves. zz Various Pathways Regulating Motor Control

As we have seen before, when considering “senses” there are clearly defined pathways, at least up to a certain hierarchical level. In motor control, however, there are several distinct pathways that cannot always be well defined and their coordination is very complex. Perhaps the simplest is the direct connection between the primary motor cortex and the motor neurons of the spinal cord6 called the lateral pathway (. Fig.  6.7). It drives trunk and limb movements. Head and neck muscles are directed by two pathways that do not originate in the neocortex but in the vestibular nucleus and the superior colliculus mediating movements that compensate for acceleration and visual tracing, respectively, called ventromedial pathways. The resulting movements, while being accessible to auto-observation, happen without conscious control. Another pathway originates in the metencephalic pontine reticular forma 



5 Rigorously there are three types: the heart is counted as a special kind of muscle, too. 6 Some of the axons of the motor cortex “relay” first at the diencephalic red nucleus before connecting to the spinal cord.

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..      Fig. 6.7  Direct and indirect connections of motor cortex to motoneurons in the spinal cord’s dorsal horn. There are several other pathways and nuclei that project to motoneurons guiding the execution of external body movements. MC motor cortex, MB midbrain, RN red nucleus, MO medulla oblongata, P pyramid, PD pyramidal decussation, RT rubrospinal tract, CT corticospinal tract

tion and passes via the medulla oblongata to the dorsal horn motoneurons. This pathway supposedly maintains balance to keep upright against the force of gravity. In order to achieve directed, coordinated, and adequate movements, two important structures are inevitable: the basal ganglia and the cerebellum. In this context, neurologists do not talk about pathways but rather of “loops,” because the stream of signals is in either direction – cortical-cerebellar as well as cortical-­basal ganglia and back. We know that we are able to plan

movements, consciously as well as non-consciously, but we are essentially still unable to unravel these reverberating networks. However, some information about the function of parts of the motor systems come from pathologies. For instance, if a person suffers from cerebellar damage, (s) he might be unable to get the sequence of muscle contraction right resulting in a sort of “ataxia,” i.e., a difficulty to reach targets in the exterior world or referring to her/his own body. Basal ganglion problems will

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result in non-­voluntary movements or stiffness (the best-­known example for this is Parkinson’s disease; see 7 5.9.2). Voluntary movements may lose its easiness and elegance.  

6.9.1  Sensory-Motor System

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The nerves that connect to skeletal muscles are never purely efferent, but always have afferent components. The reason is obvious: In order to achieve coordinated movements that adapt to a task, we need a tight cooperation of sensory and executive elements. When people started to construct walking robots, they had to fit sensors and install programs that coordinate the diverse parts constantly. Still (by 2020) those robots are somewhat clumsy and walking is just one of the many tasks of the motor system. The peripheral interplay between motor units and mechanical sensors is structurally and functionally well described. In mammals there are at least three elements that serve the necessary “sensing”: 55 Muscle spindles that are themselves muscle fibers in parallel with the corresponding muscle 55 Golgi tendon organ in series with the muscle 55 Ruffini or bulbous corpuscles that measure the angle of a joint and are situated deeply in the skin Together with the vestibular apparatus, these receptors enable kinesthesia or proprioception. This includes various hierarchical levels from reflexes that only involve two neurons, such as the knee-jerk reflex, or three neurons like the one that inhibits activation of a muscle together with its antagonist at the same time. More sophisticated levels include the cerebellum among other brain areas up to conscious proprioception that makes us aware of the positions of the various parts of the body, the whole

body, and the body relative to the outer world. The medium and higher levels can and should be trained in order to achieve a better mastering of our movements. Such training can be part of more holistic exercises, such as yoga, and has been proven to have beneficial effects on the physical, emotional, and cognitive levels. Complex motions are under multimodal control involving somatosensory, proprioceptive, and visual inputs. For example, when we give the motor commands to shoot a tennis ball, our brain integrates our sight of the ball, the touch of the tennis racket in our hand, and the posture of our arm when the brain programs motor commands to hit the ball (see also Wong, 2017). As was mentioned above, voluntary movement that may have its starting point in a decision made in the prefrontal cortex does not seem to control directly motor area 1 that sends its signals to the spinal cord. Rather, signals from neocortex have to pass through basal ganglia and back to the supplementary and premotor areas before the motor cortex can actually send signals in order to execute movements. To say “signals are sent” is not wrong, but obviously there is much more of processing and coordination going on which, by and large, is not understood yet. The cerebellum seems to program the sequence and coordination of diverse muscle groups, a task not accessible to consciousness. While body and body limb movements are mainly for “practical” purposes (even though posture, for example, can be a social signal), the facial, lip, and tongue movements fulfill important tasks in social communication, language in particular. Interestingly, there are 43 facial muscles in humans, much more than in other primates. As discussed above, speech movements necessary for speech are prepared by the dorsal stream of the auditory pathway in cooperation with motor cortex. The cognitive side of speech is different and is performed as collaboration among diverse neocortical areas.

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6.9.2  Inputs and outputs

of Sensory-Motor Systems Are Closely Linked

At first sight, inputs to the NS and its motor outputs might appear as a rather passive process by which the brain maps physical signals onto mental representations, which finally enable movements. However, our perception is not a passive filter of environmental signals, but our perception and motion are circularly interlinked: as was described for movements, our brain quickly adapts motion commands to incoming proprioceptive inputs. Thus, motor commands lead to specific proprioceptive feedback, which leads to new adapted motor commands, which in turn result in novel proprioceptive feedback etc. Similarly, our perception interacts dynamically with our actions: for example, when we perceive a salient red circle in the periphery, we will orient our eyes and head to focus the circle and touch it with our hand. Thus, we use our motor system to actively sample more specific visual or tactile signals of relevant objects in our environment, for example, to quickly identify the ripe red apple. The idea that our brain is not merely a passive input and output device, but actively uses its motor system to sample the environment, has been termed “active sensing” (Schroeder et al. 2010). Active sensing is especially prominent when we use our touch to haptically identify an object or when we actively sniff to smell an odorant. The idea that perception and action are closely interlinked was especially supported by findings of sensorimotor neurons which fired similarly when monkeys passively perceived a specific action of another monkey (e.g., nut cracking) or performed the specific action themselves (Rizzolatti et  al. 1996). These neurons seemed to mirror the perceived action and were therefore termed “mirror neurons.” These examples demonstrate that our perception (as well as our cognition) is “embodied” (Wilson 2002):

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Our perceptions, cognitions, and actions are closely interlinked because they share the same sensorimotor neural circuits rooted in a single body. However, not only our inputs to the NS are closely linked to actions, but the inputs are also closely linked to each other: At any time, we not only perceive our environment as visual, auditory, or tactile fragments, but we also relate our perceptions across the sensory channels. 6.10  Multisensory Perception

of a Multimodal World

In the previous paragraphs, we learned how signals are processed in independent sensory channels, from receptors to subcortical pathways to sensory cortical regions which form the neural correlates of our subjective experiences. Thus, our everyday environment provides us with many diverse stimuli which we perceive as visual, auditory, tactile or olfactory sensory percepts: For example, we might perceive the light emitted by a dog as a visual image of a dog, we perceive the sound emitted by a dog as a barking sound, and we perceive the chemical molecules emitted by a dog as the smell of a wet fur. However, despite the fact that different physicochemical stimuli are processed in independent sensory modalities, we do not perceive the stimuli as independent perceptual fragments (i.e., independent unisensory percepts): intuitively, we perceive a single barking dog with a smelling fur. Further, objects in our physical world often emit physicochemical signals which are systematically interrelated. For example, dogs more often make a barking sound than a meow sound. Thus, our mind and brain should not only represent multiple unisensory signals per se, but should also truthfully represent the relation across distinct signals in order to construct a coherent multisensory representation of the environment. Subjectively, we thus perceive our environment as a multisensory whole because

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our brain effortlessly relates representations of related sensory signals. Generally, we relate multisensory stimuli in two distinct ways (Ernst and Bulthoff 2004). First, we can combine complementary stimuli, which are unique to a modality, to obtain qualitatively novel representations which we could not have obtained from a single modality alone (. Fig. 6.8a). For example, when we want to select a single ripe (i.e., red and firm) apple among a collection of apples with green (unripe) or red (ripe) color and firm (ripe) or soft (overripe) touch, we need to combine our sight and touch of the apple to find the ripe one. Second, we can integrate redundant stimuli, which provide similar information in multiple modalities, to obtain more reliable representations of a single environmental property. For example, when we localize a bouncing ball, we can integrate the seen and heard location of the ball to come up with a single estimate of the ball’s location. Further, we relate unisensory representations at all levels of stimulus processing (. Fig.  6.8a). While low-level stimulus features such as the location and timing of stimuli fundamentally inform us on the interrelation of sensory signals, high-level features also determine whether and how we relate representations. For example, when a person speaks to us, the timing and location of the voice and the lip movements suggest to integrate these audiovisual representations. However, if the person speaks with a sad voice and a smiling face, these incongruent high-level emotional features provide us with a conflicting multisensory impression of an emotionally ambivalent (or ironic) person. Nevertheless, what are the advantages and difficulties of multisensory perception? When and how does our mind relate or not relate sensory representations from different sensory channels? How does our brain accomplish this feat? These are the fundamental questions when we want to understand how our mind and brain create coherent multisensory perception of a world  

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providing us with many interrelated physicochemical stimuli. 6.10.1  Advantages and Problems

of Multisensory Perception

Compared to unisensory perception, multisensory perceptions offer a number of advantages that lead to a qualitatively richer, more robust, and more reliable representations as compared to unisensory perceptions (Ernst and Bulthoff 2004). First, combining signals across the senses leads to larger and more complex perceptual spaces which allow more fine-grained distinctions between perceptual objects. For example, when we eat food, we combine (among others) the food’s gustatory and olfactory signals to perceive an enormously rich perceptual space of different flavors. Thus, we can discriminate a nearly infinite number of foods which allows us to choose tasty among disgusting or edible among non-edible (e.g., toxic) foods, and which is the neurophysiological basis of our food culture. Second, combining stimuli across the senses helps to disambiguate unisensory representations leading to more robust multisensory representations. For example, when humans are presented with two visual discs which move toward each other, coincide and then move through each other, the perception from vision alone is ambiguous (Sekuler 1997) (. Fig. 6.8b): the two discs could be perceived either as passing each other or as bouncing of each other. However, when a click sound is presented at the moment when the discs coincide, observers more often report that they perceived a bouncing off. Thus, the auditory percept of the click helped to disambiguate the visual percept of the moving discs. Third, when we integrate redundant multisensory signals, we obtain a more reliable multisensory representation. For example, when we estimate an object’s size from vision and touch, we more reliably discriminate the object size as compared to only seeing or touching the  

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..      Fig. 6.8  Categories and advantages of multisensory perception. a Multisensory perception can be roughly categorized. First, we can integrate redundant stimuli which inform us about the same property of the environment or we can combine complementary stimuli which inform us about unique properties in single modalities, thus allowing novel conclusions. Second, we can integrate or combine low-level features of stimuli such as the stimuli’s spatiotemporal appearance or high-level features whose meaning we have learned from experience. For example, we can integrate the low-level seen and heard locations of a ball to localize the ball. We can combine the unique

color and touch of an apple to determine the apple’s ripeness. We can integrate the emotional facial expression and verbal emotional expression of a person to discover a person’s ironic statement. We can combine the heard sound of a specific car and the sight of the car to infer that we perceive a sports car. b Multisensory perceptions helps to disambiguate unisensory perception. If two visual discs move toward each other, coincide and then move through each other, it is ambiguous whether the discs passed or bounced of each other. If a “click” sound is presented when the discs coincide, our visual system preferentially perceives two discs bouncing off

object (Ernst and Banks 2002). As a result of these perceptual advantages, we gain also behavioral benefits: When humans have to detect or discriminate simple audiovisual flashes and beeps, they respond faster (Diederich and Colonius 2004) and more accurately (McDonald et  al. 2000) to the combined flash-beep than to the unisensory flash or beep alone. Overall, multisensory perception enables humans to represent complex interrelations between diverse environmental stimuli and to represent the environment less ambiguously and more reliably. Because these representational advantages allow us to respond more adaptively to the challenges of our environment, our multisensory perceptual

abilities evolved as an evolutionary advantage in natural selection. However, in order to benefit from these advantages, our mind and brain had to solve specific problems of multisensory perception which do not arise in unisensory perception in the same ­manner. First, we only have access to noisy percepts of stimuli which arouse from a priori unknown objects in the environment. Yet, we should only relate multiple unisensory percepts which stem from a common object (i.e., providing interrelated signals), but should treat percepts from different objects independently. In other terms, our brain has to infer the causes which generated the sensory representations in order to correctly relate or segregate multiple unisensory rep-

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resentations (Shams and Beierholm 2010). For example, when speaking to a person in front of us, we should integrate the person’s voice and lip movements to better understand the person, but we should not integrate the voice of a person standing next to us at the same time. Second, even if we are certain that two unisensory percepts come from the same object, the problem arises as to how to weight the two percepts during integration: When speaking to a person in a quiet environment, we do not read much from the person’s lips, but give a large weight to the person’s voice. If, however, we are in a very loud environment (e.g., next to a crowded road), reading the person’s speech from the lips might give more information, so we would give more weight to the visual speech percept. A third problem of multisensory perception arises from the fact that there may be discrepancies between the unisensory percepts even if the percepts stem from the same object – imagine, for example, that you locate a moving bouncing ball which is some distance away. Due to the slow speed of sound, the sight of the ball will have moved further when the bouncing sound reaches your ears. Thus, there will be a spatial (and a temporal) disparity between the heard and the seen locations of the ball. Yet, despite these disparities, we usually are able to unify our auditory and visual spatial percepts and perceive a unique audiovisual location of the ball. In other terms, we integrate the audiovisual spatial stimuli despite their small disparity to perceive a single coherent audiovisual location of the ball. However, because we integrate unisensory percepts despite (small) disparities, we are misled to perceive multisensory illusions as an epiphenomenon of the percepts’ integration. 6.10.2  Multisensory Illusions

Whenever watching TV, we are subject to a multisensory illusion (probably without

noticing it!). Even though the actors’ voices stem from loudspeakers on the side of the TV screen, we perceive that the actors on the screen are talking (at least if the actors’ voices have not been dubbed too badly). Thus, we perceive that the spatial origin of a voice was the actor on the screen, even though in physical reality, the spatial origin was the loudspeaker. In other words, the spatial origin of the voice is illusionarily biased toward the visual spatial location of the actor because we unconsciously integrate the heard voice and seen actor location. This phenomenon is even more striking when we observe a ventriloquist (. Fig. 6.9a). Even though we deliberately know that the ventriloquist himself is producing a voice, we mislocalize the voice toward the ventriloquist’s puppet and perceive a speaking puppet. Such a “ventriloquist illusion” can also be induced and investigated experimentally. When auditory and visual spatial signals are presented with a small spatial discrepancy and observers are required to locate the auditory signal, their auditory location judgment is biased toward the visual signal (. Fig.  6.9e). This “ventriloquist effect” (i.e., a visual bias on auditory location judgments) (Radeau and Bertelson 1977) is a great experimental tool to investigate audiovisual spatial perception. The size of the ventriloquist effect can be used to investigate under which conditions human observers integrate audiovisual spatial signals and how they weight the signals in the integration process. For example, we can investigate whether the ventriloquist effect shrinks if the auditory and the visual spatial signals are presented asynchronously (i.e., with a temporal disparity) or on very distant locations (i.e., with a large spatial disparity). When we reduce the spatial reliability of the visual spatial signal (e.g., by increasing the variance of a cloud of dots which serves as visual spatial signal), we could also investigate whether we still find a ventriloquist effect when  



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..      Fig. 6.9  Multisensory illusions. a In the ventriloquist illusion, observers integrate the puppet’s moving mouth with the ventriloquist’s voice to perceive a speaking puppet. Thus, the voice’s spatial origin is illusionarily biased toward the puppet‘s mouth. (Adapted from Van Rensselaer 1955). b In the McGurk illusion, observers perceive a spoken syllable “ba” together with a lip movement of the syllable “ga” as an integrated, but illusionary, percept “da”. (Reproduced from: Massaro et  al. (1996), with the permission of the Acoustical Society of America.) c In the soundinduced flash illusion, observers perceive a single brief visual flash together with two beeps as an illusionary

double flash. d In the rubber-hand illusion, observers perceive a rubber hand as belonging to their body if their real hand is stroked in synchrony with the rubber hand. (Reproduced from: Haans et al. (2012); with permission). e In an experimental ventriloquist paradigm, human observers are synchronously presented with a visual spatial stimulus (e.g., a cloud of dots) and an auditory spatial stimulus (e.g., a short burst of noise). Typically, participants localize the noise with a bias toward the cloud of dots (i.e., the ventriloquist effect), indicating that the participants perceived an integrated audiovisual percept

actually the visual signal provides very little spatial information. Such experimental manipulations and their effect on multisensory illusions provide the researcher with very valuable evidence to investigate multisensory perception, as we will see in the remainder of this chapter. Importantly, multisensory illusions are not confined to audiovisual spatial percep-

tion, but they can be found in many more combinations of audiovisual signals and further sensory channels. When observers are presented with a spoken syllable “ba” together with a video of a mouth speaking the slightly disparate syllable “ga,” the observers integrate the two signals and report to hear an intermediate syllable “da” (. Fig.  6.9b). This “McGurk illu 

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sion” (McGurk and MacDonald 1976) demonstrates that our speech perceptions is audiovisual. Further, if accompanied by multiple beeps, a single visual flash is perceived as multiple flashes, the “soundinduced flash illusion” (. Fig. 6.9c) (Shams et  al. 2000). The sound-induced flash illusion illustrates that multisensory illusions arise from cross-­modal biases in both directions of the auditory and visual channels – while in the ventriloquist and McGurk illusion vision biases our auditory percept, the sound-­ induced flash illusion demonstrates an auditory bias on our visual percept. Numerous multisensory illusions show similar biases across many combinations of sensory modalities – when rubbing their own hands, observers perceive their skin like a parchment paper if this tactile sensation is experimentally combined with a rough rubbing sound (i.e., the parchment skin illusion) (Jousmaki and Hari 1998). Observers even adopt a rubber hand to their own body scheme (the “rubber-hand illusion” (. Fig.  6.9d) (Botvinick and Cohen 1998) or feel their own body located toward a virtual avatar’s position (the “out-of-body illusion” (Lenggenhager et  al. 2007) if the visually presented rubber hand or the avatar is stroked in synchrony with the observers. Multisensory illusions are also ubiquitous when we perceive the flavor of food. For example, a sucrose solution of constant concentration tastes sweeter when colored in darker as compared to brighter red (Johnson and Clydesdale 1982) and potato chips taste crispier if an amplified crunching sound accompanies their consumption (Zampini and Spence 2004). Overall, such multisensory illusions demonstrate the ubiquity of our multisensory perceptions in our everyday lives. Further, creating multisensory illusion in behavioral experiments allows researchers to investigate the psychophysical principles which our mind and brain follow when they create those illusions.  

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6.10.3  Principles of Multisensory

Perception

The principles of multisensory integration were first determined in psychophysical studies using perceptual illusions such as the ventriloquist paradigm (. Fig.  6.9e). To create these illusions, observers are presented with slightly discrepant signals of multiple (usually: two) modalities (e.g., audiovisual spatial signals) and are requested to report their percept in only one modality (e.g., “From which location did the sound come?”). The shift of the reported percept (e.g., “10° to the left”) as compared to the unimodal stimuli (e.g., auditory signal at −10° and visual signal at 0°) indicates a cross-modal bias (e.g., the ventriloquist effect). The cross-modal bias also reveals the observer’s relative weighting of stimuli during integration. Based on cross-modal biases, researchers formulated principles which model the psychophysical processes creating the multisensory illusions.  



zz The Modality Appropriateness Hypotheses

One striking observation across different illusions was that the different modalities were dominating the illusions in specific domains. For example, vision dominates audition in the ventriloquist effect (Radeau and Bertelson 1977). Similarly, vision dominates our proprioceptive percept of our spatial limb position (Warren and Cleaves 1971) and the seen object size dominates over the felt object size (Rock and Victor 1964). Thus, this “visual capture” showed that vision dominated the integration of spatial information. By contrast, “auditory capture” was found in the temporal domain: multiple auditory beeps perceptually multiply a single visual flash in the sound-induced flash illusion (Shams et al. 2000), auditory beeps temporally pull apart two visual flashes (Morein-Zamir et  al. 2003), and audition dominates temporal rate perception of audiovisual oscillatory signals (Shipley

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1964). Hence, visual and auditory capture showed that these modalities dominated in the spatial and temporal domains, respectively. Welch and Warren (1980) explained this pattern by the “modality appropriateness hypothesis”  – the sensory modalities process signals of a certain physical domain with high reliability (i.e., little variability) and, therefore, dominate tasks involving these signals. The modality-­specific reliability arises from the “hard-­ wired modalityspecific formats of neural coding. For example, the visual modality favors spatial processing by using a retinotopic code (i.e., adjacent points in the visual field are represented at adjacent points in the visual cortex) while the temporal resolution of the visual pathways is rather low. Conversely, the auditory modality favors temporal processing by using a spectral tonotopic code (i.e., adjacent sound frequencies are represented at adjacent points in auditory cortex), while the coding of auditory spatial information in the auditory pathways is rather limited. Thus, vision dominates audition in case of spatial perception and audition dominates vision in case of temporal perception. However, the “modality appropriateness hypothesis” could not account for the fact that the reliability of a sensory representation does not depend only on the neural representational format (e.g., retinotopy or tonotopy). But sensory reliability also depends on the strength and noisiness of the stimuli in the physical environment, which depends on specific contexts. Subjectively, we perceive changing perceptual uncertainty; for example, when it gets darker at dusk, visual stimuli progressively provide less-reliable spatial information than auditory spatial stimuli. Similarly, background noise degrades the temporal reliability of auditory stimuli. Obviously, our brain adapts multisensory perception to such changing contexts and it does not rely on a fixed, hard-wired dominance of one modality over another as suggested

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by the “modality appropriateness hypothesis.” Thus, the brain must have developed a mechanism to adapt multisensory perception to changing strength and noisiness of environmental stimuli. The Bayesian perspective on perception (Knill and Pouget 2004) was the first theory to formally acknowledge that in perception observers estimate physical properties from noisy, uncertain percepts of physicochemical stimuli and a priori expectations (see also 7 9.2.2). Thus, the Bayesian perspective makes two core predictions. First, the stimuli’s percepts are combined with prior expectations of the stimuli’s properties to yield a “posterior” percept of the stimuli (. Fig.  6.10a). Second, the Bayesian perspective predicts that observers have to infer the stimuli’s physical properties from a distribution over possible stimulus values which are encoded in neural representations. Hence, the observers represent not only a stimulus’ point estimate (e.g., the mean of the distribution of the possible stimulus values) but also the uncertainty of the stimulus’ value (i.e., the reliability or inverse of the variance of the distribution). Representing uncertainty has a direct consequence when it comes to integration and weighting of multisensory percepts: If one percept is relatively certain (say, an auditory spatial percept of a bouncing sound), but the other is momentarily very uncertain (say, a visual spatial percept of a bouncing ball in near darkness), should an observer then still give a fixed weight to the unisensory representations as suggested by the “modality appropriateness hypothesis”? Of course, the weighting of multiple unisensory percepts should optimally depend on the dynamically changing reliability of the stimuli’s percepts, not the general, hard-wired reliability of the modality per se.  



zz Reliability-Weighted Integration

If multisensory percepts arose from a common cause, the Bayesian perspective on

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..      Fig. 6.10  Psychophysical models of multisensory perception: Reliability-weighted integration. a The model of reliability-weighted integration is a Bayesian model because it incorporates prior expectations and sensory uncertainty. When we locate, for example, a bouncing ball by vision and audition, we combine our a priori expectation (e.g., we expect the ball in front of us) with our sensory percepts by weighting the prior expectation, the visual percept and the auditory percept by their relative reliability (i.e., reliability is the inverse of a probability distribution’s variance and quantifies a percept’s uncertainty). Because under normal viewing conditions vision represents object location more reliably than audition, the posterior Reliability-weighted percept ( SˆAV ) is closer to the visual ( SˆV ) than to the auditory percept Sˆ A . Reliability-weighted integration is an optimal weighting strategy because it leads to a posterior percept which

is more reliable than either of the ­unisensory percepts. Note that prior expectation and sensory percepts are formalized as probability distribution which represent not only the most likely location (i.e., a distribution’s mean S) but also the possible alternative locations due to perceptual uncertainty (i.e., a distribution’s variance σ2). b When observers localize audiovisual objects and visual reliability is high (black), the visual signal location gains a large weight on observers’ perceived location (i.e., the audiovisual perceived location approaches the unisensory visual perceived location). If the visual spatial reliability is low (blue), the auditory signal location gains a large weight on observers’ perceived location. Note that the model’s predicted weighting of audiovisual signals (solid lines) closely matches the data points. (Adapted from Alais and Burr (2004); with permission)

perception predicts that the optimal integration strategy is to weight the multisensory percepts (and the prior expectation) proportional to their relative reliability (i.e., the inverse of their sensory variance) (Ernst and Banks 2002) (. Fig.  6.10a). Reliability-­weighted integration is a statistically optimal strategy because it exploits the stimuli’s redundancy to enhance sensory reliability  – the integrated percept is more reliable than each of the unimodal percepts (i.e., an integration benefit). For example, an observer usually estimates the location of a bouncing ball from its visual location under normal viewing conditions (i.e., gives vision a large and audition a small weight), but in a twilight environment the observer

rather relies on the ball’s bouncing sound (i.e., gives vision a large and audition a small weight). If the observer follows this weighting strategy, he/she will locate the ball more reliably than using only the sight or sound of the ball. These theoretical predictions have been elegantly supported in experiments manipulating sensory reliability in visual-haptic object size estimation and audiovisual localization (Alais and Burr 2004; Ernst and Banks 2002). For example, the visual dominance in judgments of audiovisual object location (i.e., a large visual weight) gives way to an auditory dominance (i.e., a large auditory weight) if the reliability of the visual signals is degraded (. Fig.  6.10b).





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In other words, the strong visual bias on the Thus, the fixed assumption of a common perceived audiovisual signal location in the cause in the reliability-­weighted integration ventriloquist effect reverses into an auditory model is too inflexible in natural conditions bias if the visual signals are degraded. Thus, often providing many multisensory stimuli the reliability-weighted percept of the audio- from multiple objects. So how do our mind visual stimuli is more reliable than either of and brain determine whether multisensory stimuli arouse from a common cause (i.e., a the unisensory percepts. Overall, the model of reliability-weighted unitary event)? integration can account for a host of cross-­ modal biases leading to multisensory illu- zz The Assumption of Unity sions (e.g., the ventriloquist illusion, the It has long been known that human observers McGurk illusion, and the sound-induced more strongly integrate multisensory signals flash illusion). Further, it accounts for the if they assume that a unitary event gave rise to fact that our multisensory perceptions are the multisensory stimuli (Welch and Warren not static, but adapt to a dynamic environ- 1980). This assumption of unity of multisenment in which the strength and reliability of sory stimuli not only depends on structural physicochemical signals constantly change. factors like the spatiotemporal corresponThereby, the model can account for more dence between multisensory signals but also phenomena of multisensory perception depends on semantic factors. For example, if than the “modality appropriateness hypoth- observers explicitly judge the unity (i.e., “Did esis” which assumes that the weights to the signals come from a common or from integrate unisensory percepts are fixed for a independent sources?”) of audiovisual spatial given combination of multisensory stimuli, stimuli in a ventriloquist paradigm, the unity judgments decline with larger temporal and independently from the sensory context. However, the model of reliability-­ spatial disparities between the stimuli (Rohe weighted integration inflexibly assumes that and Noppeney 2015b; Wallace et  al. 2004) multisensory stimuli arose from a single (. Fig. 6.11a). If observers perceive a unity common object in the environment – in our of multisensory signals, they more strongly natural environment, usually multisensory integrate the signals into a multisensory stimuli from multiple objects impinge on our percept. This is indicated by stronger crossreceptors at any time. For example, when we modal biases in trials in which observers pertalk to a person in front of us at a party, we ceive unity as compared to non-unity trials see the person’s moving lips, but hear a mul- (Rohe and Noppeney 2015b) (. Fig. 6.11b). titude of voices which a priori could all stem Moreover, semantic factors modulate the from those lips. In such a scenario, a “forced cross-modal bias, for example the knowledge integration” of the lips and a “wrong” voice of a plausible cause of the stimuli. A seen would misattribute information, which is puff of steam from a kettle biases localizaclearly a case of suboptimal multisensory tion of a whistling sound more strongly than perception. Of course, our brain does not a light bulb biases the localization of a ringing commit such obvious attribution errors. To bell (Jackson 1953). Thus, coherent semantic avoid that unrelated multisensory signals are associations between unisensory percepts, integrated, our brain has to determine which which we have learned during our developstimuli where elicited by a common object. ment, determine whether we perceive multiple For example, if a large spatiotemporal dis- percepts as stemming from a unitary event. In conclusion, the assumption of unity crepancy suggests independent causes of the stimuli, optimal reliability-weighted integra- (i.e., a common cause of signals) determines tion gives way to a partial segregation of whether multisensory stimuli are integrated multisensory signals (Gepshtein et al. 2005). or not bound together, while the model of  



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..      Fig. 6.11  Psychophysical models of multisensory perception: the assumption of unity. a The assumption of unity (i.e., did the observer perceive audiovisual stimuli from a common or separate sources) is strongest for congruent audiovisual stpatial stimuli and declines with larger audiovisual disparity. (Adapted from Rohe and Noppeney 2015b). b The assump-

tion of unity is closely linked to the relative sensory weight in multisensory representations as indicated by cross-modal biases: the higher the percentage of common-source reports, the stronger the relative bias of the visual spatial signal on the auditory localization response (i.e., the ventriloquist effect). (Adapted from Wallace et al. 2004; with permission)

reliability-weighted integration describes how multisensory signals are integrated. How could both principles of multisensory perception be rejoined?

generated by independent causes and should thus be treated independently. The problem of the stimuli’s uncertain causal structure can be solved in a principled fashion: If a common cause of the stimuli is likely due to small stimulus discrepancies, the stimuli are integrated by weighting them proportional to their relative sensory reliability. If separate causes are likely due to large discrepancies, the stimuli are treated independently and, hence, segregated. Crucially, the stimuli’s causal structure is not a binary inference, but the observer computes a probability of a common (versus independent) cause(s) from the percepts’ discrepancy. This causal probability then decides whether the percepts are integrated or segregated: The posterior percept of the multisensory stimuli averages the reliability-weighted integrated percept and the unisensory percept proportional to the causal probability of a common versus independent causes, respectively. Thus, the posterior percept accounts for the percepts’ inherent causal uncertainty. Overall, the Bayesian causal inference (CI) model provides a rational strategy to

zz The Causal Inference Model

Observers only partially integrate multisensory signals weighted by their reliability if a common cause of the signal is uncertain which can be suggested for example by the stimuli’s temporal asynchrony or large spatial disparity (Gepshtein et  al. 2005). If observers explicitly infer that a common cause of multisensory stimuli is unlikely, unisensory percepts are not integrated, but segregated (. Fig. 6.11b). From a Bayesian perspective, these two phenomena follow from the uncertain causal structure of multisensory signals which has to be inferred from the signals’ percepts (Kording et  al. 2007) (. Fig. 6.12a). In order to obtain a veridical multisensory perception of the environment, an observer has to infer which stimulus percepts were generated by a common cause and can thus be integrated. Further, the observer has to infer which percepts were  



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..      Fig. 6.12  Psychophysical models of multisensory perception: causal inference. a The Bayesian causal inference model assumes that an observer’s multiple percepts (xV, xA) could arise from two causal structures: the percepts could arise from a common cause (SAV), for example, the speech and the lip movements of a speaking woman. In this case, the observer optimally integrates the percepts weighted by their relative reliability (cf. . Fig. 6.10a). Alternatively, the percepts could arise from independent causes (SA and SV), for example, the speech from the ventriloquist and the lip movements from a puppet. In this case, the observer should not integrate the percepts, but keep them segregated and focus on the task-­relevant percept. However, the exact causal structure is unknown to the observer. Thus, the observer estimates the probability for a common (p(C = 1| xA, xV)) versus independent causes (p(C = 2| xA, xV)) (e.g., from the percepts temporal or spatial disparity). Then the observer averages the reliability-weighted estimate (SˆAV,C =1) and the task-relevant unisensory estimate (SˆA,C = 2 or SˆV,C = 2 ) by this causal probability. Thus, the posterior auditory (SˆA) and visual (SˆV) estimates account  

for the causal uncertainty. (Adapted from Rohe et  al. 2019; with permission). b If observers infer that audiovisual spatial stimuli arouse from a common cause, the ventriloquist effect increases with larger visual reliability as a consequence of reliability-­weighted integration. The ventriloquist effect represents the visual bias on auditory localizations which varies between 1 (i.e., pure visual influence) and 0 (i.e., pure auditory influence). If observers infer independent causes, the ventriloquist effect is much weaker and does not depend on visual reliability as a consequence of the percepts’ segregation. (Adapted from Rohe and Noppeney 2015b; with permission). c In the sound-induced flash illusion, observers selectively count either the number of flashes or the number of beeps in a flash-beep sequence (cf. . Fig.  6.9c). If the flashes are task relevant, observers’ flash counts show a strong bias by the number of beeps which is more pronounced for a small numeric disparity of flashes and beeps, suggesting a common cause. If the beeps are task relevant, the observers’ beep counts show a weak but significant bias by the number of flashes. (Adapted from Rohe and Noppeney 2015b; with permission)  

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elegantly reconcile the question of whether and how to integrate multisensory stimuli. Thus, the CI model can account for phenomena of multisensory perception described by the model of reliability-­weighted integration and the assumption of unity. If the probability of a common cause is very high, the CI model predicts reliability-­weighted integration (. Fig.  6.10a). If spatiotemporal discrepancies between stimuli reduce common-cause inferences, multisensory integration is reduced as indicated by weaker crossmodal biases (. Fig. 6.11b). However, if the probability of a common cause is below 1 (i.e., the probability of separate causes is above 0), the model can account for two important additional findings. First, reliability-weighted integration is restricted to multisensory events in which observers infer a common cause (. Fig.  6.12b). If observers infer separate causes, the cross-modal bias is strongly reduced and does not depend on the stimuli’s relative reliability, indicating a segregation of the multisensory stimuli. Second, if observers selectively focus on one modality, the taskrelevant signal of the multisensory stimuli has a stronger influence on the cross-­modal bias as compared to the task-­irrelevant signal (Rohe and Noppeney 2016). This taskdependent segregation is more pronounced if a large stimulus disparity suggests independent causes (. Fig.  6.12c) because a high probability of separate causes gives a small weight to the segregated task-irrrelevant percept. Thus, observers use the posterior multisensory percept which is more relevant for the current task. To make an example for multisensory causal inference: If you are early on a party speaking to the host, you would infer that the voice and the moving lips belong to a single person and, therefore, integrate these audiovisual linguistic signals with a stronger weight on your highly reliable auditory percept (i.e., in case of a certain common cause, the posterior auditory and visual percepts converge). If the party becomes more crowded, you  

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have more potential causes of voices and your auditory perception becomes less reliable. Thus, you focus more on the host’s lip movements and give them a larger weight if you want to follow his/her remarks (i.e., you focus on your posterior visual percept). Otherwise, you could decide to focus on the interesting conversation which just started behind you, using only your posterior auditory percept from a different speaker. 6.10.4  The Neural Correlates

of Multisensory Perception

So far, we described multisensory perception based on psychophysical experiments and principles. But how does our brain relate inputs from multiple sensory channels and implement the psychophysical principles which form our multisensory perception? These questions have been mostly investigated by focusing on multisensory processes in single neurons (using electrophysiological methods) and cortical hierarchies (using M/ EEG and fMRI). zz Multisensory Interactions in Single Neurons

Earlier work on multisensory integration in single neurons focused on the superior colliculus (SC) residing in the midbrain. SC controls the change of orientation (e.g., by saccadic eye or head movements) and, therefore, needs access to information from multiple modalities (Stein and Stanford 2008). In electrophysiological experiments, researchers place electrodes in animals’ (e.g. cats’) SC neurons, present unisensory stimuli separately and bisensory stimuli jointly (e.g., moving spots and noise bursts), and then record the rate of action potentials (i.e., firing rate) as the neuron’s response to the stimulus presentation. When comparing a neuron’s firing rates after uni- versus bisensory stimulation, any significant change of a unisensory firing rate under bisensory stimulation defines some form of

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multisensory interaction in the single neuron. Using this approach, it was shown that animals’ SC neurons relate multisensory stimuli because they respond to combined visual, auditory, and tactile stimuli with

response depression or enhancement as compared to the most effective individual unisensory stimulus (Meredith and Stein 1983) (. Fig. 6.13a). In other words, some neurons increase their firing rate under

..      Fig. 6.13  Multisensory interactions in single neurons. a The plot shows the time course of action potentials (i.e., one dot) from a single neuron in a cat’s superior colliculus in response to auditory, visual, or audiovisual stimuli (i.e., one row corresponds to one trial). The neuron responds much more strongly to audiovisual than auditory or visual stimulation alone. Thus, the neuron shows multisensory response enhancement. (Adapted from Meredith and Stein (1983); Reprinted with permission from

AAAS). b Neurons in the cat’s superior colliculus demonstrate stronger response enhancement for synchronous audiovisual stimuli (ΔAV  =  0  ms) than to asynchronous stimuli (ΔAV = ±200 ms, i.e., the visual or auditory stimulus leads by 200 ms). Thus, the temporal principle predicts that large temporal disparities between multisensory stimuli reduce multisensory interactions in single neurons. (Adapted from Meredith et al. (1987); with permission)



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multisensory stimulation while other neurons decrease their firing rate under such a stimulation. Further, even an ineffective unisensory stimulus, which does not elicit a response per se, can still change the response to another effective unisensory stimulus when both stimuli are presented in combination. These forms of multisensory response profiles in a neuron indicate that the neuron is subject to multisensory interactions. However, multisensory interactions in single neurons can show quite different profiles and the multisensory response behavior in a region’s neurons is often not consistent. Importantly, single multisensory neurons are located not only in SC but also in many other regions of the brain, for example, monkeys’ posterior parietal cortex (Duhamel et al. 1998) or superior temporal cortex (Bruce et al. 1981). However, despite the variety of multisensory interaction profiles, Stein and Meredith found that multisensory interactions in SC neurons are governed by three principles (Stein and Meredith 1993). According to the spatial principle (Meredith and Stein 1986a), multisensory enhancement occurs if the multisensory signals emerge within the crossmodally registered receptive fields of the neuron. A neuron’s receptive field is defined as a region in space (e.g., a visual field) from which a stimulus elicits a response in the tested neuron. By contrast, multisensory depression or independence occurs if one of the multisensory stimuli emerges from outside of the receptive field. According to the temporal principle (. Fig. 6.13b), temporal disparities in the onset of multisensory stimuli decrease multisensory interactions (Meredith et  al. 1987). Importantly, strongest interactions were not necessarily found for synchronous stimuli, but for stimuli whose unisensory temporal response profile overlapped maximally. According to the principle of inverse effectiveness, multisensory enhancement is especially pronounced for combined multisensory stimuli whose individual unisensory  

neural responses are weak (Meredith and Stein 1986b). Overall, research in single neurons revealed similar principles of multisensory integration as psychophysical studies. Multisensory integration is especially strong if the signals’ spatiotemporal correspondence makes a common cause likely and the multisensory interactions are strongest if several stimuli with a weak neuronal response are combined, as also predicted by the model of reliability-weighted integration. However, it is very unlikely that our multisensory perceptions entirely rely on the multisensory interactions in single neurons. Rather, our multisensory perceptions correspond to multisensory representations and processes in entire cortical hierarchies. zz Multisensory Representations and Processes in Cortical Hierarchies

Cortical hierarchies consist of the functionally related cortical regions which process progressively more complex features of unisensory stimuli (. Fig. 6.14a; cf. 6.4.1). For example, in the visual cortical hierarchy, the early visual regions respond to edge contrast and orientation (e.g., V1  in the occipital lobe), intermediate visual regions respond to, for example, motion (region MT) or simple geometric shapes (e.g., V4), and higher visual regions respond to complex objects (e.g., faces in the fusiform face area). Broadly, two such hierarchies have been identified in the visual system: the dorsal pathway from occipital cortex into posterior parietal cortex represents the location of objects (“where stream”), whereas the ventral pathway from occipital cortex into temporal cortex represents the identity of objects (“what stream”) (Mishkin et  al. 1983). Similar cortical hierarchies exist in other modalities. For example, primary auditory cortex (i.e., Heschl’s gyrus in the superior temporal lobe) branches into a ventral stream into anterior temporal cortex representing auditory objects (e.g., voices) and a dorsal stream into parietal cortex rep 

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resenting sound location (Tian et al. 2001). From the perspective of multisensory perception, the crucial question is whether multisensory interaction only arise at the top of these seemingly unisensory hierarchies, in regions where the hierarchies converge (e.g., parietal cortex for spatial information), or do representations of multisensory stimuli interact in lower levels of the cortical hierarchies, too (. Fig. 6.14a). To investigate multisensory interactions in cortical hierarchies, researchers predominantly relied on fMRI and EEG (or MEG; see 7 10.3.1 and 10.7.8) experiments. With fMRI, a cortical multisensory interaction is defined by comparing the multisensory fMRI response (i.e., a BOLD response) versus the unisensory responses (i.e., a definition of multisensory interactions analogous to single neurons’ multisensory responses). This logic can be applied for simple or rather complex multisensory stimuli, for example, when comparing the fMRI response to a flash and a beep to a flash-beep or the fMRI response to a spoken word and a seen verbal lip movement and their combination. Similarly, EEG responses (i.e., eventrelated potentials, ERPs) to unisensory versus multisensory responses can be compared to define multisensory interactions. Importantly, while fMRI experiments locate multisensory interactions within a few millimeters in the cortex, EEG experiment pinpoint multisensory interactions in cortical processing time after stimulus presentation within milliseconds. Thus, fMRI experiments investigate where in the brain multisensory interactions occur (e.g., in low-level sensory cortices or higher association cortices). By contrast, EEG experiments investigate when during cortical processing such interactions occur (e.g., early or late after stimulus presentation). Using this approach, fMRI studies revealed multisensory interactions in higher association cortex such as the posterior parietal cortex (Bremmer et al. 2001) and superior temporal sulcus (Beauchamp et al. 2004) using  



6

diverse multisensory stimuli such as simple auditory, visual, and tactile moving stimuli or videos and sounds of tools or musical instruments (. Fig. 6.14b). Yet, multisensory interactions are not confined to the highest regions in cortical processing hierarchies, but emerge already at lower processing levels in putatively unisensory cortex. For example, visual signals modulate neuronal processing in auditory cortex (Kayser et al. 2007) and auditory signals modulate processing in visual cortex (Lewis and Noppeney 2010). EEG studies revealed multisensory interactions in late ERPs more than 300 ms after stimulus onset (Shams et al. 2005) suggesting cortical processing in higher regions of the cortical hierarchy. Yet, multisensory interactions also modulate ERPs as early as ~100  ms after stimulus onset suggesting multisensory interactions in low-level regions of the cortical hierarchy (Mishra et al. 2007) (. Fig. 6.14c). These neuroimaging results consistently demonstrated that multisensory interactions are not confined to the top of cortical hierarchies, but emerge at all levels of the cortical hierarchies, even in the first cortical levels of the presumably unisensory pathways. These low-level multisensory interactions could arise from direct anatomic connections between unisensory regions, top-down feedback from higher-order multisensory regions, or even via crossmodal input from the subcortical thalamus to early sensory regions (Driver and Noesselt 2008) (. Fig.  6.14a). Given the pervasiveness of multisensory interactions along the cortical hierarchy, it appeared as if, provocatively stated, the whole cortex might be multisensory (Ghazanfar and Schroeder 2006). However, multisensory interactions generally increase upstream the cortical hierarchies. In low-level regions, only a small percentage of neurons respond to multisensory stimuli (Bizley et al. 2007). In high-level regions, a majority of neurons demonstrate multisensory responses (Dahl et al. 2009). Overall, neuroscientific studies showed multisensory interactions in single neu 





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..      Fig. 6.14  Multisensory interactions in cortical hierarchies. a In the dorsal visual hierarchy (“where stream,” see 7 6.4.2), projections from the subcortical thalamus are fed forward from early visual (V1) to later visual (e.g., V3AB) regions and terminate in intraparietal regions (IPS). In the dorsal auditory hierarchy, projections from the thalamus are fed forward from early auditory regions (A1) to higher auditory regions (hA) and terminate in intraparietal regions. Multisensory interactions arise all along the visual and auditory hierarchies. Already the thalamus projects cross-modal information to early sensory regions, early sensory regions directly exchange information, and higher regions such as IPS integrate and feed multisensory information back to earlier regions. (Adapted from Rohe & Noppeney (2015a); with permission). b Upper panel: statistical maps of fMRI BOLD responses to videos of tools (red), sounds of

tools (green) or videos and sounds of tools (blue) in superior temporal cortex. Lower panel: average BOLD response (% signal change) to visual (V), auditory (A), and audiovisual (AV) stimulation in visual, auditory, and multisensory patches in superior temporal sulcus. (Reprinted by permission from Springer Nature Nature Neuroscience, Beauchamp et al. (2004) © 2004, Springer Nature). c Upper panel: event-­ related potential (ERP) in response to one visual flash (green), two auditory beeps (red), and their audiovisual combination (blue) in an occipital electrode. The audiovisual ERP shows multisensory interactions (i.e., an audiovisual response larger than the summed unisensory responses) as early as 120 ms after stimulus onset. Lower panel: topographical voltage maps of the audiovisual ERP at 120  ms after stimulus onset suggesting that multisensory interactions arose from visual occipital regions. (Adapted from Mishra et al. (2007); with permission)

rons and all along entire cortical hierarchies. However, while these studies revealed where and when in the brain unisensory stimuli lead to multisensory interactions, it remained less clear what these multisensory interactions meant for our subjective multisensory perception.

could these principles also be used to understand neural multisensory processes? At this point, it is important to note that multisensory processes were often differently envisaged in psychophysical studies as compared to neurophysiological and neuroimaging studies. The psychophysical studies derived principles from psychological and computational considerations to investigate multisensory perception. For example, this approach asked how an ideal observer would solve the signal integration problem given by redundant noisy multisensory signals, coming up with the solution of reliability-­ weighted integration (Ernst and Banks 2002). By contrast, neuroscientific studies operationalized multisensory processes by neural response properties. For example, the approach investigated whether neurons’ firing rates under uni- versus multisensory stimulation differed, leading to findings of multisensory response enhancement versus depression (Meredith and Stein 1983). These approaches partially converged on similar principles, for example, the find-

6.10.5  Bridging the Levels

of Psychophysical and Neural Analyses

In order to understand how the brain implements multisensory processes which ultimately form our multisensory perception, it does not only suffice to investigate where and when the brain shows multisensory interactions, but we also must investigate which specific multisensory processes the brain implements (i.e., in single neurons, populations of neurons, or cortical hierarchies). Specific multisensory processes were precisely formulated in the psychophysical principles of multisensory perception, so

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ing that multisensory integration in behavior and neurons crucially depends on spatiotemporal disparity of multisensory stimuli. Only recently, studies set out to close the gap between psychophysical and neural models of multisensory processes to get a comprehensive understanding at all levels of psychological and neural analyses (Fetsch et al. 2013), by applying the psychophysical principles to neural data. Neurons in monkeys’ motion-processing region in the temporal cortex, which responds to visual and vestibular motion stimuli, implement reliability-­weighted integration (Fetsch et al. 2012). The neurons gave more weight to vestibular than to visual motion stimuli when the reliability of the visual motion stimuli was degraded. Importantly, this reweighting of visual-vestibular motion stimuli was not evident in single neurons, but the collective response of numerous neurons (i.e., a neuronal population of hundreds of neurons) represented reliability-weighted integration. Thus, psychophysical multisensory principles are presumably implemented in larger circuits of the brain. In line with this notion, recent fMRI and EEG studies demonstrated that multisensory causal inference is implemented across entire cortical hierarchies (Rohe et al. 2019; Rohe and Noppeney 2015a). While low-level visual and auditory cortices represented mainly the stimuli of their preferred modality early after stimulus onset, posterior parietal cortex represented a reliability-weighted average of the audiovisual stimuli slightly later (. Fig. 6.15). Only at the top of the dorsal cortical hierarchy, in anterior parietal cortex, at a “late” processing stage, the brain combined the reliability-weighted average with the task-­relevant unisensory representation according to the probability of a common versus separate causes. This representation, which takes the observers’ causal inferences into account, then closely correlated with observers’ subjective multisensory perception. Thus, our subjective multisensory perception is based  

on the concerted interplay of multiple uniand multisensory ­ representations in lowlevel and high-level cortical regions, early and late after multisensory signals were emitted by a multisensory object. 6.10.6  Multisensory Perception

in Mental Disorders

So far, we have learned on experimental paradigms to investigate multisensory perception and presented basic principles of multisensory perception and their neural correlates. However, this knowledge has also important clinical applications. In several mental disorders, the pathopsychological symptoms affect perceptual processes including multisensory processes. Most prominently, schizophrenia patients in some cases perceive hallucinations: they hear voices or see faces (or have perceptions in other sensory modalities) without any physical stimulus. Thus, researchers investigated whether hallucinations arise from altered integration of internal mental images and external signals and/or signals from multiple modalities. For example, the integration of visual lip movements in the perception of auditory phonemes in the McGurk illusion was reduced in schizophrenia patients, while the integration of audiovisual spatial information in the ventriloquist illusion remained intact (de Gelder et al. 2003). Children with autism often suffer from specific sensory aversions and sensitivities, which suggests that autism could also change patients’ multisensory perceptions. Indeed, it was shown that autistic children were more likely than a healthy control group to perceive a double flash illusion (Foss-Feig et  al. 2010). Patients with a body dysmorphic disorder hold the belief that a part of their body parts appears abnormal (e.g., a deformed face). This belief rests upon a multisensory percept of the own body which integrates the visual appearance of a body part with

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..      Fig. 6.15  Causal inference in cortical hierarchies. a Left panel: fMRI measured the BOLD responses to audiovisual spatial stimuli along the dorsal visual and auditory spatial hierarchies (cf. . Fig.  6.14a). Right panel: for each cortical region, the plot shows the probability that an estimate of the causal inference (CI) model is represented in a region’s activation pattern (for an explanation of the CI estimates, see . Fig. 6.12a). Only higher intraparietal (IPS) regions represent the posterior auditory and visual estimates that account

for the causal uncertainty. (Adapted from Rohe and Noppeney 2015a). b Left panel: EEG measured the topographical ERP activation patterns in responses to audiovisual flashes and beeps. Right panel: for each time interval after stimulus onset, the plot shows the probability that an estimate of the CI model is represented in an ERP pattern. Only at later time points, the ERP topographies represent the ­posterior auditory and visual estimates that account for the causal uncertainty. (Adapted from Rohe et al. 2019)

its proprioceptive and tactile percept. Thus, patients might show an altered rubber hand illusion which results from integration of visual-­ proprioceptive stimuli, but surprisingly patients’ rubber hand illusions were comparable to a healthy control group (Kaplan et al. 2014). To date, researchers did not consistently find that mental disorders such as schizophrenia, autism, and body dysmorphic disorder affect multisensory processes.

However, these examples demonstrate that basic knowledge of multisensory processes and experimental tools to investigate them help to build psycho- and physiopathological models of mental disorders. Thus, aberrant multisensory processes in mental disorders might help to develop sensitive and specific diagnostic markers of disorders and, potentially, guide therapeutic interventions (e.g., cognitive behavioral therapy or neurofeedback).





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References

6

Alais D, Burr D (2004) The ventriloquist effect results from near-optimal bimodal integration. Curr Biol 14(3):257–262 Beauchamp MS, Argall BD, Bodurka J, Duyn JH, Martin A (2004) Unraveling multisensory integration: patchy organization within human STS multisensory cortex. Nat Neurosci 7(11):1190–1192. nn1333 [pii]. https://doi.org/10.1038/nn1333 Bizley JK, Nodal FR, Bajo VM, Nelken I, King AJ (2007) Physiological and anatomical evidence for multisensory interactions in auditory cortex. Cereb Cortex (New York, NY : 1991) 17(9):2172–2189. bhl128 [pii]. https://doi.org/10.1093/cercor/bhl128 Botvinick M, Cohen J (1998) Rubber hands ‘feel’ touch that eyes see. Nature 391(6669):756. https:// doi.org/10.1038/35784 Bremmer F, Schlack A, Shah NJ, Zafiris O, Kubischik M, Hoffmann K, Zilles K, Fink GR (2001) Polymodal motion processing in posterior parietal and premotor cortex: a human fMRI study strongly implies equivalencies between humans and monkeys. Neuron 29(1):287–296. S0896-­6273(01)00198-2 [pii] Bruce C, Desimone R, Gross CG (1981) Visual properties of neurons in a polysensory area in superior temporal sulcus of the macaque. J Neurophysiol 46(2):369–384 Contreras M, Ceric F, Torrealba F (2007) Inactivation of the interoceptive insula disrupts drug craving and malaise induced by lithium. Science 318(5850):655–658. https://doi.org/10.1126/science.1145590 Dahl CD, Logothetis NK, Kayser C (2009) Spatial organization of multisensory responses in temporal association cortex. J Neurosci 29(38):11924– 11932. 29/38/11924 [pii]. https://doi.org/10.1523/ JNEUROSCI.3437-09.2009 de Gelder B, Vroomen J, Annen L, Masthof E, Hodiamont P (2003) Audio-visual integration in schizophrenia. Schizophr Res 59(2–3):211–218. [pii]. https://doi.org/10.1016/s0920-­9964(01)00344-9 Dehaene S, Naccache L (2001) Towards a cognitive neuroscience of consciousness: basic evidence and a workspace framework. Cognition 79(1–2):1–37 Diederich A, Colonius H (2004) Bimodal and trimodal multisensory enhancement: effects of stimulus onset and intensity on reaction time. Percept Psychophys 66(8):1388–1404 Driver J, Noesselt T (2008) Multisensory interplay reveals crossmodal influences on ‘sensory-specific’ brain regions, neural responses, and judgments. Neuron 57(1):11–23. S0896-6273(07)01019-7 [pii]. https://doi.org/10.1016/j.neuron.2007.12.013 Duhamel JR, Colby CL, Goldberg ME (1998) Ventral intraparietal area of the macaque: congruent

visual and somatic response properties. J Neurophysiol 79(1):126–136 Ernst MO, Banks MS (2002) Humans integrate visual and haptic information in a statistically optimal fashion. Nature 415(6870):429–433 Ernst MO, Bulthoff HH (2004) Merging the senses into a robust percept. Trends Cogn Sci 8(4):162– 169. S1364661304000385 [pii]. https://doi. org/10.1016/j.tics.2004.02.002 Fetsch CR, Deangelis GC, Angelaki DE (2013) Bridging the gap between theories of sensory cue integration and the physiology of multisensory neurons. Nat Rev Neurosci 14(6):429–442. nrn3503 [pii]. https://doi.org/10.1038/nrn3503 Fetsch CR, Pouget A, DeAngelis GC, Angelaki DE (2012) Neural correlates of reliability-based cue weighting during multisensory integration. Nat Neurosci 15(1):146–154. nn.2983 [pii]. https://doi. org/10.1038/nn.2983 Foss-Feig JH, Kwakye LD, Cascio CJ, Burnette CP, Kadivar H, Stone WL, Wallace MT (2010) An extended multisensory temporal binding window in autism spectrum disorders. Exp Brain Res 203(2):381–389 Gepshtein S, Burge J, Ernst MO, Banks MS (2005) The combination of vision and touch depends on spatial proximity. J Vis 5(11):1013–1023. 5/11/7 [pii]. https://doi.org/10.1167/5.11.7 Ghazanfar AA, Schroeder CE (2006) Is neocortex essentially multisensory? Trends Cogn Sci 10(6):278–285. S1364-6613(06)00104-5 [pii]. https://doi.org/10.1016/j.tics.2006.04.008 Haans et  al (2012) Individual differences in the rubber-­ hand illusion: Predicting self-reports of people’s personal experiences. Acta Psychol 141: 169–177 Hickok G, & Poeppel D (2000) Towards a functional neuroanatomy of speech perception. Trends Cogn Sci 4(4):131–138. https://doi.org/10.1016/s13646613(00)01463-7 Hickok G, & Poeppel D (2004) Dorsal and ventral streams: a framework for understanding aspects of the functional anatomy of language. Cognition, 92(1–2):67–99. https://doi.org/10.1016/j.cognition.2003.10.011 Hickok G, & Poeppel D (2007) The cortical organization of speech processing. Nat Rev Neurosci 8(5):393–402. https://doi.org/10.1038/nrn2113 Hickok G (2012) The cortical organization of speech processing: feedback control and predictive coding the context of a dual-stream model. J Commun Disord 45(6):393–402. https://doi. org/10.1016/j.jcomdis.2012.06.004 Jackson C (1953) Visual factors in auditory localization. Q J Exp Psychol 5(2):52–65 Johnson J, Clydesdale F (1982) Perceived sweetness and redness in colored sucrose solutions. J Food Sci 47(3):747–752

191 Inputs, Outputs, and Multisensory Processing

Jousmaki V, Hari R (1998) Parchment-skin illusion: sound-biased touch. Curr Biol 8(6):R190. [pii]. https://doi.org/10.1016/s0960-9822(98)70120-4 Kaplan RA, Enticott PG, Hohwy J, Castle DJ, Rossell SL (2014) Is body dysmorphic disorder associated with abnormal bodily self-awareness? A study using the rubber hand illusion. PLoS One 9(6):e99981 Kayser C, Petkov CI, Augath M, Logothetis NK (2007) Functional imaging reveals visual modulation of specific fields in auditory cortex. J Neurosci 27(8):1824–1835. 27/8/1824 [pii]. https://doi. org/10.1523/JNEUROSCI.4737-06.2007 Kim T, Kerschensteiner D (2017) Inhibitory control of feature selectivity in an object motion sensitive circuit of the retina. Cell Rep 19(7):1343–1350 Knill DC, Pouget A (2004) The Bayesian brain: the role of uncertainty in neural coding and computation. Trends Neurosci 27(12):712–719 Kording KP, Beierholm U, Ma WJ, Quartz S, Tenenbaum JB, Shams L (2007) Causal inference in multisensory perception. PLoS One 2(9):e943 Lenggenhager B, Tadi T, Metzinger T, Blanke O (2007) Video ergo sum: manipulating bodily self-­ consciousness. Science 317(5841):1096–1099. 317/5841/1096 [pii]. https://doi.org/10.1126/science.1143439 Lewis R, Noppeney U (2010) Audiovisual synchrony improves motion discrimination via enhanced connectivity between early visual and auditory areas. J Neurosci 30(37):12329–12339. https://doi.org/10.1523/JNEUROSCI.5745-09. 201030/37/12329. [pii] Maoiléidigh DÓ, Ricci AJ (2019) A bundle of mechanisms: inner-ear hair-cell mechanotransduction. Trends Neurosci 42:221 Massaro DW, Cohen MM, Smeele PM (1996) Perception of asynchronous and conflicting visual and auditory speech. J Acoust Soc Am 100(3): 1777–1786 McDonald JJ, Teder-Salejarvi WA, Hillyard SA (2000) Involuntary orienting to sound improves visual perception. Nature 407(6806):906–908. https:// doi.org/10.1038/35038085 McGurk H, MacDonald J (1976) Hearing lips and seeing voices. Nature 264(5588):746–748 Meredith MA, Nemitz JW, Stein BE (1987) Determinants of multisensory integration in superior colliculus neurons. I.  Temporal factors. J Neurosci 7(10):3215–3229 Meredith MA, Stein BE (1983) Interactions among converging sensory inputs in the superior colliculus. Science 221(4608):389–391 Meredith MA, Stein BE (1986a) Spatial factors determine the activity of multisensory neurons in cat superior colliculus. Brain Res 365(2):350–354 Meredith MA, Stein BE (1986b) Visual, auditory, and somatosensory convergence on cells in superior

6

colliculus results in multisensory integration. J Neurophysiol 56(3):640–662 Mishkin M, Ungerleider LG, Macko KA (1983) Object vision and spatial vision: two cortical pathways. Trends Neurosci 6:414–417 Mishra J, Martinez A, Sejnowski TJ, Hillyard SA (2007) Early cross-modal interactions in auditory and visual cortex underlie a sound-induced visual illusion. J Neurosci 27(15):4120–4131 Morein-Zamir S, Soto-Faraco S, Kingstone A (2003) Auditory capture of vision: examining temporal ventriloquism. Brain Res Cogn Brain Res 17(1):154–163. https://doi.org/10.1016/ s0926-­6410(03)00089-2. [pii] O'Connor DH, Fukui MM, Pinsk MA, Kastner S (2002) Attention modulates responses in the human lateral geniculate nucleus. Nat Neurosci 5(11):1203 Radeau M, Bertelson P (1977) Adaptation to auditory-­ visual discordance and ventriloquism in semirealistic situations. Percept Psychophys 22(2):137–146 Rauschecker JP (2018) Where, when, and how: are they all sensorimotor? Towards a unified view of the dorsal pathway in vision and audition. Cortex; a journal devoted to the study of the nervous system and behavior 98:262–268 Rensselaer Av (1955). Fun with ventriloquism. New York: Garden City Books. Rizzolatti G, Fadiga L, Gallese V, Fogassi L (1996) Premotor cortex and the recognition of motor actions. Cogn Brain Res 3(2):131–141 Rock I, Victor J (1964) Vision and touch: an experimentally created conflict between the two senses. Science 143(3606):594–596 Rohe T, Ehlis A-C, Noppeney U (2019) The neural dynamics of hierarchical Bayesian causal inference in multisensory perception. Nat Commun 10(1):1907. https://doi.org/10.1038/s41467-01909664-2 Rohe T, Noppeney U (2015a) Cortical hierarchies perform Bayesian causal inference in multisensory perception. PLoS Biol 13(2):e1002073 Rohe T, Noppeney U (2015b) Sensory reliability shapes perceptual inference via two mechanisms. J Vis 15(5):1–16 Rohe T, Noppeney U (2016) Distinct computational principles govern multisensory integration in primary sensory and association cortices. Curr Biol 26(4):509–514 Schroeder CE, Wilson DA, Radman T, Scharfman H, Lakatos P (2010) Dynamics of active sensing and perceptual selection. Curr Opin Neurobiol 20(2):172–176. https://doi.org/10.1016/j. conb.2010.02.010 Sekuler R (1997) Sound alters visual motion perception. Nature 385(6614):308 Shams L, Beierholm UR (2010) Causal inference in perception. Trends Cogn Sci 14(9):425–432

192

6

T. Rohe and M. L. Zeise

Shams L, Iwaki S, Chawla A, Bhattacharya J (2005) Early modulation of visual cortex by sound: an MEG study. Neurosci Lett 378(2):76–81 Shams L, Kamitani Y, Shimojo S (2000) What you see is what you hear. Nature 408(6814):788. https:// doi.org/10.1038/35048669 Shipley T (1964) Auditory flutter-driving of visual flicker. Science 145(3638):1328–1330 Stein BE, Meredith MA (1993) The merging of the senses. The MIT Press, Cambridge, MA Stein BE, Stanford TR (2008) Multisensory integration: current issues from the perspective of the single neuron. Nat Rev Neurosci 9(4):255–266. nrn2331 [pii]. https://doi.org/10.1038/nrn2331 Tian B, Kuśmierek P, Rauschecker JP (2013) Analogues of simple and complex cells in rhesus monkey auditory cortex. Proc Natl Acad Sci 110(19):7892–7897 Tian B, Reser D, Durham A, Kustov A, Rauschecker JP (2001) Functional specialization in rhesus monkey auditory cortex. Science 292(5515):290– 293. 292/5515/290 [pii]. https://doi.org/10.1126/ science.1058911

Usrey WM, Alitto HJ (2015) Visual functions of the thalamus. Ann Rev Vision Sci 1:351–371 Wallace MT, Roberson GE, Hairston WD, Stein BE, Vaughan JW, Schirillo JA (2004) Unifying multisensory signals across time and space. Exp Brain Res 158(2):252–258. https://doi.org/10.1007/ s00221-004-1899-9 Warren DH, Cleaves WT (1971) Visual-proprioceptive interaction under large amounts of conflict. J Exp Psychol 90(2):206–214 Welch RB, Warren DH (1980) Immediate perceptual response to intersensory discrepancy. Psychol Bull 88(3):638–667 Wilson M (2002) Six views of embodied cognition. Psychon Bull Rev 9(4):625–636 Wong HY (2017) On proprioception in action: multimodality versus deafferentation. Mind Lang 32(3):259–282 Zampini M, Spence C (2004) The role of auditory cues in modulating the perceived crispness and staleness of potato chips. J Sens Stud 19(5):347–363

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Neuroplasticity in Humans Hubert R. Dinse Contents 7.1

Introduction – 194

7.2

Characteristics of Neuroplasticity – 194

7.2.1 7.2.2 7.2.3 7.2.4 7.2.5 7.2.6

7.2.8

 ifferences between Developmental and Adult Plasticity – 194 D Drivers of Neuroplasticity – 195 Time Scales of Plastic Changes – 196 Region-Specificity of Neuroplasticity – 196 Relation between Brain Changes and Altered Behavior – 197 Cortical Maps and Beyond – Brain Variables Affected by Neuroplasticity – 198 Milestones of Experimental Neuroplasticity Research in Animal Models – 199 Neuroplasticity as a Novel Discipline – 202

7.3

Neuroplasticity in Humans – 203

7.3.1 7.3.2 7.3.3

I mpact of Modified Use and Practice – 203 Perceptual Learning – 206 Neuroplasticity Evoked by Peripheral or Central Stimulation – 208 Plastic and Perceptual Changes without Physical Stimulation – 215 Rapid, Switch-Like Plasticity – 216 General Performance-­Promoting Conditions – 217 Predicting Learning Outcome – 219 Neuroplasticity in the Elderly – 221 Maladaptive Neuroplasticity – 225 Perspectives and Potential of Neuroplasticity – 228

7.2.7

7.3.4 7.3.5 7.3.6 7.3.7 7.3.8 7.3.9 7.3.10

References – 229

© Springer Nature Switzerland AG 2021 M. L. Zeise (ed.), Neuroscience for Psychologists, https://doi.org/10.1007/978-3-030-47645-8_7

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194

7.1

7

H. R. Dinse

Introduction

“Plasticity” originally is a property of materials and means that an object is deformable. It contains the word “plastikos” (i.e. “formable”) derived from a Greek verb “plassein” meaning to form. “Neuroplasticity” means that the brain’s functions and their underlying structures are not rigid and fixed, but can actively reorganize themselves dependent on what “has happened to and with them”. In this chapter, factors are presented that are important in neuroplasticity, particularly human neuroplasticity. Plastic changes may last from seconds to lifetime. Neuroplasticity is present throughout life span, albeit not to the same degree. Why is neuroplasticity advantageous? Genetic information and heritable features that evolve during evolutional time span are of ultimate advantage for survival and are, without exception, structurally fixed. However, to cope successfully with the ongoing changes of external conditions occurring during the lifespan of an individual, additional mechanisms are required that allow rapid and effective plastic adaptations to the altered needs of the environment that are not specified by genetic constraints. However, the outcome of plastic changes is not necessarily beneficial. It is now well established that a number of symptoms such as forms of dystonia or tinnitus are a result of so-called maladaptive plasticity (see 7 7.3.9). Despite the advantage of plastic capabilities, their efficacy might not have developed to their maximal possible outcome (Dinse and Tegenthoff 2019). The reason is that neural systems must possess sufficient generic stability to warrant secure functioning. Too fast and too powerful acting plastic processes would jeopardize constancy of brain processing. Therefore, there is a trade-­ off between modifiability and stability. Plastic changes may involve almost all brain structures at molecular, subcellular, cellular levels and the level of networks.  

Neuroplasticity is behind many phenomena manifest at the behavioral level. In other words, neuroplasticity is not a unitary process, but must be regarded as a phenomenon that develops under quite diverse conditions, with different underlying mechanisms acting on different timescales (see 7 7.2.3).  

7.2

Characteristics of Neuroplasticity

7.2.1

Differences between Developmental and Adult Plasticity

About 50 years ago, an article was published whose title sounded almost like a manifesto: “Development of the brain depends on the visual environment” (Blakemore and Cooper 1970). The authors argued that visual experience was required in forming a  well-­ functioning visual system. Electro­ physiological recordings in kittens and cats and behavioral evidence had demonstrated that the properties of neurons in the visual pathway, such as detecting certain features, like angular velocity, size or orientation of an object, among others, depended critically on what the animals had seen during development. Thus, it became clear that brains organize themselves during development based on their “experience”. Later it became clear that such changes are not confined to ontogenetic development, but that the adult brain is also capable of dynamic reorganization (see 7 7.2.1). The reasons for the most striking and crucial differences between developmental and adult plasticity is that in contrast to adult plasticity, reorganization and plastic changes during development rely to a large extent on maturational and growth processes, promoted by plastic changes of ­synaptic connections. Accordingly, ontogenetic plasticity involves much more mor 

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phologic restructuring as compared to adult neuroplasticity. This includes the creation and deletion of synapses on a large scale as well as the directed growth of neuronal and astrocytic processes, among others. In contrast, neuroplasticity in the adult is mainly mediated by rapid and reversible modifications of synaptic efficacy. However, according to new data and the development of new technologies (i.e., voxel-based morphology in magnetic resonance (MR) imaging; see 7 7.3.1), even that rule of thumb turned out to be too simplistic: large-­scale amputations in the adult have been shown to involve sprouting and outgrowth of connections into neighboring regions at cortical and subcortical levels. Long-term potentiation (LTP) was shown to cause the appearance of new spines on the postsynaptic dendrite. In the intact brain of adults, structural changes have been reported for a number of very specific cases, such as taxi drivers, who show a structurally enlarged hippocampus, and for jugglers, who show structurally enlarged visual cortical areas. Despite these new insights, it must be emphasized that the plastic capacities of the ontogenetic period are substantially larger than those ever observed during adulthood. For example, shifting language acquisition to the contralateral hemisphere has been reported as a major compensatory process after brain injury during early life, but never in adult brains. There are single-case reports where individuals appeared almost normal under everyday requirements, although brain scans revealed a complete missing of one hemisphere, a finding implying unprecedented compensatory mechanisms present only during very early development. It appears conceivable that these major differences in the amount of plastic capacities have long hindered the recognition of the subtler changes occurring in adults, and that therefore the neuroscience community explicitly regarded adult brains as static and non-plastic.  

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Two interesting questions remain: first, what defines the end of the ontogenetic period? Many features of neuronal development and the development of behavioral abilities have quite diverse time courses. Sexual maturation is often regarded as the onset of adulthood. However, in humans, the process of myelination ends only at an age of 30. Second, can the end of the developmental period be reinstalled artificially? Pharmacological and molecular mechanisms in the context of binocular vision revealed that among others maturation of intracortical inhibition and changes in the extracellular matrix are major factors controlling developmental plasticity (Takesian and Hensch 2013). Accordingly, one can speculate that it might become possible in the near future to restore juvenile plastic capacities in the adult, offering new options in treatment of brain damage. 7.2.2

Drivers of Neuroplasticity

Perceptual, behavioral, and cognitive performance are not constant, but change permanently throughout lifespan. Besides the obvious impact evoked by injury of either the body or the brain and nerves, early development and aging are major factors driving significant alterations of individual performance. Other factors that instigate plastic changes arise from constraints during everyday life conditions. Examples are particularities of occupation including lifestyle and prolonged episodes of intense sensory stimulation, such as those occurring in blind Braille readers or musicians. While it takes several 10,000  hours of intense practice to develop musical skills typically observed in professional musicians, even short periods of several minutes of training and practicing can induce plasticity processes leading to significant gains in ­performance. A central paradigm in neuroplasticity is built around the Hebbian concept (1949)

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stating that episodes of high temporal correlation between pre- and postsynaptic activity are prerequisites to induce changes in synaptic efficacy. Historically, the idea that cooperative processes are crucially involved in generating long-lasting changes of excitability can be traced back to the nineteenth century (James 1890). In fact, since Hebb, the aspect of simultaneity has become a highlight in the field of neural plasticity, although the exact role of Hebbian mechanisms in use-dependent plasticity remains controversial. To take a somewhat more general approach, let us assume a dynamically maintained steady state of brain representations, a so-called mean environment, that emerge from the idiosyncratic experience, actions, and thoughts accumulated throughout the life. Neuroplasticity is then assumed to operate on these representations. Brain changes are likely to occur when conditions arise that deviate from the mean environment. 55 A straightforward way to alter the steady state in a bottom-up way (see 7 Chap. 6) is by changing the input statistics. Aspects that are specifically effective in driving plastic changes are simultaneity, repetition, frequency, or, more generally, spatio-temporal properties of inputs. Synaptic plasticity mechanisms such as LTP and LTD, or spiketiming-­dependent plasticity (STDP) are assumed to provide the neural substrate enabling effects of altered input statistics. The efficacy of drivers of neuroplasticity by means of modified inputs is employed by a new research field, where novel stimulation protocols are implemented and tested to allow a rapid and targeted induction of neuroplastic changes in human individuals (see 7 7.3.3). 55 Alternatively or additionally, different forms of attention can modulate the processing of a stimulus or of a scene. Further, the relevance of a stimulus or a scene can change dependent on context, history, and behavioral task,  



thereby modifying the processing of the physically defined attributes. In addition, reinforcement by reward or punishment modulates plasticity processes as does motivation. Feedback about task handling also plays an important role. There is general agreement that modification of early sensory processing by attention, reinforcement, and stimulus relevance reflects top-down influences. As a rule, the so-called neuromodulatory systems specific for various neurotransmitter systems (see 7 4.3.6) mediate these effects.  

7.2.3

 ime Scales of Plastic T Changes

Plastic changes can develop within seconds to minutes up to years. Similarly, their persistence ranges from minutes to life-long maintenance. Accordingly, numerous overlapping and non-overlapping mechanisms must be assumed to provide the underlying neural substrate enabling the emergence of these different plasticity forms. In . Fig. 7.1, some selected neuroplastic phenomena are listed to illustrate the temporal scale for the emergence and persistence of plastic changes.  

7.2.4

Region-Specificity of Neuroplasticity

Massive and enduring plastic changes have been described for practically all brain functions and modalities, confirming the contemporary view that all cortical areas are modifiable. These findings demonstrate that the brain in adults are not hard-wired but are highly dynamically organized throughout life. However, there are also substantial variations in plastic changes between brain regions. For example, when comparing plasticity in somatosensory and visual cortical areas, there appear to exist regional differences in the inducibility, magnitude, stabil-

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..      Fig. 7.1 Time course and persistence of plastic changes. (TMS Transcranial magnetic stimulation. For further details see respective paragraphs)

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exercise, food, culture everyday life life style training, practice, experience repetitive stimulation TMS perceptual learning tool use / body ownership seconds minutes hours weeks months years

ity, and time course of changes (Dinse and Böhmer 2002). Such dissimilarities in plasticity might be due to differences in cellular, pharmacological, and histochemical properties reflecting area-specific constraints of the molecular equipment available in that area. While this can explain existing differences in the outcome of plastic changes, the reasons for the emergence of such differences in cellular properties remain a question. Furthermore, the visual cortex is characterized by a number of so-called functional maps that are overlaid across the retinotopic gradient, thereby generating a highly complicated form of topological structure. Up to now, comparable topological features have not been described for the somatosensory cortex. It has been suggested that these global topological constraints may impose forces that stabilize the underlying cortical networks, thereby limiting and restricting plastic changes. As an alternative explanation, it is possible that although visual and somatosensory cortex are regarded as primary cortical areas, the type of preprocessing occurring subcortically and at the level of the retina renders both areas dissimilar in terms of their position within a hierarchy of bot-

time

tom-­up and top-down processing, thereby affecting the readiness and susceptibility for plastic reorganization. As a result, parts of the observed dissimilarities may reflect genuine modality-specific differences, building on important constraints associated with the processing of modality-specific sensory information. Comparative studies focusing on modality-specific features of cortical plasticity will reveal further insight into principles governing neocortical organization. 7.2.5

 elation between Brain R Changes and Altered Behavior

A central question in neuroplasticity is how behavioral and perceptual changes are linked to changes in cortical processing. In other words, how much of plastic changes that can be monitored today can be attributed to what often is called learning. To be able to address this question, strategies are needed to assess performance and cortical reorganization in the same individual through a combination of psychophysical/ behavioral tests and non-invasive imaging. Such data sets are a prerequisite to study the

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correlation between individual changes in behavior and individual changes in brain organization. In the pioneering study of Recanzone et al. (1992), training monkeys over several weeks in a tactile frequency discrimination task led to a significant expansion of the cortical maps representing those skin portions stimulated with the different frequencies. However, performance and amount of plastic changes were highly variable across animals. In humans, prolonged LTP-like sensory stimulation applied to the index finger (see 7 7.3.3) resulted in an overall improvement of tactile acuity, although the amount of improvement was variable throughout the individuals as was the amount of cortical changes (Dinse et  al. 2003; Pleger et al. 2003). These examples demonstrate that both in animal models and in human, enlargement of cortical sensory maps is associated with a perceptual gain. Map expansion has therefore been interpreted as a recruitment of processing resources, and is now regarded as a general feature of cortical plasticity. If changes of cortical maps reflect changes in cortical processing causally related to the processing of tactile information, it can be hypothesized that they should correlate with the changes in individual performance. In fact, in monkeys as well as in human subjects, there is a significant correlation between cortical map changes and the parallel changes in tactile perceptual performance: little gain in discrimination abilities was associated with small changes in cortical maps. On the other hand, those individuals who showed a large cortical reorganization also had lowest thresholds. There is another important aspect to the study of joint changes of behavior and brain organization: monitoring learning-induced changes provides a useful window into the rules and constraints that govern perception and behavior also under baseline, i.e., non-­ learning conditions. For example, under baseline conditions, the regional extent of  

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the visual cortical map representing the visual field and the so-called Vernier acuity, a form of hyperacuity, correlate, which indicates that individual Vernier acuity is limited by the individual cortical magnification. A similar finding was reported for tactile acuity, where the size of the cortical map representing the skin of the fingers correlated with their tactile acuity. These findings bear two important implications: first, small differences in performance must not be due to measurement artifacts or noise, but may reflect true differences in individual brain organization. Second, given more and more refined ways to monitor brain changes in humans, the demonstration of specific brain reorganization might become an objective measure of learning capabilities. In a way, the amount of individual skill becomes predictable from outside based on brain activation monitored.

7.2.6

Cortical Maps and Beyond – Brain Variables Affected by Neuroplasticity

Animal experiments on cortical reorganization, which had initiated the discovery of developmental and adult neuroplasticity, concentrated largely on the analysis of receptive fields and on the areal extent of representational maps. Both variables are still widely in use, and a huge amount of data is available that allows valuable comparison between different species and modalities. Moreover, new imaging techniques such as fMRI (functional magnetic resonance imaging) (see 7 7.3.1 and 10.7.8) allow studying plastic changes in humans. These studies have in common that they describe changes of neural representations in terms of activation size (i.e., the size of  

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the cortical point-spread function) thereby linking human and animal studies. Higher mammals contain complete and ordered topographic maps of the receptor sheets of the retina, cochlea, and skin located in visual, auditory, and somatosensory cortex, respectively. These are denoted as retinotopic, cochleotopic (tonotopic), and somatotopic maps. The basic principle is that adjacent locations are represented at adjacent locations in the cortex. Exceptions such as the face-hand border arise from the problem to map a three-dimensional object onto a two-dimensional surface. In the Anglo-American literature, the outcome of an electrophysiological mapping experiment in the somatosensory system has been called a ‘representational map’, or simple a ‘representation’. The entity in question is the topographic location of the body surface, so a map was interpreted as a map of a particular body part. In that view, a map contains a ‘representation’ of the body, but the term ‘representation’ lacks any further philosophical implication different from the century-old controversial discussion about the potential presence and occurrence of mental “representations” among philosophers and cognitive scientists. . Figure  7.2 illustrates the main features of cortical maps and ways to assess them methodologically. Besides the analysis of cortical maps, novel techniques made it possible to assess other aspects of cortical processing. Temporal processing, i.e., the computation of sequential events gains more and more interest. Under natural conditions, stimuli never appear in temporal isolation. Therefore, timing and sequencing imposes severe constraints that modulate neuron responses. A window that allows studying the relation between learning, reorganization, and underlying mechanisms is provided by the analysis of what is called “paired pulse behavior”. When two stimuli are given briefly (around 10  ms) one after the other, the response to the second stimu 

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lus is greatly suppressed (paired-pulse suppression) or increased (paired-pulse facilitation). Paired-­ pulse suppression is widely used in humans and serves the noninvasive assessment of cortical excitability and its changes during plastic processes. In addition to the analysis of local processing properties, a more complete understanding of the underlying mechanisms requires investigation of global and interaction processes as provided by functional connectivity analysis. Functional connectivity is based on correlation analysis, and provides information about how distant brain regions cooperate. It can be assessed either by multi-site EEG recordings or by means of so-called resting state BOLD (blood-­ oxygen-­level-dependent) signals using MR imaging (see 7 10.7.8).  

7.2.7

Milestones of Experimental Neuroplasticity Research in Animal Models

A serious of seminal animal studies, mostly addressing the somatosensory system, showed for the first time the existence and relevance of plastic changes following injury, experience, and altered use. The first studies demonstrating the presence of adult neuroplastic changes investigated the effects of deafferentation or of amputation. The main highly surprising effect consisted of an expansion of cortical territories representing intact skin portions into cortical regions that formerly represented the deafferented areas (Merzenich et  al. 1984). As a result, the regions representing a lost limb were not silenced, but came to represent neighboring areas. In case of a hand amputation, former “hand neurons” developed representations of the face and upper arm, which both are adjacent in the map of the somatosensory homunculus (. Fig. 7.3). Much more dramatic cortical reorganizations were reported after mapping the cor 

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..      Fig. 7.2  Top: Examples of somatotopic maps of the skin of the human body surface used to draw a so-­ called “homunculus”. Shown are the original homunculus from Wilder Penfield as well as a homuncular equivalence for monkeys and rats. Bottom: There are two complementary ways to study cortical maps and cortical activity distributions (here schematically illustrated for the somatosensory cortex). Receptive fields are mapped by inserting microelectrodes into cortex and by recording action potentials from single cells or multiple unit activity from small clusters of neurons. A receptive field (RF) is defined as that region on the skin where stimulation evokes action potentials. This procedure maps the activity recorded in the cortex into stimulus space. When moving the electrode to an adjacent location in the cortex, a systematic shift in the corresponding receptive field

location will be encountered. A complete topographic map can be obtained when a large number of electrode penetrations are combined in such a way that the penetration coordinates are related to the corresponding receptive field coordinates. A RF can therefore be regarded as the window through which neurons see the outside world. The inverse approach is taken when cortical activity distributions are measured. In contrast to RF mapping, a stimulus, ideally a small, “point-like” stimulus, is applied to a fixed location, and the entire activity in the cortex evoked by that stimulus is recorded. This type of activity distribution is often referred to as “point spread function”. A frequently employed technique to measure activity distributions is functional magnetic resonance imaging (fMRI). (Modified from Dinse and Merzenich 2002 with permission)

tex of monkeys that had undergone deafferentation of the dorsal roots (C2-T4) several years before, thereby depriving a cortical area of over 1 cm2 of its normal input from the arm and hand (Pons et  al. 1991). Similar to the findings reported above, all of

the deprived area had developed novel responses to neighboring skin areas, including the face and chin. These data indicate that the duration after limb loss plays a crucial role in determining the amount of cortical reorganization.

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..      Fig. 7.3  Topographic reorganization in the cortical area 3b (primary somatosensory cortex) of an owl monkey after 2  months of a surgical amputation of digit 3 (middle finger). Representations of the hand surfaces derived after multiple electrode mapping are shown before and after amputation, with cortical territory representing fingers 2 (pink), 3 (yellow), and 4

(blue) highlighted. Before amputation (left), all fingers are represented in a comparable patch of cortical surface. After amputation, the representations of digits 2 and 4 invade the territory of the amputated finger 3. As a result, the former digit 3 area is not silenced, but develops response to the neighboring fingers. (Modified from Merzenich et al. 1984 with permission)

The first study demonstrating a close link between perceptual improvement and reorganization was the study by Recanzone et al. (1992). These authors showed that tactile frequency discrimination training in adult owl monkeys over several months leads to a significant reduction of frequency discrimination threshold. When the cortical areas representing the skin area of the trained fingers were mapped, large-scale cortical reorganization became apparent, which included changes of receptive fields and of topographies of cortical representational maps. Most notably, there was a significant correlation between the individual enlargement of cortical territory representing the skin surface stimulated during training and the individual improvement in

performance indicating a close relationship between the perceptual improvement and the amount of cortical map expansion implying a causal relationship between cortical and perceptual changes (see 7 7.3.3). The concept of use-dependent plasticity predicts that cortical maps can be altered by an artificial manipulation that changes the normal amount of intensity of “usage” of a given body part. To demonstrate that use-­ dependent plastic processes are similarly occurring during everyday life, the cortical representations of the ventral trunk skin of female rats during nursing behavior were studied. The rationale for this was that during nursing behavior the amount of touch, i.e., the use of the nipple-bearing skin, is significantly higher compared to non-nursing  

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conditions. It was found that the ventral trunk representations were significantly enlarged compared to matched postpartum non-lactating or virgin controls. The greatest representational change was observed for the area between the forelimbs and hindlimbs providing compelling evidence for the relevance of altered use as a driver of neuroplasticity under natural life conditions (Xerri et  al. 1994). Most notably, these effects were fully reversible: after the end of the nursing period, the trunk representations returned to baseline conditions, which provided further evidence that brain organization is maintained highly dynamic. Taking advantage of new techniques that allow recording action potentials from many chronically implanted microelectrodes simultaneously in behaving animals, Chapin and coworkers demonstrated that a pool of motor cortex neurons can be used for real-­ time device control (Chapin et  al. 1999). First, rats were trained to position a robot arm to obtain water by pressing a lever. Then, action potentials were converted by means of mathematical transformations into a socalled neuronal population function that accurately predicted lever trajectory. Next, these functions were electronically converted into real-time signals for robot arm control. After switching to this neurorobotic mode, the animals routinely used these brainderived signals to position the robot arm and obtain water. With continued training in the neurorobotic mode, the animals stopped moving the lever by their own. Instead, the animals had somehow “understood” to use their own brain activity – one could say their “thoughts”  – to control external devices without actually moving themselves. This approach, nowadays called BCI  – brain computer interface  – is meanwhile taken into clinical routine, where paralyzed human patients can move a robot arm merely by their real time recorded brain activity. The ability of brains to handle such tasks is explained by the idea that the patient’s brain incorporates the robot arm

into the motor and sensory cortical representations of their homunculi. 7.2.8

Neuroplasticity as a Novel Discipline

Given the obvious needs for plastic processes, it appears only natural that brain plasticity of various forms represents a general and ubiquitous feature of brain functioning. It is therefore surprising that the notion of adult neuroplasticity has been established only since the late 1980s (. Fig.  7.4). Before that, the neuroscience community explicitly regarded adult brains as static and non-plastic. Why neuroplasticity effects, particularly in the adult brain, have been overlooked for such a long time? As outlined above, brain changes occurring during development can be huge. It is conceivable that the lack of comparable brain reorganization in adults have led to an underestimation of adult neuroplasticity. In addition, given that adult plastic changes can be small and subtle, highly sensitive methods and techniques are needed to detect them. This is the reason that early experiments in adult plasticity almost exclusively focused on animal models. In the 1970s, electrode mapping techniques were developed that allow precise measurement of cortical map topographies. Only then, the techniques have become widely available allowing to draw detailed maps with sufficient spatial detail demonstrating clearly that cortical maps were not rigid but could be changed substantially, even in adult brains. Thus, signatures of brain reorganization were described in terms of cortical map changes (see 7 7.2.6 and 7.3.1). It can be concluded, therefore, that lack of adequate technologies contributed significantly to the late discovery of neuroplastic changes. That neuroplasticity is a relatively novel discipline of brain research is particularly evident when considering neuroplastic  



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60000

publications “neuroplasticity”

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40000 30000 20000

10000 0 1980

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..      Fig. 7.4  Graph illustrating the number of publications devoted to aspects of “neuroplasticity” published between 1980 and 2019. Noteworthy, the number of publications addressing “brain research” increased as well over the last decades. However, in

1980, only 0.04% of all brain research–related papers addressed plasticity topics, while today 3% of all brain research papers deal with neuroplasticity. (Author’s search on PubMed; 7 https://www.­ncbi.­nlm.­nih.­gov/ pubmed/)

changes in humans. The development and broad utilization of non-invasive imaging and recording techniques at the beginning of this century made it possible to study impacts of brain injury as well as modified use and training in human populations. Another prerequisite that fostered the understanding of neuroplasticity was the rapid availability of fast computers needed for increasingly more complex data analysis. It is therefore important to keep in mind that our current knowledge will be necessarily a “snapshot” rather than a full understanding of neuroplastic processes. Extrapolating from the history of neuroplasticity research, it can be assumed that many facets of brain changes have been overlooked even today due to inappropriate technologies, implying that brains are changing even more dynamically than is known today. New methods together with even more sophisticated ways of data analy-

sis will almost certainly alter the way we look at how brains can change.



7.3

Neuroplasticity in Humans

7.3.1

I mpact of Modified Use and Practice

Having the new non-invasive imaging techniques at hand, researchers started investigating how modified use and practice impacted brain organization in specific human subpopulations showing advanced or impaired behavioral capacities. For example, to study the impact of use-dependent plasticity, human individuals were selected, characterized by significant differences in hand use. These studies confirmed the data from previous animal studies and provided overwhelming evidence that extensive use

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D1 30 D5 dipole strength (nA·m)

D5

25 20

String players

15 10 5 0

Controls

0 5 10 15 20 Age at inception of musical practice

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..      Fig. 7.5  Effects of long-term string instrument playing on somatosensory cortical finger representation. Left: MEG current dipoles elicited by stimulation of the thumb (Dl) and fifth finger (D5) of the left hand are superimposed onto an MR image. The arrows represent the location and orientation of the dipoles for each of the two digits averaged across musicians (blue) and controls (yellow). The length of the arrows represents the magnitude of the dipole moment. The average locations of D5 and D1 are shifted medially for the

string players compared to controls; the shift is larger for D5 than for Dl. The dipole moment is also larger for the musicians’ D5, as indicated by the greater length of the blue arrow. Right: The magnitude of the dipole moment as a function of the age of inception of musical practice; string players are indicated by filled circles, control subjects by hatched circles. Note the larger dipole moment for individuals beginning musical practice before the age of 12. (Modified from Elbert et al. 1995 with permission)

and practice result in substantial changes of associated cortical representations. Among the first studies was the one by Elbert et  al. (1995), who reported that the cortical representation in primary somatosensory cortex of the play fingers of string players was enlarged compared to non-­ musician controls. Interestingly, the amount of cortical reorganization in the representation of the fingering digits was correlated with the age at which the person had begun to play (. Fig.  7.5). Similar findings in somatosensory cortex consisting of a functional enlargement of cortical territory were described for blind Braille readers, who displayed an increased cortical representation of their reading finger. In highly skilled musicians, functional magnetic source imaging1 revealed that the representation of piano tones in auditory cortex was enlarged,

but not the representations for pure tones of similar fundamental frequency. Again, this type of reorganization was correlated with the age at which musicians began to practice. In addition, musicians with absolute pitch were characterized by distinct neural activities in the auditory cortex. Similarly, auditory cortical representations for tones of different timbre (violin and trumpet) were enhanced compared to sine tones in violinists and trumpeters, preferentially for timbres of the instrument of training (Schlaug 2015). These results demonstrate that changes in cortical maps depend on the amount of use allocated by an individual to conform to the current needs and requirements of environmental constraints. But what are the functional implications of these changes? Conceivably, the observed changes of cortical organization are the substrate mediating the altered performance observed behaviorally. However, there is controversy about the specificity of the neural changes accompanying such changes. According to one view,



1 Magnetic source imaging is a combination of Magnetic Resonance Imaging and magnetoencephalography.

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the plastic changes are highly specific in the sense that they allow for improvement of the trained motor or perceptual skill only, i.e., neural changes arising during training are assumed to have little consequences on cortical processing beyond that skill. In an alternative scenario, neural changes result in a widespread modification of the entire sensory processing. In this case, far-reaching consequences in terms of perceptual and cognitive skills are to be expected that generalize widely beyond the trained task. In other words, is a training-induced improvement paralleled by other perceptual changes, either positive or negative, that are manifested independent from the trained performance? In blind Braille readers, the expansion of their reading finger is associated with an improved tactile acuity. However, spatial localization abilities on these fingers were significantly impaired indicating a trade-off behind these opposing capabilities. Similarly, the tactile acuity of professional pianists is also superior to that of non-musician controls. The significant correlation of their individual thresholds with the daily practicing duration suggests that the superior performance is related to their musical abilities. Piano playing per se has little to do with the aspect of tactile acuity, except for the case that professional playing is based on extreme usage of the fingers. In contrast, the enhanced discrimination abilities in blind Braille readers can be explained by the unusual and extensive use of the fingers to gather fine-scale spatial tactile information. Accordingly, professional piano players seem to benefit from their daily routine by developing significantly reduced tactile discrimination thresholds, although piano playing in contrast to Braille reading is less obviously related to tactile acuity abilities. New techniques in magnetic resonance (MR) data acquisition and voxel-by-voxel morphometric analysis of gray matter volume provided new and additional insights into structural changes of the living brain

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that develop during plastic reorganization. These studies demonstrated that neuroplastic changes as described above can be correlated to various types of structural changes. The existence of grey matter differences between pianists and non-musicians extending from the premotor region to the primary somatosensory cortex and into the anterior parietal lobe confirmed that musician’s brains differ not only in terms of functional expanded representations, but also in size (Gaser and Schlaug 2003). In another study, structural MR scans of the brains of licensed London taxi drivers were analyzed and compared with those of control subjects who did not drive taxis. The posterior hippocampi of taxi drivers were significantly larger relative to those of control subjects and the volumes correlated with the amount of time spent as taxi driver (Maguire et al. 2000). These findings are in line with the idea that the posterior hippocampus stores a spatial representation of the environment and can structurally expand to accommodate elaboration of this representation in people with a high dependence on navigational skills. Further, in the brains of volunteers who had learned to juggle, a transient and selective structural change in brain areas associated with the processing and storage of complex visual motion has been demonstrated (Draganski et al. 2004). In another experiment, voxel-based morphometry MR images were obtained at three different time points while medical students learned for their medical exam. During the learning period, gray matter increased significantly in the posterior and lateral parietal cortices, bilaterally. This morphological expansion did not change significantly during the semester break 3  months after the exam. In contrast, in the posterior hippocampus, a different time pattern was found: here, the initial increase in gray matter during the learning period was even more pronounced 3 months after the exam. These results indicate that the acquisition of a great amount of highly abstract information

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can be related to a particular pattern of structural gray matter changes. The discovery of a stimulus- and context-­ dependent alteration in the brain’s macroscopic structure contradicts the traditionally held view that adult cortical plasticity is exclusively based on molecular, submicroscopic changes. Accordingly, there is a capacity for local plastic change in the structure of the healthy adult human brain in response to environmental and/or internal demands. 7.3.2

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Perceptual Learning

For a non-expert, looking at an X-ray image does not reveal much except the existence of many shades of grey. For a radiologist, the grays will easily form complex structures, possibly showing early signs of cancer. This remarkable acquired ability is due to the fact that perception is not constant but depends crucially on practice. Having viewed thousands of X-ray images, a radiologist has trained their visual system to see meaningful structures where the non-trained fails. The process of training and practicing our senses to improve perceptual abilities is called perceptual learning and has been shown for all sensory modalities. Perceptual learning is a form of implicit learning where perceptual performance improves through training or pure exposure to stimulation (Gibson 1953). In the previous sections of this chapter covering neuroplasticity, brain changes have been described following various interventions and manipulations, but in many cases their implications for behavior and performance were not immediately evident. In contrast, for a long time, perceptual learning has been a domain of psychology; most data were created by describing changes in perceptual performance, whereas their neurophysiological underpinnings remained unclear. According to Goldstone (1998), perceptual learning is based on different “mechanisms”, such as imprinting, differentiation, and unit-

ization. However, their neurophysiological basis remains controversial, because, among other reasons, they are hard to reconcile with neurophysiological findings. As for neuroplasticity in general, despite many years of research, the rapidly developing field of perceptual learning does not provide yet general and conclusive statements about rules and properties of perceptual learning. Similar to other neuroplastic processes, perceptual learning is not achieved by a unitary process: there are peripheral, specific changes and more general, strategic ones, and mechanisms driven by feedback and reward and those that operate on the statistical structure of the stimuli. The clarification of the differential contribution of these bottom-up and top-down influences is subject of current research (Watanabe and Sasaki 2015). Training-induced perceptual learning can occur on many different time scales. In some training tasks, a few trials are sufficient to drive perceptual improvement. In other situations, performance improves only after weeks or months of practicing. In studies of long-term training, one typically finds an early phase of rapid improvement followed by a second phase of much slower learning (. Fig. 7.6). A major characteristic of perceptual learning is its high specificity to stimulus parameters such as location or orientation of a stimulus with little generalization of what is learned referring to other locations or to other stimulus configurations (Poggio et  al. 1992). Selectivity and locality of this type implies that the underlying neural changes are most probably occurring within early cortical representations that contain well-ordered topographic maps to allow for this selectivity (. Fig. 7.7). In addition, a transfer of the newly acquired abilities is often considered an important marker of the processing level at which changes are most likely to occur: limited generalization is taken as evidence for locally limited effects in early representations.  



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..      Fig. 7.6  Perceptual and motor skills improve over time of practicing. There are at least 2 phases, with a first phase of rapid improvement over time, and a second later one, where improvement develops asymptotically at much slower rates. Typically, skills evolve over days to months, but gain in performance can be obtained even after years of practicing. While the first phase is believed to be largely due to task und strategy learning, the second phase involves very specific changes in cortical processing

Feedback, reinforcement, and attention are major factors fostering perceptual learning. Feedback provides valuable information about the correctness of performer’s responses during learning. As a rule, correct feedback conditions yield larger improvements of performance, but under certain conditions within-session learning can occur without feedback. There is a long-lasting debate about the anatomical sites in the brain that mediate the changes in perception induced by perceptual learning. Is this happening in early stages of processing such as primary sensory areas characterized by narrow-tuned and highly localized receptive fields? This bottom-­up route is easily compatible with the high specificity of perceptual learning. Alternatively, higher-order stages and decision areas with very large and broadly tuned neurons might influence in a top-down process the early stages of processing. The first demonstration of alterations of cortical sensory processing developing during a perceptual learning task showed that tactile frequency discrimination training in monkeys over many sessions leads to per-

..      Fig. 7.7  Time course and specificity of perceptual learning of a Vernier task. Vernier acuity describes the ability to discern a disalignment among two line segments. Horizontal a and b and vertical b Verniers schematically shown in blue were 20 arc min long and 2 arc min wide with a constant offset between 15 and 20 arc sec. Percentages of correct responses in a 2-alternative forced choice

task improved rapidly during the initial period of learning, that is, during about 100 presentations. Each block consisted of 40 trials. b Shows effect of switching from vertical to horizontal Verniers (or vice versa) after block 20. Data show no transfer of learning due to high specificity of features (here orientation of stimuli) learned. (Modified from Poggio et al. 1992 with permission)

performance

In contrast, transfer of learned abilities is taken as evidence for the involvement of higher processing levels often observed in task and strategy learning. However, transfer and generalization are highly task-­ specific, and depend on subtleties of training conditions.

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ceptual improvement in parallel to an expansion of the maps in somatosensory cortex representing the used finger (see 7 7.2.5). Most importantly, it was shown that there is a linear correlation between the individual degree of perceptual improvement and the individual amount of cortical map expansion. This implies that cortical map size can be regarded as a reliable predictor of the individual performance. Other studies suggest that cortical changes induced by perceptual learning might be more complex. For example, V1 neurons of monkeys trained in an orientation discrimination task fired less when the trained orientation was their preferred one compared to the activity of neurons with other preferred orientations. Recent imaging data from human subjects suggest that there are distinct temporal phases in the time course of brain activation induced in perceptual learning: within the first weeks of visual texture discrimination training, brain activation in a primary visual cortex subregion corresponding to the trained visual field quadrant and task performance both increased. Later, while performance levels saturated reaching maintenance levels, brain activation decreased to the level observed before training (Yotsumoto et  al. 2008). These data indicate that there seem to be substantial modality-specific constraints as well as complex dependencies on task conditions (Maniglia and Seitz 2018). Novel approaches based on monitoring large-scale network changes might be a more appropriate way to unravel the neurophysiological basis of perceptual learning.  

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7.3.3

 europlasticity Evoked by N Peripheral or Central Stimulation

Independent of the duration and type of training, it is generally agreed that cellular and subcellular modification of synaptic efficacy is the principal neural substrate for

learning. While it is well documented that synaptic plasticity mechanisms either facilitate or suppress transmission at synapses to alter communication between nerve cells, their relevance to behavioral experience remains debated. In particular, the lack of adequate input stimuli for the induction of LTP and LTD (see 7 4.3.2) in humans has hindered direct evaluation of the impact of such protocols on human behavior. Which role is played by LTP or LTD in human plasticity and learning? Are these relevant processes at all to understand what happens during every day learning? Synaptic plasticity studies use specific stimulation patterns to induce long-lasting changes in synaptic transmission, but the implications of this requirement for temporally specific protocols in everyday learning outside the laboratory have remained unclear. For training- and practice-based plasticity to occur, sensory inputs are varied in frequency, temporal pattern, number of stimuli, duration and intensity, time course and size. But it is difficult to exactly quantify the numerous changes in input parameters that occur during training. Therefore, linking the principles of synaptic mechanisms that induce plasticity at the cellular level to the principles at the systems level is far from straightforward. An interesting alternative is offered by a reverse approach: using the broad knowledge of brain plasticity to design specific sensory or central stimulation protocols that allow changing brain organization and, thus, perception and behavior. The idea is to translate protocols that induce plasticity at a cellular level into sensory stimulation protocols. What for a long time appeared as a dream has now become routine: the targeted and specific modulation of brain activity from outside, effortless without training or attention.  

zz Repetitive Sensory Stimulation

Repetitive sensory stimulation protocols have the unique advantage of offering complete control of the timing and spatiotem-

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..      Fig. 7.8  Schematic illustration of the assumed chain of changes evoked by repetitive sensory stimulation. Sensory stimulation of a finger induces a cascade of synaptic plasticity events, leading to macroscopic

reorganization producing changes of behavior and perception. All fMRI activations are real measurements before, during, and after application of stimulation

poral allocation of the stimulation. Moreover, this approach is not only an ideal tool for applying known cellular stimulation protocols to humans to assess whether they affect human perception and behavior, but also a means to systematically determine the appropriate timing for the induction of perceptual and cortical changes in humans (. Fig.  7.8). This in turn can result in temporal stimulation protocols that have so far not been investigated in synaptic plasticity research (Dinse and Tegenthoff 2019). Another advantage is that the experimental designs applied in humans can be transferred one-to-one to animal models, which allows further investigation of pharmacological and molecular mechanisms underlying repetitive sensory stimulation effects.

The concept of sensory stimulation protocols to induce plasticity and learning has attracted substantial interest and is currently investigated in many laboratories. Unfortunately, depending on the laboratory, different terms are used to refer to processes that are essentially comparable, such as peripheral nerve stimulation, somatosensory stimulation, unattended-based learning, repetitive sensory stimulation, high-frequency stimulation, or tetanic stimulation. The term co-activation emphasizes the relevance of Hebbian learning, where synchronous neural activity is instrumental to drive plastic changes. The term exposure-­ based learning has been introduced to indicate that mere exposure is sufficient to drive perceptual changes. The frequently used term passive stimulation or passive learn-



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..      Fig. 7.9  Effects of repetitive tactile stimulation on tactile acuity and associated cortical reorganization. Left: BOLD (blood-oxygen-level-dependent) signals detected pre and post after repetitive stimulation in the primary contralateral somatosensory cortex (SI) in the postcentral gyrus and in the contralateral secondary somatosensory cortex (SII) in the parietal operculum above the Sylvian fissure. Activations are projected on an axial, sagittal, and coronal T1-weighted, normalized MRI slice. Comparing pre- with post condition demon-

strates enlarged activation and increased BOLD signal intensity in SI and SII contralateral to the stimulated finger. Right: Linear correlation analysis between changes in BOLD signals in SI and stimulation-induced changes of two-­point discrimination thresholds (tactile acuity) (r = 0.744; p = 0.002). No such correlation was found for SII.  The normalized enlargement as calculated as the number of activated voxels per cluster K  =  ((rightpost  - rightpre)  - (leftpost  - leftpre))/rightpre. (Modified from Pleger et al. 2003 with permission)

ing is meant to indicate that a subject is exposed to sensory stimulation in a taskfree situation without actively attending the stimulation. To provide a direct proof for the relevance and efficacy of the in vitro LTP/LTD protocols in driving perceptual changes in humans, they were translated into tactile high- and low-frequency stimulation pattern. Only 20 minutes of intermittent 20 Hz high-frequency LTP-like stimulation applied to the index finger induced an improvement in tactile discrimination thresholds, whereas low-frequency 1  Hz LTD-like stimulation resulted in a reduced discrimination performance. In both cases, effects of stimulation were specific for the stimulated finger with no effect on the other fingers. These results indicate that brief stimulation protocols (