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Handbook Of Clinical And Experimental Neuropsychology
 9780863775420

Table of contents :
Cover
Half Title
Title Page
Copyright Page
Table of Contents
List of Contributors
Part I: Methodological Problems in Neuropsychology
1.Neuropsychology: Introductory Concepts
2.Behavioural Methods in Neuropsychology
Introduction
Stimuli and Presentation Techniques
Measures of Performance
Experimental Paradigms
3.Electrophysiological Methods in Neuropsychology
Introduction
The Autonomic Nervous System
Retinal Activity and Eye Movements
Brain Activity
4. The Evaluation of Experimental Data
Introduction
Measurement
Sampling: Group Vs.Single Case Studies
Neuropsychological Tests and Diagnostic Practice
Evaluation of the Effects of Treatments
Advances in Data Analysis
Acknowledgements
5. Neuroimaging Methods in Neuropsychology
Introduction
Anatomical Imaging
Functional Imaging
Conclusions
6. The Methodological Foundations of Neuropsychology
The Neural Basis of Mental Activity
A Simulation Approach: Connectionist Modelling
The Neuropsychological Method
Cognitive Neuropsychology
Some Specific Methodological Problems
Acknowledgements
Notes
Part II: Language Disorders in Neuropsychology
7. Development of The Concept of Aphasia
The Principle of Localisation and The Associationistic Model
The Noetic School and The Unitary Interpretation of Aphasia
Empirical Classifications and Geschwind’s Neo-Associationist Model
Luria and The Concept of Functional Systems
Linguistic Interpretations of Aphasia
8. The Neurological Foundations of Language
Introduction
Neurological Correlates of the Aphasie Syndromes
Neurological Correlates of Aphasie Symptoms
Aphasia in Special Populations
Functional Mapping of The Cerebral Organisation of Language in Normal Subjects
Conclusions
9. Clinical Aspects of Aphasia
Definition of Aphasia
Why a Diagnosis?
Diagnostic Criteria
Conclusions
10. Phonological Disorders in Aphasia
Introduction
Production Disorders
Comprehension Disorders
The Relationship Between Production Disorders and Comprehension
11. Lexical-Semantic Disorders in Aphasia
Introduction
Semantics
The Lexicon: A General Model
The Representation of Complex Words
Comprehension and Production in Aphasia
Factors Influencing Retrieval and Understanding of Words
Modality-Specific Aphasias
Category-Specific Aphasias
The Question of Multiple Semantic Systems
Access (Refractory) Vs. Storage Deficits
The Central (Semantic and Conceptual) Levels of Representation
12. Grammatical Deficits in Aphasia
Introduction
Agrammatism as A Production Deficit
Agrammatism as A Deficit of Central Mechanisms
Dissociations Between Production and Comprehension Deficits
Analyses of Grammatical Production Deficits
Paragrammatic Production
Problems With Research on Clinically Defined Grammatical Disorders
Grammatical Production Deficits
Grammatical Comprehension Deficits
Anatomo-Clinical Correlates of Grammatical Disorders
Conclusions
Acknowledgements
Notes
13. Disorders of Conceptual Thinking in Aphasia
Introduction
History
Revival of Research in the 1960s
Tentative Hypotheses and Recent Research
Conclusions
Appendix: Practical Implications
14. Acquired Dyslexias and Dysgraphias
Orthographic Systems
Acquired Dyslexias
Computational Models
The Diagnosis of Dyslexia
Cognitive Classification of The Acquired Disorders of Reading
Central Dyslexias
Peripheral Dyslexias
Models of Writing
Central Agraphias
Peripheral Agraphias
Part III: Memory Disorders
15. Neuropsychological Disorders of Memory
The Architecture of Human Memory
Deficits of Short-Term Memory
Disorders of Ltm: Amnesia
Notes
Part IV: Recognition Disorders
16. Agnosia
Anatomo-Functional Organisation of the Visual Cortex
Perceptual Deficits
Visual Agnosia
Tactile Agnosia
17. The Neuropsychology of Music
Normal Subjects
Brain-Damaged Subjects
Single Cases
Music Production
Conclusion
Part V: Movement Disorders
18. Apraxia
Ideomotor Apraxia
Melokinetic Apraxia
Ideational Apraxia
Trunk Apraxia
Oral Apraxia
19. Constructional Apraxia
Definition
Assessment of Constructional Abilities
Part VI: Spatial Disorders
20. Visuospatial and Imagery Disorders
Spatial Perception and its Disorders
Optic (Visuomotor) Ataxia
Bâlint-Holmes Syndrome
Right Hemisphere Developmental Learning Disability
Spatial Memory and its Disorders
Disorders of Topographical Orientation
Reduplicative Paramnesia For Places
Visuospatial Imagery
21. Unilateral Neglect and Related Disorders
Clinical Manifestations
Allied Disorders
Clinico-Anatomical Correlations
The Course of Unilateral Neglect
Interpretation of the Syndrome
Spatial Features
Influence of Stimulation
Anosognosia
Somatoparaphrenia
Dyschiria and its Interpretation
Implications For Cognitive Sciences
22. Disorders of Body Awareness and Body Knowledge
Introduction
Clinical Aspects
Mechanisms Underlying Bilateral Disturbances of Body Knowledge
Hemisomatoagnosia
Somatoagnosic Illusions and Hallucinations
Concluding Remarks
Part VII: Attentional Disorders
23. Neuropsychology of Attention
Introduction
Level of Selection
Automatic and Controlled Processes
One or Many Attentional Systems?
Acknowledgements
24. The Frontal Lobe
Structure and Connectivity of the Frontal Cortex
Functions of the Frontal Eye Field and Premotor Cortex: Attending to the Present
Functions of The Prefrontal Cortex: Planning For the Future
Acknowledgements
25. Acute Confusional State
Introduction
Clinical Manifestations of the Acute Confusional State
Etiological Factors
Neuropsychology
Conclusions
Part VIII: Special Syndromes
26. Calculations and Number Processing
Introduction
The Number Processing System
Calculation
Other Components
Calculation, Number Processing, and Other Cognitive Systems
Anatomo-Clinical Correlates
Conclusions
Acknowledgements
Notes
27. Neuropsychology of Emotions
What are Emotions?
Theoretical and Applicative Aspects
Characteristics of The Emotional and Cognitive Systems
The Role of Subcortical and Cortical Structures in The Spontaneous Expression and Control of Emotions
Cortical Regulation of the Basic Mechanisms of Emotion
Emotional Disorders in Brain-Damaged Patients
Conclusions
28. Interhemispheric Disconnection Syndromes
Introduction
Historical Development
Symptomatology
Temporary Unrelated Symptoms
Mind and Consciousness in the Split Brain
29. The Neuropsychological Approach to Consciousness
Preliminary Definitions
Explanatory Practicability
The Mapping of Consciousness in the Brain
The Diachronic Articulation of Consciousness
The Causal Role of Consciousness
Neural Mechanisms of Consciousness
Conclusions
Acknowledgements
Notes
Part IX: Dementia
30. Dementia: Definition and Diagnostic Approach
The Meaning of the Term “Dementia”
Neuropsychological Taxonomy of The Dementias
Descriptive Definition of Dementia
Operational Definition of Cpcd
Diagnostic Approach
Conclusions
31. Alzheimer’s Disease
Introduction
Memory Disorders
Deficits of The “Instrumental” Functions
Deficits of The “Control” Functions
Tentative General Understanding of Ad
Diagnosis, Contact With Relatives, and Ethical Issues
Acknowledgements
32. Non-Alzheimer Dementias
Introduction
Degenerative Dementias
Dementias Associated With “Extrapyramidal” Pathology
Vascular Dementia
Dementias and Cognitive Disorders Associated With Infectious Pathology
Dementia of Normal Pressure Hydrocephalus (Nph)
Cognitive Disorders Associated With Multiple Sclerosis (Ms)
Dementia Associated With Metabolic and Deficiency States
Dementia and Psychiatry
Miscellaneous
33. Slowly Progressive Isolated Cognitive Deficits
Overview
Introduction
Definition
Slowly Progressive Aphasia
Semantic Dementia
Slowly Progressive Aphemia
Slowly Progressive Gerstmann Syndrome
Slowly Progressive Apraxia
Slowly Progressive Amusia
Slowly Progressive Prosopagnosia
Slowly Progressive Unilateral Visuospatial Neglect
Slowly Progressive Simultanagnosia
Slowly Progressive Isolated Anterograde Amnesia
Conclusions
Acknowledgements
Note
34. Language Disorders in Dementia
Claudio Luzzatti Introduction
Language Modifications in the Elderly
Language Disorders in Alzheimer’s Dementia
The Cognitive Neuropsychological Approach to Ad
Language Disorders and Dementia of Various Aetiologies
Primary Progressive Aphasia and Dementia
General Conclusions
Notes
Part X: Recovery of Functions
35. Recovery of Cerebral Functions
Cerebral Plasticity
Neuropsychological Disorders
The Prognosis
Conclusions
36. Aphasia Rehabilitation
A Brief History
Effectiveness of Rehabilitation
A Theory of Rehabilitation
Conclusions
37. Visual, Visuospatial, and Attentional Disorders
Introduction
Disorders Involving Reductions of The Visual Field
Heminattentive Disorder
Constructive Apraxia
Basic Attention Disorders
General Conclusions
Note
38. The Rehabilitation of Memory
Introduction
A Brief Theoretical Framework
Methods of Memory Rehabilitation
Effectiveness of Rehabilitative Methods
Conclusions
References
Subject Index

Citation preview

HANDBOOK OF CLINICAL AND EXPERIMENTAL NEUROPSYCHOLOGY

Taylor & Francis Taylor & Francis Group http://taylorandfrancis.com

Handbook of Clinical and Experimental Neuropsychology Gianfranco Denes Neurology Division, Ospedale Civile, Venice

Luigi Pizzamiglio University of Rome “La Sapienza,” Italy

First published 1999 by Psychology Press Published 2020 by Routledge 2 Park Square, Milton Park, Abingdon, Oxon OX14 4RN 52 Vanderbilt Avenue, New York, NY 10017 Routledge is an imprint of the Taylor & Francis Group, an informa business Copyright© 1999 by Taylor & Francis All rights reserved. No part of this book may be reprinted or reproduced or utilised in any form or by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying and recording, or in any information storage or retrieval system, without permission in writing from the publishers. Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe. British Library Cataloguing in Publication Data

A catalogue for this book is available from the British Library Typeset by Facing Pages, Southwick, W. Sussex ISBN 13: 978-0-86377-542-0 (hbk)

Contents List of contributors

xi

Evaluation of the effects of treatments Advances in data analysis Acknowledgements

PART I: METHODOLOGICAL PROBLEMS IN NEUROPSYCHOLOGY 1. Neuropsychology: Introductory Concepts

3

2. Behavioural Methods in Neuropsychology

15

Giacomo Rizzolatti and Luigi Pizzamiglio

Maria Pia Viggiano Introduction Stimuli and presentation techniques Measures of performance Experimental paradigms

3. Electrophysiological Methods in Neuropsychology

15 15 27 30

33 35 37 39

4. The Evaluation of Experimental Data in Neuropsychology

57

69

Daniela Perani and Stefano F Cappa Introduction Anatomical imaging Functional imaging Conclusions

69 71 79 93

6. The Methodological Foundations of Neuropsychology

95

Giuseppe Vallar The neural basis of mental activity A simulation approach: Connectionist modelling The neuropsychological method Cognitive neuropsychology Some specific methodological problems Acknowledgements Notes

33

Luciano Mecacci and Donatella Spinelli Introduction The autonomic nervous system Retinal activity and eye movements Brain activity

Erminio Capitani and Marcella Laiacona Introduction Measurement Sampling: Group vs. single case studies Neuropsychological tests and diagnostic practice

5. Neuroimaging Methods in Neuropsychology

65 66 68

96 101 105 107 113 130 130

PART II: LANGUAGE DISORDERS 7. Development of the Concept of Aphasia

57 57

Guido Gainotti The principle of localisation and the associationistic model The noetic school and the unitary interpretation of aphasia

60 63 v

135 136 144

vi CONTENTS

Empirical classifications and Geschwind’s neo-associationist model 148 Luria and the concept of functional systems 150 Linguistic interpretations of aphasia 152

8. The Neurological Foundations of Language

Stefano F Cappa and Luigi A. Vignolo Introduction Neurological correlates of the aphasie syndromes Neurological correlates of aphasie symptoms Aphasia in special populations Functional mapping of the cerebral organisation of language in normal subjects Conclusions

9. Clinical Aspects of Aphasia

Anna Basso and Roberto Cubelli Definition of aphasia Why a diagnosis? Diagnostic criteria Conclusions

10. Phonological Disorders in Aphasia

Gianfranco Denes, Carlo Semenza and Emanuela Magno Caldognetto Introduction Production disorders Comprehension disorders The relationship between production disorders and comprehension

11. Lexical-Semantic Disorders in Aphasia

Carlo Semenza Introduction Semantics The lexicon: A general model The representation of complex words Comprehension and production in aphasia

155 155 155 164 166 169 177

181 181 183 185 193

195 195 200 210 214

215 215 216 217 223 225

Factors influencing retrieval and understanding of words Modality-specific aphasias Category-specific aphasias The question of multiple semantic systems Access (refractory) vs. storage deficits The central (semantic and conceptual) levels of representation

12. Grammatical Deficits in Aphasia

Gabriele Miceli Introduction Agrammatism as a production deficit Agrammatism as a deficit of central mechanisms Dissociations between production and comprehension deficits Analyses of grammatical production deficits Paragrammatic production Problems with research on clinically defined grammatical disorders Grammatical production deficits Grammatical comprehension deficits Anatomo-clinical correlates of grammatical disorders Conclusions Acknowledgements Notes

13. Disorders of Conceptual Thinking in Aphasia Luigi A. Vignolo Introduction History Revival of research in the 1960s Tentative hypotheses and recent research Conclusions Appendix: Practical implications

14. Acquired Dyslexias and Dysgraphias Gianfranco Denes, Lisa Cipolotti and Marco Zorzi Orthographic systems

228 231 233 236 237 239

245 245 247 248 251 251 254 255 258 264 268 269 270 270

273 273 274 277 281 286 287

289 289

CONTENTS

Acquired dyslexias Computational models The diagnosis of dyslexia Cognitive classification of the acquired disorders of reading Central dyslexias Peripheral dyslexias Models of writing Central agraphias Peripheral agraphias

290 298 300 300 301 307 310 315 317

Giuseppe Vallar The architecture of human memory Disorders of LTM: Amnesia Deficits of short-term memory Notes

321 321 327 358 368

PART IV: RECOGNITION DISORDERS 16. Agnosia

Ennio De Renzi Anatomo-functional organisation of the visual cortex Perceptual deficits Visual agnosia Tactile agnosia

17. The Neuropsychology of Music Anna Basso Normal subjects Brain-damaged subjects Single cases Music production Conclusion

371 371 372 374 403

409 410 412 412 413 413

PART V: MOVEMENT DISORDERS 18. Apraxia

Ennio De Renzi and Pietro Eaglioni Ideomotor apraxia

19. Constructional Apraxia

Dario Grossi and Luigi Trojano Definition Assessment ofconstructional abilities

434 435 437 438

441 441 442

PART VI: SPATIAL DISORDERS

PART III: MEMORY DISORDERS 15. Neuropsychological Disorders of Memory

Melokinetic apraxia Ideational apraxia Trunk apraxia Oral apraxia

vii

421 421

20. Visuospatial and Imagery Disorders

453

21. Unilateral Neglect and Related Disorders

479

Paolo Nichelli Spatial perception and its disorders 454 Optic (visuomotor) ataxia 461 Bâlint-Holmes syndrome 464 Right hemisphere developmental learning disability 467 Spatial memory and its disorders 467 Disorders of topographical orientation 471 Reduplicative paramnesia for places 472 Visuospatial imagery 474

Edoardo Bisiach Clinical manifestations Allied disorders Clinico-anatomical correlations The course of unilateral neglect Interpretation of the syndrome Spatial features Influence of stimulation Anosognosia Somatoparaphrenia Dyschiria and its interpretation Implications for cognitive sciences

479 481 481 482 482 487 489 490 492 492 493

22. Disorders of Body Awareness and Body Knowledge 497 Gianfranco Denes Introduction Clinical aspects Mechanisms underlying bilateral disturbances of body knowledge

497 498 502

viìi CONTENTS

Hemisomatoagnosia Somatoagnosic illusions and hallucinations Concluding remarks

504 504 505

PART VII: ATTENTIONAL DISORDERS 23. Neuropsychology of Attention

Carlo A. Marzi Introduction Level of selection Automatic and controlled processes One or many attentional systems? Acknowledgements

24. The Frontal Lobe

509 509 510 514 516 524

525

Pietro Faglioni Structure and connectivity of the frontal cortex 525 Functions of the frontal eye field and premotor cortex: Attending to the present 534 Functions of the prefrontal cortex: Planning for the future 547 Acknowledgements 569

25. Acute Confusional State

Carlo Caltagirone and Giovanni A. Carlesimo Introduction Clinical manifestations of the acute confusional state Etiological factors Neuropsychology Conclusions

571 571 572 574 576 578

PART VIII: SPECIAL SYNDROMES 26. Calculations and Number Processing

Gabriele Miceli and Rita Capasso Introduction The number processing system Calculation Other components

583 583 584 594 606

Calculation, number processing, and other cognitive systems Anatomo-clinical correlates Conclusions Acknowledgements Notes

27. Neuropsychology of Emotions

Guido Gainotti What are emotions? Theoretical and applicative aspects Characteristics of the emotional and cognitive systems The role of subcortical and cortical structures in the spontaneous expression and control of emotions Cortical regulation of the basic mechanisms of emotion Emotional disorders in brain-damaged patients Conclusions

28. Interhemispheric Disconnection Syndromes

Giovanni Berlucchi and Salvatore Aglioti Introduction Historical development Symptomatology Temporary unrelated symptoms Mind and consciousness in the split brain

29. The Neuropsychological Approach to Consciousness Edoardo Bisiach Preliminary definitions Explanatory practicability The mapping of consciousness in the brain The diachronic articulation of consciousness The causal role of consciousness Neural mechanisms of consciousness Conclusions Acknowledgements Notes

607 608 610 611 611

613 613 614 614 618 621 629 633

635 635 638 642 665 667

671 671 673 675 677 679 680 682 685 685

CONTENTS ix

PART IX: DEMENTIA 30. Dementia: Definition and Diagnostic Approach Hans Spinnler and Sergio Della Sala The meaning of the term “dementia” Neuropsychological taxonomy of the dementias Descriptive definition of dementia Operational definition of CPCD Diagnostic approach Conclusions

31. Alzheimer’s Disease

Hans Spinnler Introduction Memory disorders Deficits of the “instrumental” functions Deficits of the “control” functions Tentative general understanding of AD Diagnosis, contact with relatives, and ethical issues Acknowledgements

32. Non-Alzheimer Dementias

François Boiler and Silvia Muggia Introduction Degenerative dementias Dementias associated with “extrapyramidal” pathology Vascular dementia Dementias and cognitive disorders associated with infectious pathology Dementia of normal pressure hydrocephalus (NPH) Cognitive disorders associated with multiple sclerosis (MS) Dementia associated with metabolic and deficiency states Dementia and psychiatry Miscellaneous

689 689 690 691 693 694 696

699 699 713 724 732 741 744 746

747 747 748 756 761 764

34. Language Disorders in Dementia

Claudio Luzzatti Introduction Language modifications in the elderly Language disorders in Alzheimer’s dementia The cognitive neuropsychological approach to AD Language disorders and dementia of various aetiologies Primary progressive aphasia and dementia General conclusions Notes

769

PART X: RECOVERY OF FUNCTIONS

770

35. Recovery of Cerebral Functions

770 771 773

33. Slowly Progressive Isolated Cognitive Deficits 775 Sergio Della Sala and Hans Spinnler Overview

Introduction 775 Definition 776 Slowly progressive aphasia 778 Semantic dementia 781 Slowly progressive aphemia 784 Slowly progressive Gerstmann syndrome 788 Slowly progressive apraxia 788 Slowly progressive amusia 794 Slowly progressive prosopagnosia 795 Slowly progressive unilateral visuospatial neglect 796 Slowly progressive simultanagnosia 797 Slowly progressive isolated anterograde amnesia 799 Conclusions 805 Acknowledgements 807 Note 807

775

Anna Basso and Luigi Pizzamiglio Cerebral plasticity Neuropsychological disorders The prognosis Conclusions

36. Aphasia Rehabilitation Anna Basso A brief history

809 809 810 813 824 838 840 845 845

849 850 856 862 867

869 869

x CONTENTS

Effectiveness of rehabilitation A theory of rehabilitation Conclusions

37. Visual, Visuospatial, and Attentional Disorders

Pierluigi Zoccolotti Introduction Disorders involving reductions of the visual field Heminattentive disorder Constructive apraxia Basic attention disorders

870 872 873

875 875 876 877 882 883

General conclusions Note

38. The Rehabilitation of Memory

Giovanni A. Carlesimo Introduction A brief theoretical framework Methods of memory rehabilitation Effectiveness of rehabilitative methods Conclusions

References Subject index

885 885

887 887 887 888 889 896

899 1095

List of Contributors Salvatore Aglioti, Department of Neural and Visual

Ennio De Renzi, Neurological Clinic, University of

Sciences, Human Physiology Section, University of Verona, Strada le Grazie, 37134 Verona, Italy. Anna Basso, Neurological Clinic, University of Milan, Via Sforza 35, 20122 Milano, Italy a n d IRCCS S Lucia, Via Ardeatina 306, 00179 Roma, Italy. Giovanni Berlucchi, Department of Neural and Visual Sciences, Human Physiology Section, University of Verona, Strada le Grazie, 37134 Verona, Italy. Edoardo Bisiach, Lurago Marinone, 22070 (CO), Italy. François Boiler, INSERM Unit 324, 2 ter rue d’Alésia, 75014 Paris, France. Carlo Caltagirone, Neurological Clinic, University of Rome, Viale dell’Umanesimo 10,00144 Roma, Italy a n d IRCCS S Lucia, Via Ardeatina 306,00179 Roma, Italy. Rita Capasso, Neurological Clinic, Catholic University, Largo Gemelli 8, 00168 Roma, Italy a n d IRCCS S Lucia, Via Ardeatina 306, 00179, Roma, Italy. Erminio Capitani, Neurological Clinic, University of Milan, Via di Rudini’ 8, 20142 Milano, Italy. Stefano Cappa, Neurological Clinic, University of Brescia, Spedali Civili, 25125 Brescia, Italy. Giovanni A. Carlesimo, IRCCS S Lucia, Via Ardeatina 306, 00179 Roma, Italy. Lisa Cipolotti, Neuropsychology Department, National Hospital for Neurology and Neurosurgery, Queen Square, London WC13, UK. Roberto Cubelli, Department of Psychology, University of Padua, Via Venezia 8, 35100 Padova, Italy. Sergio Della Sala, Department of Psychology, University of Aberdeen, King’s College, Aberdeen AB9 2UB, UK. Gianfranco Denes, Neurology Division, Ospedale Civile, Camp San Giovanni e Paolo, 30122 Venezia, Italy.

Modena, Via del Pozzo 71, 41100 Modena, Italy.

Pietro Faglioni, Neurological Clinic, University of

Modena, Via del Pozzo 71, 41100 Modena, Italy. Gainotti, Neurological Clinic, Catholic University, Largo Gemelli 8, 00168 Roma, Italy. Dario Grossi, Department of Neurological Sciences, Frederico II University, Via S. Pansini 5, 80131 Napoli, Italy. Marcella Laiacona, Medical Centre of Veruno, Neuropsychology Unit, Neurology, S. Maugeri Foundation, IRCCS, 28010 Veruno (Novara), Italy. Claudio Luzzatti, Institute of Psychology, School of Medicine, University of Milan, Via Tommaso Pini 1, 20134 Milano, Italy. Emanuela Magno Caldognetto, Centro di Fonetic CNR, Largo Salvemini 5, 35100 Padova, Italy. Carlo A. Marzi, Department of Neural and Visual Sciences, Human Physiology Section, University of Verona, Strada le Grazie, 37134 Verona, Italy. Luciano Mecacci, Department of Psychology, University of Florence, Via san Niccolo’ 93, 50125 Firenze, Italy. Gabriele Miceli, Neurological Clinic, Catholic University, Largo Gemelli 8, 00168 Roma, Italy. Silvia Muggia, Neurological Clinic, University of Milan, Via di Rudini’ 8, 20142 Milano, Italy. Paolo Nichelli, Neurological Clinic, University of Modena, Via del Pozzo 71, 41100 Modena, Italy. Daniela Perani, Consiglio Nazionale delle Ricerche, Istituto di Neuroscienze, Via Olgettina 60, 20132 Milano, Italy. Luigi Pizzamiglio, Department of Psychology, University of Rome “La Sapienza,” Via dei Marsi 78, 00185 Rome, Italy a n d IRCCS S Lucia, Via Ardeatina 306, 00179 Roma, Italy.

Guido

XI

xii HANDBOOK OF CLINICAL AND EXPERIMENTAL PSYCHOLOGY

Giacomo Rizzolatti, Institute of Human Physiology,

University of Parma, Via Gramsci 15,43100 Parma, Italy. Carlo Semenza, Department of Psychology, University of Trieste, Via Università 7, 34123 Trieste, Italy Donatella Spinelli, Department of Psychology, University of Rome “La Sapienza”, Via dei Marsi 78, 00185 Roma, Italy a n d IRCCS S. Lucia, Via Ardeatina 306, 00179 Roma, Italy. Hans Spinnler, Neurological Clinic, University of Milan, Via di Rudini’ 8, 20142 Milano, Italy. Luigi Trojano, S. Maugeri foundation, IRCCS, Rehabilitation Center of Telese, Loc. S. Stefano in Lanterna, 82037 Telese (BN), Italy. Giuseppe Vallar, Department of Psychology, University of Rome “La Sapienza”, Via dei Marsi 78, 00185

Roma, Italy a n d IRCCS S Lucia, Via Ardeatina 306, 00179 Roma, Italy. Maria Pia Viggiano, Department of Psychology, University of Florence, Via san Niccolo’ 93, 50125 Firenze, Italy. Luigi A. Vignolo, S. Maugeri foundation, IRCCS, Neurological Clinic, University of Brescia, Spedali Civili, 25125 Brescia, Italy. Pierluigi Zoccolotti, Department of Psychology, University of Rome “La Sapienza”, Via dei Marsi 78, 00185 Roma, Italy a n d IRCCS S. Lucia, Via Ardeatina 306, 00179 Roma, Italy. Marco Zorzi, Department of Psychology, University of Trieste, Via Università 7, 34123 Trieste, Italy a n d Department of Psychology, University College London, Gower Street, London WC1E 6BT, UK.

Part I

Methodological Problems in Neuropsychology

Taylor & Francis Taylor & Francis Group http://taylorandfrancis.com

1 Neuropsychology: Introductory Concepts Giacomo Rizzolatti and Luigi Pizzamiglio

Therefore, it deals with one of the oldest and most basic scientific and philosophical problems: the relationship between mind and brain. The means used by neuropsychology to tackle the problem are not, however, the deductive ones of philosophy but those of the experimental sciences. Neuropsychology is an eminently interdisciplinary science, converging with neurology, neuroanatomy, neurophysiology, neurochemistry, psychology, linguistics, and artificial intelligence. It is difficult to say exactly when neuropsychology began. However, the Cartesian model posed the following problem for the first time with the clarity necessary for its verification and “falsification”. The brain is the site of the mind. However, it is also the point of arrival for sensory information and the point of departure for voluntary motor commands. Is it possible to conceive of the brain as a homogeneous structure, or does the dichotomy between neurological and psychic functions imply an anatomo-functional inhomogeneity? Given that there are receptive cortical areas and other efferent ones, is the remaining part of the brain homogeneous or can it be separated into areas with different functions? A scientifically

Although the historical priority of an idea or of a theory is always debatable, it is generally accepted that the first coherent conception of human and animal behaviour expressed in neurological terms was the Cartesian one. Figure 1.1 shows a graphic representation of the Cartesian conception. The nervous system is subdivided into two basic levels: a lower level, which can be assimilated in anatomical terms in the spinal cord and the brain stem, and an upper level, corresponding to the brain. Sensory information arrives at both levels. At the lower level it activates circuits, so that the organism responds to sensory stimuli with motor responses. This lower level is the level of reflexes. The sensory information that arrives in the brain is also transformed into motor commands. However, the sensorimotor transformation is not mechanical, as it is in the lower level, but occurs through the action of the mind. The latter creates a representation of the external world, stores sensations in the form of memories and decides how to act in the external world. Neuropsychology is the discipline that studies the processes belonging to the mental level in the Cartesian schemata through experimental means. 3

4 RIZZOLATTI AND PIZZAMIGLIO

FIGURE 1.1 The Cartesian model of the central nervous system

satisfactory answer to this question was given in the second half of the nineteenth century. The period extending from 1860 to 1900 is the period of the great neurological and neurophysiological discoveries. The empirical and conceptual bases of neuropsychology were laid down during these 40 years. Broca’s studies (1861a, 1863, 1865) showed that a correlation exists between language motor disorders and lesions of the left frontal regions. Wernicke (1874) localised sensory aphasia in the posterior part of the superior left temporal gyrus and provided a systematic picture of the aphasias. Development of Wernicke’s concepts brought Lichtheim (1885) to propose the anatomo-functional schema of language centres, which has constituted the base of classification of the aphasias up to the present time. In 1870 Fritsch and Hitzig demonstrated that electrical stimulation of an area in the frontal lobe produces isolated movements of contralateral limbs in the dog. This zone—the motor area—was soon defined in other mammals, including humans. The discovery of the motor area and the facility with which the experiment was replicated definitively defeated the antilocalisationist positions (Flourens, 1823) and opened the era of the electrophysiological study of the cerebral cortex in animals and in humans. Ferrier (1876) demonstrated the existence

of motor areas in the monkey and suggested that the parietal lobe has visual functions. Munk (1878) established that the visual functions are primarily localised in the occipital lobe. Wernicke (1895) demonstrated that the somatosensory and somatoperceptual functions are localised in the parietal lobe. Bianchi (1895) described the spatial hemineglect syndrome in monkeys and suggested that the frontal lobe is involved in processes of memory and learning. The century closed with Liepmann’s (1900a) description of various types of apraxia and the possible neuronal circuits underlying voluntary movements. The years stretching from the beginning of the 1900s to the end of the Second World War were less fruitful in terms of results than the preceding era. New discoveries were made, better descriptions and better localisation of syndromes were obtained, and the limits of the concept of localisation were debated, but the questions posed by researchers did not seem radically different from those posed at the end of the 1800s. Various factors concurred during this period of conceptual stagnation in neuropsychological research. The first was the success of the preceding era. Results of experiments on animals and clinical observation had shown that the brain was basically organised in a way rather similar to the nervous

1. INTRODUCTORY CONCEPTS 5

centres forming the lower level of the Cartesian model (spinal cord, brain stem). Also, in the cerebral cortex there were sensory areas, motor areas, and intermediate areas (associative) linking the sensory and motor areas. Why should the function of these circuits be described with concepts such as mind, attention, consciousness? A neurophysiological explanation could and should be sufficient. This point of view was reinforced by Pavlov’s (1927) experiments in Russia and Thorndike’s (1932) and Watson’s (1914) in the United States. If a slightly acid solution is placed in the mouth of a dog, it salivates. The response to the stimulus is a pure physical fact, so no mental explanation seems necessary. Now, if a sound is associated with the administration of the slightly acid solution, the animal will salivate when it hears the sound before, or also in the absence of, the administration of the solution. The response to the sound (conditioned response) follows precise laws as does the natural (unconditioned) reflex. Therefore, it is not logical to postulate two independent explanation systems for such similar phenomena. The turning point reached by psychology through the learning experiments freed it (and neuropsychology as well) from many of its problems. If attention does not exist, but is simply a verbal description of certain behaviours, there is

no sense in studying it, at least in neuropsychological terms. If there is no mental process during learning, and a certain nervous pathway is simply “reinforced”, the only real problem is that of localising the pathway or pathways involved in learning. Pavlov did not deny the dichotomy between the brain and the lower centres. According to his conception, learning is a specific function of the cerebral cortex. Therefore, the dichotomy between the brain and lower levels was accepted but was then resolved in terms of innate connections and learned connections. The Cartesian schema in Fig. 1.1 was substituted by that in Fig. 1.2. Once this schema is accepted, the task of the neuropsychologist is no longer that of explaining mental functions, which do not exist, but of localising the areas in which the associations responsible for the various behaviours occur. The strongly antimentalistic intellectual climate that characterised the first 40 years of this century changed progressively and radically after the war. The works of Hebb (1949) and Broadbent (1958) reinstated and gave scientific dignity to terms such as attention and “set” (predisposition to respond in a certain way). Moruzzi and Magoun’s (1949) experiments demonstrated that a precise neuronal substrate exists for attention, at least in its intensive dimension. Sperry’s (1976) experimental results

FIGURE 1.2

The Behaviouristic model of the central nervous system.

6 RIZZOLATTI AND PIZZAMIGLIO

and theories brought the concept of consciousness to the fore. The brain-mind problem reappeared, and solutions that implied a brain-mind interaction were proposed both in a materialistic (Sperry, 1976) and spiritualistic (Eccles, 1986) vein. In a decade, more or less coinciding with the 1970s, psychology was transformed from behaviourism to cognitivism. The development of machines that showed intelligent behaviour changed the way of tackling the study of brain functioning, passing from a passive attitude of observation to an active one of builders of robots with “mental” faculties. Modem neuropsychology was bom from the contribution of these new ideological tendencies and new scientific knowledge. Besides the ideological factors, which created a favourable situation for the development of neuropsychology, a series of factors linked to the progress of neighbouring disciplines favoured its growth. Progress in neurosurgery and new radiological and brain imaging methods permitted anatomo-clinical correlations that were inconceivable only 10 years before. New neurophysiological techniques made it possible to study neurone activity in nonanaesthetised animals with freedom of movement during the execution of complex tasks. Psychology offered methods and models of a complexity incomparable to the simple models borrowed from nineteenth-century psychology. Making use of these advances, neuropsychology assumed its individuality and independence, which increasingly separated it from clinical neurology. The term neuropsychology (Bruce, 1985), introduced in the 1950s, substituted the term brain pathology (Kleist, 1934a) or study of the higher nervous functions (Pavlov, 1927) and marked the birth of a new discipline, which was autonomous with regard to techniques and problems. A chronological description of recent neuropsychological discoveries is beyond the scope of this chapter. A brief history of neuropsychology, subdivided into its basic sections—cerebral localisation, hemispheric dominance, memory, aphasia, agnostic disorders—has been published by Benton (1988). The reader can find essential information there. However, there are two interesting examples of how the various disciplines

forming modem neuropsychology concur in the study of a neuropsychological problem. An example of the multidisciplinarity of the neuropsychological approach, which has relevance for the brain-mind problem, is that of neglect. A second example is the problem of hemispheric dominance. Neglect is a disorder characterised by the inability to perceive and respond to stimuli presented in a particular area of space. The presence of neglect, at least in its most serious forms, can be determined by observing the patient’s behaviour in carrying out normal activities. The patient appears to ignore the space contralateral to the lesion. If the physician speaks to the patient from this side he or she does not respond or look towards where the voice of the physician is coming from, turning around to the opposite side. Often, when eating, patients, take food from only half of the plate. If they have to make a drawing, they execute only the part ipsilateral to the lesion. Neglect can affect not only extrapersonal but also personal space. For example, patients can forget to wash the part of their body contralateral to the lesion, or forget to shave half of their face. They can forget to dress the half of their body contralateral to the lesion. Finally, even when they have no motor deficits, patients do not explore the space opposite to the lesion either with their eyes or by turning their head. More rarely there can be partial or total absence of contralesional limb movements in the absence of paralysis. For a complete description of the neglect syndrome see Bisiach’s chapter in this volume. What problems are posed by neglect? The first, common to all neurological syndromes, is the site of the lesion. This problem can be divided into two parts, one anatomical and one functional. Is the syndrome due to hypofunctioning or to nonfunctioning of the anatomically lesioned nervous tissue or to an alteration of other centres connected with it? In lower-level neurological syndromes, the anatomical explanation coincides with the functional one. For example, a lesion that causes flaccid paralysis affects (with very rare exceptions) the spinal motoneurones or their extensions. The lesioned mechanism is the conduction of the nervous impulses from spinal centres to the muscle. The situation is different when the lesion involves

1. INTRODUCTORY CONCEPTS

the higher nervous centres. In the case of neglect in humans, even if various cortical areas can be affected, the most frequent lesion is that of the right parietal lobe. How can this observation be explained? There are various possibilities. The first is that the neuronal substrate whose destruction produces the syndrome is in the right parietal lobe. This explanation seems to be the simplest and the most immediate. However, it is not necessarily true. In fact, it is possible that the information that is indispensable for awareness of contralateral space (lesioned in neglect) passes through the parietal lobe, but is used by other structures in the frontal lobe, in the cingulate gyrus, or even in the subcortical centres. In this case, the syndrome is due to a disconnection of the centres really responsible for the functioning of those that provide lower-order information necessary for obtaining this awareness. A third possible explanation is that the lost function in neglect does not result from the activity of a centre, but of an entire circuit, of which the parietal lobe is part. It is obvious that postmortem techniques and traditional radiological methods cannot answer these questions. They can only localise the site of the anatomical damage. The problem of functional localisation of the deficit will be clarified in the future when new methods of functional investigation of cerebral activity, based on measures of cerebral blood flow or on measures of cerebral metabolism, become more diffused and more precise. Naturally, attentive clinical observation should be added to this, with particular emphasis on atypical cases of neglect, which can provide hints about other areas involved besides the right parietal lobe. Once the centres whose lesion causes the deficit are identified, it becomes possible to investigate their functioning, with less indirect (and vague) observations than those made through their destruction, whether experimental or due to illness. The nervous system is a machine with the primary task of processing information. The most direct approach for discovering what is processed is to record the electrical activity of single neurones. Each neurone can be imagined as a microcircuit with various entrances and one exit. The recording of single neurones in certain conditions (for

7

example, in animals with freedom of movement) permits one to establish which are the entrances (that is, the type of information arriving at the neurone) and, correlating the discharge with the animal’s behaviour, which is the exit. The technique of microelectrode recording has been little used in patients, as the morbid situation rarely justifies its application. On the contrary, it has been largely used in animals, giving a very rich picture of how sensory information is processed by the nervous system. Neglect represents a typical case in which the microelectrode technique can be usefully employed to clarify a neuropsychological syndrome. In fact, neglect can be obtained in animals and the areas involved in the syndrome can be studied with the microelectrode technique. In the monkey, experimental neglect similar to that most commonly observed in humans (neglect of extrapersonal space) is obtained with frontal lobe lesions (area 8). Recording in this area, various types of neurones can be found, schematically divisible into three functional classes: neurones that respond to visual stimuli (visual units), neurones that are activated during ocular movements (motor units), neurones that respond to visual stimuli and are activated during ocular movements (visuomotor units). Recording from areas of the lower parietal lobe, anatomically connected to area 8, has revealed neurones with essentially similar characteristics, while in other parts of the same lobe the neurones respond to somatosensory stimuli and are activated during skeletal movements. Leaving aside the details of the neuronal properties of the areas whose lesion produces neglect (for a thorough treatment see Rizzolatti & Berti, 1990; Rizzolatti et al., 1994), what seems to be the main characteristic of these areas is the transformation of sensory information into movements directed towards a goal. Neurophysiological data are consistent with the clinical aspects of the syndrome. The clinical disorder is neither purely sensory nor purely motor. The neurones of the areas involved are not purely sensory and cannot be defined as motor. However, the problem still remains of why a lesion, which may even be very small experimentally, brings about global neglect of an area of space and not a

8 RIZZOLATTI AND PIZZAMIGLIO

sensorimotor deficit. Why is a monkey with a lesioned area 8 not only not able to move its eyes towards an interesting object presented in the contralateral space, but also does not react to emotional stimuli appearing in this space? Why does the destruction of a visuomotor centre accompany a deficit in awareness of the existence of the contralateral space? Obviously there is something in the syndrome that cannot be reduced to the function of neurones of the lesioned area, but requires a higher-order integration. The concept that the brain is an instrument that processes information is at the base not only of neurophysiology but also, and more explicitly, of cognitive psychology. Unlike neurophysiology, psychology makes no reference to cerebral areas or centres. The mind, which in some way coincides with the brain, is conceived as a set of structures, some in series, others in parallel, where information is represented in different forms. Rules exist for passing from one stage of representation to another. Although some cognitive psychologists consider the correlation between stages of psychological processing and nervous structures of little or no importance, the concept that the way in which psychological processes unfold depends strictly on the nervous structures at their base is being increasingly accepted (McClelland & Rumelhart, 1986). Two of the psychological concepts used in recent years to explain the deficits observed in neglect have been particularly successful. The first is that the basic deficit of neglect is attentional. The information that comes from the space contralateral to the lesion is processed normally along the various centres (or stages) that lead to conscious perception. However, the neurological lesion impairs an “attentional circuit”, localised in the parietal lobe and also including the frontal lobe and the cingulate gyrus. Without this circuit, spatial information does not become conscious, or at any rate is not usable in a conscious way. However, even in the absence of a lesion of the primary sense or motor pathways, the patient is not able to utilise this information appropriately, denies having perceived it, and does not react to it. A second interpretation is that the deficit is representational. The lesioned circuit (or stage) is

not responsible for focalising the images coming from the contralateral space, but is the place where spatial images are formed. The parietal lobe or the fronto-cingulate-parietal circuit represents the stage where the images of space, coming from the external world or from long-term memory, are organised to give rise to an analogous (pictorial) representation of the external world. It is beyond the scope of this introductory chapter to discuss whether these interpretations are correct. What is important to underline here is how the problem of spatial awareness, and thus of neglect, has developed from a problem of neurological localisation to become a problem concerning attention, mental representation, and the relationships of these “mentalistic” terms with cerebral neurophysiological organisation. The interaction among disciplines belonging to the neurosciences and cognitive disciplines has allowed for a new view of the problem without taking anything away from the richness of the phenomenon. A second example that shows the peculiarity and originality of the neuropsychological approach is hemispheric dominance. The concept of hemispheric dominance was bom in the last century from the need to schematise some important clinical-neurological observations made by Dax (1865) and by Broca (1863). The clear anatomical documentation that focal lesions of the left hemisphere provoke aphasie disorders in right-handed subjects, and the subsequent observation made by Broca that right hemispheric lesions generate aphasias in lefthanded subjects, suggested that there is an association between functional latéralisation for language and for manual control. The concept of hemispheric dominance was successively extended to other cognitive functions such as praxes (Liepman, 1900a) and the representation of body schema (Gerstmann, 1930), both linked to the left hemisphere. Data gathered since the 1940s has shown visuospatial and visuoconstructive disorders in patients with focal lesions of the right hemisphere (see Benton, 1988, for a historical reconstruction). The concept of hemispheric dominance, with reference to motor control and cognitive capacities,

1. INTRODUCTORY CONCEPTS

raised great scientific interest due to the establishment of a selective presence only in the human species. If some behavioural characteristics are specific to the species, they must present “a systematic relationship with identifiable states of organisation of the nervous system” (Berlucchi & Tassinari, 1987, p.84). Thus, the hemispheric asymmetry observed in the human species has made necessary an accurate comparison between behavioural characteristics in the various species and organisation of the nervous system. In this perspective, comparative studies (neuroanatomical, radiological, embryological, neuroendocrine, and paleoneurological) have been carried out in various animal species in order to interpret the meaning of hemispheric asymmetries in humans. Without going into the details of studies that will be illustrated in the following chapters, we will only comment on the complex confluence of multidisciplinary notions on this topic by examining motor and cognitive dominance separately. In humans, motor dominance and in particular manual dominance presents as a population characteristic and not as an individual variant. In other words, a proportion of people, variable between 90 and 98%, present right manual dominance; these proportions are largely independent of the populations and cultural factors considered (Warren, 1980); they can be documented through the study of paintings of ancient civilisations or the discovery of utensils with unimanual handles in historical periods going back to several millennia before Christ and even to prehistoric periods (Porac & Coren, 1981). Also, side preference is observable in very early periods of neonatal life (Michel, 1983). In mammals, in particular in anthropoid monkeys most similar to humans, a preference is found in the stable use of one limb in the same individual; but, unlike humans, this is distributed in equal proportions between the two sides of the body in each species. However, examples of lateralisations characteristic of an entire species exist in animals phylogenetically distant from humans; examples of these asymmetries are found in the fiddler crab and in several orthopterans (crickets) that produce their characteristic chirping by systematically rubbing one elytron on the contralateral one, which remains

9

immobile. Another example is found in some types of passerines that produce their most modulated song in one of two laryngeal syringes and under the control of song nuclei in only one cerebral hemisphere. These examples of systematic asymmetry in various animal species do not speak in favour of a peculiarity only for the human species; at the same time, they allow for experimental investigation of the characteristics of the nervous system that can explain the functional significance of this organisation. Berlucchi and Tassinari (1987) observed that in all the animal examples cited, including humans, manual preference actually subserves a distribution of tasks between the two sides, which collaborate in the execution of a complex motor performance. Both in the case of bimanual actions, and in the use of elytrons or claws, one limb executes fine, precise, rapid, and phasic (dominant side) movements, while the opposite side maintains a stable position by means of tonic muscle contraction. From the anatomical point of view, it has been shown in many species of mammals that the control of fine movements is often supported by pyramidal neurones directly connecting cortical areas with peripheral motoneurones; motor synergies at the base of postural tone are more supported by pyramidal neurones with greater functional distance from peripheral motoneurones, as intermediate neurones interpose in the direct corticalspinal connections (Heffner & Masterton, 1983). Also, the pyramidal neurones that control the largest claw in the fiddler crab are of greater dimensions and have a larger dendritic tree than the corresponding neurones of the smaller claw (Young & Govind, 1983). Therefore, the motor preference of one side can be traced in part to structural differences of single neurones and in part to different organisational modalities of the nervous system (connections with greater or lesser functional distance between cortex and motoneurones). On the basis of these data, Berlucchi and Tassinari (1987, p.98) speculatively suggest that “in the genesis of the nervous system the differential innervation of neurones with different functional tasks are facilitated if these neurones are separated in space rather than mixed.”

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The basis of hemispheric latéralisation could, however, derive from a need for economy in the organisation of the central nervous system. Passing on to consider the cognitive functions such as language, praxis, visuospatial abilities, memory, etc., more than a century of clinical observations clearly show how unilateral cerebral lesions produce functionally different consequences depending on which hemisphere is lesioned. Comparative research, analogous to that illustrated for manual dominance, has also been carried out in the area of cognitive abilities. However, in this case, with rare and not completely convincing exceptions, lesions of one or the other hemisphere are followed by the same disorders in various animal species, including anthropoid monkeys. Therefore, the human species is the only one that has unilateral decision-making centres, from time to time allocated to one or the other hemisphere, with the probable advantage of making coordination more efficient between structures concurring in the organisation of complex adaptive behaviours. The presence of functional asymmetries in humans has induced searching for a possible structural substrate of this organisation in the human brain. An important step in this direction was made in Geschwind and Levitsky’s (1968) research: examining 100 human brains they found that the posterior and upper portion of the temporal lobe, the part called planum temporalis, was more developed on the left in 65 cases, and on the right in 11 cases. The presence of this anatomical asymmetry, in the Wernicke’s area indicated as basic for linguistic processes, raised great interest and allowed for enrichment of this first important result. First of all the macroscopic asymmetry revealed in autopsies can also be documented in vivo through the radiological study of the sylvian fissure (Le May & Culabras, 1972); the asymmetry of the sylvian course brings diversity to bone casts of the fissure and has therefore permitted the discovery of analogous findings in prehistoric craniums as well (cranium of Peking man, Le May, 1976). Galaburda and colleagues (1978) extended these results, specifying that differences in the extension

of the cytoarchitectonie areas of the region in question correspond to macroscopic asymmetries. Finally, the presence of temporal asymmetries was observed in several-week-old infants (Chi et al., 1977; Witelson & Pallie, 1973). Falzi and colleagues (1982) investigated the same problem in Broca’s area, which is also involved in linguistic functions; the macroscopic asymmetries between the left and right area presented with the same proportion described by Geschwind and Levitsky (1968) for the temporal planum. However, the suggestive similarity between functional and anatomical asymmetries should be considered with caution for two reasons: the first regards the finding of analogous temporal asymmetries in anthropoid monkeys which, as mentioned earlier, do not accompany corresponding functional latéralisations; the second regards the numerical difference between percent of anatomical asymmetries (about 65% of cases in all studies) and functional ones, which are much greater for language. Even with these uncertainties about giving significance to the data summarised up to now, in this context we need only recall the great interest and multidisciplinary effort produced by the development of the concept of hemispheric dominance. Returning to the proposal made by Berlucchi and Tassinari on manual dominance, it may be that also in the case of cognitive processes, the different way of processing information profits from a different functional organisation of the nervous substrates involved. The distribution of the cognitive processes in the two sides of the brain is advantageous for optimal functional performance, maintaining cerebral volume constant. These theoretical topics can be brought closer to the alternative way of conceptualising cognitive processes. Dichotomisations in terms of processes underlying these operations followed a first interpretation of the function of the left hemisphere as prevalently linked to linguistic capacities and the right one to spatial processing. Borrowing some concepts from the verbal labels of computer science, processing in series and analytical processing were adopted for some linguistic processes, while parallel processes and

1. INTRODUCTORY CONCEPTS

global processes were postulated for several spatial operations. The common element in these most recent formalisations of the problem of cognitive asymmetries is the emphasis placed on the different operative modalities with which various aspects of surrounding reality are processed. This explicit reference to the operational modality could require or make more economical a different organisational approach to the neurological structures involved. Therefore, the questions deriving from this move towards verifying whether differences actually exist; for example, in the way in which areas involved in different processes are connected, whether biological factors can be identified that are responsible for this organisation, and when these organisational needs occur during the course of ontogenetic development. Although there is no documentation of a different architecture in the connections between different areas of the two hemispheres, at least two research areas can provide indications about the nature of the biological processes underlying hemispheric differentiation and when they occur during development. These two areas are the behavioural study of subjects with numerical anomalies in sex chromosomes, and by recent suggestions regarding a possible relationship between sex hormones and cerebral development. The common basis of these two approaches is the notion that the two cerebral hemispheres do not mature in a symmetrical way. In fact, anatomical (Yakovlev & Rakic, 1966), behavioural (Corballis & Morgan, 1978) and electrophysiological (Thatcher et al., 1987) evidence indicates that the left hemisphere presents more precocious development than the right and, more in general, that, during the course of ontogenesis, critical periods exist during which one hemisphere shows maturational acceleration. These alternating increases in the two hemispheres can be observed until the end of maturation of the central nervous system. During foetal life, there is more precocious development of the left hemisphere, that is, of the hemisphere involved in verbal or analytical functions; the right hemisphere develops

11

successively, which is in turn involved in the control of spatial and global functions. The presence of an excess or of a lack of sexual heterochromatin causes an alteration of the maturational rhythm of the left hemisphere and, as a consequence, of the pattern of latéralisation of hemispheric functions, besides a modification of verbal or spatial processing ability. In particular, a lack of sex heterochromatin, such as in Turner’s (XO) syndrome, brings about an acceleration of cell multiplication (Netley & Rovet, 1982) with resulting rapid development of the left hemisphere. The accelerated maturation of this hemisphere also brings about an extension in the right hemisphere of the organisational modality typical of the left hemisphere. As a consequence of this maturational perturbation, adults with Turner’s syndrome present normal linguistic ability accompanied, however, by a less asymmetrical representation of language, demonstrated by means of verbal dichotic stimuli (Netley & Rovet, 1982). Also the “invasion” of the right hemisphere by “linguistic” type organisational schema brings about a decrease in performance in visuospatial ability, repeatedly observed in this syndrome (Waber, 1979). Speculatively, the excess of heterochromatin present in Klinefelter’s (XXY) syndrome should slow down the development of the left hemisphere in critical developmental periods, leaving development of the right hemisphere unaltered. As a consequence, in individuals with Klinefelter’s syndrome good spatial reasoning capacity is observed, with a normal pattern of cognitive latéralisation, and reduced verbal reasoning ability (Rovet & Netley, 1979). However, this interpretation of the role of sex chromosomes in the development of hemispheric dominance (Levy, 1969) is inadequate for satisfactory explanation of the possible individual variations in the development of dominances in subjects with normal sex chromosomes. Geschwind (1984) and Geschwind and Galaburda (1987) proposed an interpretative mechanism apparently similar to that of Levy (1969) by identifying the biological factor responsible for modifications of the maturational course of the two hemispheres in level of production of testosterone in critical periods of

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cerebral development. In their model, an excess of testosterone in the first 3 to 4 months of foetal life causes a delay in maturational development of the left hemisphere, and a lack of this hormone produces the contrary effect. On the basis of this hypothesis, Hier and Crowley (1982) explained a decrease in spatial abilities observed in a group of patients with congenital hypogonadotrophic hypogonadism. However, this finding was not confirmed by Cappa and colleagues (1988) in an analogous population of subjects with congenital hypogonadism nor in a case of testicular féminisation. The hypothesis of a relationship between testosterone levels and development of spatial abilities linked to the right hemisphere does not therefore seem confirmed. However, these authors described a link between congenital hypoproduction (or insensitivity in the case of testicular féminisation) of testosterone and organisation of cognitive functions, in particular short-term memory, but without relation to hemispheric latéralisation. Today, the attempt to link genetic, endocrinological, and immunological knowledge to the development and organisation of the cerebral hemispheres is based on a very loose and highly imaginative grouping of facts that are still very distant. Even presentation of the hypotheses that have been formulated requires the use of figurative language, for example “invasion of the right hemisphere by linguistic functions”. The explanations deriving from it have more of a metaphorical flavour than of a causal sequence of events. It is also easy to predict that progress of knowledge in this area will be slowed down by the difficulty, or even impossibility, of using animal experimentation, given the lack of convincing cognitive asymmetries. In this line of research, the current explosion of neuroimaging studies has brought a series of behavioural observations to the focus of attention relative to possible differences in hemispheric latéralisation between the two sexes in the human species. Lateralised visual presentation of verbal and nonverbal stimuli showed a systematic superiority of one hemisphere over the other (respectively left and right for the tasks cited) in

males (Rizzolatti et al., 1971); this superiority was much less evident for females (Hellige, 1993; Pizzamiglio & Zoccolotti, 1981; Rizzolatti & Buchtel, 1977). Two recent brain-imaging studies have raised researchers’ interest in the possible different functional organisation of the brain in the two sexes. Gur and colleagues (1995) studied regional distribution of glucose metabolism (using the PET technique) in 61 normal adults of both sexes. In this study a largely superimposable profile of metabolic activity emerged for both sexes but, at the same time, several significant differences also emerged. In particular, males presented greater metabolic activity in the lateral and ventromedial regions of the temporal lobes, in the hippocampus, the amygdala, and the fronto-orbital areas. On the contrary, females presented more intense metabolism in the posterior and medial parts of the cingulate gyrus. These results on the metabolism of the temporo-limbic system and the cingulate gyrus have suggested the possibility that these differences are at the base of a different way of processing emotional experience. The same study also showed other hemispheric differences, independent of sex: metabolic activity of the associative cortical areas is prevalent in the left hemisphere, and the ventro-limbic and medialtemporal regions are prevalent in the right hemisphere. These differences between sexes and between hemispheres were observed in a rest condition. Therefore it would be interesting to study how this diversity changes during the performance of a mental activity. A second study showed sexual differences during the performance of linguistic tasks. Shaywitz and colleagues (1995) studied the level of activation of 19 males and 19 females during the performance of tasks of orthographic, phonological, and semantic recognition through the use of magnetic resonance with eco-planner. Tasks of phonological and semantic recognition activate both temporal (superior and medial temporal gyrus) and frontal (inferior frontal gyrus) areas: however, hemispheric asymmetries were shown in the two sexes only on the phonological task. In particular, males showed a strong activation of the left inferior frontal gyrus, and females a more diffused

1. INTRODUCTORY CONCEPTS

activation involving both left and right inferior frontal gyrus. On the one hand, this finding confirms numerous preceding studies indicating greater bilaterality in the representation of language in women (McGlone, 1980) and on the other it documents that this different hemispheric representation is specific for several components and cannot be extended to all aspects of linguistic processing. In conclusion, we believe that the two neuropsychological problems we have discussed represent clear examples of the complexity and multidisciplinary nature of modern neuropsychology. The following chapters will demonstrate the truth of this statement in greater detail. Before concluding, it is important to note that in contemporary neuropsychology two ways of approaching neuropsychological problems are present, which result in different descriptions of cerebral activities. One description has the concepts

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of cognitive psychology as its base; the other has neurophysiology and anatomy. It is possible that the two descriptions are intrinsically different and have no common base of reference. However, the recent development of techniques and of both psychological and physiological conceptions favour the opposite alternative. Neurones are not only generators of impulses, but inserted in a network they function as stages of progressively more complex information processing. On the other hand there is the concept that the implementation of psychological processes seems correlated with a more complex organisation of the nervous system. The possibility of a unitary description of neuropsychological functions in which the complexity of mental processes is brought out, simultaneously taking into consideration the specific, peculiar way in which these functions are executed, seems to be the most important (and most fascinating) task of neuropsychology at the end of the twentieth century.

Taylor & Francis Taylor & Francis Group http://taylorandfrancis.com

2 Behavioural Methods in Neuropsychology Maria Pia Viggiano

behavioural techniques in neuropsychology may be found in some chapters of the book edited by Hannay (1986), as well as in other specific contributions on tachistoscopic stimulation, dichotic listening, reaction times, etc., which will be quoted.

INTRODUCTION When the experimental method was adopted by neuropsychology around the 1960s the problem was to set up research conditions in which the parameters of stimulus presentation and method of data recording and analysis were established accurately. Some experimental sets, based on tachistoscopic visual stimulation or dichotic listening, became paradigmatic for a large number of neuropsychological studies. The experimental approach made it possible to compare the performance of large samples of brain-injured patients and normal subjects. This chapter will describe stimuli, presentation techniques, and experimental paradigms most frequently used in neuropsychology. Reference will be made to studies that have become a starting-point for further research, thanks to their methodological characteristics. A presentation will also be given of the most common problems that emerge with the various methodologies and the solutions adopted to overcome them. A detailed discussion of issues and methodological problems inherent in the use of

STIMULI AND PRESENTATION TECHNIQUES A wide variety of techniques have been used in neuropsychology, which differ both in sensory modality and complexity. One of the most critical problems from the methodological point of view is the lack of homogeneous criteria on the basis of which the complexity of stimuli can be graded. This leads to a certain idiosyncraticity of stimuli used by various investigations. However, the introduction of the computer made it possible to obtain easily reproducible standard sequences of stimulation, and it is now possible to repeat the same experiment in different laboratories. Two large categories of stimuli may be distinguished, meaningful and meaningless (Snodgrass, Levy-Berger, & Haydon, 15

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VIGGIANO

1985), and these categories can, in turn, be differentiated into visual stimuli, auditory stimuli, and tactile stimuli. Verbal stimuli form a category by themselves, but they will be illustrated in relation to the sensory modality of presentation, visual or auditory. Within each group of stimuli, there may be other differentiations, generally based on physical characteristics and complexity of processing.

Visual stimuli Meaningless visual stimuli (gratings, random patterns, etc.) have been used to study the processing of visual information independently of verbalisation and attribution of meaning. Meaningful visual stimuli (drawings of objects, faces, etc.) have often been used to study the relative information processing and the dissociation between the ability to verbalise the visual stimulus and the capacity to recognise its meaning, for example in the case of split-brain patients. The following account lists the visual stimuli that can be presented by means of slide projectors, tachistoscopes, oscilloscopes, TV monitors, and computers, and can be used in research based on experimental paradigms. Gratings and checkerboards. Gratings and checkerboards (Fig. 2.1) have been employed particularly in research on deficits in the primary processing of visual information due to brain lesions (Hannay, 1986). Gratings are periodic variations of luminance in space: light and dark bars, which alternate regularly. The number of bars contained in a grating may vary, making it possible to study the properties of the visual system in the analysis of spatial frequency (the number of cycles in one degree of visual angle). Gratings may be stationary, or presented by means of periodic variations in the spatial dislocation of the light and dark bars (the light bar becomes dark and vice versa). The temporal frequency with which the bars are alternated is also an important dimension of the visual stimulus. Moreover, the difference in luminance between the bars is another of the basic properties analysed by the visual system: the contrast is properly defined as the difference between the maximum value of luminance of one

bar and the minimum value of the other, divided by the sum of the two luminances. Contrast sensitivity is the reciprocal of the threshold of K, that is, the minimum value of contrast (K) at which a grating of a specific spatial frequency can be detected. In normal adult subjects, the relationship of contrast sensitivity and spatial frequency assumes the shape of an inverted U: at intermediate spatial frequencies (3-5 cycles/ degree), sensitivity is greater than for lower or higher frequencies. Gratings are very suitable for evaluating the integrity of basic visual processes (Spinelli & Zoccolotti, 1992). For example, many studies have demonstrated that in cases of cerebral lesion there may be selective losses of contrast sensitivity for limited ranges of spatial frequency, although the consequences of these deficits at the level of the processing of more complex visual information are not yet clear. Furthermore, no relationship has yet been found between the localisation of cerebral lesions and the range of spatial frequencies for which there is a selective loss of sensitivity (Bodis-Wollner & Diamond, 1976; Hess, Zihl, Pointer, & Schmid, 1990; Mecacci, 1993,1997). Checkboards vary in the dimensions of the squares and the temporal frequency with which the black and white squares alternate. Checkboards, like gratings, have been used in electrophysiological research to control the integrity of basic visual processes in neuropsychological syndromes (Vallar et al., 1991; Viggiano, Spinelli, & Mecacci, 1995), and in relationship to the area and the extension of the lesion (Halliday, 1993). Random patterns. The best-known series of random stimuli is the one produced by Attneave and Arnault (1956). Each stimulus is derived from a matrix of 100 X 100 dots chosen at random to delineate its perimeter (Fig. 2.1). The values of association and content have been measured for 1,100 stimuli of this kind(Vanderplas, Sanderson, & Vanderplas, 1965). These random patterns have also been used in studies with a lateralised tachistoscopic presentation (Hellige, 1978) and they have often been employed in research on brain-injured patients (McCarthy & Warrington, 1992). Other stimuli, derived from matrices made up of black or white

2. BEHAVIOURAL METHODS

FIGURE 2.1

Examples of visual stimuli.

17

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squares (Attneave, 1955; Kimura & Durnford, 1974) (Fig. 2.1) or of regular and irregular geometrical patterns (Bisiach, Capitani, & Faglioni, 1975; Kimura, 1963) (Fig. 2.1) have been used to study the effects of unilateral lesions on visual perception and recognition memory. Drawings. Outlines of common objects have been used in many studies. At present, a series is available o f260 drawings of objects for which measurements have been made of familiarity, visual complexity, imaginability, and agreement among subjects about the name to be attributed to each drawing (Snodgrass & Vanderwart, 1980) This series of drawings is also available in a version for computer presentation (Fig. 2.1). These drawings can be used not only to study disturbances of perception and recognition (Berti, Maravita, Frassineto, & Umiltà, 1995), but also in research on semantic categorisation deficits in brain-injured patients, and on the problem of the selectivity of such deficits for stimuli representing animate and inanimate objects ( Capitani, Laiacona, Barbarotto, & Trivelli, 1994; Laiacona, Capitani, & Barbarotto, 1993). Fragmented drawings. Another widely used type of stimulus in neuropsychology is represented by drawings from which fragments are missing, making them difficult to identify. Various studies have been carried out on the performance of patients with unilateral lesions in tasks of visual recognition, generally with more serious deficits in cases with right-side lesions. Generally the fragmented pictures of Street (1931) or Gollin (1960) are used. The previously mentioned drawings by Snodgrass and Vanderwart also exist in a series with different levels of fragmentation (Snodgrass & Corwin, 1988) (Fig. 2.1), which may be used to assess perceptual closure in brain-injured patients (Viggiano & Pitzalis, 1998). Faces. One subgroup of visual stimuli which represents a specific category of complex visual information is that of faces (Fig. 2.1). Several studies have been conducted in order to verify the superiority of one visual field (and the specialisation of the contralateral hemisphere) in the processing of faces, in normal and brain-injured subjects.

Studies on hemisphere specialisation in the identification of faces have employed unknown faces (for example, in the work by Rizzolatti, Umiltà, & Berlucchi, 1971), as well as familiar faces (politicians, actors, etc.; for example in the study by Marzi & Berlucchi, 1977), or the faces in the series prepared by Benton and Van Allen, which includes photographs taken from different angles and in different lighting conditions (Farah, 1990; Piischel & Zaidel, 1994). Performance in the processing of faces has often been compared with performance in the processing of verbal material, and differences have been interpreted with reference to various models of hemisphere specialisation (see the later section on tachistoscopic presentation). To make recognition more difficult, chiaroscuro faces prepared by Mooney (1957) have been used, as in the research by Milner, Corkin, and Teuber (1968) on the case of HM (Fig. 2.1 ), or faces filtered on the basis of spatial frequency content, as in the research by Sergent (1987). Sometimes performance in face recognition by prosopagnosic patients has been compared with perception of elementary stimuli such as gratings, in order to evaluate the specificity of the deficit in relation to the damaged cerebral area (Sergent & Signoret, 1992). In this kind of study, the details that can facilitate the recognition of single faces are eliminated. Special series of faces expressing different emotional states have been prepared for studies on the recognition of facial expressions of emotions (Buchtel, Campari, De Risio, & Rota, 1978; Ekman & Friesen, 1975; Hansch & Pirozzolo, 1980; Landis, Assai, & Perret, 1979; Pizzamiglio, Caltagirone, & Zoccolotti, 1989; Pizzamiglio, Zoccolotti, Mammucari, & Cesaroni, 1983). Chimeric pictures. A kind of visual stimulus that recurs in clinical and experimental neuropsychology literature is the “chimeric” picture (each stimulus is divided in half and the parts of different stimuli are recombined to create a new picture; Fig. 2.1). For example, in the work carried out by Levy, Trevarthen, and Sperry (1972), perception was studied in patients with section of the cerebral commissures, using a variety of stimuli (animals, flowers, faces, etc.) which were presented either in their original form or in a chimeric form. The

2.

chimeric stimuli were presented by means of a tachistoscope at the centre of the visual field, in such a way that each of the two parts stimulated only one hemifield, one half the left hemifield, and the other half the right one. After tachistoscopic presentation, subjects were shown a group of similar figures, and they were asked to indicate which of them they had previously seen. In patients with split brain, in whom the perceptual “completion” of the two halves was not achieved, the picture indicated was generally the one whose half had been presented in the left hemifield (right hemisphere) if the response was given by using the hand, or in the right hemifield if the response was verbal. The drawings of Snodgrass and Vanderwart (1980) have been used to obtain chimeric pictures, and to study the syndrome of unilateral neglect (Berti & Rizzolatti, 1992; Buxbaum & Brauch Coslett, 1994). Verbal stimuli. Verbal stimuli, presented visually, include letters, words and sentences. Most studies have used words, sometimes comparing the processing of meaningful and meaningless words. As regards meaningful words, a large literature exists, dealing with the characteristics that must be controlled for their experimental use. The most important of these characteristics are the following: 1. Frequency of use (for English, Thorndike & Lorge, 1944; Kucera & Francis, 1967: for Italian, Bortolini, Tagliavini, & Zampolli, 1972; Burani & Thornton, 1993; Thornton, Iacobini, & Burani, 1994: for other languages, Lesser & Trewhitt, 1982). 2. Mean age of acquisition: words are classified on the basis of the age of acquisition during development, with the result that certain words (for example, “mother”) are found to be learned before others (a list o f220 drawings with the age of acquisition of the relative names in English can be found in Carroll & White, 1973). 3. Length (Landauer & Streeter, 1973). 4. Degree of concreteness (concrete words compared with abstract words), imaginability (the extent to which a word evokes a corresponding mental image), and meaningfulness (number of associations evoked by the

BEHAVIOURAL METHODS

19

word), (a list o f925 English nouns together with the values of these three characteristics can be found in Paivio, Yuille, & Madigan, 1968). 5. Category of membership (a list of words divided by categories, such as fruits, birds, quadrupeds, etc., can be found in Battig & Montague, 1969; for Italian categories, see Capitani, Laiacona, & Barbarotto, 1993; Capitani, Laiacona, Barbarotto, & Trivelli, 1994; Laiacona, Barbarotto, Trivelli, & Capitani, 1993). See the publications by Capitani et al. for a list of the various characteristics of the words that can be associated with the objects to be named or described (for example, the drawings of the aforementioned series of Snodgrass & Vanderwart, 1980). This characteristic is relevant particularly in research on deficits of naming and semantic memory for limited categories of animate and inanimate objects. As regards meaningless words, there are various ways of generating this kind of verbal material. Generally, words have been generated that either conform to the graphemic and phonemic rules of English (“legal” words) or do not (“illegal” words). In lexical decision tasks, subjects must decide whether the stimulus presented to them is a word or not. In an attempt to study processes of decodification and memorisation of meaningless verbal material, experiments have also been carried out in which subjects had to learn and memorise meaningless words, with different degrees of pronounceability (Bisiacchi, Cipolotti, & Denes, 1989; Goodglass, Hyde, & Blumstein, 1969). Effects o f the physical characteristics o f stimuli. One important problem that arises in the choice of visual stimuli regards the characteristics of their presentation. The intensity, the duration of the visual stimulus, and the interval between one stimulus and the next have crucial effects on primary processing. Although duration is a very important characteristic for the identification of stimuli, it varies considerably from one experiment to another (although it is usually lower than 100-150msec, in order to avoid eye movements). It is possible that the disagreement between data referring to

20

VIGGIANO

hemisphere latéralisation in the processing of visual stimuli may largely depend on the use of levels of intensity and the duration of presentation of different stimuli (Sergent, 1983; Sergent & Hellige, 1986). Another important characteristic is the visual angle subtended by the stimulus. Although the size of the stimulus as a function of observer’s distance is an essential piece of information in order to know the extension of the retinal stimulation, this information is sometimes omitted. The visual angle can be calculated if the dimensions of the stimulus and the distance from the observer are known (one cm of stimulus at a distance of 57cm from the observer subtends a visual angle of about one degree). In research on hemisphere specialisation, the localisation of the stimulus in the visual hemifield also varies considerably in different studies: the stimulus is projected into the hemifield at a distance that varies from 1-2° up to 10° from the fixation point. Gradual and significant effects on performance depending on this distance from the fixation point may be found. Instruments fo r the presentation o f stimuli. In the past, simple and complex visual stimuli were generally presented by means of a slide projector or a tachistoscope, whereas nowadays computer presentations are generally used. In the study by Berlucchi, Rizzolatti, & Umiltà (1971), a slide projector was used with which it was possible to present stimuli with a total exposure duration of 100ms. The stimuli appeared in the left or right visual hemifield (5° to the left or to the right of the central fixation point). In other classic studies, such as that of Kimura and Durnford (1974), a typical tachistoscope with a mirror was used. This apparatus, in the version used for studies on the effects of latéralisation, consists of three fields or exposure channels, one for the fixation point, and the other two for the presentation of stimuli. Thanks to the mirrors, the three fields are superimposed and, depending on the lamp that illuminates one of the three fields, the subject sees that the fixation point is alternated with the stimulus presented in the field of exposure to the left or to the right of the fixation point itself. The exposure time of the stimulus in these classic experiments was between 10 and 150ms.

Lateralised tachistoscopicpresentation. The use of this technique has become very widespread in the research field on hemisphere specialisation in normal subjects and in brain-injured patients. Early studies on patients with “split brain” employed a projector or a tachistoscope with two channels to present a stimulus (for example, the word key case, or a chimeric face), the two halves of which appeared one on the left and the other on the right of the fixation point. If the task consisted of naming the stimulus, the patient generally named the half that appeared in the right visual hemifield (case for the word key case) and was transmitted to the left hemisphere (specialised in verbal functions). If the task did not require the verbalisation of the response, an advantage was found for the left hemifield (stimulus transmitted to the right hemisphere) (Sperry, 1968). The performance was tested in monocular vision (Levy, Trevarthen, & Sperry, 1972). The relationship between the hemifield stimulated, the type of material or task, and hemisphere specialisation was studied systematically in normal subjects starting from the early 1960s (several monographs and reviews are available: Bradshaw & Nettleton, 1983; Bryden, 1982; Davidson & Hugdahl, 1995; Hellige, 1983, 1993; Kim & Levine, 1992; McKeever, 1986). The early work concentrated on the specialisation of the left hemisphere and therefore on the advantage of the right hemifield in the processing of letters and words (for example, in the work of Bryden & Rayney, 1963, where the superiority of the right hemifield in identifying single letters was shown). Other studies aimed to show the superiority of the left hemifield for visual-spatial material which could be processed more rapidly and/or efficiently by the right hemisphere. The main problem that arose during these early studies was that of using stimuli that could not be verbalised and would thus not involve the functions of the left hemisphere. Other studies concentrated on the “shift” of advantage from one hemifield to the other (and thus from one hemisphere to the other), using the same kind of material that could be verbalised only for a limited range of values of their structural characteristics (for example, in tasks discriminating between lines with a different orientation: Fontenot & Benton, 1972; Um iltaetal., 1974).

2.

Rizzolatti, Umiltà, and Berlucchi (1971) found a clear difference between the two hemifields, by comparing performances in a task discriminating between verbal material (single letters) and visualspatial material (unfamiliar faces). This experiment is representative of many other studies on the lateralisation effect. By means of a projector, subjects were presented with “positive” stimuli (for example, the letters F and R, to which they had to respond by rapidly pressing a button) and “negative” stimuli (for example, the letters A and E). The exposure duration of stimuli was 100ms. Vision was monocular (the right eye for some subjects and the left one for others). Motor response was carried out either with the right or with the left hand in an equal number of trials, in order to balance the effects of manual preference in relation to the hemisphere involved. Results (the superiority of the left hemifield for the discrimination of faces, and of the right hemifield for the discrimination of letters) were not related to the hand used for the response. The difference in reaction times for the two hemifields (18.5ms less for the right hemifield in the case of letters; 15.5 ms less for the left hemifield in the case of faces) was used as a measurement of hemisphere specialisation (there is a more rapid “response” from the hemisphere contralateral to the hemifield stimulated and specialised for the material presented). This index proved to be more sensitive than accuracy (the number of correct responses or alternatively, the number of errors, in relation to the hemifield stimulated): the number of errors was, in fact, found to be the same for the two hemifields (for the problem of the relationship between reaction times or speed of response and response accuracy, see later). Starting from the 1970s, the tachistoscopic presentation of stimuli whose processing involved the one or the other hemisphere differentially was used in many neuropsychology studies applying experimental designs comparable to those adopted in normal subjects. Furthermore, different groups of patients, generally with unilateral lesions, were compared in order to verify the effect of the side of the lesion on performance (this kind of approach for the study of the processing of verbal information in the visual mode and visual-spatial information was also followed in research on the processing of

BEHAVIOURAL METHODS 21

auditory and auditory-verbal information, using the technique of dichotic listening, which will be illustrated later). As an example of the use of the tachistoscopic presentation for a comparison between groups of patients, the work of Benton, Hannay, and Varney (1975) on visual-spatial performance in patients with left- or right-side lesions and in normal subjects may be mentioned. The task consisted in identifying the slope of lines or couples of lines presented centrally. After an interval of 2 seconds from the presentation of the stimulus (which lasted 300ms) a second stimulus was presented for 6 seconds, showing the 11 possible slopes of the lines, and the subject had to indicate which one corresponded to the slope of the line or lines previously seen. The performance of patients with left-side lesions was in no way different from that of normal subjects, whereas that of patients with right-side lesions was significantly lower (in particular for the identification of the slope of pairs of lines). These results were in agreement with those obtained in normal subjects (Fontenot & Benton, 1972; Umiltà et al., 1974) as a demonstration of the specialisation of the right hemisphere for visual-spatial tasks. In the application of the tachistoscopic technique, in particular in research on lateralisation effects, various problems of methodological and procedural nature arise (Bradshaw & Nettleton, 1983; Bryden, 1982; Davidson & Hugdahl, 1995; Hellige, 1983, 1993; McKeever, 1986). Problems connected with the presentation of the stimulus and with some characteristics of the subjects are listed next. A special section will deal with the problems inherent in the measurement of responses, reliability, and validity of measure. 1. E c c e n t r ic it y o f th e s tim u lu s w ith r e s p e c t to th e

In order to ensure that the stimulus presented in one hemifield is projected directly to the contralateral hemisphere, the stimulus is placed at a certain distance from the fixation point. However, the distance between the fixation point and the stimulus may have a considerable effect on performance, because an extremely peripheral stimulus may prove to be too “degraded” perceptively. Furthermore, as the value of eccentricity varies considerably from

f ix a t io n p o in t.

22 VIGGIANO

one study to another, it is difficult to compare results, because the effects of the visual “quality” of stimuli interact with field effects. Usually, the distance between the centre of fixation and the side of the stimulus closest to the fixation point is about 4-5° and should not go below 2-1.5° (Sergent & Hellige, 1986). 2. Effects o f physical characteristics o f the stimulus. As has already been said, the effects of physical characteristics of the stimulus are important. In particular, the duration and the luminance of the stimulus have an important effect on performance. Below 100ms, there is an interaction between these two physical variables (Roscoe-Bunsen law), and consequently stimuli with a short duration and a high luminance correspond perceptively to stimuli with a long duration and a low luminance. Control of these variables is important in particular when it is desirable to underline the difficulty of the task by presenting stimuli with low luminance and short duration, bearing in mind that there may be considerable individual differences in the relative thresholds. In order to ensure that all subjects are placed in the same conditions of difficulty, it has been proposed to vary the values of a specific characteristic, for example, duration, until the subject reaches a threshold of recognition, say, of 75%. This level of recognition must be guaranteed to all subjects, determining a suitable duration for each of them (Hannay, 1986). A large part of the disagreement between results about effects of visual latéralisation might depend on the variety of values of physical characteristics of the stimuli in the various experiments. As the two hemispheres, according to Sergent (1982,1983), are sensitive to different ranges of values of the physical properties of visual stimuli (in particular in relation to spatial frequency), the same stimulus might activate either of the two hemispheres depending on the specific values of physical characteristics such as duration and luminance (this problem is discussed in detail in the special issue of Brain and Cognition, 1986, no. 2; see also Hellige, 1993; Grabowska & Nowicka, 1996; Christman, 1997; Mecacci, 1997).

3. Unilateral and bilateral presentation. In unilateral presentation, the stimulus appears in a random order either in the left or in the right hemifield. In bilateral presentation, two stimuli appear simultaneously, one in the left hemifield and the other in the right one. It has long been the object of discussion what the advantages and disadvantages of the two types of presentation are (Beaumont, 1982; Bryden, 1988; Kim & Levine, 1994). In bilateral presentation, there may be a bias of attention towards one of the two hemifields, which may annul the aims of the lateralised presentation. On the contrary, in unilateral presentation, the subject does not know in advance in which hemifield the stimulus will be presented. In some studies with a bilateral presentation, an arrow has been used, situated near the fixation point, indicating the hemifield for which the relative stimulus has to be reported (Schmuller & Goodman, 1979, 1980). 4. Monocular and binocular vision. Both monocular and binocular vision have been used with varying motivations at different times in various studies using tachistoscopic presentation—although the tendency is to prefer binocular vision, in order to balance the effects, due to differences of acuity between nasal and the temporal hemiretina. (Consequently, an advantage of the right hemifield might partly depend on the stimulation of the nasal hemiretina during vision with the right eye, and vice versa an advantage of the left hemifield might stem from stimulation of the left nasal hemiretina.) (McKeever, 1986). 5. Hand side. Several studies have examined the relationship between the hand used for the motor response (reaction times), the hemifield stimulated, and the hemisphere. In the uncrossed condition, the hemifield stimulated and the hand are on the same side; therefore the hemisphere controlling the hand also receives the information directly from the hemifield stimulated (right hemifield-left hemisphere / right handleft hemisphere). In the crossed condition, the hemifield stimulated and the hand are not on the same side, and the hemisphere that receives the

2. BEHAVIOURAL METHODS 23

information directly is different from the one that controls the hand (right hand-left hemisphere /left hand-right hemisphere). In the uncrossed condition, there is no need for interhemisphere transmission in order to produce the motor response (the same hemisphere receives the stimulus and produces the response); in the crossed condition, interhemisphere transmission is required (one hemisphere receives the stimulus and passes the information on to the other hemisphere, which produces the response). In an experimental design in which the two hands alternate in the same lateralised task, it is thus possible to study the interhemispheric transmission time (mean: 2-3ms), by comparing the times of the two conditions, uncrossed and crossed (Bashore, 1981; Berlucchi, Heron, Hyman, Rizzolatti, & Umiltà, 1971 ; McKeever, 1986). This problem has been extended to include the more general question of stimulus-response spatial compatibility, that is, between the hemifield in which the stimulus appears and the hand used for the motor response (Umiltà & Nicoletti, 1990). Considering, above all, individual differences in hand preference (see later), and in order to avoid false results due to an effect of the dominant hand in experiments with lateralised presentation, it is necessary that the execution of responses is balanced within the same subject, alternating groups of trials in which the right or left hand is used. 6. Hand preference and familial left-handedness. As regards the difference between right-handed and left-handed people, and the effects of the presence or absence of left-handed people in the

family of the subject in relation to performance in tasks with tachistoscopic presentation (as well as in dichotic listening; see later), there is an extremely large literature (Bryden, 1982, 1988; Davidson & Hugdahl, 1995; Hellige, 1993) (see Table 2.1). The superiority of the right hemifield for verbal material, and of the left hemifield for visual-spatial material has been confirmed in about 70-80% of right-handed subjects and in about 60-70% of left-handed subjects (the differences between the two groups of subjects are, however, generally lower for visual-spatial material; this finding can be explained by the lower degree of latéralisation of visual-spatial functions). Familial left-handedness has the effect of altering the differences between the two groups, for example, reducing the degree of advantage of the right hemifield for verbal material in right-handed subjects (McKeever, 1986). In order to avoid problems of methodology and interpretation, it is advisable, where possible, to prepare experimental designs in which at least the hand preference factor is balanced (using a similar number of righthanded and left-handed subjects). 7. Sex. There is also large literature regarding sex differences and their effects on performance in tasks with tachistoscopic presentation (effects that are also found for results obtained with dichotic listening). Classical data suggest lower effects of latéralisation in females than in males (McGlone, 1980). Like hand preference, sex represents an independent variable whose effects must be controlled in neuropsychological experimental designs. In

TABLE 2.1 Relationship between left (L), bilateral (B), right (R) hemispheric latéralisation and hand preference.

Right-handed Left-handed I

(Following Bryden, 1988)

V erb al F u n c tio n s

V isuospatial Fu n c tio n s

L a té ra lis a tio n

L a té ra lis a tio n

B

R

33

0

67

30

32

38

L

B

R

L

97 51

0 34

3 15

I

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studies on normal subjects, it is possible to choose a relatively similar number of males and females; in neuropsychological research, the number of male and female brain-injured subjects may not be balanced, creating problems of statistical comparison and theoretical interpretation. 8. Eye movements. It must be guaranteed that subjects do not move their eyes during stimulus presentation, so that the portions of the two retinas projecting to the ipsilateral hemisphere are actually stimulated. To control eye movements and to eliminate, if necessary, contaminated trials, various methods can be used, including fixation by means of a mirror reflecting eye movements (Umiltà et al., 1978) or a telecamera, or else electroculographic recording (in this case the electric signals recorded indicate “false” responses: Butler & Norsell, 1968). Furthermore, the use of brief exposures of the stimulus, not more than 100-150ms, reduces the interference of eye movements (Pirozzolo & Rayner, 1980). To force subjects to stare at the centre of the screen, and not to move their eyes into the left or right hemifield, before the stimulus appears, subjects may be asked to identify the figure or the symbol that appears at the centre of fixation. It has been objected, however, that this task might involve the verbal functions of the left hemisphere, preactivating this hemisphere with respect to the material subsequently presented (with an increase of the advantage for the right hemifield; seeMcKeever, 1986).

Auditory stimuli Many kinds of auditory stimuli have been used in neuropsychological research: tones, words, sentences, musical sounds, etc. The evaluation of auditory deficits by means of audiometrie techniques and psychophysical methodologies has often been used to verify the presence of peripheral disorders in aphasic patients (Hannay, 1986; see Chapter 10 by Denes, Semenza, & Caldognetto in this book). The most widely used auditory stimuli in experimental research on disturbances of

auditory and, in particular verbal, information processing have been the following: 1. Lists of numbers and words transmitted in groups of three pairs (for example Kimura, 1967). 2. Consonant-vowel syllables, transmitted as a pair, in which only the consonant changes, (for example, /ba/ to the left ear and /ga/ to the right ear) (Shankweiler & Studdert-Kennedy, 1967); this type of stimulus reduces the effects of memory and semantic analysis compared with numbers and words, and makes it possible to study the phonological competence of the two hemispheres more directly. 3. Monosyllabic words (consonant-vowelconsonant) similar except for the initial letter, presented in pairs with a rhyming effect (for example, “coat” / “goat”, in which the first word is transmitted to the left ear and the second to the right ear, “pig” / “dig”, etc.: Wexler and Halwes, 1983). 4. Musical stimuli (strings: Gordon, 1970; tunes: Kimura, 1964). 5. “Environmental” noises (starting up the engine of a car, the sound of a toothbrush in contact with teeth, etc.: Curry, 1967; a telephone ringing, the ticking of a clock, etc.: Knox & Kimura, 1970). The presentation of auditory stimuli in neuropsychology has generally been carried out by means of the dichotic listening technique. Dichotic listening. The technique of dichotic listening was initially developed to study selective attention and it has gradually become a widespread tool to determine hemisphere functional specialisation in normal and brain-injured subjects (the most systematic description of the various issues related to this technique is in Hugdahl, 1988). In early experiments (Broadbent, 1958; Kimura, 1961), groups of three pairs of numbers (or words) were transmitted simultaneously to the two ears: one stimulus of each pair was directed to the right ear and the other to the left ear. After each group of three pairs, subjects were invited to repeat as many stimuli as they remembered in the order they chose. The typical result was that subjects repeated the

2.

numbers transmitted to the ear to which they paid more attention. In the condition of free attention, in which the subject did not have to pay attention to one of the two ears, subjects generally repeated first, or to a greater extent, the material transmitted to the right ear (Kimura, 1961). The advantage of the right ear for verbal material (letters, numbers, words) was explained on the basis of the following anatomicalfunctional aspects: the larger number of projection fibres from one ear to the contralateral hemisphere (in this case the “privileged” path is right ear-left hemisphere); the specialisation of the left hemisphere for the processing of verbal information; the partial or complete suppression of the input transmitted along the ipsilateral pathway (left ear-right hemisphere) by the “stronger” contralateral pathway. Similar explanations have been used to account for the advantage of the left ear (right hemisphere) for musical material and auditory stimuli like environmental noises, the emotional tone of language, etc., considering the superiority of the right hemisphere for this kind of processing. Various procedures have been adopted to evaluate the effects of dichotic listening. In early experiments, subjects were invited to recall stimuli after each group of three pairs; then, in order to reduce the possibility that subjects might shift their attention from one ear to the other during the presentation of the three pairs, the choice was made to present one pair of stimuli at a time, and invite subjects to recall them immediately. Another procedure consists in presenting a first pair of dichotic different stimuli and subsequently another pair of dichotic stimuli in which the same stimulus is transmitted to the two ears; the subject is then asked to indicate if a stimulus of the first series is present in the second (Kimura, 1964; Kimura & Folb, 1968). Or, a pair of stimuli can be transmitted and then a single probe stimulus follows; the subject has the task of deciding whether the probe stimulus is the same or different (verbally or by pressing a button to measure reaction times) (Sidtis, 1981, 1982) The widespread debate about results regarding the advantage of the right ear for the recall of verbal material presented dichotically essentially contrasts two hypotheses: one based on the aforementioned

BEHAVIOURAL METHODS 25

anatomical-structural model, and the other on the shifting of attention towards a specific source of stimulation, generally the one contralateral to the hemisphere specialised for the type of information that the subject is engaged in processing (for the various models introduced in order to explain the data of dichotic listening, see the reviews in Hugdahl, 1988; see also Bryden, 1982, 1988; Kim & Levine, 1992). Considering the enormous heterogeneity of the stimulus material used, the types of tasks, the types of measurements, the order and the mode of response, the various indices of latéralisation, etc., Bradshaw, Burden, and Nettleton (1986) called for a certain caution in interpreting the results of dichotic listening in order to determine hemisphere specialisation. One of the most recent studies on the reliability of dichotic listening (Jâncke, Steinmetz, & Volkmann, 1992) compared the performance of 52 normal subjects in four tests: recall of digits, presented in groups of three pairs each (the recall took place at the end of each group); recall of consonant-vowel syllables presented in pairs (the recall took place after each pair); detection of a consonant-vowel syllable presented at random in the series of pairs of syllables (the technique of “dichotic monitoring”: Geffen & Caudry, 1981); and recall of pairs of Morse signals. As the correlation between performances in the various tests was found to be very low, it is clear that the type of task significantly influences the performance in dichotic listening and the extent of the advantage of one ear compared with the other. The relationship between hand preference and the advantage of the right ear for verbal material has been studied by comparing right-handed and left-handed subjects in various tasks of dichotic listening. As can be seen from Bryden’s review (1988), in which the results of numerous studies were examined, and on the basis of other studies (see Table 2.2), the advantage of the right ear is present in a greater number of right-handed (about 81%) than left-handed (about 64%) subjects, even if the difference between the two groups depends largely on the kind of task. In many studies, the advantage of one ear over the other is determined by comparing the percentages of correct answers for the two ears. According to Wexler and Halwes (1983), the difference between the two ears must be

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TABLE 2.2 Percentage of right- and left-handed subjects having right ear dominant for dichotic verbal stimuli in different tasks. Task

Recall of lists1 Recall of lists2 Recall of single pairs1 Recall of single pairs2 Dichotic monitoring1 Dichotic monitoring2 Pairs of rhyming words3

R ig h t-h a n d e d

L e ft-h a n d e d

81.1 85 79.7 77 90.9 65.5 85

59.3 61 68.2 61 70.4 57.5 71

1Review by Bryden (1988) 2Jancke, Steinmetz & Volkmann (1992) 3Wexler & Halwes (1983)

determined statistically. The percentage of subjects presenting an advantage of one ear compared with the other varies depending on the level of significance chosen. The relationship with sex has been studied in order to verify the hypothesis of a different hemisphere asymmetry between males and females. On the basis of Bryden’s review (1988), the advantage of the right ear (left hemisphere) for verbal material was present in 75% of right-handed females and in 81 % of right-handed males (see also Hiscock & Mackay, 1985). Thus the advantage of the right ear seems to be associated more with hand preference rather than with sex. The technique of dichotic listening was applied in neuropsychology by Kimura (1961) to study hemisphere specialisation for verbal material in patients with unilateral temporal lobectomy. In order to verify the degree of reliability of the results of dichotic listening as an index of the dominance of the left hemisphere for language, Kimura compared the data of dichotic listening with the effects of an injection of sodium amytal. The drug was found to block the verbal functions in the hemisphere contralateral to the ear that presented an advantage in dichotic listening (the dominant hemisphere for language on the basis of dichotic listening was correctly predicted in 80% of cases). In a similar comparison between the results of dichotic listening and the effects of sodium amytal, Strauss, Gaddes, and Wada (1987) found that 86%

of subjects with language centres in the left hemisphere had an advantage of the right ear. Zatorre (1989), using pairs of rhyming words, found an advantage of the right ear in 33 (94%) out of 35 patients whose language was represented in the left hemisphere on the basis of the sodium amytal test, and an advantage of the left ear in all four patients with language centres in the right hemisphere. In the work by Hugdahl and Webster (1992) four patients with lesions in the left hemisphere (one patient was left-handed) were tested with the dichotic listening technique (pairs of consonant-vowel syllables). The reduction of the normal advantage of the right ear over the left ear was explained by the effects of the lesion in the left hemisphere. Grote et al. (1995) argue that data of dichotic listening, obtained statistically in relatively large samples of patients, should not be used directly as a generalised index of the hemispheric functional localisation of verbal functions, but that data referring to single cases, in which there may be remarkable individual differences, should also be considered, at least in a complementary manner. The technique of dichotic listening was also used in the study of cognitive functions of patients with split-brain (Milner, Taylor, & Sperry, 1968; Sparks & Geschwind, 1968). Results were interpreted as evidence of the anatomical-structural model: due to the section of the interhemispheric callosal commissure, only contralateral transmission was possible, and interhemispheric

2. BEHAVIOURAL METHODS 27

transmission was destroyed. For this reason, the information that arrived at the right ear could be transmitted to the contralateral left hemisphere and adequately processed, whereas the information from the left ear arrived at the right hemisphere and could not pass over from there to the left hemisphere in order to be processed (as happens in normal subjects). Thus, in situations of dichotic listening with competing verbal stimuli, callosal patients tend to have an advantage of the right ear to a greater degree than normal subjects. In fact normal subjects can partially pass on the material transmitted to the left ear, which arrives at the left hemisphere from the right hemisphere via callosal pathways. In the study of Sugishita et al. (1995), carried out on 5 patients with partial section of the callosum and 50 control subjects, it was found that only in the case of lesions to the splenium might a strong suppression of the left ear during dichotic listening of consonant-vowel syllables be found. In other patients, in whom the splenium was intact, it was possible for auditory information to be transferred from the left ear to the right hemisphere and from there, via the intact callosal connections, to the left hemisphere, with the result that the advantage of the right ear over the left one was not so evident as in cases with the section at the level of splenium. Besides research and diagnosis, the technique of dichotic listening has been employed to study the processes of recovery of cognitive deficits, generally verbal, following surgery and/or a rehabilitation programme. In some cases, a recovery of the advantage of the right ear for verbal material has been demonstrated in aphasic patients. In the study of Castro-Caldas, Guerreiro, and Confraria (1984), it was observed that only four out of nine aphasic patients displayed a recovery of the advantage of the right ear, which had been compromised because of a lesion. In the other five patients, no such recovery was observed. CT scans showed that the two groups differed in the site of lesions. The five patients in whom there was no recovery had lesions in the Heschl’s gyrus, and in the geniculo-temporal pathways, whereas there were no lesions in these pathways in the four patients who displayed a recovery (see also Hugdahl & Webster, 1992; Moore & Papanicolau, 1988).

MEASURES OF PERFORMANCE The performance of subjects in the tasks listed earlier is measured by evaluating the accuracy of responses (correct responses or errors), and recording reaction times. In neuropsychological research, the choice of these measures is often determined by the condition of the patient. For example, in the case of paralysis of an arm, the measurement of reaction times can be carried out only with the unaffected hand, without the possibility of balancing the trials with respect to the hemifield-hemisphere-hand relationship; in cases of aphasia, it is obviously impossible to ask subjects to produce accurate verbal responses. The main measures used in neuropsychological research are the following. Tachistoscopic presentation: Test—retest reliability o f measures. The limited number of studies dealing with the problem of the stability of behavioural measures (reaction times, correct responses, errors) obtained in tasks with tachistoscopic presentation have examined both the variation of measures themselves within a block of trials (in the same experimental session), and the variation between one session and another after an interval of days (Brysbaert & d’Ydewalle, 1990; Fennell, Bowers, & Satz, 1977; McKeever, 1986; Resnick, Lazar, Gur, & Gur, 1994). Generally, there is a greater correlation between the two or three sessions following the first one than between the first session and the following ones. This finding has been partly explained by effects due to familiarisation with the task. The recommendation is to administer a relatively high number of trials to the subject, in different blocks or in different sessions, analysing the stability between the measures obtained in different blocks or/and sessions statistically. If the subjects have performed different tasks (for example, a verbal task and a visual-spatial one), it may be interesting to compare the values of stability in the two tasks, in order to detect any differences not only in the field effects, but also in the stability of performance. Obviously, this aspect involves specific problems for brain-injured patients,

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for whom it may be more tiring to endure repeated long sessions. Correct responses and errors. A large number of neuropsychological research studies evaluate the performance of brain-injured patients by measuring the number of correct responses or errors produced during the clinical examination or experimental test. For example, in the study of Graf and Schacter (1985) on amnesic patients and normal subjects, the performance in tests of implicit memory (completion of fragmented words) and explicit memory (recall of words) was evaluated on the basis of the number of correct responses. In general, many studies on memory in normal and brain-injured subjects measure the number of correct responses, especially when recall is tested. When recognition tests are used, subjects may be asked to respond by pressing a button if they remember previously seeing or hearing the stimulus presented. The reaction time for correct responses may then be compared with the reaction time associated with errors in recognition. Indices of laterality (lateralised tachistoscopic presentation anddichotic listening). The choice of indices of laterality has been (Bradshaw, Burden, & Nettleton, 1986; Sprott & Bryden, 1983) and still is much debated. Although the simple difference (D) between the percentage (P) of correct responses (or errors) for the right side (r) and for the left side (1) D = Pr-P/

has often been used as an index, it is considered appropriate to correct the difference in relation to the overall performance achieved by each subject. Among the various correction formulas (Repp, 1977), the following formula is often used for correct responses (POC = percentage of correct responses)

POCnj( ~~

Pr

(Pr+P/)

and for errors (POE = percentage of errors)

POE =

d-PQ

(2-Pr-P/)

The laterality quotient (LQ) corresponds to the ratio between the difference between the two sides, right and left, and the sum of the two performances: LQ =

(r-Q (r+D

X100

Other indices of laterality include phi (Kuhn, 1973) associated with overall performance (Repp, 1977), and A, (Bryden, 1982; Bryden & Sprott, 1981; Brysbaert & d'Ydewalle, 1990; Sprott & Bryden, 1983), which is independent on overall performance. The various indices are closely correlated both among themselves and with overall performance, as has been demonstrated, for example, for dichotic listening by Hellige, Zatkin, and Wong (1981). Reaction times. The technique of reaction times has undoubtedly been the most widely used in experimental psychology and neuropsychological research in recent decades. It is based on the measurement of the interval of time between the presentation of a stimulus (visual, auditory, or tactile) and the execution of a response (generally pressing a button with one finger). The technique of reaction times has been applied with reference to different methods: the subtractive method, the additive method, and the double task method (Massaro, 1975; Snodgrass, Levy-Berger, & Hay don, 1985; Sternberg, 1969). The subtractive method determines the differences in the time of information processing in relation to the complexity of information itself and to requirements of the experimental task. The time taken to respond to the presentation of a stimulus (the condition of the "simple reaction time") is less than the time required in the condition in which one must respond to a particular stimulus, for example, a very intense flash of light, and not to another one, for example, a less intense flash of light ("choice reaction time"). The difference between the choice reaction time and the simple reaction time (subtraction method) indicates the time required by the increase in complexity of the information

2. BEHAVIOURAL METHODS 29

processing, passing from a simple process of detection of the stimulus to a relatively more complex process of discrimination between two stimuli. In the additive factor method, two or more factors or independent variables are manipulated, and one dependent variable (reaction time), or more than one, can be measured (for example, in psychophysiological research, it is possible to measure both reaction times and variations of electrophysiological indices). Using the additive method, interactions between independent variables can be revealed. For example, in research on hemisphere specialisation for visual material, there may be at least three factors: type of stimulus, hemifield stimulated, and hand for the execution of the response. By means of an experimental design of this kind, additive or interactive hypotheses may be made about the effect that the factors have on reaction times, and therefore about the time required for the information processing (“mental chronometry”). In the use of reaction times, the following problems arise (Snodgrass, Levy-Berger, & Hay don, 1985): 1. Anticipation of responses in simple reaction times, if the subject can foresee the moment of stimulus presentation (reaction times lower than 100ms may be considered as errors of anticipation; to eliminate this inconvenience, the interval between the warning stimulus and the test stimulus may be varied randomly, so that the subject cannot foresee the moment of presentation; this problem is not relevant for reaction times in a choice task, because the anticipations are randomly distributed among the various stimuli). 2. “Too long” reaction times (outliers), due to a variety of reasons (distraction, complex processing, uncertainty about the button to push), which involve a distortion of the subject’s mean. In order to avoid this problem, various expedients may be adopted: rejecting times that exceed a value fixed in advance by the experimenter (for example, one second); rejecting times that differ by more than two or three standard deviations from the subject’s mean, or substituting the mean with the median,

thus eliminating the effects of too long (and too short) times. 3. Relationship between reaction time and errors: speed of execution may penalise accuracy (with a consequent increase in the number of errors) and vice versa. Errors should not exceed 5% for any experimental condition. In order to avoid an increase in the number of errors during a session due to fatigue it is advisable, above all in research on brain-injured patients, not to go beyond 300 trials per session, distributing them into groups of 30 trials with brief intervals of about two minutes (McKeever, 1986). 4. Relationship between detection and criterion: some works on reaction times with lateralised presentation have applied the signal detection theory (Green & Swets, 1966) in order to determine the effects on performance of subjective criteria and instructions. In other words, it is possible to evaluate the sensitivity of the subject independently of nonsensory factors (Bryden, 1976; Hannay, 1986). The same approach has been followed for the study of recognition memory, for example in aphasic and non-aphasic brain-injured patients (Riege, Metter, & Hanson, 1980). All these problems are more complicated when reaction times are used with brain-injured patients: reaction times are globally longer, and the number of errors and anticipations increases. Thus, mental chronometry presents some specific critical aspects in neuropsychology (Milner, 1986). The lengthening of reaction times has been studied in detail in brain-injured patients, to verify whether it depends on the extension or the severeness of the lesion and on the type of task (Benton, 1986; Dee & Van Allen, 1973; De Renzi & Faglioni, 1965). Furthermore, an attempt has been made to verify the importance of the interaction between age and effects of the lesion, considering the known positive correlation between lengthening of reaction time and ageing (Hicks & Birren, 1970; Vrtunski, Patterson, Mack, & Hill, 1983). Some studies have pointed out differences in reaction times depending on the side of the lesion (Dee & Van Allen, 1973; Howes & Boiler, 1975), and the involvement in the lesion of one or two hemispheres (Newcombe & Ratcliff, 1979).

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Furthermore, it has been studied whether, in braininjured patients, a long sequence of trials produces a further lengthening of reaction times due to fatigue, or a decrease due to practice (Schweinberger, Buse, & Sommer, 1993). Various criteria have been adopted in connection with the correction of outlier reaction times, which are very frequent in brain-injured patients. Milner (1986) compared the effects of various calculation criteria on the results of simple reaction times, using visual stimuli with three levels of luminance in patients with callosal agenesis and controls: (a) calculation of the arithmetic mean excluding reaction times shorter than 150ms and longer than 1000ms (these “cleaned-up” reaction times are the basic data for subsequent analysis); (b) calculation of the arithmetic mean rejecting from the basic data reaction times that differ by more than three standard deviations from the mean; (c) calculation of the geometric mean from the basic data; (d) calculation of the harmonic mean from the basic data; (e) calculation of the median from the basic data. The analysis of variance results have been relatively similar for the five calculation methods, although the exclusion of the values that are too low or too high, or the calculation based on the median, produce more informative results.

EXPERIMENTAL PARADIGMS Various paradigms present in experimental psychology have been adopted in neuropsychology, among which the following are the most common. Simple task and choice task. Reaction times associated with simple tasks are obtained in a condition in which there is a single stimulus, to which a response is to be given (for example, pressing a button with the right hand every time a particular target stimulus appears on the screen in front of the subject, and not pressing it in response to other stimuli; the so-called go-no-go condition). In choice tasks, subjects must press, for example, a button on the right in response to a stimulus X and a button on the left in response to a stimulus Y. Brain-injured patients display a generalised delay

in simple reaction times, and this delay is considerably accentuated for choice reaction times. Furthermore, it has been found that the delay in choice reaction times is greater in cases of left-side than right-side lesion (Benton, 1986; Dee & Van Allen, 1973). Double task. In a double task, the subject is invited to carry out two tasks simultaneously (Gopher & Donchin, 1986). The two tasks may interfere with each other because they involve the same process or processing stage (listening to the news on TV and at the same time listening to music on the radio) or they require paying attention to two different tasks (listening to the news and typing out a text). The following is an example of a double task: a series of visual stimuli is projected and the subject’s task is to press a button at the presentation of a given target stimulus; the same subject is also invited to perform a second task at the same time as the first one (for example, counting backwards). One particular procedure of the double task method is that of the “secondary task”. A primary task, to which the majority of attention resources are dedicated in order to achieve an optimal performance, is joined to a secondary task, on the hypothesis that the latter will be carried out using the attention resources not engaged in the first task. The resources are thus distributed between the primary task and the secondary one. The double task method has been widely used in research on subjects’ ability to control and distribute their attention during the execution of two tasks. Interest has also focused on the way in which attention is distributed; that is to say, whether the two tasks are performed in a parallel way or there are shiftings in attention from one task to the other, thus presupposing a serial chaining. The results of these studies tend to show that the mind has limited processing capacities or resources, and that the subject’s performance in a double task depend on the characteristics of the task itself, whether the two tasks use the same resources or not. The relationship between performances in the primary and secondary tasks may be represented by a curve of the “performance operating characteristics” (POC) (Gopher & Donchin, 1986). This curve indicates that the engagement of resources in one task (with a relative increase in

2. BEHAVIOURAL METHODS 31

performance) makes the performance in the other task decrease proportionally. The paradigm of the double task has been applied in order to study the effects of hemisphere overloading. Kinsboume and Cook (1971) studied the effect of verbalisation on the simultaneous motor performance of the right hand or the left hand. Their results revealed that performance with the right hand was lower than that with the left hand, probably because the same hemisphere was involved in two tasks that interfered with each other (for the development of this kind of research, see Hiscock, 1986; Kinsboume & Hiscock, 1983). Masking. Experiments on the effects of masking have been conducted by means of tachistoscopic presentation: after presentation of the stimulus, for example a word, a second stimulus follows, composed of dots, gratings, etc., with the function of interfering with the processing of the first stimulus. This condition is called “backward masking”; however, the masking stimulus may also precede the target stimulus (so-called “forward masking”). By varying the time interval between a target stimulus and the masking stimulus, it is possible to measure the time needed to complete the processing of the first stimulus (Humphreys & Bruce, 1989). Posner paradigm. Subjects have the task of deciding whether two stimuli, presented simultaneously or at variable time intervals, are the same or different on the basis of certain characteristics; the aim is to establish the levels of information processing in relation to the physical characteristics of the stimuli, their cognitive meaning, and instructions. In the classic experiment of Posner and Mitchell (1967), the stimuli were letters of the alphabet which could be physically identical (AA, aa), differ physically but have the same name (Aa,aA), or be different both in their name and their physical characteristics (AB, ab). The task was to decide whether the two stimuli were “the same” or “different”, on the basis of one characteristic: physical identity, or the same name. Results indicated that the time required to compare the two stimuli on the basis of their physical characteristics was about 7 0 -100ms lower than the

time needed to compare them on the basis of their name. Two stages of processing could thus be distinguished, the first related to the analysis of the physical characteristics of the stimuli and the second to their meaning. Priming. Performance in a task, for example the recognition of a word or an object, is facilitated if the word has previously been seen. The effects of priming have been studied in particular in connection with tasks of explicit and implicit memory. Generally, a priming experiment consists of a study phase in which some stimuli are presented, for example words such as “TYPEWRITER”, “LAKE”, “ELEPHANT”, etc., and a subsequent test phase in which the subject is asked to recall the words previously seen, or fragments of words to be completed are presented, such as “T—EW—T-R”, or “-AK-”. Subjects are invited to complete the words on the basis of the words seen in the previous study phase (explicit memory) or to complete them freely, using words that come into their mind (implicit memory). Also in the latter case, albeit unconsciously, subjects often complete the fragments with words previously seen. Furthermore, in both cases, completion takes place more rapidly compared with completion of fragments belonging to words not previously seen. Priming experiments have also been carried out on neuropsychological patients in order to study whether a brain lesion produces differentiated effects on explicit and implicit memory, in agreement with the hypothesis of the existence of two memory systems (Tulving & Schacter, 1990). Graf and Schacter (1985) conducted priming experiments comparing the performance of amnesic patients with that of normal subjects. The experimental design included a study phase during which words like “MOTEL”, “ELEMENT”, etc. were presented, and a test phase in which some subjects had to recall the words seen in the study phase, while others had to complete fragments of words freely. Results showed that the level of performance of amnesic patients in the completion task (implicit memory) was no different from that of normal subjects. However, when amnesic patients were asked to recall the words previously seen (explicit memory), their level of performance

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was lower than that of normal subjects. The priming paradigm has been applied for the study of other neuropsychological disturbances, for example, unilateral hemineglect (Berti & Rizzolatti, 1992; Làdavas, Paladini, & Cubebi, 1993). Stroop test. As is known, the Stroop test reveals interference in the processing of incongruous information; it has been used to study performance in tasks that require a “global” or “local” processing of letters made up of elements that are congruous or otherwise. This version of the Stroop test is also known as the Navon paradigm (Navon, 1977). This paradigm has been used to verify the hypothesis that global analysis is carried out by the right

hemisphere and local analysis by the left hemisphere (Van Kleeck, 1989). For example, in the study of Doyon and Milner (1991), local processing was evaluated by asking patients to pay attention to the single letters that made up the large letter (Fig. 2.2), and to indicate as quickly as possible whether the letters presented were the same or different, compared with a target letter. Global processing, on the other hand, was evaluated by asking patients to carry out the same task, focusing their attention on the whole of the large letter, and ignoring the single components. A comparison between the performance of patients with unilateral left- and right-side lesions allowed the authors to verify the hypothesis of local-global hemisphere dichotomy.

FIGURE 2.2

Large letters (global level) created by small letters (local level) in a congruent (left side) and incongruent (right side) condition (Doyon & Milner, 1991).

3 Electrophysiological Methods in Neuropsychology Luciano Mecacci and Donatella Spinelli

between the two series of phenomena, we acknowledge that this method has a great meaning for psychology.

INTRODUCTION Psychophysiology: A historical overview

This perspective was later defined as “psychophysiology”, i.e. the investigation of effects produced by independent psychological variables on dependent physiological variables (Stem, 1964). Skin electrical activity was investigated in relation to psychological phenomena by the French physician Fere (1888) and the Russian physiologist Tarchanoff (or Tarkhanov, 1890). In particular, Tarkhanov observed that variations in skin electrical potentials might be generated even when external stimuli were absent, that is, following images and thoughts produced spontaneously by the subject. The “psychogalvanic reflex” became the most frequently investigated physiological response, in relation to emotions. A classic example are the studies on free associations by Jung and his coworkers collected in the second volume of Jung’s Works (Jung, 1907). The basic turning-point in the study of brain electrical activity was represented by Berger’s discovery of the human electroencephalogram

In the second half of the nineteenth century, a new perspective was developed in research on the physiological bases of psychological processes. This approach was different from other contemporary types of investigation, which were based either on electrical stimulation and ablation of cerebral areas in animals or on clinical investigation of brain-injured patients. The method was noninvasive and was based on the study of electrical activity recorded on the skin or scalp during psychological activity. The first interesting results from this approach were obtained by Russian physiologists. Danilevsky (1891, p.629) wrote that: the study of brain electrical phenomena represents a possible way for investigating the objective material processes which are the substrate of subjective, psychological phenomena. By knowing the existence of a regular, strictly connected relationship 33

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(Berger, 1929). Berger became interested in brain electrical activity as a consequence of his studies on the relationships between brain and mind (he wrote the book Psychophysiologie on this topic in 1921). He distinguished two groups of brain electrical waves recorded on the scalp: “alpha” and “beta” waves. In 1934, Adrian and Matthews showed the blockage or desynchronisation of the alpha rhythm when the organism passes from a state of relaxed wakefulness with eyes closed to a state of arousal with eyes open. Research on electrophysiological correlates of psychological processes was reinforced by the work published by Moruzzi and Magoun (1949) on the functions of reticular formation. In 1949 the journal Electroencephalography and Clinical Neurophysiology was founded. From then on, electroencephalography became the main technique for studying the wakefulness-sleep cycle and activation levels. The work by Aserinsky and Kleitman (1955) was also very influential, as it showed that rapid eye movements are present during the so-called paradoxical sleep when dreams are produced. In 1951, Dawson introduced a new technique that made it possible to obtain what was then called “averaged evoked potential”. If a stimulus was presented repeatedly and the brain electrical activity was simultaneously recorded, it was possible to compute the correlated averaged evoked activity. These potentials had already been described in 1939 by Davis, who observed that auditory stimuli produced remarkable voltage variations in the electroencephalogram, but the technique for extracting them by averaging became available only later. In addition to indices of cerebral and autonomic activity, muscular electrical activity was also soon considered a physiological index of psychological processes. In the works by Darrow (1929), Jacobson (1930), and Davis (1939), muscular electrical activity was correlated with “mental work” and performance level. Classical works on psychophysiology are collected in Porges and Coles (1976).

Psychophysiological investigation in neuropsychology Differences in the theoretical and methodological approaches between neuropsychology and

psychophysiology have probably impeded the application of electrophysiological techniques in neuropsychology. In the 1950s and 1960s, psychophysiology was influenced by the behaviourist model. Physiological responses were considered, in the same way as behavioural responses, as expressions of the organism’s activity in response to external stimuli (for instance, in Ax’s classic work in 1953, the physiological responses to stimulus-situations producing fear and rage were recorded). The mind and the brain were considered as a “black box”, and processes inside the box, such as sensory analysis, attention etc., were generally not investigated. Only later, in the 1970s, were electrophysiological data used as a tool to study the inner processes that precede behavioural responses. Moreover, psychophysiological research was generally carried out on healthy subjects and less on patients with neurological and psychiatric disorders (for more details on the theoretical and methodological principles of psychophysiology, see Coles, Donchin, & Porges, 1986; Martin & Venables, 1980). In contrast, the main interest of neuropsychology has always been the anatomy and the function of the central nervous system; thus, most research was devoted to the inside of the “black box”, which was ignored by psychophysiology until the 1960s. Furthermore, neuropsychology favoured the investigation of the central nervous system over the autonomic nervous system and the muscular system. Moreover, subjects were brain-injured patients, rather than healthy persons. These differences between the two approaches, and the fact that the equipment necessary for electrophysiological recording was rarely available in hospitals, might well explain why psychophysiological works with a neuropsychological perspective are relatively few and often not very relevant for understanding neuropsychological disorders. This situation has rapidly evolved in the last few years and the number of psychophysiological studies on neuropsychological themes has increased. Moreover, at present, there is a promising perspective of linking electrophysiological data with results gathered by means of the powerful new neuroimaging techniques such as PET and fNMR.

3. ELECTROPHYSIOLOGICAL METHODS

A general review of the applications of electrophysiological techniques to neuropsychological research is given in this chapter. As these applications are very heterogeneous, we have grouped them according to the psychophy siological indices investigated. Skin and heart electrical activity, eye movements, and brain activity recorded on the scalp are the most commonly used measures. Examples have been selected almost exclusively from studies on patients with brain lesions.

THE AUTONOMIC NERVOUS SYSTEM Electrodermal activity is probably the neuroautonomic function most used in psychophysiological studies. Electrodermal activity is associated with the functions of sweat glands, richly innervated by fibres of the autonomic nervous system. This activity is a complex reaction modulated by several control centres of the central nervous system, and in particular reflects the functions of the autonomic nervous system. Variations in electrodermal activity in relation to various sensory, cognitive, and emotional processes have been investigated since the end of the nineteenth century (Fere, 1888; Tarchanov, 1890). The term “psychogalvanic reflex”, introduced by Veraguth (1907), was used to indicate these electrodermal variations and acquired a large popular following. In current research, other terms are preferred in order to distinguish between the basic activity of the skin (tonic activity) and activity in reaction to stimuli (phasic activity). Moreover, a distinction is made in relation to the type of recording: recording of spontaneous variations in electric potential between two electrodes applied on the skin (endogenous variations or skin potential) or recording of skin resistance to a weak current between electrodes (exogenous variations or skin conductance). Electrodes are placed on the skin of the fingers, palm, or arm. Skin potential and skin conductance are measured in millivolts and micromhos/cm2, respectively (general reviews may be found in Andreassi, 1995; Edelberg, 1972; Martin & Venables, 1980; Prokasy & Raskin, 1973; Roy, Boucsein, Fowles et al., 1993).

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Cardiac activity is also a commonly used neuroautonomic index. Electromyocardic signals are recorded by skin electrodes placed close to the heart and on the arms. In psychophy siological research, the number of beats in the time unit or interbeat intervals (in msec or sec) are generally used. Other neuroautonomic indices are blood pressure and respiratory frequency (see reviews in: Andreassi, 1995; Brener & Connally, 1986; Cacioppo & Tassinary 1990; Obrist, 1981; Turner, 1995). Early research hypothesised that all neuroautonomic responses varied in the same direction as a function of activation. For instance, an increase in skin conductance and heart frequency was thought to be associated with an increase in the activation level. In the 1950s, the Laceys introduced the principle of “directional fractionation”, which indicates that the values of different neuroautonomic responses may increase or decrease differentially depending on the type of stimuli and tasks. In particular, when the subject’s attention is directed towards external inputs, such as visual or auditory stimuli, skin conductance increases while heart frequency decreases. On the other hand, when the subject is instructed to ignore external stimuli and concentrate on a cognitive task, such as mental computation, both skin conductance and heart frequency increase (Lacey, 1967). In the past, electrodermal activity has been studied mainly in the area of emotions; for example, see the works by Jung and co-workers on free associations collected in Jung (1907). In the 1960s, “perceptual defence” was investigated with these techniques in several works (Andreassi, 1980). However, arousal, orienting reflex, and emotional reactions are also studied today in both normal subjects and patients. One example of research in this sector with neuropsychological patients is related to the idea of hemispheric specialisation for emotional responses, an hypothesis proposed by Gainotti (1972). In a series of studies, autonomic indices (electrodermal activity and heart frequency) and behavioural responses (facial expressions and avoidance behaviour) were recorded during the viewing of film sequences with high or neutral emotional value. In patients with right brain lesions, variations in electrophysiological indices were not related to

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the emotional content of films, contrary to what was found in control subjects and patients with left lesions. This result could not be due to a cognitive deficit, because patients with right lesions were able to describe and to understand the film content. Moreover, as all patients exhibited emotional facial expressions, they were actually able to express their emotion. However, avoidance behaviour (such as gaze-shifting during very difficult sequences) was present only in normal subjects and in patients with left lesions. Overall, these results were interpreted as evidence that patients with right brain lesions have a specific disorder of autonomic nervous reactivity to emotional stimuli, and that the right hemisphere plays a crucial role in the production of responses suitable for coping with emotional stimuli, such as avoidance behaviour and variations in neuroautonomic parameters associated with emotions (Caltagirone, Zoccolotti, Originate et al. 1989; Mammuccari, Caltagirone, Ekman et al., 1988; Zoccolotti, Caltagirone, Benedetti et al., 1986; Zoccolotti, Caltagirone, Pechinedda et al., 1993). These researches show the advantage of simultaneously collecting both behavioural and electrophysiological responses. Performances and concurrent physiological variations in a specific condition or task are documented, thus allowing more in-depth conclusions. Moreover, an interesting possibility offered by this approach is that of studying unconscious processes of stimuli in brain-damaged patients. Two examples of this will be presented, one regarding the study of heminattention (or neglect) and the other prosopagnosia. Hemianesthesia is commonly caused by defective sensory processing; however, unilateral neglect may also produce contralesional defects in the perception of tactile stimuli. In these cases it is difficult to separate the attentional deficit (heminattention) from the primary sensory deficit (hemianesthesia). Vallar, Bottini, Sterzi et al. (1991) used the electrophysiological technique to discriminate between these two alternatives in one case of right-brain damage with left neglect and left hemianesthesia. Somatosensory stimuli were delivered to the left and right hand. About 50% of the nonreported stimuli to the left hand produced skin conductance responses, indicating that the

early somatosensory processing of stimuli was not entirely disrupted. Thus, the patient’s hemianesthesia was due to a defective access of relatively saved early analysis to the conscious processes required for verbal response. Other studies showed a dissociation between recognition performance and electrophysiological data in prosopagnosic patients. The patients did not distinguish between familiar and unfamiliar faces and could not associate a correct name with a familiar face. However, electrodermal data gave evidence of some kind of discrimination without awareness (Bauer, 1984; Tranel & Damasio, 1985). In particular, in a study by Tranel and Damasio (1988), larger-amplitude skin conductance responses to familiar than to unfamiliar faces were recorded in four patients. On the other hand, none of the patients was able to give discriminatory verbal ratings of these faces. Autonomic responses proved discriminatory even for faces that the patients came into contact with only after becoming agnosic. The authors suggested that the processing responsible for formation and maintenance of a new face “trace” can be independent of conscious experience. Thus, information relative to faces would be submitted to normal processing, but the output of this processing would remain beyond awareness (see also Damasio, Tranel, & Damasio, 1990a). Another example of studies of neuroautonomic indices on patients further illustrates the potential contribution of this technique to the understanding of brain functions. Patients with ventromedial frontal brain damage may show severe defects in decision making and planning, especially evident in abnormal social behaviour. In these patients the autonomic responses to socially meaningful and emotional stimuli (such as pictures representing social disaster, mutilation, nudity etc.) were abnormal, while elementary unconditioned stimuli (such as loud noise) produced normal autonomic responses. It was proposed that, as a consequence of brain damage, social stimuli failed to activate somatic states at the most basic level. According to the authors, the presence of intact responses to unconditioned stimuli indicated that a different network exists to cope with stimuli that do not require the complex processing required by social

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stimuli (Damasio, Tranel, & Damasio, 1990b). The ability to discern the outcome of social behaviour in terms of punishment and reward would depend on visceral feedback mediated through interactions between ventromedial frontal cortex and autonomic centres. This pathway would be disrupted in patients with damage to the prefrontal cortex (Bechara, Tranel, Damasio et al., 1996).

RETINAL ACTIVITY AND EYE MOVEMENTS Electrical activity of the eye is recorded in two different forms: electroretinogram (ERG) and electro-oculogram (EOG). ERG is generally picked up with a corneal electrode, which records the activity following a flash of light. This activity consists of various components which arise in different layers of the retina (i.e. photoreceptors, cells in the inner nuclear layer etc.). The first evidence from an electroretinogram was given by A.F. Holmgren in 1865, but ERG clinical applications were due to the pioneering work by Riggs (1941) and Karpe (1945). This technique is commonly used in clinical ophthalmology to assess retinal functioning. Simultaneous recordings of ERG and evoked potentials make it possible to have a complete evaluation of the functions of the visual system and to localise the site of the deficit (e.g. Maffei & Fiorentini, 1990). For detailed reviews on ERG, recording techniques and clinical application, see Ikeda (1993) and Halliday and Kriss (1993). EOG is based on the fact that the anterior part of the eyeball is electrically positive compared with the posterior part. When illumination is constant and the eyes are fixed straight ahead, a steady voltage is recorded from electrodes located on the periocular region (or on the cornea); if the eyes move, variations are recorded (EOG). Thus, the EOG is associated with the exploratory functions of eye movements (Carpenter, 1977). The EOG is often replaced by a nonelectrophysiological technique, based on infrared rays. This technique has been used to investigate visual perception, cognitive strategies, and reading

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(e.g. d’Ydewalle & van Rengsbergen, 1993, 1994; O’Regan & Levy-Shoen, 1987; Rayner & Pollatsek, 1989; Yarbus, 1967). Most of the studies measure the number, amplitude (degrees), direction, and velocity (degrees/sec) of saccades, while the subject is performing a visual task. Recent technological advances make it possible to superimpose the pattern of eye movements on the visual scene, in order to study the subject’s scanpath. Next, some research will be reported to illustrate the variety of investigations on neuropsychological themes afforded by eye movement recording. In all cases the main information offered by this technique is an accurate description of exploratory behaviour. This reveals phenomena that would otherwise remain undetected, such as the dissociation between conscious perception of the stimulus and the ability to fixate it (see agnosia) or the use of different strategies in exploring the visual scene (see between-objects and within-objects neglect) or accomplishing visual linguistic tasks (see aphasia). Moreover, other phenomena already observed can be properly quantified, such as the presence/ absence of compensatory strategies in relation to the type of brain damage (see hemianopia and neglect).

Hemianopia In research on reading and visual exploration, eye movements have been investigated in patients affected by hemianopia. In a recent study on a large group, Zihl (1995a) showed that degree of reading impairment depended on the extent of visual field damage; patients with right-sided loss were more impaired. The amplitude of saccades was reduced and fixations were longer. Further, saccade length, which is typically very flexible in expert readers, seems to have a reduced variability in right hemianopic patients, indicating a sort of “automatic pilot” in their reading (De Luca, Spinelli, & Zoccolotti, 1996). Compensatory exploration strategies in a visual searching task have been shown in hemianopic patients: their eyes move to pick up information from the blind hemifield; scanning is normal, although in some cases it is slow (Zihl, 1995b). When hemianopia was associated with unilateral spatial neglect, no compensatory strategies were present (e.g. Girotti, Casazza, Musicco et al., 1983).

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Neglect Research on eye movements during reading in patients with neglect showed that the pattern is characterised by return sweeps with a landingpoint half-way along the line; then a series of regressive saccades followed until a reasonable continuation of the sentence is found, independently of the real beginning of the line (Kamath & Huber, 1992). Eye movement recordings were used to support the view that the ability to orient between-objects or within-objects can be independently damaged in patients with neglect. Scanning of simple visual scenes or line drawings composed of various objects were compared with scanning of one single face or object. The patients failed to move their eyes to locate objects positioned in the contralateral side of the scene; on the contrary, they were able to make contralesional saccades when looking at a single object, i.e. fixating both left and right eye of the face (Kamath, 1994). One patient with the symmetric defect has also been described. This involved the failure to scan the right side of individual objects, while scanning of the contralesional side of the visual scene was intact (Walker, Findlay, Young et al., 1996). Eye movements in patients with neglect have also been studied during sleep. During wakefulness, saccades towards the left were comparable to saccades towards the right; during sleep, saccades towards the left were almost totally absent. On the contrary, they were present in patients with right brain damage but without neglect. These results suggest that attentional areas damaged in neglect have control over rapid eye movement production during sleep (Doricchi, Guariglia, Paolucci et al., 1993). Improvement of neglect due to rehabilitative training did not affect REM asymmetry (Doricchi, Guariglia, Paolucci et al., 1996).

Agnosia In pioneering studies (e.g. Luria, PravdinaVinarskaya, & Yarbus, 1962; Tyler, 1968) of cases of simultaneous agnosia, eye-movement paths were reported to be disorganised with respect to the

typical pattern observed in healthy subjects. However, it is possible that in these cases brain lesions were very large, also involving oculomotor cortex and frontal and parietal lobes (see Girotti, Milanese, Casazza et al., 1982). On the other hand, Rizzo and Hurtig (1987) reported dissociation between the capacity to look at the stimulus and its conscious perception. The patients studied had lesions limited to the bilateral superior associative occipital cortices and were suffering from simultaneous agnosia, i.e. they complained that the objects in the visual environment would “disappear” from view. Eye movements were measured by EOG and showed normal fixation, normal tracking, and normal scanning of visual images. Thus, the processing was sufficient to permit accurate driving of oculomotor mechanisms, but conscious experience of the stimulus was intermittent.

Aphasia In aphasic patients, analysis of the patient’s gaze during reading may be more informative than a simple description of reading errors (see Huber, Luer, & Lass, 1988a, b). Distinct reading behaviours have been described in patients with Wernicke’s and Broca’s aphasia. In the former, saccades were very short, showing a kind of “step by step” reading, while in the latter, fixation times were longer and many regressions were present. Special strategies used by Broca’s patients in processing sentences were discovered. Moreover, by using pictorial material, aphasic patients were investigated in tasks involving recognition of semantic relationships between words, and recognition of images and sentences. Results suggested that the understanding of single information elements and the choice of problem-solving strategies were not grossly modified in patients compared with controls. However, difficulties were observed in aphasic patients. At the end of tasks they often gave incorrect responses and had very long reaction times. The authors suggested that difficulties depended on the necessity to integrate many decisions to solve the task. A behaviour typical of these patients was the repetitive control of relevant elements; however, the correct solution was not reached.

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Developmental dyslexia In dyslexics, eye movements in reading are altered, with longer fixation duration, shorter rightward saccades, and a higher number of regressions (e.g. Adler-Grinberg & Stark, 1978). In some cases, the pattern of eye movements was so altered, that it was proposed that the disorder can be considered one of the main causes of developmental dyslexia. This hypothesis was tested by studying eye movements in non-reading tasks in dyslexics. Results were contradictory: Pavlidis (1981) reported eye movement disorders both in reading and in non-reading visual tasks. On the contrary, many other studies (e.g. Olson, Kliegl, & Davidson, 1983) have shown normal saccades in non-reading tasks. This supports the view that the abnormality of eye movements is secondary to the linguistic problems.

BRAIN ACTIVITY Electrical brain activity is generally recorded by means of electrodes placed on the scalp. Sometimes, during surgical operations, intracranial recordings are also made. Electrical activity is recorded as electroencephalogram (EEG), evoked potentials (EPs), event-related potentials (ERPs), and slow potentials (SPs). In this review, EPs and ERPs will be considered. Only brief information will be given about EEG, brain mapping, intracranial recording, transcranial magnetic stimulation and magnetoencephalography. (For a discussion of the SP technique, see Birbaumer, Elbert, Canavan et al., 1990; McCallum & Curry, 1993.)

EEG The EEG is the recording of electrical potential variations generated by millions of cerebral neurones. These variations are associated with the wakefulness-sleep cycle, ongoing psychological processes, etc. To record EEG, several electrodes are usually placed on the head. To permit comparison of data from different subjects (with different head sizes), a standard system for placing electrodes on the scalp was adopted.

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Location of electrodes is based on the length of two reference lines measured in each subject: the inion-nasion and left-right ear distances (10-20 international system; Jasper, 1958). Electrodes located above occipital, temporal, parietal, frontal, and central areas are labelled O, T, P, F, and C, respectively. Even and odd numbers indicate right and left sides; Fz, Cz, Pz, and Oz are electrodes placed on the midline. Recorded activity is amplified and filtered. EEG rhythms are classified in relation to the frequency band of ongoing electrical potential oscillations (expressed in cycles/sec or Hz). The alpha rhythm, with a frequency between 8 and 13 c/sec and an amplitude of around 10 microvolts, is typical of a relaxed state with eyes closed. Opening the eyes, and also mental activity, produce blockage of the alpha rhythm (desynchronisation reaction) and presence of the beta rhythm, with a smaller amplitude and a higher frequency (between 13 and 35 c/sec). The theta rhythm, with a frequency between 4 and 8 c/sec and a large amplitude (up to 100 microvolts) is usually associated with sleepiness; the delta rhythm characterised by a very low frequency, less than 4 c/sec, and a large amplitude (about 100 microvolts) is recorded in deep sleep states. Since Berger’s (1929) early research on the human EEG, this brain electrical activity has been considered the main physiological index of psychological processes. A lot of work has been published on the relationship between EEG rhythms and sensory-motor performance, perception, conditioning, learning, memory, intelligence, etc. (see Andreassi, 1995). However, the EEG is less employed nowadays in psychophysiological research since the spread of the EP technique, which makes it possible to detect more precisely the correlation between brain activity and psychological processes. The EEG reflects the overall activity of the brain or of wide cerebral areas, and it is a general index of activation level. In the past, the EEG was an important means for localising brain lesions; for this purpose today it has largely been replaced by anatomical techniques, such as CT scanning and MRI. Description of the cellular basis, measurements, and correlates of EEG can be found in

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Barlow, 1993; Duffy, Iyer, and Surwillo, 1989; Fish, 1991; Pilgreen, 1995. In the clinical routine, searching for alterations of electrical activity is often performed through computerised EEG analysis. The computer, more efficiently and reliably than the human eye, divides the brain electrical activity into frequency domains; then it analyses the temporal consistency of this activity for each electrode, creates a map of the spatial distribution of the activity and, in some cases, performs a statistical comparison with normative data (Rossi & Tecchio, 1994). Thus, for the purpose of clinical diagnosis, quantified EEG is a more powerful instrument with higher reliability than the traditional EEG. Data on the use and validity of computerised techniques for EEG analysis in neuropsychology are growing. Advantages have been stressed (Chiappa, 1986; Duffy, 1986) and also critical remarks have been made (Epstein, 1994; Tyler, 1986). One typical example of the application of EEG in neuropsychological research is the study of the functional asymmetry of the two hemispheres. The prevalent electrical activation of one of the two hemispheres should indicate that it is involved in the ongoing process for which it is specialised. In patients with left brain damage and aphasia the activation of the two hemispheres during a verbal task was studied. Compared with controls, the right hemisphere appeared to be more activated. This sort of “compensatory” activation of the right hemisphere suggested that language recovery in patients with aphasia may be guided through a progressive involvement of the non-language hemisphere (see: Moore, 1984,1986; Papanicolau, Moore, Levin et al., 1987; Papanicolaou, Moore, Deutsch et al., 1988).

Evoked potentials (EPs) and event-related potentials (ERPs) Evoked potentials recording is based on the EEG technique with some modifications. A single EP is a very small signal, masked by the overall ongoing brain electrical activity (EEG), and it has to be extracted from this noise to become visible. This result is obtained by averaging. Averaging is carried out in the time immediately following stimulus

presentation and for the duration desired (e.g. one second). Stimulation is repeated many times (50-300), and each time the concurrent electrical activity is recorded and averaged. Averaging cancels waves not synchronised with the stimulus, while synchronised waves sum up. Thus the evoked electrical sign becomes evident. An example of the morphology of the final brain electrical activity is presented in Fig. 3.1. The latency of the peak is measured from stimulus onset. Positive and negative peaks can be well distinguished. Note that in the figure, positive is up; however, in the literature both positive up and negative up may be found. Evoked potential morphology is related to the physical characteristics of the stimulus, but may also depend on the tasks the subject has to accomplish. Barrett (1993) distinguishes between sensory EPs and cognitive EPs. Another widely used term is “event related potentials” (ERPs) for the entire class of non-spontaneous electrical potentials, distinguishing between exogenous (produced by external stimuli) and endogenous (produced by operations performed by subjects) components. Waves evoked by external stimuli are called exogenous (“obligatory”, “sensory”, “primary”); waves associated with cognitive operations are called endogenous (“cognitive”, “secondary”). According to the time course of the ERP, endogenous components are earlier, while endogenous components are later. In this chapter both terms will be used. When exogenous components have to be measured, a few electrodes (at least one active and one reference electrode plus the ground electrode) are placed on the scalp in appropriate positions. For instance, in the case of auditory stimulation, the active electrode is generally placed on the vertex; in the case of visual stimulation, electrodes are placed on the occipital lobes etc. However, different montages of electrodes are used by different laboratories. For instance, the reference electrode can be on mastoids, earlobes, Fz, etc. For investigations on brain-injured patients, the socalled Queen Square montage (from the name of a London hospital) is widely applied; a set of active electrodes are placed on the scalp and the reference electrode on Fz (for the techniques of recording and measuring, see Picton, 1988). This is much

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discouraged nowdays due to the fact that the frontal lobes are often activated by the sensory stimulus; thus, frontal leads are far from being neutral as an ideal reference should be. As a general rule, therefore, reference electrodes on the earlobe, mastoid, or shoulder are encouraged. When research is devoted to endogenous components, a larger number of electrodes are used, generally placed along a central line on Fz, Cz, Pz, and Oz, and laterally to left and right. Of course, more complex procedures for data analysis are required when several electrodes are used (see brain mapping). The reader interested in the literature on EPs and ERPs can consult the section “Evoked potentials”, as well as the Supplements and Handbooks, of the journal Electroencephalography and Clinical Neurophysiology entirely devoted to research carried out by means of this technique. Technical aspects may also be found in Brain Topography.

Relevance of EPs and ERPs for neuropsychological research It is generally assumed that a given number of morphological components, such as P I00, P300 etc., related to ongoing sensory and cognitive processes can be identified in the EPs. The different time onsets of these components tap the timing of the various sensory and cognitive processing.

Research should describe these components and localise their cerebral generators. Disentangling EP or ERP components corresponds to identifying the portion of electric wave (a peak) produced by a single source (see Naatanen, 1982). This task is not easy: a voltage peak may be the output of the activity of several generators, each involved in different operations, summed at the electrode. The method of separating (discriminating) different components summed up into the same peak, is based on the analysis of latency, on the amplitude distribution over the scalp, and on differential sensitivity to experimental manipulations; principal component analysis may also be applied (Rugg, 1992). In general, the larger the number of active electrodes scanning the activity of various brain areas from the scalp, the higher the chance to discriminate different components and their characteristics. Investigation of patients, particularly with focal brain damage, may make a remarkable contribution towards solving this problem. For instance, it may be found that a component is missing after a specific type of brain damage, suggesting that the injured area is relevant in producing such a component. On the contrary, it may rule out that one brain area is the main source for a specific component when the morphology (amplitude, latency) of the wave is not altered after the lesion. Thus, neuropsychological

FIGURE 3.1

Sketch of visual EPs. Main exogenous (continuous line) and cognitive (dashed and dotted lines) components are indicated. Note a family of negative (N) waves around 150-200msec, P300 and N400.

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research in the damaged brain may contribute to a better understanding of electrical phenomena in the healthy brain. However, other aspects are particularly relevant for neuropsychology. Disorders in brain activity are directly investigated instead of being deduced in relation to impairments in behavioural performance. In fact, while neuropsychological techniques investigate overt behaviour, EPs and ERPs reveal processing stages that do not have access to conscious experience and remain covert. This opens two possibilities. On the one hand, ERPs may reveal functional abnormalities even in the absence of perceptual impairment and anatomical damage. This was the case in studies on multiple sclerosis, where abnormalities of the visual ERP were documented despite normal visual acuity, visual field, and colour vision (Chiappa, 1983). On the other hand, in cases of defective perception, ERPs might show that stimulus processing can be preserved, at least in part (e.g. see the case of hemineglect). The technique has very good temporal resolution (in the order of milliseconds). The latency and the amplitude of components depend on the timing and synchronicity of firing of the neuronal pools underlying sensory and cognitive processing. In the next sections it will be illustrated that these processes (at least some of them) have been related to particular components. This makes it possible to localise the deficit at various stages of processing. Abnormalities of the various components may indicate disorders at various stages of processing (sensory, attention, memory, etc.). Finally EPs and ERPs are not invasive and there are no impediments for repetition of the test; thus they may be important for prognosis and monitoring of the illness. The main limits of the EP and ERP techniques are essentially the insensitivity in the spatial localisation of neural generators, and the great variability in the healthy population. A typical example of failure in spatial resolution is given by the so-called “paradoxical latéralisation”. It is generally assumed that maximal ERP amplitudes are recorded at the scalp electrodes closest to its source. However, it has been shown that a stimulus presented to

one visual hemifield evokes a paradoxically larger potential over the ipsilateral occipital scalp (Barrett, Blumhardt, Halliday et al., 1976; Blumhardt & Halliday, 1979). Such a paradox stemmed from the limited amount of recording electrodes and has been solved by mapping out the scalp distribution of hemifield VEPs and by tridimensionally localising their dipolar source within the calcarine cortex (see Onofrj, Bazzano, Malatesta et al., 1991). The spatial resolution may be improved by using special techniques for recording and data analysis utilising dedicated algorithms for Equivalent Current Dipole localisation (see brain mapping). However, not all processes are equally represented at the level of electrodes: processes occurring deep in the cortex and subcortical activity might not be measurable on the scalp. Overall, neural generators cannot be assessed on the basis of single ERP information, and additional information is required such as brain-damaged patients’ data, magnetoencephalographic data, intracranial recording, fMRI etc. Individual variations in the healthy population may be partly ascribable to differences in the anatomy of the cortex and its circumvolutions, as well as to conduction volumes (e.g. thickness of skull bones). This variability may be an obstacle for the reliability of between-comparisons in the patient population; thus, within-designs appear to be a better experimental approach in many cases (Barrett, 1993). However, in recent years, combined electrophysiological and structural approaches have partly overcome the individual anatomical variabilities by integrating EPs with MRI (e.g. Rossini, Narici, Martino et al., 1994; Rossini, Rossi, & Tecchio, 1996). Another point of interest concerns the duration of electrophysiological testing. It is assumed that EP and ERP components are stable over time, but this is just a necessary simplification of what really occurs from trial to trial. Indeed, during testing with patients one should expect remarkable fluctuations. Applying techniques of signal analysis, such as that introduced by Woody (1967), might reduce the testing duration. This might be an advantage for patients unable to hold their attention for long sessions.

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Finally, the usefulness should be stressed of methods for evaluating the reliability of the electrical signals recorded, such as the statistics developed by Victor and Mast (1991) or the measurement of the standard deviation of the amplitude and phase of the signal, and the simultaneous recording of signal and noise (at a temporal frequency uncorrelated with the stimulus) in order to evaluate the signal-noise ratio (technique developed by Porciatti, Burr, Morrone, & Fiorentini, 1992). These methods are particularly useful in research on patients, where signals are often weak and variable.

Sensory components EP and ERP morphology is characterised by a sequence of positive (P) and negative (N) peaks. The component’s latency is measured with respect to stimulus onset. Thus, P I00 indicates a positive peak about 100msec from stimulus onset. Sensory (or primary, exogenous, early, obligatory) components are present in the first 100-150msec. Auditory EPs (AEPs) are generated by auditory stimuli such as clicks, tones, words, etc. AEPs are characterised by a series of waves produced at subcortical (brainstem potentials) and cortical level. Brainstem potentials are recorded in the first 10msec and are used for the diagnosis of disorders in the auditory pathways. Subsequent components, produced at the cortical level, at middle (10-50msec) and long (100msec or longer) latency reflect the processing of physical properties of the auditory stimuli (frequencies, loudness, duration, etc.). Visual EPs (VEPs) are generated by visual stimuli such as flashes of light, gratings, checkerboards etc. VEPs are characterised by components produced at the cortical level (Fig. 3.1). The component most frequently considered is P I00; its amplitude and latency are modulated by the physical properties of a visual stimulus (such as intensity, duration, contrast, etc.). Somatosensory EPs (SEPs) are evoked by electric shocks of moderate intensity, generally applied to the wrist medial nerve. SEPs are characterised by subcortical components (up to N18, probably related to thalamus and sensory radiation activities) and cortical components with

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short (up to 30msec, generated at parietal, rolandic and frontal areas), middle (up to 70msec) and long (beyond 70msec) latencies. Two main types of EP recording are used. Transient EPs are recorded when relatively long interstimulus intervals are used. This should permit brain activity to return to resting conditions after each stimulus. Steady-state EPs are recorded when the stimulus rate is high. In this case, as the response becomes sinusoidal in shape, Fourier analysis is generally used for data analysis. AEPs, VEPs, and SEPs are widely used for diagnosis of neurological disorders. Overviews of the rich literature on sensory EPs and their use in neurological and psychiatric research can be found in Picton (1988), Regan (1989), Halliday (1993) and Rossini (1994).

Attentional modulation of sensory components The possibility of peripheral gating as a mechanism of attention in humans has been investigated by studying brainstem waves, the short latency components of the somatosensory evoked potential and ERG. Results have generally been negative (for a review, see Hillyard & Picton, 1987). However, more recently effects of attention have been reported on a variant of brainstem potential—that is, the frequency following potential (FFP), termed thus because its power-spectrum peak is placed very close to the stimulation frequency. FFP latency (latency is about 6msec) is shortened if subjects pay attention to the stimulus (Hoorman, Falkenstein, & Hohnsbein, 1994). On the other hand, many works have shown that cortical sensory evoked potential components are influenced by attention in auditory (Hillyard, Hink, Schwent et al., 1973; MeCallum, Curry, Cooper et al. 1983; Woldorff, Gallen, Scott et al., 1993; Woldorff, Hansen, & Hillyard, 1987), visual (Hillyard, 1993; Mangun, 1995; Morgan, Hansen, & Hillyard, 1996; Rugg, Milner, Lines et al. 1987) and somatosensory (Desmedt, Tran Huy, Bourget et al., 1983) modalities. However, negative results have also been reported (for example, see Linden, Picton, Hamel et al., 1987). Overall, consistent with the idea of a perceptual facilitation of the attended input, these data suggest that attention— and the

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related changes induced in the ongoing EEG—may modify the early cortical processing of the stimulus, an effect that is shown by modulation of the amplitude of the component itself. A different mechanism was proposed by Naatanen and Picton (1987) for the auditory modality. In this case, the enhancement of the N 1 component results from the effect of another negative-going wave (“processing negativity”, see next section) which overlaps in time with N 1. Some studies have tried to localise the early ERP attention effects. For instance, in the visual domain, studies with various techniques (scalp current density topography ERP, MRI, and cerebral regional blood flow), based on Posner’s cueing paradigm, have argued that the enhancement of P I00 evoked by inputs from pre-cued attended locations take place at the level of the extrastriate area (see review by Mangun, 1995). Effects of early sensory modulation in attentional tasks have also been shown in patients with brain lesions. Positive components with a latency of about 30msec (produced by the primary auditory cortex and areas 1 and 2 of postcentral gyrus) appeared to be disinhibited after a lesion in the dorsolateral prefrontal cortex (Knight, Scabini, Woods, 1989a; Yamaguchi & Knight, 1990). Further research confirmed that sensory modulation of the auditory cortex was impaired in patients with frontal lesions: P 1 amplitude, with a latency around 50msec, was not modulated by attention (Alho, Woods, Algazi et al., 1994). Thus, it was proposed that in healthy subjects these early attentional effects are controlled at the dorsolateral prefrontal level. The advantage of this early control in normal subjects would be to avoid processing of nonrelevant information. On the contrary, as a result of the chronic absence of this modulatory activity, all external events would appear equivalent and would not be filtered. It is likely that changes in the modulatory activity of the prefrontal cortex would contribute to attention disorders typical of prefrontal patients (Knight, 1991).

Cognitive components The main cognitive components will be briefly described; more information can be found in the reviews by Kutas and Hillyard (1984a), Hillyard

and Kutas (1983), Hillyard and Picton (1987), Picton (1988), Rugg (1992), Barrett (1993), Rugg and Coles (1995), Gevin and Cutillo (1995). As in the case of sensory components, cognitive components are indicated by referring to peak polarity and latency. However, whereas the latency label of sensory components is generally very close to the latency really recorded (that is, P I00 actually has a latency around 100msec, with variations of about 10msec, depending on stimulus features and individual variations), the latency values of the cognitive components vary much more, as an effect of cognitive tasks and individual characteristics. Thus, what is known as P300 may be recorded also at 600msec or later. It is possible to describe the time course of brain information processing on the basis of the latencies of ERP components. For instance, the semantic analysis reflected in a negative component around 400-600msec (N400) occurs later than the selective attention operations shown by negative components whose peak is around 200msec (N200). This temporal sequence does not necessarily mean that operations are performed sequentially: they might also be performed in parallel by distributed neural networks requiring that different time durations be completed. Components with a latency of less than 150msec are relative to primary analysis of stimulus features. Moreover, there is a negative wave (labelled processing negativity PN, or Nd negative displacement) which begins very early (5 0 -100msec) and lasts for several hundredths of msec. This component reflects the shifting of selective attention. For instance, in a task of dichotic listening where instructions are to pay attention to stimuli transmitted to one ear and to ignore stimuli transmitted to the other ear, processing negativity is larger for stimuli to which attention is paid (Naatanen, 1990). A set of negative waves with a latency around 200msec (N2) follows. These components emerge especially in an oddball task, where rare target stimuli are randomly presented within a series of more frequent and non-target stimuli; occasionally new stimuli (i.e. stimuli different from target and non-target) are also presented, without subjects having been previously informed of them. Two

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subcomponents have been described. The N2a component, also called mismatch negativity (MMN), is produced by novel stimuli irrespective of whether they are noticed by the subjects. N2a is thought to be an index of pre-attentive mechanisms of sensory memory and to reflect a system of controlling and evaluating variations of ongoing auditory information (e.g. Naatanen, 1992; Tervaniemi, Maury, & Naatanen, 1994; Tiitinen, May, Reinikainen et al., 1994). The N2b component is produced by rare target stimuli and its amplitude is inversely proportional to the stimulus frequency. Around 300msec, a positive wave emerges, the so-called P300 or P3, widely investigated by research on ERPs and cognitive processes. The peak latency of this component may vary between 300 and 800msec in relation to the type and/or difficulty of the task; in some cases, particularly in memory tasks, a different label is used, that is P600. In experiments using the previously described oddball paradigm a distinction was made between two sub-components: P3a, with short latency (250-550msec) in response to unexpected stimuli, novel enough to attract attention; and P3b with longer latency, associated with processing of target stimuli. Thus, the P3a component, larger over frontal areas, often following the N2a, is associated with the presence of a new signal, and is a marker of involuntary automatic attention (orienting response). Using another paradigm (a serial picture recognition memory task) it was shown that P3a is an index of a rapid working memory system. In this experiment, P3a amplitude evoked by a picture is enhanced, with respect to the first presentation of the same figure, only if it immediately follows the first trial. If a delay longer than four seconds is given, P3a amplitude is reduced to the value recorded in the first presentation. Thus, P3a would be an index of a frontally mediated rapid working memory system for stimuli held in memory for less than four seconds (Nielsen-Bohlman & Knight, 1994). In the same experiment, a clear dissociation was observed with the later component N400, not present at short delay and enhanced at long delay. This component results from the activity of limbic areas, and reflects long-term memory processes (see later).

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The P3b component (or P3), particularly large over the parietal midline, relates to operations necessary for processing target stimuli in the oddball condition. Although the meaning of P3 is debated (see the discussion by Verleger, 1988 and Donchin & Coles, 1988), this component is generally considered to be an index of processes associated with phasic voluntary attention and complex categorisation operations. Indeed, P3 peak latency correlates with the time required to categorise the evoking stimulus (Kutas, McCarthy, & Donchin, 1977). However, it seems that P3 characteristics are also partly determined by fluctuations in the arousal state of the subject due to various biological and environmental factors such as circadian rhythms, intake “common” drugs, e.g. caffeine, etc. (for a review, see Polich & Kok, 1995). Many experiments have shown that P3 is related to memory tasks. In Sternberg’s (1966) procedure, items are presented for memorisation and later an item is presented that the subject must classify as being part of the memory set or not. A positive potential is generated by the probe; its latency is about 400msec and increases with increased set size (e.g. Pratt, Michaelewski, Barrett et al., 1989). In word recognition memory tasks, ERPs show the repetition effect. Thus, after a study phase, old words (previously seen or heard by the subject) presented to the subject produce a phasic positive deflection with onset at 300-400msec, larger than that evoked by new words. The effect is larger over the left hemisphere and most marked at parietal sites and is closely tied to processes necessary for recollection (see a review in Rugg, 1994). Overall, the general finding is that more positive P3 is generally associated with more efficient memory. Most research on the negative component around 400msec is related to semantic processing, such as semantic priming (e.g. Rugg, 1985). N400 is produced by verbal stimuli incongruent at the semantic level with previous information (e.g. Kutas & Hillyard, 1984b). For example, the word “socks” will produce an ERP with a large N400 if this verbal stimulus follows the words “He spread the bread with ...”, while the word “butter” will not have the same effect because it is semantically congruent. The amplitude of N400 is inversely

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proportional to the coherence of the stimulus with the context. This phenomenon would not be confined only to the linguistic domain, but also to the cross modal conceptual domain (e.g. pictures: Nigam, Hoffman, & Simons, 1992). For a review on N400, see Kutas and Van Petten (1994).

EPs and ERPs in neuropsychology Compared with neurological and psychiatric research, a lower—but increasing—number of works have been devoted to studying neuropsychological disorders (reviews may be found in Barrett, 1993; Knight, 1991; Papanicolaou, 1987; Rugg, 1992; Viggiano, 1996). In the following sections, some examples will be presented of the applications and the contribution of EP and ERP techniques in neuropsychological investigations. Dissociation o f components and data on neural generators As discussed earlier, work on brain-damaged patients might be informative for assessing neural generators of EP and ERP components. An example can be given by the investigation of the P300 source. One hypothesis was that P300 is produced by the interhemispheric comparison of information through the corpus callosum. However, a study of P300 distribution in patients with section of the corpus callosum showed that this component was spared (Kutas, Hillyard, Volpe et al., 1990). Studies with intracranial electrodes showed the presence of locally generated potentials in the temporal lobe structure, functionally similar to the scalp-recorded P300 (e.g. Stapleton & Halgren, 1987). This suggests that P300 reflects activity of bilateral temporal lobe generators. Thus, a reduction in the amplitude of P300 was expected in patients with damage to this cerebral region. However, patients with unilateral anterior temporal lobectomy (e.g. Stapleton, Halgren, & Moreno, 1987; Sheffers, Johnson, & Ruchkin, 1991) and one patient with extensive dysfunction of the left medial temporal lobe (Rugg, Pickles, Potter et al., 1991) did not show any significant differences in P300 amplitude, topography, and latency with respect to controls. Thus, these results contrast with the idea that the

temporal lobe (and particularly the anterior portion of it) make a substantial contribution to the scalp P300. Other studies have dissociated P3a and P3b components. Two groups of patients were studied: one with prefrontal lesions and one with parieto-temporal lesions. P3b was normal in patients with prefrontal damage (Knight, 1984) and it was absent in patients with temporo-parietal damage (Knight, Scabini, Woods et al., 1989b; Yamaguchi & Knight, 1990). On the other hand, P3a was reduced in both groups of patients, suggesting that stimulus novelty activates widely distributed circuits. More recently, it has been shown that P3a was specifically reduced in patients with posterior hippocampal lesions, while P3b was intact. It was concluded that the hippocampal region makes an important contribution to P3a generation, while parieto-temporal regions are most involved in P3b production (Knight, 1996). Developmental disorders and ageing Several developmental neuropsychological syndromes have been investigated using EP and ERP techniques; see for instance the recent studies on autism (Lincoln, Courchesne, Harms et al., 1995), Down syndrome (Karrer, Wojtascek, & Davis, 1995) and attention-deficit hyperactivity disorder (Satterfield, Schell, & Thomas, 1994). One of the questions these studies might help to solve is whether deficits are due to damage in cerebral centres responsible for cognitive functions, or to basic processing impairment, or both (see review by Steinschneider, Kurtzberg, & Vaughan, 1992). Many works have been devoted to developmental dyslexia. This syndrome has been considered from two points of view: as a specific cognitive disorder in the processing of verbal material, or as a disorder determined at least in part by a sensory deficit. The latter hypothesis was supported by EP studies showing abnormality of early visual components in many children with reading disability. For instance, the morphology of EPs by checkerboards was found to be altered (Mecacci, Sechi, & Levi, 1983); abnormalities of binocular processing were found (Solan, Sutija, Ficara et al., 1990); the response of the transient system was

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impaired (e.g. Lehmkuhle, Garzia, Turner et al., 1993; Livingstone, Rosen, Drislane et al., 1991; May, Lovegrove, Martin et al., 1991). Recently, a deficit in the early auditory processing of dyslexics was shown: the MMN component to changes introduced in trains of sounds (such as “da-da-dada” and “da-da-da-ga”) present in controls was absent in these children (Kraus, McGee, Carrell et a l , 1996). The hypothesis has been advanced that a deficit in the transient visual system (Lovegrove, 1991) or the magnocellular pathway (Livingstone, Rosen, Drislane et al., 1991) may be at the root of dyslexia (on this point, see also Frith & Frith, 1996; Mecacci, 1997). However, other works have failed to confirm the presence of EP abnormalities in dyslexics (e.g. Victor, Conte, Burton et al., 1993; Johannes, Kussmaul, Munte et al., 1996). The hypothesis that specific deficits in processing language are present in children with reading disability has been investigated (e.g. Ackerman, Dykman, & Oglesby, 1994). An alteration of the N400 component during a rhyming task was found in dyslexics. Moreover, priming effects on N400 were shown to be different in dyslexics compared with controls (Miles & Stelmack, 1994). The conclusion that no single factor can be isolated as the cause of reading disorders was drawn by Neville, Coffey, Holcomb et al., (1993). These authors studied basic processing of visual and auditory information and linguistic processing of sentences. Abnormalities were found in both of them. The use of MEG provided further information on processing of words in dyslexics (Salmelin, Service, Kiesila et al., 1996). Finally, the hypothesis was also advanced that the reading disorder depends on an attentional deficit. Many works have investigated N200, P300, and N400 in children with learning disorders (including dyslexia) and have found some morphological abnormalities in tasks requiring subjects’ attention (e.g. Harter, Anllo-Vento, Wood et al., 1988; Harter, Diering, & Wood, 1988; Klorman, 1991; Satterfield, Schell, Nicholas et al., 1988). Sensory and cognitive components of ERPs have also been used to investigate the effect of

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ageing. The latency of sensory components was found to be longer in aged subjects (e.g. Allison, Hume, Wood et al., 1984; Fiorentini, Porciatti, Morrone et al., 1996). However, the delay was more marked for late components related to cognitive processes. P300 has been particularly studied as a function of ageing and a progressive increase in latency has been found during the lifespan from age 15. Some authors have also found a decrease in P300 amplitude (for reviews, see Barrett, 1993; Polich, 1996). Memory decay in ageing has been associated with changes in P300. For instance, in auditory oddball tasks, elderly people performed poorly and a modification of the scalp foci of P300 with respect to younger subjects was present (Fabiani & Friedman, 1995). Also, P300 amplitude was decreased in a visual recognition memory task when delay between stimuli was long; the electrophysiological change was associated with poor performance (Nielsen-Bohlman & Knight, 1995). Overall, cognitive components are altered in the elderly. However, their involution is more evident in the case of pathologies responsible for cognitive impairment, indicating abnormal slowing of mental functioning (see the study by Goodin, Squires, & Starr, 1978 on patients with various types of dementia, showing very long latencies in 80% of cases). On the other hand, stroke by itself does not seem to produce a specific delay in cognitive components. According to Ladurner, Schimke, Wraneck et al. (1990), stroke patients without cognitive disorders have the same latency of P300 recorded in controls, whereas patients with stroke and dementia have a clear latency delay. In patients with cerebrovascular accident, amplitude and latency measurements were also made by Gummow, Dustman, and Keaney (1986). These authors found that amplitudes were reduced, but latencies were normal. The reduction in amplitude was present both for target and non-target stimuli, suggesting an aspecific effect. According to these authors, the amplitude reduction by itself cannot be considered an index of cognitive deterioration, but might reflect decreased cortical intercommunication associated with damage to subcortical brain structure.

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Disorders in auditory processing and language Integrity of auditory pathways and primary auditory cortex is assessed by inspection of brainstem potentials and middle-long latency components, respectively. Bilateral temporal lobe lesions produce a variety of disorders ranging from auditory threshold elevation to cortical deafness (i.e. the inability to perceive sounds, in the absence of a peripheral deficit). Brainstem potentials were normal in all patients; however, middle- and long-latency cortical components showed remarkable variability. For instance, in a case of cortical deafness middle- and long-latency components were absent (e.g. Ozdamar, Kraus, & Curry, 1982). On the other hand, in a case of auditory agnosia (i.e. inability to interpret both verbal and nonverbal sounds, even though the patient can hear them) middle- and late-latency EP components were present but slowed (e.g. Rosati, De Bastiani, Paolino et al., 1982). A review of the effect of bilateral lesion of the auditory cortex on the long-latency auditory EP components was presented by Woods, Clayworth, Knight et al. (1987). In some cases, responses were reduced or abolished whereas in other cases they were unaffected. The authors noted that the infarction responsible for bilateral lesion of the superior temporal plane commonly extends outside the auditory cortex. They proposed that abnormalities in middle- and long-latency auditory EPs do not reflect damage to primary auditory cortex per se, but rather the degree of damage of adjacent regions. Abnormalities in the middlelatency component would be associated with subcortical lesions; abnormalities in the longlatency component would reflect lesions extending to the multi-modal areas of the inferior parietal lobule. To investigate verbal information processing, the relevant wave is N400, associated with semantic evaluation of congruity between verbal stimuli and their context. As already mentioned, this late component appeared to be abnormal in dyslexic children with learning disorders. An example of dissociation between brain activity (N400) and behavioural response was shown in a case of global aphasia (Revonsuo &

Laine, 1996). Congruous and incongruous words were given at the end of a sentence. Normal N400 variations were recorded as a function of congruity (i.e., N400 was more negative to incongruous final words). On the contrary, the patient’s performance was at the chance level. This finding suggests that implicit semantic activation of the conceptual level can take place even in the absence of conscious, explicit comprehension of the meaningfulness of linguistic stimuli. The difference between the two hemispheres in processing semantic properties of verbal information emerged in comparing two groups of patients, one with left hemisphere lesions and aphasia, and the other with right hemisphere lesions without aphasia (Hagoort, Brown, & Swaab, 1996). Pairs of words were auditorily presented: some were unrelated, some belonged to the same semantic category (e.g. church-villa) and some were associatively related (e.g. bread-butter). The latter relationship is the closest. In control subjects, N400 amplitudes varied as a function of the distance between the words in a pair; unrelated words produced the largest N400 effect. As expected, the size of this effect on N400 was reduced in left-injured patients with severe aphasia. In right-injured patients, N400 effect was normal for associative pairs, while a trend in amplitude reduction was observed for semantic pairs. This suggests that the right hemisphere is involved in processing of semantically distant relationships between words. In addition to N400, other ERP components, such as MMN and P300, have been studied in patients with language disorders. For example, MMN was investigated during vowel processing in aphasics with anterior and posterior lesions. The component was found to be absent in the case of posterior lesions and normal in the case of anterior lesions. Overall, the left temporo-parietal area seems to be crucial for vowel discrimination (Aaltonen, Tuomainen, Laine et al., 1993). In a study of P300 component it was shown that P300 to positive probes was altered in patients with conduction aphasia and severe deficit in verbal short-term memory, particularly for auditory stimuli. On the other hand, morphology and latency of P300 recorded in a

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classic oddball task were normal. The authors suggested that the disorder in conduction aphasia is one of memory rather than response selection (Starr & Barrett, 1987). Disorders in visual information processing and visual perception Integrity of retinal function is investigated by means of ERG, while the integrity of visual pathway and early cortical processing is based on the evaluation of P100 component or on steady-state VEPs. Typically, in hemianopic subjects, the stimuli presented to the blind hemifield do not produce activity. Different patterns of results were reported in cases of “blindsight”, cortical blindness, and residual vision. In one case of “blindsight”, PI 00 to target stimuli in the blind hemifield was absent, while the late component P300 was present. It was proposed that stimuli presented to the blind field activate associative cerebral areas through pathways different from geniculo-striate ones (Shefrin, Goodin, & Aminoff, 1988). In patients with cortical blindness due to bilateral damage of occipital lobes a dissociation was found where EPs were normal, at least in some experimental conditions, in the total absence of vision. The analysis of cerebral blood flow in these patients suggested that visual EPs were due to the activity of small spared regions of area 17: the larger these spared portions of visual cortex were, the more reliable were the EPs. Moreover, residual vision was present in patients when the spared portion of area 17 was large enough. It was proposed that “blindsight”, like residual vision, could be due to small spared portions of area 17, rather than to the contribution of the extrastriate visual system (Celesia, Bushnell, Cone Toleikis et al., 1991). Recently, ffytche, Guy, and Zeki (1996) studied a patient with residual vision. The lesion involved most of the striate cortex of one hemisphere, leading to homonymous hemianopia. An earlier PET study (Barbur, Watson, Frackowiak et al., 1993) showed that when the subject was aware of a moving stimulus in the blind hemifield, V5 area was active. Moreover, high-speed moving stimuli could be detected better than slow-moving stimuli. In the

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electrophy siological study, EPs were recorded from stimuli presented in the blind hemifield. The speed of the stimulus was critical. At low velocity, EPs were absent and the subject did not perceive the stimulus; at high velocity, EPs were present and the subject could discriminate stimulus onset and direction of motion. Moreover, the use of anatomical MRI data for precise localisation of the electrodes confirmed previous PET data: the signals were not generated in area V I, but in V5. The conclusion of this work is that in this patient conscious experience was correlated with electrical activity in V5. The presence of parallel pathways specialised for fast motion to areas V 1 and V5 was also confirmed in a study based on EP, MEG, and PET data on normal subjects showing that signals evoked by fast-moving stimuli are present in V5 before V 1 (ffytche, Guy, & Zeki, 1995). Another neuropsychological disorder investigated by recording brain electrical activity is prosopagnosia. Small (1988) reported that ERPs for faces recorded over both hemispheres were normal, while P I00 latency to checkerboards was longer over the right hemisphere. These results suggested a deficit in sensory processing rather than a specific defect in face processing. Renault, Signoret, Debruille et al. (1989) found a variation of P300 in relation to face familiarity. In the experiment, known and unknown faces were presented in two different probability conditions (familiar faces were presented with the probability of 33% and 50% respectively). Although faces were not recognised, P300 amplitude for known faces varied as a function of the probability of presentation. Moreover, the latency was longer for familiar than for unfamiliar faces, and even longer for relatives’ faces and the patient’s own face, suggesting slower processing. Electrophysiological data were interpreted as an index of covert recognition in the absence of overt behavioural recognition. In cases of visual agnosia, dissociation between electrophysiological data and perception have also been reported: patients could not recognize visual stimuli, but EPs could be recorded (Bodis-Wollner, Atkin, Raab et al., 1977; Celesia, Archer, Kuroiwa et al., 1980; Kooi & Sharbrough, 1966; Onofrj, Fulgente, & Thomas, 1995; Spehlmann, Gross, Ho et al., 1977).

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Disorders in attention Much work on attention in patients with brain lesions has been carried out by Knight and coworkers. A part of this research, on the modulatory role of the frontal area on sensory processing, has already been summarised in the previous section. Disorders in sustained focused attention and disorders in phasic attention have to be distinguished. The Nd component is the index of sustained attention directed towards a stimulus coming from a given channel, i.e. from one of the two ears or the two limbs, or from one of the two visual hemifields. The presence of Nd is correlated with improvement of performance for that channel. A remarkable difference is shown in cases of left or right brain damage. Patients with focal damage to the dorsolateral frontal right cortex did not exhibit the Nd component to contralesional ear stimuli in a task of sustained attention. The electrophysiological impairment is associated with the behavioural deficit. On the contrary, patients with left frontal lesions do not show any Nd abnormality either to left or right ear attended stimuli and they do not have any behavioural deficit (Knight, Hillyard, Woods et al., 1981). Thus, ERPs in patients support the hypothesis that Nd is the index of focused attention. Frontal lobes are thought to make an important contribution to the production of this component. Moreover, results are in agreement with neuropsychological data on the asymmetry of effects of right and left lesions in human subjects as regards attentional mechanisms (Knight, 1991). The hypothesis that frontal lobes are important for orienting attention is confirmed by data on another ERP component. The MMN component (produced by deviant tones, to which subjects— engaged in another cognitive activity—were not to pay attention) was found to be reduced in patients with frontal lesions, especially in recordings from the injured hemisphere and for deviant tones presented to the ipsilesional ear (Alho et al., 1994). As regards phasic attention, the subcomponents P3b, related to voluntary attention, and P3a, index of automatic involuntary attention, should be considered. As already described in the previous section on dissociation of components, P3b was normal in patients with prefrontal damage (Knight, 1984), although it was absent in patients with

parieto-temporal damage (Knight et al., 1989b; Yamaguchi & Knight, 1990). However, P3a was reduced in both groups of patients. Thus, the response to stimulus novelty is widely distributed in the brain, although a crucial role seems to be played by the hippocampal region. According to Knight (1996), the possible role of this region may be to maintain a template of the recent past for comparison with incoming sensory information. Hemispheric asymmetry for control of spatial attention was also shown by recordings in one splitbrain patient. Shorter RTs and larger P300 potentials to stimuli falling in the rightmost space were observed; further, the right hemisphere, unlike the left hemisphere, gives P3b responses of about the same magnitude to stimuli falling in either visual hemifield (Proverbio, Zani, Gazzaniga et al., 1994). Overall, ERP data support the view that the right hemisphere has bilateral control of visual space, while in the left hemisphere control is restricted to the contralateral space (Kinsboume, 1987). Visual agnosia restricted to one hemispace (generally the left one) is typical of patients with unilateral spatial neglect. In this case a dissociation between electrophysiological data and perception was shown: the EP exogenous component (PI00 ) to stimuli presented in the left hemifield was normal, while perception was absent (Vallar, Sandroni, Rusconi et al., 1991). On the other hand, the endogenous component P300 appears to be altered for stimuli generated in the neglected hemifield, at least for the visual modality (Lhermitte, Turell, Le Brigand et al., 1985). These data support the interpretation of neglect as a disorder that concerns exclusively the postsensory level (see also Garcia-Larrea, Brousolle, Gravejat et al., 1996, for a study on “Parkinson’s neglect”). On the contrary, other works have found abnormalities in steady-state visual EPs that indicate the presence of disorders also at sensory levels (Angelelli, De Luca, & Spinelli, 1996; Spinelli, Burr, & Morrone, 1994; Viggiano, Spinelli, & Mecacci, 1995). In particular, EPs to stimuli presented in the neglected hemifield had latencies longer than EPs to ipsilesional stimuli. Other studies showed that manipulation of both visual stimulus properties (luminance and contrast) and subject condition (head-trunk rotation) had a

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similar effect on performance and EP quality (Doricchi, Angelelli, De Luca et al., 1996; Spinelli & Di Russo, 1996). In particular, the longer latencies to stimuli in the neglected hemifield were present only to luminance stimuli, while they were absent for equiluminant stimuli, that is, chromatic patterns (Spinelli, Angelelli, De Luca et al., 1996). These data supported the proposal that the delay of EPs to contralesional stimuli might result from disruption of the fast response of the magnocellular pathway, not active in the case of isoluminant stimuli. As anatomical damage to the occipital lobes of patients could be excluded in many cases, it was suggested that changes in the top-down modulation of the higher cortical centre on the occipital lobes might be responsible for the phenomenon (Spinelli et al., 1996). Disorders in memory In patients with memory disorders the positive late component P300 (with a peak of450-600msec) has been mostly investigated. For instance, the P3 amplitude was decreased compared to controls when patients with disorders in recent memory were engaged in phonemic and semantic processing of spoken words. On the other hand, in the same patients, the P3 evoked by tones during a tone discrimination task was normal. Therefore, the P3 components elicited by tonal and verbal discriminations may reflect different neural processes and may be differentially affected by the memory disturbances. The abnormalities of P3 suggested a failure of elaboration of the stimuli that might cause an encoding disorder (Meador, Hammond, Loring et al., 1987). In normal subjects, there is a large effect of word repetition: P3 evoked by repeated words is more positive-going than that evoked by non-repeated words. In patients with a verbal memory deficit following left temporal lobectomy this repetition effect was eliminated (Smith & Halgren, 1989). Right temporal lobectomy did not affect the repetition effect on ERP (Smith & Halgren, 1989). However, in patients with damage in the right parahippocampal and lingual gyri, extending to posterior hippocampus and occipital cortex, the repetition effect was eliminated (Swick & Knight, 1995).

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Auditory ERP abnormalities were observed in amnesic patients. Abnormalities of P3 were related to dipole orientation (rather than dipole strength) and were present only when lesions involved the hippocampus (O’Donnel, Cohen, Hokama et al., 1993). Abnormal topography of P3 was reported also by Onofrj, Fulgente, Nobilio et al. (1992) in patients with bilateral temporal lobe lesions and amnesia. On the other hand, Rugg, Pickles, Potter et al. (1991) did not find any modification of P300 in one patient with a severe disorder in verbal longterm memory due to extensive damage to the left medial temporal lobe. Discrepancy between results might be due to different etiology of the brain damage. Polich and Squire (1993) studied a relatively large group of amnesic patients with bilateral hippocampal lesions using the same paradigm. P3 component evoked by targets was of smaller amplitude and longer latency than in control subjects. However, the component was identifiable, indicating that the hippocampus is not the major source of P3b. This was confirmed by recent work: the posterior scalp P3b was not affected by hippocampal lesions while P3a was specifically reduced (Knight, 1996).

Monitoring and prognosis by means of EP and ERP techniques EPs and ERPs may represent a useful technique for prognosis and for monitoring the course of patients’ illnesses. For instance, follow-up with somatosensory EPs in cases of stroke and cerebral ischaemia is a good diagnostic tool for measuring the evolution of the cerebral dysfunction (de Weerd, Looijenga, Veldhuizen et al., 1985). The presence or absence of somatosensory ERPs has been used as a prognostic criterion in patients with heminattention (Ring & Finnegan, 1989). The prognostic reliability of brainstem, somatosensory, and visual EPs has been assessed in closed-head injury patients (e.g. Anderson, Bundlie & Rockswold, 1984; Campbell, Suffield, Deacon et al., 1987). Other examples of application are the monitoring of individuals at risk for cognitive dysfunctions, such as in the case of pre-term newborns (Kurtzberg & Vaughan, 1986), or

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children whose neurological evaluation at birth is below normal (De Sonneville, Visser, & Njiokiktjien, 1989). EPs may also be used for monitoring treatment effects. For instance, performance improvement in a selective attention task in patients submitted to rehabilitative treatment has been associated with changes in the N200 component (Baribeau, Ethier, & Braun, 1989). Predictive capacities improve if a high number of electrodes are used (e.g. in patients with closedhead injuries: Thatcher, Cantor, McAlaster et al., 1991).

Brain mapping The technique is based on recording electrical brain activity with a large number of electrodes. When the number of electrodes increases, data analysis is very complex and computerised programs are necessary. A development of the technique is the topographical description of the EEG or EPs or ERPs recorded on the scalp. Very high numbers of electrodes are used (21,32,64, or more); the recorded activity is stored with a high-capacity device and processed. At each time each electrode gives a data point; interpolation methods are used to estimate the electrical potential values at scalp locations between actual recording sites (generally between four electrodes). A topographic map is created, where voltage values, measured and interpolated, are transformed into colours, according to a colour code. The same colour is attributed to areas with the same voltage. Other ways of presenting such a large amount of information are grey scale, contour maps with isopotential lines (e.g. Ragot & Remond, 1978), and three-dimensional head models with spherical interpolation (spline map topography; e.g. Perrin, Pernier, Bertrand et al., 1987). In any case, the topographic map represents the voltage distribution on the scalp at a given instant in time. Besides the description of voltage distribution, another type of topographical analysis is the current source density (CSD), which estimates the head ingoing and outgoing current flow (e.g. Pernier, Perrin, & Bertrand, 1988). The description of the relation of ERPs recorded at different scalp locations may help to understand the functional coordination between different brain

areas. There are various measurements of the similarity (or interdependence) between the activity at the various electrodes, for instance the correlation (e.g. Gevin, 1987) and the covariance (e.g. Gevin, Bressler, Morgan etal., 1989). One of the main goals of EP or ERP studies is to localise the sources of the electric waves. The problem is to compute the equivalent brain sources from the voltage difference measured at the scalp. The method is based on two assumptions. The head is modelled as a spherical volume, and the sources are modelled as equivalent dipoles. Source estimation calculates the location, strength, and direction of the dipoles. Two methods are used for transforming scalp-recorded brain activity in brain source imaging: the single-timepoint and spatio-temporal methods. In the first case, which is more diffuse, dipoles are computed at a single instant of time. In the spatio-temporal case, two kinds of images are computed. One is related to the spatial image of the discrete multiple sources and the other is related to the temporal image of a source current waveform reflecting the time course of the local activity in circumscribed brain areas (e.g. Sherg & Ebersole, 1993). Thus, the localisation and the time course of the neuronal generators are estimated using a method that combines topographic profile analysis and spatio-temporal source analysis (brain electrical source analysis, BESA by Berg & Sherg, 1990). The temporal accuracy of the technique is very high and the poor spatial accuracy has been improved by these recent methods. Further improvement may be obtained by associating electrophysiological data with individual anatomical data (from MRI) and with magnetoencephalographic technique, which is peculiarly sensitive to tangentially oriented dipoles and, unlike EEG, is blind to the effects of the extracerebral layers (skull, meninges etc.; see for a review Hari, 1996).

Intracranial stimulation and recording In some clinical cases (e.g. surgically treated epilepsy) electrical stimulation of cortical regions and/or recording with surface or deep electrodes is performed. These experiments provide more direct information about brain electrical activity than EPs

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recorded on the scalp (limited by the fact that placement of intracranial electrodes is determined by clinical necessity). The specialisation of one cortical region for a specific stimulus can be tested. For instance, specific waves in response to faces have been recorded in small regions of the fusiform gyrus and inferior temporal gyrus. Electrical stimulation of the same regions produced temporary impairment in naming faces. Interestingly, individual differences in the localisation of these areas were evident (Allison, Ginter, McCarty et al., 1994). Different responses for familiar and unfamiliar faces were recorded in amygdala, hippocampus, and temporal lobes, showing that limbic and temporal structures are involved in recognising the familiarity of faces (Seek, Mainwaring, Ives et al., 1993). More complex processing (e.g. memory functions) can only be studied by intracranial recording. For instance, it was shown that the posterior temporal cortex is specifically involved in short-term processing, whereas the amygdala, hippocampus, and anterior temporal cortex are involved in both short-term and long-term memory (Guillem, N’Kaoua, Rougier et al., 1996). ERP sources have been investigated by intracerebral studies. For instance, it was found that the intracranial recordings associated with the scalp P3 were widely distributed in the brain (Wood, Allison, Goff et al., 1980). The presence of large potentials, showing polarity reversal during oddball tasks which evoke P3 at the scalp, were observed in association with changes in unit activities in the medial temporal lobe (e.g. Stapleton & Halgren, 1987). The hippocampal region involvement in P3 generation has also been shown (McCarthy, Wood, Williamson et al., 1989; Smith, Halgren, Sokolik et al., 1990).

Transcranial electromagnetic stimulation Magnetic stimulation is a new and safe method of interfering with brain activity in humans. The technique, developed in the 1980s (Barker, Jalinous, Freenston et al., 1985) is noninvasive and is based on the application of a brief and strong magnetic field to a specific region of the subject’s head. The induced electric current crosses the scalp, the skull, and the meninges with minimal activation of the

pain receptors and transiently blocks the function of cortical neurones (for details see Wasserman, Grafman, Berry et al., 1996). Magnetic stimulation of brain (and spinal roots) have been widely used to study the motor cortex and nervous propagation in various neurological diseases, and to describe the reorganisation of neural connections after brain damage (for a review see Rossini & Rossi, 1997). Moreover, transcranial stimulation has been used to study other brain functions, such as visual perception (Amassian, Cracco, Maccabee et al., 1989), language (Pascual-Leone, Gates, & Dhuna, 1991), attention (Pascual-Leone, Gomez-Tortosa, Grafman et al., 1994), and memory (Grafman, Pascual-Leone, Alway et al., 1994). In all cases magnetic stimulation temporarily inactivates the cortical region to which it is applied, confirming the functional role played by that area. Thus, according to the site of application, it produces suppression of visual perception (occipital cortex), suppression of colour perception (occipital-temporal areas), speech arrest (left temporal lobes), neglect (right parietal lobe), or recall deficits (left mid-temporal and bilateral dorsofrontal lobes). Recently, magnetic stimulation has been also applied to the left prefrontal cortex, showing effects on mood regulation (Pascual-Leone, Catala, & Pascual-Leone, 1996).

Magnetoencephalography (MEG) Brain electrical activity produces a magnetic field that can be measured close to the head by means of a special recording system. Magnetoencephalography (MEG) measures the spontaneous variations of this magnetic field in time, while the Evoked Fields represent the MEG variations with respect to an external stimulus. Waves of Evoked Fields are indicated by the same label used for Evoked Potentials, followed by an m; for example, MMNm is the magnetic counterpart of the mismatch negativity. This technique, used for the first time by Cohen (1968), is very complex from a technical point of view; it is sensitive only to events that take place near the scalp, but is noninvasive and has a better capacity for spatial localisation than EEG (of the order of 2-3mm), at a parity of temporal resolution.

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On the other hand, EEG may show currents that are not visible for the magnetometer because they originate in too deep portions of the brain or have a radial direction. Thus, the simultaneous recording of EEG and MEG might be useful. MEG reliability has improved through the use of new detector devices. Biomagnetic signals have to be extracted from noise. To increase the signal to noise ratio, evoked signals are averaged and filtered. Multichannel recording developed from single channel recording, with detector devices distributed on the scalp surface, in order to record the whole distribution of the brain magnetic field (helmet or whole-head systems). Spatial resolution is a function of the number of sensors. Data from the various channels are integrated to build up the spatial distribution of the magnetic field, as in electric brain mapping. The intensity, position, and direction of the source or sources are then calculated on the basis of the dipole (or multidipole) fitting algorithm and spherical head model (Romani & Rossini, 1988). To localise sources accurately, individual brain anatomical data are necessary; these can be obtained through brain imaging techniques such as MRI, which provide excellent spatial resolution. A review by Naatanen, Ilmoniemi, and Alho (1994) shows the value and results of the MEG technique and underlines the advantages offered by the simultaneous use of MEG (to improve the localisation of generators) and EEG (to detect activities not revealed at the magnetic level), as well as the opportunity to associate these techniques with neuroimaging ones (PET and fNMR). MEG has been applied in topographic studies of brain activity. The retinotopic map of the occipital lobes (Ahlfors, Ilmoniemi, & Hamalainen, 1992), the tonotopic organisation of the auditory cortex (Romani, Williamson, & Kaufman, 1982), and the somatotopic organisation of the somatosensory cortex (Okada, Tanenbaum, Williamson et al., 1984) have been described. MEG has also been applied to the study of cognitive components, generally with localisation aims. For instance, the auditory cortex was found to generate both Ndm in attention experiments (e.g. Arthur, Lewis, Medwick et al., 1991; Woldorff, Gallen, Scott et al., 1993) and MMNm evoked by

pitch deviant stimuli (Tiitinen, Alho, Huotilainen et al., 1993). The primary auditory cortex was found to offer the neural basis of the echoic memory, as measured by N lm characteristics (Lu, Williamson, & Kaufman, 1992), and languagespecific memory traces were localised in the left auditory cortex through the MMN paradigm (Naatanen, Lehtokoski, Lennes et al., 1997). Moreover, short-term brain plasticity phenomena have been documented (Rossini, Martino, Narici et al., 1994). An interesting example of application of MEG to neuropsychological problems can be found in the study of dyslexia. Different time courses of cortical activation were found in dyslexics and control subjects during passive viewing of words briefly presented. The maximal difference was localised in the left temporo-occipital region which was not activated (or was activated later) in dyslexics, while a sharp firing was displayed at about 180msec following word presentation in controls. This supports the view that perception of a word as a single unit is impaired in dyslexics. On the other hand, dyslexics showed, earlier than controls, an activation of the left inferior frontal lobe which is involved in the silent noun generation task. This suggests that dyslexics use a different processing system in reading (Salmelin, Service, Kiesila et al., 1996). The number of studies using MEG in neuropsychological patients is low at present, probably because there are few hospitals equipped with this instrument. Studies should increase following the spread of whole-head MEG systems in research and clinical departments devoted to functional brain imaging.

Summary The recording of sensory EPs is routinely used in clinical research to investigate all sensory modalities. Broad experience ensures high reliability of results obtained with this technique. For this reason, one of the most interesting contributions of EP recording to neuropsychology is probably that of assessing the presence/absence of deficits at a sensory level, dissociating pure cognitive disturbances from impairment due, at least in part, to sensory disorders.

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On the other hand, ERPs also offer the possibility of detecting specific impairments at different levels of cognitive processing (e.g. attention, memory, semantic analysis, etc.) or in different aspects of a cognitive function (e.g. sustained and phasic attention). This approach represents a promising prospect for neuropsychology. However, in some cases, results show considerable variability. This is probably due to the great difference in the nature and extent of brain damage, which may have highly differentiated effects on ERP morphology. The association of electrophysiological recordings with the new

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imaging techniques more accurately assessing brain damage could reduce this variability in the future. At present, EPs and ERPs are the most powerful method for tapping the timing of sensory and cognitive processing. On the other hand they have poor spatial resolution. The systematic association of electrical brain recording with anatomical and functional neuroimaging techniques may lead to a more powerful spatio-temporal description of brain activity. Finally, the potential value of ERPs in prognosis and monitoring, both in patients and in individuals at risk, should be underlined.

Taylor & Francis Taylor & Francis Group http://taylorandfrancis.com

4 The Evaluation of Experimental Data in Neuropsychology Erminio Capitani and Marcella Laiacona

2. Sampling, i.e. how many experimental units are needed and how we can sample them in order to obtain results of general validity.

INTRODUCTION

Psychometric data may be collected for prognostic, diagnostic, or research use (Cronbach, 1949). For prognostic (or predictive) use, it is not necessary to study the factors behind the score obtained, as only this latter is used for predicting other variables (e.g. the capacity for some task or professional duty). However, the aim of a neuropsychologist is often to discover what lies behind a given behaviour, and to verify if, among the causative factors, there is a disease present. Moreover, neuropsychological scores are increasingly considered as the measure of clinical trials, both when treatment is psychological, as in language rehabilitation, and when it is pharmacological, as in the drug therapy of dementia. Before discussing some of the problems encountered in clinical practice, it might be useful to elucidate two preliminary aspects:

Thereafter we shall review some common problems in the analysis of data, with special reference to the diagnostic process, experimental designs in clinical trials, and some new approaches to statistical analysis.

MEASUREMENT

Objects and processes

Psychometric scores may have different relationships with the underlying psychological reality. Following the standard approach, we can assume either (a) that this relationship is deterministic, in analogy with the mathematical concept of "function": the underlying psychological variable is an object that determines the expected value of the measure. Due to the faulty reliability of the measure, to this value should be added a variable error (with an expected value of

1. The measurement process, i.e. the relationship between the underlying ability and its actual measure. 57

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zero), which causes the inconsistency among repeated measures of the same subject. Alternatively (b) we may conceive the underlying psychological reality as a process ruled by probabilistic laws. An example is the actual retrieval of a word from the phonological lexicon, after a process of research, which at each subsequent trial may be successful or not (Faglioni & Botti, 1993). In this case, the variability among the different trials carried out by the same subject simply derives from the probabilistic nature of the phenomenon. The classical psychometric theory conforms to the former approach. The latter approach is a more recent one, and applies well to the study of certain processes, such as learning and forgetting. Probabilistic models allow us to estimate the parameters corresponding to different stages of the underlying psychological process, and will be discussed later in this chapter. We will now discuss some aspects of the classical approach that are relevant for the neuropsychologist.

Problems concerning measurement scale Measurement signifies mapping from the values of an underlying variable (that may be very complex) to a simpler measurement variable (a digit or a label). The general problem of measurement (e.g. Narens & Luce, 1986) is to define the function that associates the measure with what is measured (which we will hereafter call the object or ability). According to Stevens (1946) and subsequent authors (e.g. Suppes & Zinnes, 1963), numbers are assigned to objects, so that the interesting empirical relationships among the objects should be reflected in the numbers that express their measure. These numbers lie on a scale endowed with certain properties; we should ascertain what these properties are in order to know whether a given statistical analysis is allowed. Stevens maintains that the admissible statistical processing also depends on the properties of the measurement function, and not only on the distribution of the collected data and on other statistical considerations. This limitation, (generally recognised by many scholarly textbooks of statistics, e.g. Siegel, 1956), has led several researchers to confine themselves to the so-called

“non-parametric” methods, given that measures have only ordinal scale properties. According to the classical system of classification, measurement scales are of four types: nominal, ordinal, interval, and rational, (i) In nominal scales, numbers are simply labels or names (e.g. the numbers on football players’ jerseys), (ii) With ordinal scales, measures have an intrinsic quantitative value and can be arranged in increasing or decreasing order. However, let us suppose that the same interval separates different measures (e.g. 5 is the difference between scores of 15 and 10, but also of 25 and 20). With the ordinal scale we cannot be sure that equal differences in scores reflect equal differences between the underlying abilities. It follows that, if the average measure of two groups is the same, the means of the underlying abilities need not be the same. Therefore, all the statistics and operations based on the arithmetical mean will not be allowed, and we should restrict ourselves to nonparametric statistics or to the analysis of frequency tables, (iii) When equal intervals between the measures imply equal intervals between the objects, the scale has an interval property: we can resort to statistics based on arithmetical mean, such as the analysis of variance and related procedures, (iv) The limitation of interval scales is that the origin of the scale does not correspond to a true absence of the object; this latter property only applies to physical or time scales, which are defined “rational scales”. Only with rational scales does the ratio between different measures correspond exactly to the ratio between the underlying objects. These points were first criticised in a delightful and provocative paper by Lord (1953), and more recently by other authors whose positions are summarised by Gaito (1980) and Michell (1986). In short, numbers resulting from a measurement process would become in some sense independent from the underlying objects, (“the numbers do not know where they come from”) and the measurement scale limitation should not influence the statistical analysis of data. Other authors (e.g. E.W. Adams et al., 1965) support in general Stevens’ statement, but consider psychological tests as a special case. It is extremely difficult to decide if a scale has an interval property. In the psychological and still more in the neuropsychological field, the

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underlying objects can be known only through other measures to which exactly the same problems apply. Moreover, most tests are designed with questions or sets of questions of increasing difficulty. With such tests, not only is the interval property in doubt but, strictly speaking, so is the ordinal one (Michell, 1986). We believe that the ultimate choice of whether or not to use parametric methods should be left to the researcher. When constructing a new test, one should empirically optimise its scale properties, but even if the interval properties are not known with certainty, in our opinion, the analysis of data by means of parametric methods may be allowed, if the other statistical conditions permit their use. As a matter of fact a deviation from the interval property could, by chance, favour one of the experimental groups and give rise to possible biases. However, this likelihood is evenly distributed among the groups and is a matter of chance. In the comparison among groups, biases arising from a faulty knowledge of the scale properties may introduce a further source of statistical error (whose expected value is zero) that can mask the systematic effects and their experimental transparency. The effect is, as with low reliability, to lower the power of the experiment rather than impair its protection against type I errors. Accordingly, the differences actually observed largely retain their significance. Other problems of relevance to neuropsychology are the intrinsic restrictions of scores that are upper- and lower-limited. For instance, we cannot conclude that two groups present deficits of equal severity when both average scores fall near to zero. Another constraint concerns the comparison among different tests whose scores have been standardised on the basis of the mean and standard deviation (SD). With the common standardisation procedure (difference from the mean in SD units) the standard scores are also often upper- or lowerlimited. For instance, if in a given test the mean is 7 and the SD 4, it is not possible to achieve a standard score lower than (0 - 7)/4 , i.e. -1.75; whereas in a different test with mean 13 and SD 4, the poorest subjects could get a standard score of (0 - 1 3)/4, i.e. = -3.25. It would be obviously wrong to conclude that the standard score o f-1.75 in the former test is better than the score o f-3.25 in the latter; a similar

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argument applies to top scores. This can be a source of biases when the qualitative diagnosis in a given patient is based on a comparison among different tasks. The combination of the asymmetrical distribution shape with the closed scale can give rise to a biased prevalence of some types of diagnosis. Experiments affected by such biases are studies of the parallelism of the multivariate profiles between a group of severe patients (e.g. suffering from Alzheimer’s disease) and a group of less severe patients. We may be interested to verify whether the two groups are wrong on the same tasks, although at different levels of severity. The profile of Alzheimer patients may depend on the present availability of a scale of sufficient extent, and the profile may be artifactual if this space does not coincide in the different tests. Upper and lower limits of the scale also influence the dispersion of the scores. For instance, if we want to verify the hypothesis of an increasing variability of the scores with age (Rabbitt, 1981), we could artifactually observe the opposite pattern: with a closed scale test, the performances of elderly subjects could be flattened around zero (with a consequent low variability), if the test is very difficult for old subjects.

Measurement errors and reliability The theory of measurement errors has been widely studied and is discussed in standard textbooks of psychometrics (e.g. Lord & Novick, 1968). We will consider here only variable errors, that arise from random inaccuracies due to many causes. The expected value of variable errors is zero for each observer and subject, and variable errors constitute a kind of “background noise” of the measurement: test reliability is the relative freedom from variable errors. We can evaluate reliability in different ways (Guilford, 1965; Gulliksen, 1987; Helmstadter, 1966; Lord & Novick, 1968): most of the methods derive from correlation assessments between two measurements of the same subject. After having estimated the reliability, which ranges between 0 and 1, we should evaluate whether it is satisfactory. In brain-damaged patients a low consistency between two subsequent examinations could arise from fluctuations in the underlying ability; for this reason it is better to evaluate the reliability with

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normal subjects, even if the regions of the scale that are tested in the two samples may be different. The reliability can be measured against a fixed reference, considered the minimal acceptable level (e.g. 0.60 or 0.70), but this approach is not entirely satisfactory. The classical psychometric theory (e.g. Gulliksen, 1987) studies the relationship between the test reliability, the score variability between subjects, and the confidence limits of the true score o f a single subject. On this basis, we can compute the confidence limits of the true score of each subject, with a controlled risk. If a test is imperfectly reliable, but its variability between subjects is low, the confidence limits of the true score and of the underlying object variable may be still acceptable for clinical use. The combined use of a statistical consideration (the correlation between two measures) and of a metric consideration (the range of the object variability) is of more general interest. Sometimes the statistical significance is wrongly interpreted as implying a relevant and meaningful difference between the underlying objects. This is not always true: when the variability is very low, there can be significant effects even when the difference between the objects, although systematic, is quite negligible in practice. In some experiments, particularly in clinical trials, the discussion of this point probably tends to be overlooked. For a further discussion of this subject, the reader is referred to Wilcox (1987). The importance of considering reliability in aphasia diagnosis is widely discussed by Willmes (1985). Finally, it has been shown (Chapman & Chapman, 1973) that, in studies involving tests of differing reliability, the most reliable test can disclose a greater impairment than the others. This could introduce a further bias in the comparison of different tests in a group of braindamaged patients.

SAMPLING: GROUP VS. SINGLE CASE STUDIES Quantitative and qualitative problems In the last few decades group studies have been a standard practice in neuropsychology. This is

largely due to the fact that single performances, besides including systematic effects, are also influenced by some random components whose expected value (their hypothetical mean) is zero. The analogy with what was said concerning measurement and reliability is evident. Very recently, however, the use of group studies has been criticised as inappropriate for testing finergrained hypotheses about the structure of the cognitive system. It has been claimed that defects presented by the subjects of the group under scrutiny may not be homogeneous. Consequently, averaging over the group cannot provide useful information, as no “systematic effects” are shared by the subjects. Accordingly, only single case studies (or at least “multiple-single-cases” studies) are considered informative. This debate is treated elsewhere in this book and is well represented in the recent literature. However, it should be borne in mind that, even for single case studies, there are substantial statistical problems concerning the reliability and comparability of different tasks. We discuss this point later. In some experimental situations, group studies cannot be disposed of, e.g. the construction of diagnostic tools and clinical trials. In group studies, there are several criteria for choosing the sample size: 1. The representative criterion: at least p% of the population, with a controlled risk, should be included between the extremes observed in the sample. This size is best ascertained through non-parametric tolerance limits, as reported by several authors (e.g. Ackermann, 1985; Gibbons & Natrella, 1966; Owen, 1982). Normative studies, where the extreme observations are the main interest, generally conform to this criterion. To correctly estimate the outer values of a distribution, as a general rule, samples of considerable size are needed. As an example, at least 93 subjects are needed if we want at least 95% of the population to be included between the extremes of the sample with a 5% error risk. 2. The need for fair protection and a sufficient power in the statistical analysis of the experiment. Here we should evaluate and check the power of the experiment, i.e. the risk of a

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type II error (the missed detection in the sample of differences existing in the population). In some instances, the experimenter can estimate a priori the power of the comparison on the basis of the number of subjects, the desired protection against type I error, and the size of the differences considered interesting. A more extensive presentation of this subject is found in Cohen (1988) and in Wilcox (1987). However, studies with brain-injured patients are faced with further problems and peculiar restrictions, which also concern the qualitative aspects of the sample: 1. Subjects sampled in experimental studies are often different with respect to age, education, and length and severity of disease, and these variables can influence performance. Therefore, big samples and specific statistics are needed in order to rule out the influence of unbalanced concomitant variables. 2. Samples may be unrepresentative because of selection, and in studies aimed at comparing the severity of different groups we must be sure that the most severe subjects of each group have not been excluded. This can be done as follows: (i) Sampling a continuous series of patients. We should register the dropouts (due to death, or the fact that they were too severe to be tested) and compare their incidence among groups. If the percentage of dropouts is higher in a given group and this group is performing better, such an outcome could be artifactual. The same could be possible in experiments where groups are performing at the same level, but with a different dropout rate. (ii) The source from which patients are sampled should be homogeneous. Mixed recruitment is dangerous. Concerning in-patients and out-patients, for instance, the former are generally more severe at onset, but are less selected with respect to their prognosis; regarding the latter, the length of illness is greater and sometimes patients are sampled as out-patients because they did not recover in the early stages of illness. If the sampling

is mixed, subjects with a greater length of illness may have, on the whole, more severe brain damage. Further sampling problems concern longitudinal surveys, such as the study of improvement of an acute illness or of the worsening of a progressive pathology. If the aim is to individuate which variables influence improvement (e.g. rehabilitation) or decline (e.g. the onset age of Alzheimer’s disease), we should consider that in their evolution subjects start from different baselines. To compare their follow-up, we should assume (a) that the scale of the scores has the interval property, and (b) that each subject should have the real possibility to change his/her score, especially if the scale is upper-limited and a subject starts with a rather high score (being only slightly damaged). In a strict sense, the upper limit of recovery is the premorbid (unknown) level, which could be as low as the mere normality threshold. In this case, the difference between the first and the second examination of a moderately impaired subject who recovers could be similar to that of a subject who starts from a much lower score but improves little. This point would make it problematic in evolutive studies to consider all the originally observed subjects. It would be better to take into account only subjects with a given degree of severity. This selection limits the generality of the results, in as much as they are restricted to a subgroup of the former sample. A remedy for this problem is to match subjects for initial severity in the different treatments of the trial. We need to split the possible initial scores into different regions, and, within each region, to randomly assign the subjects to different treatments according the usual rules of experimental designs. The onset severity bias may affect the comparison of different groups (e.g. left and right brain-damaged patients, or amnesic and demented patients): left brain-damaged patients are generally seen earlier by a doctor, because language may be impaired, sometimes even after a very small lesion; right brain-damaged patients may be less disturbed by small lesions and may not want to see a doctor, also because of the greater frequency of anosognosia.

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In addition to the choice of the group (or groups) of brain-damaged patients on which to verify the experimental hypothesis, we generally need a control group. This can consist of: (a) normal subjects, in order to get norms for a diagnostic approach to single patients; (b) patients not affected by cerebral damage, in order to see, with group studies, if a given task is specifically hampered by a cerebral lesion. Very often we resort to in-patients not suffering from central nervous system diseases, as these are similar to neurological in-patients for all general and environmental conditions apart from the specific cerebral lesion; (c) brain-damaged patients, when the aim is to define the characteristic profile of impairment with reference to a group of tests. As an example, to classify a case of fluent aphasia such as Wernicke, or Conduction or Sensory Transcortical aphasia, we should compare the patient’s performance on comprehension and repetition tasks with that of a large sample of nonselected fluent aphasics.

Single case studies Also with single cases, a rigorous quantitative evaluation of the data is needed in order to distinguish real from random effects. We report just a few of the most useful methods suitable for single case studies. 1. When dealing with continuous measures (e.g. reaction times), repeated in different experimental conditions, one can resort to the usual variance and covariance analyses, which provide information about the interaction of the different factors controlled by the experiment. When the data structure calls for a frequency analysis, we can use contingency tables of two or more dimensions, following the standard procedures based on generalised linear models (Aitkin et al. 1989). 2. In some tasks, such as confrontation naming, it may be interesting to evaluate which variables significantly influence the performance of a subject; relevant variables may be continuous (e.g. word frequency and familiarity or visual complexity of the stimulus) or categorical (e.g. the semantic category). In these cases one can make use of logistic regression analysis (Aitkin

et al. 1989), a transformed linear model where the correct response is scored 1 and the wrong response 0. The variables included in the model can be evaluated, ruling out their overlap. For applications concerning the study of semantic memory, see Laiacona et al., 1993a, b; Capitani et al., 1993. 3. Sometimes it is possible to analyse the patient’s performance by means of a binomial model, i.e. as a sequence of trials, independent of each other and governed by a general success probability. This is the case when the patient responds with a forced multiple choice paradigm. We can calculate the success probability expected by chance, and the score region where the responses are significantly different from chance. After a given number of correct responses, we can estimate the confidence limits of the rate of correct responses, which may be asymmetric (“likelihood profile”, Aitkin et al., 1989): this avoids the inclusion of impossible values, i.e. above 1 or below 0. 4. On the basis of the reliability of a given test, we can set the confidence limits of the score for a single subject, by means of the rules that link the variability between subjects with that within subject (Gulliksen, 1987; Huber, 1973). In this way we can verify if the performance of a subject at two different and subsequent examinations has really improved. We find the best example of this approach in the standardisation of the Aachener Aphasie Test (Willmes, 1985; Willmes et al., 1988). 5. In analysing single subjects, it is interesting not only to verify if performances vary from one examination to another, but also if they are consistent. For example, in repeated confrontation naming, it is useful to study if right or wrong responses always concern the same stimuli or not. Recently Faglioni and Both (1993) have criticised the methods used to date in approaching this problem, and have suggested a solution based on the analysis of stochastic models and Markov chains. Their paper reports an example of this method applied to naming analysis. Stochastic methods based on Markov chains are a very interesting method,

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recently made available to the neuropsychologist. Working on single cases, they enable a powerful analysis of qualitative and quantitative models of cognitive impairment, particularly of learning and forgetting (Faglioni et al., 1992; Kingma & Van den Bos, 1987a, b).

NEUROPSYCHOLOGICAL TESTS AND DIAGNOSTIC PRACTICE Normality and mastery Neuropsychological tests are used in clinical practice to assess the normality of a given subject. It is worth underlining the difference between two concepts that sometimes are not adequately differentiated: mastery and normality. The former is the ability with which a given task is accomplished, independent of how many subjects are able to do it. On the contrary, normality is a judgement concerning a reference sample. It tells us if the performance of a subject is explained (with the limit of chance deviation) by a given model (more or less complex). For example, on the basis of a reference sample and by means of multiple regression analysis, we can determine the expected score on the Token Test of a healthy subject whose age and education are known: if their actual score is lower, we should wonder if the observed discrepancy results from chance or if we need to add to the basic model a factor (e.g. an illness) that lowers the performance. From the mastery perspective, the effects of age and education are not relevant, but they are fundamental from the normality perspective. Elderly and less well educated subjects can show performances that are normal with respect to their reference sample, but nevertheless below the level necessary to master a given task.

Scores adjusted for other variables If we want to adjust a score, e.g. for age and education, we need to estimate the contribution of these variables by means of a linear covariance model (Aitkin et al., 1989) and then we can adjust the observed score in order to remove the influence of the concomitant variables. As an example, in

Raven’s progressive matrices (PM47, Basso et al., 1987) the best linear model of the expected score of a subject (j) is: yj = 29.69 + 5.18[ln (100 - agej) - 4.03] + 2.98[(Veaucationj) - 3.21], 29.69 is the average PM47 in the reference sample; 4.03 and 3.21 are the means of In (100-age) and of education (square root); agej and educationj are age and education. The adjustment brings the observed score back to the value expected if age and education had been at their average; this adjustment can be made simply by reversing the sign of the parameters of the regression equation, and adding the obtained value to the raw score. Some important consequences of adjustment on the scale properties of the tests are discussed by Capitani and Laiacona (1988, 1997).

Outer and inner tolerance limits We will now consider the normality judgement. Generally, a threshold is fixed on the score distribution of a test, under which performances are judged to be not normal. From the perspective of inferential statistics, we should evaluate the risk of error associated with this judgement. Tolerance limits can be used to find the optimal threshold on the basis of the number of subjects in the sample and of the risk we want to control. Tolerance limits may be parametric or nonparametric (Ackermann, 1985), and only the latter are reliable when the shape of the scores’ distribution is not strictly normal. Moreover, the use of nonparametric tolerance limits is in order when working with scores adjusted for age and education (Capitani & Laiacona, 1988, 1997). We should distinguish between two types of tolerance limits: the outer and the inner limit. The error risks in declaring that a subject is not normal or that a subject is normal cannot be controlled with a unique threshold. We need two thresholds: the outer limit, under which the subject’s score can be declared not normal with a controlled risk, and the inner limit above which the subject’s score can be declared normal with a controlled risk. If we take as a reference the tail corresponding to the worst 5% of the population, the outer limit will be more peripheral, and the inner limit more central than the 5th percentile of the sample. In the score range included between these different thresholds the

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error risk is not controlled for either the normality, or non-normality judgement. The width of this “uncertainty region” is inversely proportional to the number of subjects belonging to the reference sample. An example of this procedure applied to a screening test for cognitive decline is reported by Brazzelli et al. (1994).

Normality judgement and test reliability As pointed out earlier, there is a certain oscillation of the observed score around the true score, due to imperfect test reliability. Some authors have stressed the relevance of this point when tests are used for diagnostic purposes (Willmes, 1985). If the test reliability is low and the confidence limits of a single subject’s true score are wide enough, a given patient could score, by chance, sometimes above and sometimes below the thresholds, and repeated examinations would give rise to inconsistent diagnostic judgements with respect to the critical region of the outer 5% of normal sample. If we use outer and inner tolerance limits, it is possible for the subject to score sometimes within the uncertainty region, and sometimes in a region where the risk is controlled. In principle, to judge that a given subject is not normal, we could require that even the upper confidence limit of his/her true score should be below the outer threshold, and vice versa for judging a subject as normal. However, according to this policy, the scale extent where no definite judgement is possible would further expand. We should conclude that the simultaneous control of all risks is expensive and can be obtained only with very reliable tests and large reference samples.

Univariate and multivariate tolerance limits When two constructs have a special link (e.g. word comprehension and repetition), it may be interesting to assess whether the combination of their measures is normal as a whole. Even if both measures taken separately are within the norm, it does not follow that they will be still normal when considered together. For instance, a systolic blood pressure of lOOmmHg is still in the normal range, and the same applies to a diastolic pressure of 90mmHg; however, a blood pressure of 100/90 is certainly unusual. There are methods for

constructing tolerance limits for the set of two or more variables (Ackermann, 1985), which may be useful when a diagnosis stems from the comparison between two or more measures.

Normality judgements and discriminant analysis Discriminant analysis is a group of different techniques that allow us, on a probabilistic basis, to classify subjects into groups providing that we have previously collected enough observations for each of these groups. If the groups are only two, we can use logistic regression analysis; when groups are more than two, other statistical methods must be applied, parametric or nonparametric, which are generally included in the standard statistical libraries (see later). In principle, we could also use discriminant analysis when we wish to classify subjects as “normal” or “not normal”. What are the differences between classifications based on discriminant analysis and on tolerance limits? In the first place, for constructing tolerance limits of the normal population we need only one reference group, composed of normal subjects, whereas for discriminant analysis at least two reference samples should be available. In the former case (tolerance limits) it follows that the judgement of “not normal” is a “negative” diagnosis and does not require that subjects be classified in any precise diagnostic category. With discriminant analysis, on the other hand, the predetermined reference samples should cover all the diagnostic alternatives. The different approaches of discriminant analysis and tolerance limits can be better clarified through an example. Let us assume that in a pathological group, for instance of AD patients, 30% of the subjects are not impaired in a given cognitive ability. As the best threshold between normality and AD should optimise the number of correct group assignments, this threshold will be influenced by the percentage of AD patients that are normal on this cognitive task. Consequently the diagnostic threshold between AD and normal subjects will be higher than the normality threshold obtained through tolerance limits. It follows that some normal subjects with low but still normal performances on

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this task, as regards tolerance limits, will be classified as AD patients by discriminant analysis. It should be borne in mind that some true pathological subjects can still score within the norm on a given cognitive ability, albeit the latter may be statistically impaired in the group as a whole. It is clear that the two methods are very different. Discriminant analysis is useful where the need is to classify subjects among different nosographic groups, but can be misleading when used for normality judgements, where tolerance limits are more appropriate.

EVALUATION OF THE EFFECTS OF TREATMENTS Experimental designs for assessing drug effectiveness Clinical neuropsychologists utilise both pharmacological treatments (e.g. the therapy of Alzheimer’s disease) and behavioural (“cognitive”) treatments. As a general rule, in neuropsychological studies neither the patient nor the doctor should know whether the patient has been given the treatment under scrutiny or an inert treatment (placebo). It should be remembered that the doctor’s expectation about a treatment’s efficacy often also has a significant effect on the patient’s performances (Rosenthal, 1985). The experiment can be based on either groups or single cases: for a general review see Der Simonian et al. (1982), Pocock (1993), and Longstrath et al. (1987). Group studies entail a homogeneous treatment within each group. One can distinguish between parallel studies (each group undergoes one treatment only) or crossover studies, where the same subject is given different treatments at different moments, and each subject acts as his or her own control. Choosing between parallel or crossover designs depends on different factors: the crossover approach is more powerful and needs fewer subjects, but, in general, is feasible only if the effect is fully reversible, i.e. if we assume that the improvement stops with the end of treatment, and if the underlying pathology does not evolve

with time. In general, studies of Alzheimer patients are of a parallel type. Several neuropsychological measures are used in clinical trials concerning Alzheimer’s disease: they range from general, compact, and comprehensive tests, such as the MMSE (Folstein et al., 1975) or the MODA (Brazzelli et al., 1994), to more detailed tests focused on single abilities. The tests used for assessment should have normative data, good reliability, and should have been previously used for determining the natural evolution of the disease. This allows us to evaluate the rate of decline of the scores over time: only in this way is it possible to convert the difference between treated and nontreated subjects into a slowing of the expected decline. In judging the efficacy of a given treatment it is important to take into account the real size of the effect and not just its statistical significance.

Experimental designs for behavioural treatments The experimental design for the evaluation of behavioural treatments is more complex. First of all, as with psychotherapeutic treatments (Prioleau et al., 1983), there is the problem of the control group and of the placebo effect. This is particularly a problem in the study of aphasia treatment. If we take as the control group those patients who cannot participate in the treatment because of practical problems (e.g. the distance from the clinical structures), we could select the subjects on the grounds of severity, economical status, motivations, cultural background, and their use and knowledge of the language. The placebo effect is what is shared by the treatment given by trained therapists and the treatment given by untrained volunteers. Some authors have considered as control subjects patients rehabilitated by untrained volunteers who acted in the same setting as the trained therapists (e.g. David et al., 1982; Hartmann & Landau, 1987). However, even in this case, we cannot exclude the intervention of the operator’s expectations, as the therapists obviously know their qualification level. Current studies of aphasia treatment follow different approaches, and often conform to single case or crossover designs. Howard et al. (1985) studied the effect of naming rehabilitation taking

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into account “multiple baselines”: two different groups of words were rehabilitated consecutively, one group acting as a control for the other. We can further complicate the study using different treatment strategies in the different stages of the experiment. For this approach we must assume that it is possible to treat only part of the words, so that we can envisage a selective effect. This approach will be more informative if we observe stabilised patients: in this case all changes can be attributed to the treatment (both to its specificity and to the placebo effect) and not to the natural evolution of the patient. The main problems of this approach are (i) the selection of the sample, as it is rather problematic to include acute patients that are still spontaneously recovering, and (ii) statistical problems resulting from the comparison of scores possibly lying on different scales. The debate concerning the single case approach with regard to the rehabilitation of aphasic disturbances is very interesting. We refer, for a review, to Coltheart (1983) and to the debate, published in the British Journal o f Disorders o f Communications (1986), in the Forum “Evaluating intervention”: Howard and Pring criticise group studies and support the single case approach, whereas Fitz-Gibbon underlines the limits of this approach and suggests resorting more extensively to other methods such as evaluating the size of effects (and not only their significance) and metaanalysis. In any case we should underline the different implications deriving from group studies and from single case studies. With the former approach the implications of a positive result are general, i.e. it applies to all patients of that type rehabilitated in that way; whereas with the single case approach we can infer only that the patient studied shows a significant improvement. The conceptual advantage of group studies seems obvious, but problems arise when results are negative. Negative results could arise simply from having studied patients who are too heterogeneous and from the fact that questions such as “is language rehabilitation effective?” are underspecified. Metaanalysis is a useful method that allows the results coming from different studies to be pooled. With this method, perhaps, we can overcome the lack of

power of single experiments and can take into account all the positive and negative results published. As an example of meta-analysis we refer to the study by Robey (1994) on aphasia rehabilitation, where one can find an illustration of the method used, a debate on the power of the experiments, and updated references on this topic.

ADVANCES IN DATA ANALYSIS New methods of data analysis In the last 10 years the broad use of personal computers (PCs) has radically changed data management in all experimental fields. Nowadays all researchers have at their disposition high computational power and comprehensive statistical libraries. The standard statistical methods (such as variance, covariance and regression analysis, contingency tables analysis, simple nonparametric methods, factorial analysis, etc.) are available in easy-to-use statistical packages, such as the SAS, the SPSS, the GENSTAT etc. The evolution in statistical methods can be considered from two points of view: (a) better choice of the methods appropriate for simple problems, such as the comparison of two groups, so that the computation of the significance level is closest to the real probability evaluation of the risk of being wrong in claiming a given result; (b) the possibility of coping with more complex problems, for which, previously, no satisfactory methods were available to non-specialists. Until the last few years, the most accurate solutions for simple problems were hampered by a shortage of programs. As an example, in comparing two groups very often the researcher automatically uses the Student’s i-test, even when this method is not appropriate and allows only a rough evaluation of the error risk. An interesting review of these problems and of the available solutions has been made by Wilcox (1987), to whom the reader is referred for a careful discussion of this topic. Myers (1990) is another useful textbook. Controlling the power of the experiment is very often a neglected aspect. The missed rejection of a null hypothesis (lack of effects or differences)

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prevents us from deciding, with a controlled risk, if the two groups under consideration really belong to the same population. With rather simple experiments, however, we can effectively control this risk. With this approach, the size of the effect to which the experiment should be sensitive must be defined. For a wide discussion on this topic we refer the reader to Cohen (1988). Finally, we will mention a recent example of the radical improvement in the analysis of “simple” problems. For a set of nonparametric methods, such as the Wilcoxon test, the analysis of contingency tables 2 x n, etc., some procedures (Mehta & Patel, 1992) allow us to compute not only the asymptotic, but also the exact probability of having sampled by chance the observed data under the null hypothesis. These programs can work by simulation methods (Monte Carlo estimates) and can sample in a very short time a huge number (in the order of tens of thousands) of simulated cases with which they compute the probability of observing the data in question. This is a new approach to the computation of significance, and in the near future it could be widened to include more complex and general statistical models. Coming now to more complex problems, we should remind the reader of the advantages of the procedures based on generalised linear models. The general structure of these models enables unification, from a more abstract perspective, of variance, covariance, multiple regression analyses, the analysis of multidimensional contingency and of the survival tables, and logistic regression analysis. For these types of analyses, the GLIM is a standard program. Its theoretical basis and applications are presented by Aitkin et al. (1989). As already mentioned, logistic regression allows us to analyse more deeply and satisfactorily some problems that are common in clinical and experimental neuropsychology. For example, in the analysis of confrontation naming, if we want to reveal which factors influence the patient’s performance, we can design a linear model, with a binomial error, where the answers have a dichotomic value (1 for the right and 0 for the wrong response). Taking into account all the pictures, we can check the influence of a set of variables (e.g. the name frequency, its category, the visual complexity

of the corresponding picture etc.) disentangling the exclusive effect of each variable from its overlap with the others. An example of this procedure and the GLIM macro instruction for the automatic analysis of a naming task is reported by Laiacona et al. (1993b) and by Capitani et al. (1993). We feel it useful to introduce another procedure that might foster neuropsychological research even if it is still marginally represented in the literature: the analysis of LISREL models (Joereskog & Soerbom, 1989), which consists of different subgroups of simpler models, among which confirmatory factorial analysis (CFA) has some interesting applications. CFA is a generalisation and an extension of the classical factorial analysis (exploratory) and enables the formulation of clearcut hypotheses about the relationships between observed and latent variables that are explicitly declared at the outset of the study. For example, we can assume that, within a given neuropsychological battery, certain tasks are influenced by some latent variables and not by others: we can statistically verify this hypothesis, testing the significance of the connections between observed and latent variables, as well as those between the latent variables themselves. For these methods, which because of their complexity cannot be further elucidated in this chapter, we refer the interested reader to some introductory texts (Byrne, 1989; Hayduk, 1987) and to the statistical program LISREL (Joereskog & Soerbom, 1989) that is available singly or is assembled in some standard statistical packages. Finally, we would like to recall the potential impact on neuropsychological analysis of stochastic models based on Markov chains, with particular reference to the study of memory (Kingma & Van den Bos, 1987a, b; Faglioni et al., 1992). Recently, Faglioni and Botti (1993) applied this method to consistency analysis in a picture confrontation naming task; we refer the reader to this paper for a critical review of the different methods formerly employed for this problem. The method suggested by Faglioni and Botti hypothesises that words are in two possible states (inside or outside the lexicon) and, in the former case, that they can be retrieved at each trial on a probabilistic basis. Taking into account the performance of a given subject on repeated trials

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we should consider how many words are always retrieved, how many are never retrieved, and how many are inconstantly retrieved. Statistical analysis calculates the percentage of words still present in the lexicon and the probability of their actual retrieval with the value of the corresponding parameters and confidence limits. In this way, we can judge whether the subject presents a storage degradation, or access difficulties or both. The model suggested by Faglioni and Botti is a very general one, and allows the introduction of some other interesting parameters in order to quantify, for example, if the fraction of words that are retained within the lexicon changes over time or after

treatment. However, we should remember that the general analysis of these models, apart from some rather simple instances presented in the paper by Faglioni & Botti, requires complex mathematical programs that are not yet available for personal computers.

ACKNOWLEDGEMENTS We are deeply indebted to Professor P. Faglioni for his invaluable teaching. Dr. R. Allpress revised the English text.

5 Neuroimaging Methods in Neuropsychology Daniela Perani and Stefano F. Cappa

scientific status to the study of anatomo-clinical correlations altogether. The renaissance of interest in the neurological side of neuropsychology is relatively recent, starting from the 1960s, and can be considered as the consequence of several factors. In the first place, developments in neurophysiology, showing the high degree of specialisation present at each level of the nervous system, have finally discredited the idea of “equipotentiality” of nervous tissue. The influence of several researchers worldwide, such as Hecaen, Luria, and Geschwind, must not be neglected: besides their personal contributions, they prompted a rediscovery of the large body of anatomo-clinical knowledge that had disappeared from the scientific arena during the “globalist” period. Finally, a major breakthrough has been the development of neuroimaging methods. These tools have provided a new impulse to the study of the neural basis of cognitive function, and have extended the field of inquiry from lesions to functional investigations of brain activity in normal subjects engaged in cognitive tasks. The aim of this chapter is to provide an overview of neuroimaging methods in cognitive research.

INTRODUCTION The date of birth of neuropsychology as a specialised field of inquiry is often said to coincide with the publication of the first case study of a cognitive disorder (aphasia), which included a postmortem study of the brain. Paul Broca, reporting in 1865 the case of a patient with a severe disorder of language production, whose brain was shown at autopsy to harbour a softening centred on the third frontal convolution, inaugurated the anatomoclinical method in neuropsychology. The importance attributed to the investigation of the neural basis of cognitive functions has since waxed and waned in the history of neuropsychology. The early period (from Broca’s observation to the First World War) was, with a few exceptions, characterised by “localisationist” doctrines. These tended to ascribe complex functions, such as auditory language comprehension, to circumscribed cerebral areas, which were localised on the basis of anatomo-clinical correlation studies in patients. This era was followed by a period of supremacy of “globalist” theorising, which denied 69

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Technical information has been kept to the minimum required for a correct interpretation of the practical applications of the different methodologies. Neurophysiological methods, which represent the main complementary resource for cognitive neuroscience, are discussed in Chapter 3 by Mecacci and Spinelli.

Historical aspects The anatomo-clinical method is based on the observation of a patient’s clinical picture, combined with the results of the macroscopic and microscopic pathological examination of the brain post-mortem. This type of investigation of course provides a precise morphological definition of a cerebral lesion. However, the limitations are self-evident: as a rule, the time of the clinical observation is distant from the moment of pathological evaluation, making the symptom-lesion correlation difficult to interpret. In the case of vascular lesions, the patient’s demise is often due to neurological complications, such as brain oedema, or to further strokes, which modify both the clinical picture and the pathological findings. With a few exceptions, this approach can be applied only to single cases, as the lack of homogeneity in the collection of clinical and neuropsychological data and in the pathological examination itself hampers the comparison between individual patients. The development of neurosurgery seemed to open a new avenue of investigation. Actually, the characteristics of some of the neurosurgically relevant pathologies, such as brain tumours, sometimes prevent useful anatomo-clinical correlations, because of their progressive nature. Furthermore, intra-operatory definition of anatomical localisation was often imprecise. The most remarkable exception to these limitations is functional neurosurgery, in particular for epilepsy. Studies of patients with localised cortical ablations are one of the most productive areas of neuropsychological investigation (Milner, 1971). Another important source of information has been the study of war injuries, in particular penetrating bullet wounds, in large series of veterans (Luria, 1970; Newcombe, 1969; Teuber, 1962). Also in this case the precision of lesion localisation was limited in the older series, in which

the only methods for assessment were the plain skull x-ray, showing the penetration point, and the surgical reports. The birth of neuroradiology in the 1920s, with the introduction in clinical use of cerebral angiography and pneumoencephalography, initially had a limited impact on neuropsychological research. The methods were invasive, preventing any pure research application. Furthermore, as already observed, the prevailing theoretical climate in psychology between the two world wars was largely hostile to cerebral localisation. Until the 1960s, the only method that was sometimes used for a gross localisation of brain lesion was the electroencephalogram. It was at this time that the isotopic scan (brain scintigraphy) began to be applied to the study of lesion site in aphasic patients (Benson, 1967; Karis & Horenstein, 1976). The landmark study by Frank Benson tried to correlate lesion site with the clinical dichotomy between nonfluent and fluent aphasias proposed by Harold Goodglass and his colleagues (1964). The results were that nonfluent aphasics, whose speech is characterised by reduced output, short phrase length, frequent hesitations, and articulatory impairment, had lesions that involved the anterior, prerolandic region of the left hemisphere. Fluent aphasics, whose speech production rate was normal or supernormal, without articulatory impairment but with profuse phonological and/or lexical errors, had lesions limited to the retrorolandic regions of the left hemisphere. The historical importance of this study for cognitive neuroscience cannot be overemphasised, as it represents one of the first examples of application of a neuroimaging method to the study of a cognitive model. The results of this study have been repeatedly confirmed, which is remarkable given that bidimensional brain scintigraphy was a rather gross method, both from the point of view of sensitivity (a pathological permeability of the blood-brain barrier was a necessary requirement for the accumulation of the tracer) and of the precision of localisation. The following years have been characterised by an unprecedented development in brain imaging techniques, due to the rapid progress in radiological sciences and in computerised methods of data handling. The first result of these developments has

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been Computerised Tomography (CT), which, until the introduction in clinical use of Magnetic Resonance Imaging (MRI), has been the gold standard for lesion localisation in vivo. Largely in parallel with methods for the in vivo study of brain anatomy, the assessment of the functioning of the human brain (functional brain imaging) has become gradually possible. The original methods for the assessment of cerebral blood flow were the first steps of a progression that has led to emission tomographic methods (single photon emission computerised tomography— SPECT—and positron emission tomography—PET). Nowadays it is possible to measure in vivo multiple parameters of regional cerebral physiology, such as blood flow and oxidative and glucose metabolism. The most recent adjunct to the array of functional imaging methods is functional magnetic resonance (fMR), which will be discussed later in this chapter.

ANATOMICAL IMAGING Computerised tomography (CT) Technical aspects CT was the first radiological method to allow a direct visualisation of brain tissue and of its modifications induced by disease. The formation of a CT image depends on the transmission of an x-ray beam through a thin section of the brain. The transmission results in an attenuation of the radiation beam, which depends on the tissue absorption coefficient, and is measured by external detectors. These measurements are repeated for multiple entry points, at different angles. An algorithm, implemented on a dedicated computer, calculates from the attenuation data the absorption coefficients of the tissue volumes (voxels), into which the section can be subdivided. The corresponding CT image represents these elements bidimensionally (pixels): the absorption coefficient is expressed as a density unit according to an arbitrary scale (named after the CT scientist and Nobel Prizewinner Hounsfield), where 0 corresponds to the density of water, 1000 to bone

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density. These numerical values are then represented with a colour scale (usually black to white, with different shades of grey). The CT images usually reach the clinician in this form, on radiological films or as computer printouts. Significant technical developments have taken place from the introduction of CT in the early 1970s: scanning times are reduced, the sections are thinner, spatial resolution is increased and artefacts have been reduced. A crucial factor for these ameliorations has been the modification of the radiation beam/detector ratio, from the single beam/single detector of the first-generation CT to the detector ring with a rotating radiation source of fourth-generation CT. The increase in spatial resolution is due to the decreasing size of the voxels, leading to a reduction of partial volume effects (the averaging of the densities of tissues with different absorption coefficients, within the same volume of tissue). Neuropsychological applications Schematically, CT scan has been used in neuropsychological research as a tool to localise the site and extent of focal lesion, to assess and quantitate brain atrophy, and to measure hemispheric asymmetries. Focal lesions. Cerebrovascular lesions (infarctions and haemorrhages) are the localised brain lesions most frequently responsible for neuropsychological disorders in adult patients. On CT, infarcted brain is usually apparent as a focal decrease in tissue density 12-24 hours after the onset of clinical symptoms. The lesion borders are indistinct in the acute phase, which is characterised by perilesional oedema. They become more evident with the passage of time, as the CT lesion comes to reflect the circumscribed area of parenchymal necrosis (Goldberg & Lee, 1987). A CT obtained in the period between two and three weeks post stroke can give false negative results, due to the transient lesion isodensity (fogging effect: Becher, Desh, & Hacker, 1979). The ideal period for the definition of lesion site and extent in the case of infarctions is thus the chronic phase (Damasio & Damasio, 1989). On the other hand, haemorrhage lesions are evident immediately after stroke, due to

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the large difference in density between blood and brain tissue. The minimal size of a lesion visible on CT depends on the spatial resolution of the equipment, as well as on its location with reference to areas of different intensity (partial volume effect) and the quality of the examination, which requires patient collaboration. For research purposes, it is usually necessary to localise the area of altered density shown by CT with reference to anatomical structures, i.e. the main gyri or, in further detail, Brodmann’s areas (Ba). In the case of an individual patient, the accuracy of lesion localisation depends in the first place on the spatial resolution of the equipment and on the possibility of identifying “landmark” anatomical structures, such as the main sulci (Ebelin, Huber, & Reulen, 1986; Seines, Knopman, Niccum, & Rubens, 1983). It is then usually necessary to make reference to an anatomical atlas, in particular if the aim is to compare lesion location in different patients. The crucial problem is the large inter-individual variability in the size and configuration of the brain surface structure (see Thompson, Schwartz, Lin, Khan, & Toga, 1996, for a recent approach to post-mortem cortical morphometry). Several methods, with different degrees of complexity and claims to accuracy are available: • Axial diagrams: the early methods used in neuropsychological-CT research were based on the transfer of the area of altered intensity from the CT image to a standard axial diagram. Ventricular landmarks were used as references to help the manual mapping (Kertesz, Harlock, & Coates, 1979; Naeser& Hayward, 1978).The inclination of the axial CT section and its width were assumed be the same as the diagram, and the differences between the actual CT sections and the diagram from the point of view of size, sulcal pattern, etc., were disregarded. The mapping to axial section has subsequently been refined, making reference to more adequate atlases, which, while leaving open the problem of inter-individual differences have provided sections with different degrees of inclination with respect to the orbito-meatal line (Damasio & Damasio, 1989; Matsui & Hirano, 1978).

• Lateral diagrams: another simple method for lesion localisation is based on the transfer of the lesion from the CT sections to a diagram that represents the lateral convexity of the brain. Several procedures have been published and largely employed in neuropsychological research: they share the advantage of taking into account the slice inclination with respect to the orbito-meatal line, and using multiple reference landmarks, besides ventricular structures (Luzzatti, Scotti & Gattoni, 1979; Mazzocchi & Vignolo, 1978) (Fig. 5.1). These methods however, still fail to take into account the problem of inter-individual variability in gyral pattern. • Semiautomatic methods have also been proposed for a more objective and precise lesion quantification, such as the one developed by the Aachen group (Blunk, De Bleser, Willmes, & Zeumer, 1981). The lesion is first transferred to an axial diagram, with a superimposed grid. Each square of the grid is computed as damaged (1) or intact (0). These lesional scores can be manipulated in different ways: their sum provides an index of lesion size; or they can be plotted in a 3-D graph, providing a representation of the frequency of involvement of a given structure. It is possible to define a priori regions of interest on the grid, which are conventionally considered as involved by a lesion if more than 30% of the component “squares” are damaged (for examples of applications, see Poeck, De Bleser, & Graf von Keyserlingk, 1984; Willmes & Poeck, 1993). • Stereotactic mapping: stereotactic methods have been developed for functional neurosurgery, with the precise aim of taking into account individual variation in size and overall shape of the brain. The cornerstone of stereotaxy is the so-called “proportional method” (Talairach & Tournoux, 1988). This method takes as reference three lines, which have been shown to hold a constant and proportional relationship with subcortical and (to a lesser degree) cortical structures: the intercommissural line, which joins the anterior (AC) and posterior (PC) commissure, and two vertical lines perpendicular to the AC-PC line, anterior to the

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PC and posterior to the AC. Several standard proportional grids, based on this reference system and reproducing the most common brain sizes are available. The stereotactic approach is presently incorporated in most PET data analysis methods (Friston et al., 1989); Evans et al., 1992). It has also been applied to the analysis of CT images (see for example the study of von Cramon, Hebei, & Schuri, 1985, on lesion localisation within the thalamus). Vanier et al. (1985) have suggested and validated the utilisation of the lateral scannogram provided by the standard CT procedure to locate the lines of reference, with the help of bony landmarks such as the external auditory meatus. It is then possible to apply a proportional fractionation to each CT slice and make reference to the stereotactic atlas for lesion or structure localisation. The procedure is of course much simpler with MRI, which allows the direct visualisation of the AC and PC on a sagittal section (Steinmetz, Fuerst, & Freund, 1989). Dementia. CT has an important clinical role in the diagnostic evaluation of mental deterioration, because it allows clinicians to rule out potentially

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treatable causes of dementia, such as subdural haematoma or low-pressure hydrocephalus. Its usefulness in the positive diagnosis of degenerative dementia is more limited. It has been clear since the introduction of CT in clinical practice that the presence of dementia in individual patients cannot be predicted on the basis of the presence or degree of brain atrophy (except in severe cases). Several methods have been employed for atrophy evaluation. Visual inspection by a radiologist does not differentiate probable Alzheimer’s disease (AD) from normal ageing (Jacoby & Levy, 1980). Using a planimetric quantitative method, Damasio, Eslinger, Damasio, Rizzo and Huang (1983) have shown that demented subjects had significantly more atrophy than controls. The atrophy indexes were inversely correlated with the neuropsychological test scores both in AD and multiinfarct dementia (MID) patients (Eslinger, Damasio, Graff-Radford, & Damasio, 1984). Automated computed morphometry methods, which can measure the size of other cerebral structures, besides the ventricular system, have been suggested to be an effective tool for AD diagnosis (Ichinuya, Kobayashi, Arai, Ikeda, & Kosaka, 1986), but its complexity has probably prevented widespread application. Much interest

FIGURE 5.1

An example of a lateral diagram of the left hemispheric convexity, used to map CT lesion (method of Mazzocchi and Vignolo). The area of maximal lesion overlap (9 subjects out of 10) in patients with impaired sentence comprehension as assessed with the Token test, lies in the posterior part of the left superior temporal gyrus. I = insula; L = lenticular nucleus; IC = internal capsule.

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was aroused by the report that thin CT slices parallel to the main axis of the temporal lobe showed a dilatation of the transverse fissure and of the adjacent choroido-hippocampal sulcus in AD patients (De Leon, George, Stylopoulos, Smith, & Miller, 1989). The discriminative power with normal ageing was not elevated, but may be improved by simple linear measurements (Jobst, Smith, & Szatmari, 1992). A diffuse hypodensity of white matter (leucoaraiosis) can also be observed in elderly subjects, and is frequently associated with cognitive deterioration (Tarvonen-Schroder et al., 1996). Hemispheric asymmetries. The seminal anatomical observation that the planum temporale (PT) is asymmetric, with a larger left extension in most brains (Geschwind & Levitsky, 1968) was followed by many studies, which have confirmed that the two hemispheres are not the mirror image of each other. The neuropsychological interest of these observations resides in the relationship of PT asymmetry with hemispheric specialisation. Le May and Kido (1978) were the first to suggest that hemispheric asymmetries could be studied in vivo, using CT. They showed that in right-handers the most frequent asymmetry pattern was longer left occipital and right frontal lobes, while left handers failed to show any consistent asymmetry pattern. The original observation, however, was not replicated (Chang Chui & Damasio, 1980; Koff, Naeser, Pieniadz, Foundas, & Levine, 1986): the prevalent left occipital-right frontal asymmetry pattern seems to be the most frequent CT pattern in the general population, including left handers. A CT-pathological correlation study in 15 righthanded subjects (Pieniadz & Naeser, 1984) has shown a good correlation between occipital length and PT asymmetry. This observation has led to the hypothesis that the “typical” asymmetry pattern on CT is not related to handedness, but to hemispheric dominance for selected aspects of language function, such as language comprehension. This was supported by clinical observations: for example, a global aphasic with “atypical” asymmetry pattern showed an unexpectedly fast recovery of auditory comprehension (Pieniadz, Naeser, Koff, & Levine, 1983). Furthermore,

left-handers who had become aphasic after a left or right hemispheric stroke were found to have a milder disorder of auditory comprehension if the longer occipital lobe was contralateral to the lesion (as, for example, in the case of a “typical” asymmetry in a patient with a right hemispheric lesion—Naeser & Borod, 1986). These data must be considered with caution, given the evidence that the pattern of asymmetry has a limited usefulness in predicting language latéralisation in crossed aphasies: Henderson, Naeser, Wiener, Pieniadz, and Chang Chui (1984) found a typical pattern in 11 out of 15 crossed aphasies, while Naeser and Borod (in the study just mentioned) found “typical” asymmetries in 3 out of 4 left-handers who had become aphasic after a right hemispheric lesion. The reliability of planimetric measurements of hemispheric asymmetries is limited, as minimal variations in the incidence angle can result in large variations (intra-subject correlation with CT and MRI was, respectively, only 0.78 and 0.79 in a study by Chu, Tranel, & Damasio, 1994). Threedimensional morphometric MRI methods seem to provide more robust measurements of hemispheric asymmetries (see next section).

Magnetic resonance imaging Technical aspects The physical principles responsible for magnetic resonance image formation are different from those of traditional radiology, and are clearly described in several publications (see, for example, Brown & Semelka, 1995; Villafana, 1987). The present introduction will be limited to basic concepts. MRI is based on the properties of some atomic nuclei which, when exposed to a magnetic field and stimulated by a radiofrequency of defined wavelength, re-emit part of the absorbed energy as a radio signal (Fig. 5.2). Hydrogen is presently the most extensively employed nucleus for clinical applications. Whereas CT is based on a single property of the tissue (electron density), the determinants of the MR signal are multiple. Besides proton density, two other parameters, the T1 and T2 relaxation times, are essential. They express the time required by the radiofrequency-excited atomic nuclei to return to the baseline energetic level. The

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T1 relaxation time reflects the time course of the recovery of magnetisation along the longitudinal axis, while T2 reflects the decay of magnetisation on the horizontal plane. T1 and T2 depend, respectively, on the energetic exchanges of the atomic nuclei with the surrounding molecular milieu, and among themselves. In water, where the protons are dispersed in a homogeneous milieu, and the chances of energetic exchange are low, both T1 and T2 are long. The situation is reversed in fat tissue. The T1 and T2 relaxation times of the different components of the central nervous system are thus different, and reflect closely the chemical composition of the tissue (grey matter, white matter, cerebrospinal fluid) (Fig. 5.3). The T1 recuperation time (called also spin-lattice relaxation) is exponential, and its length is in the

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order of hundreds of msec, while the T2 decay time (also called spin-spin relaxation) is shorter, and is measured in tens of msec. They are conventionally expressed, respectively, as the time required to reach 63.2% of maximal magnetisation (Tl), and the time required to reach 36.8% of initial magnetisation (T2). The MR signal intensity of the different normal and pathological components of brain tissue depends on these intrinsic parameters; an important role is also played by the modalities of application of the radiofrequency, which are manipulated by the examiner. In particular, it is possible to modify the interval between the successive applications of the radiofrequency (repetition time—TR), and the timing of the detection of its “echo” (echo time—TE), in order to magnify the intrinsic differences of the

FIGURE 5.2

(A) Schematic drawing representing the excitation of an atomic nucleus within a magnetic field by a radiofrequency. This results in the emission of a “resonance” frequency. (B) Spatial resolution is provided by the superimposition of a magnetic gradient on the field: the atomic nuclei in different spatial locations can be localised according to the characteristics of the emitted frequency.

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FIGURE 5.3

Time course of the recuperation of magnetisation on the longitudinal axis (T1-A), and of the decay of magnetisation on the transversal plane (T2-B) for the main constituents of the central nervous system.

components of the tissue, and thus to increase image contrast. Fig. 5.4 shows the relative intensities of brain and CSF using a long (2s) or short (0.5s) TR. In the case of a short TR, given that the brain T1 is shorter than that of CSF, the recuperation after 0.5s will be larger, and decay will start from higher values; with a long TR (2s) this difference disappears, brain and CSF will start to decay from the same energetic level and the time course will reflect only the different T2. The echo time can make use of this difference: at 50ms the brain will appear more intense than CSF, whereas at long echo times the CSF will be more intense. The sequences used for cerebral imaging (such as multiple spin-echo) allow the manipulation of these parameters in order to differentiate optimally the components of cerebral tissue, such as grey and white matter, or to increase the sensitivity for the presence of pathological areas. As a memory aid, it is useful to remember that when an image is principally influenced by T1 (T1 weighted; short TR and TE), the signal intensity is inversely related to the length of T l, whereas with T2 weighted images (long TR and TE), the signal intensity is directly related to the length of T2.

Besides intensity, the other important parameter of the MR signal is frequency. The difference in frequency allows the spatial localisation of the resonating protons, thus providing the basis of image formation. Differences in frequency can be produced by the superimposition of a magnetic gradient on the baseline magnetic field. It is possible to perform MR sections according to any plane, both orthogonal and oblique, which represents a remarkable advantage in comparison to CT. In order to increase spatial resolution, it is necessary to detect small differences in frequency. This requires the repetition of the excitation process hundreds of times to form a complete image. With spin echo (SE) sequences, based on the application of pairs of radiofrequency stimuli, the time required for the acquisition of a series of images ranges from 3 to 15 minutes. A family of sequences called “gradient echo” (GRE), based on the superimposition of gradients to the main magnetic field, reduce effectively acquisition time. The main difference between SE and GRE is that in the latter case the magnetisation decay on the transversal plane does not depend only on “true” spin-spin relaxation, but is largely influenced by the

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dyshomogeneities of the magnetic field: this is called “effective” T2 or T2* (T2 star). The characteristics of the many commercial GRE sequences allow optimal image contrasts for different clinical indications (for an accessible introduction see Elstir, 1993). The reduction of time between sequential excitations is extremely important for functional MR (fMR) (see later): at the cost of some loss in signal to noise ratio, images can be acquired in about one second. Because the field of application of fMR is functional imaging, it will be discussed after PET. Neuropsychological applications Focal lesions. Areas of cerebral infarction appear as hypointense areas in T1-weighted images, whereas they are hyperintense in T2 (De Witt, 1986). This is due to the lengthening of both relaxation times induced by the tissue ischemia. MR is superior to CT in the early detection of cerebral infarction, even in the first few hours after

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onset (Kertesz, Black, Nicholson, & Carr, 1987). Chronic infarctions are surrounded by a hyperintense “halo”, which has been ascribed to Wallerian degeneration (Kertesz et al., 1987). Periventricular hyperintensity and clinically silent areas of altered intensity are frequently observed in patients with focal ischemic lesions. They are significantly more frequent in patients with hypertension, or other risk factors for cerebrovascular disease (Kertesz, Black, Tokar, Benke, Carr, & Nicholson, 1988), but ageing perse appears to play an important role (Ylikoski et al., 1995). In normal, elderly subjects their presence predicts poorer performance on attentional tasks and slowed information processing (Ylikoski, Ylikoski, Erkinjuntti, Sulkava, Raininko, & Tilvis, 1993). Haemorrhages are characterised during the acute phase by a short T1 area surrounded by a long T1 border. They are hyperintense in T2 weighted images (De Witt, 1986; Kertesz et al., 1987). CT thus maintains its role in the early diagnosis of

FIGURE 5.4

Dfferentiation of cerebrospinal fluid and brain tissue by the manipulation of repetition and echo times (for full explanation see the text).

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haemorrhagic lesions. In the chronic phase, MR is useful to differentiate a post-haemorrhagic area from ischemia, because of the short T1 of the former. The advantage of using MR for the topographical diagnosis of lesions associated with neuropsychological deficits lies in the excellent spatial and tissue resolution, which allows the direct detection of sulci and gyri. Anatomical MRI is the best available instrument for the in vivo study of brain morphology. It allows a detailed assessment of the morphology of neuropsychologically crucial structures, such as the hippocampus and the parahippocampal gyri (Press, Amaral, & Squire, 1989) and the mammillary bodies (Chamess & De La Paz, 1987), which can then be submitted to quantitative evaluations. Several 3D reconstruction algorithms, which can be applied to thin, high-resolution MR slices, have been developed for brain morphometry (Filipeck, Kennedy, Caviness, Rossnick, Spraggins, & Starewicz, 1989; Steinmetz et al., 1989). The most recent methods provide an accurate reconstruction of the gyral anatomy of individual subjects (Andreasen et al., 1994; Damasio & Frank, 1992): this is an aspect of practical significance, given the large intersubject variability in sulcal and gyral structures (Thompson et al., 1996), and the fact that sulcal boundaries separate functionally different areas (Rademacher, Caviness Jr, Steinmetz, & Galaburda, 1993). Stereotactic normalisation of MRI in 20 normal subjects has been shown to leave a residual variability in the perisylvian region in the order of 1.5-2cm, due to the different course of the sylvian fissure, in particular of the anterior and posterior ascending rami (Steinmetz & Seitz, 1991). A study of the parietal opercular region by the same group (Steinmetz, Ebeling, Huang, & Kahn, 1990) showed four different patterns of sulcal topography, both within subjects and within hemispheres. Dementia. MR plays an important role in the study of dementing conditions. The first investigations (Erkinjuntti, Sipponen, Livanainen,

Ketonen, Sulkava, & Sepponen, 1984), which employed low magnetic field machines, underlined the lack of white matter lesions in Alzheimer’s disease (AD) and suggested that MR could be the choice method for the differential diagnosis with vascular dementia. Subsequent investigations have indicated a more complex picture, with AD subjects showing areas of altered signal intensity, especially in the T2 weighted images. Periventricular hyperintensities and small hyperintense foci cannot be considered characteristic either of AD or of vascular dementia, as they can be found in normal elderly subjects (Erkinjuntti, Gao, Lee, Eliasziw, Merskey, & Hachinski, 1994; Fazekas, Chawluk, Alavi, Hurtig, & Zimmerman, 1987). The burden of hyperintense brain areas has been reported to be negatively correlated with regional blood flow in the hippocampus in AD subjects (Waldemar, Christiansen, Larsson, Hogh, Laursen, Lassen, & Paulson, 1994). The measurement of atrophy has been the focus of a large number of investigations, with the aim of providing a useful tool for the differential diagnosis of early AD from normal ageing. Simple methods, based on linear measurements of the mesial temporal regions, have shown fair specificity and sensibility (Frisoni, Bianchetti, Geroldi, Trabucchi, Beltramello, & Weiss, 1994; Scheltens et al., 1992). Volumetric measurements have indicated an inverse relationship between age and hippocampal volume (Bhatia, Bookheimer, Gaillard, & Theodore, 1993); a further correlation with performance on memory tests has been found in elderly, nondemented subjects (Soininen et al., 1994; Launer et al., 1995). Hippocampal, temporal horn (Killiany, Moss, Albert, Sandor, Tieman, & Jolesz, 1993), and amygdala volume (Cuenod et al., 1993) have all shown some discriminative value between AD and normal ageing. Semiautomatic methods, based on image segmentation algorithms, allow a more precise measurement of the volumetric variation of different brain structures with age (Pfefferbaum, Mathalon, Sullivan, Rawles, Zipursky, & Lim, 1994), and appear to be promising tools for early AD diagnosis (DeCarli et al., 1995). In the progressive focal neuropsychological syndromes MRI usually shows focal areas of

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atrophy (for example, of the left hemispheric language areas in progressive aphasia cases— Karbe, Kertesz, & Polk, 1993), which corresponds well with the areas of hypoperfusion and hypometabolism shown by functional imaging. A focal frontal and temporal atrophy is typically found in patients with Pick’s disease and fronto-temporal dementia (Frisoni et al., 1996; The Lund and Manchester Groups, 1994). Besides AD and vascular dementia (Corbett, Bennet, & Kos, 1994), MR has been used in other neurological conditions associated with cognitive deterioration, such as multiple sclerosis (Anzola et al., 1990) and HIVassociated encephalopathy (Hall et al., 1996). Hemispheric asymmetries. The in vivo study of hemispheric asymmetries, which began with CT scan, has been successfully approached with MRI. Kertesz, Black, Polk, and Howell (1986) have shown a marked asymmetry in the sulcal demarcation of the posterior parietal operculum, which was correlated with handedness. Steinmetz, Rademacher, Jaencke, Huang, Thron, and Zilles (1990) using MR morphometry have shown that the left hemispheric prevalence of the planum temporale is associated with a larger extent of the intrasylvian cortex behind the planum in the right hemisphere. With the same method, Steinmetz, Volkmann, Jaencke, and Freund (1991) have confirmed quantitatively the correlation between planum asymmetry and handedness, with lefthanders’ brains being less asymmetric, especially if the left-handedness was familial. This finding has been confirmed using a different methodology (Rossi et al., 1994): in this study there was also a trend towards lesser asymmetry in females. Musicians with perfect pitch have been shown to have stronger PT asymmetry than non-musicians or musicians without perfect pitch (Schlaug, Jaencke, Huang, & Steinmetz, 1995). The asymmetry of the PT (Foundas, Leonard, Gilmore, Fennel, & Heilman, 1994) and also of the pars triangularis (a portion of Broca’s area—Foundas, Leonard, Gilmore, Fennel, & Heilman, 1995) assessed with MRI has an excellent concordance with hemispheric language dominance as indicated by the Wada test.

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FUNCTIONAL IMAGING Regional cerebral blood flow (rCBF) Technical aspects The global measurement of cerebral blood flow (CBF) became possible with the Kety and Schmidt (1948) technique, based on Fick’s principle. Given that the flow can be calculated from the arteriovenous difference in the concentration of a metabolically inert and freely diffusible gas, its substitution with an isotopical tracer (such as 133Xe) allows the external measurement of the variations in local concentration (Lassen & Ingvar, 1961). Practically, what is measured is the clearance of the tracer from the different cerebral areas, which depends strictly on regional cerebral blood flow. The tracer can be given directly in the carotid artery, by inhalation, or by venous infusion. The clearance curves can be analysed with different methods: the simplest is the assessment of the initial slope (Initial Slope Index). The calculated values are to be considered as relative perfusion indexes, because of the tracer recirculation and the shunting from extracerebral flow from the external carotid artery. Neuropsychological applications The measurement of rCBF has been applied to patients with cerebrovascular lesions associated with neuropsychological disorders, and has shown that the areas of reduced perfusion are larger than the regions of structural damage shown by CT (Skyhoj Olsen, Larsen, Herning, Bech Skriver, & Lassen, 1983). These earlier observations have been corroborated with tomographic methods, such as SPECT and PET (see later). The main novelty of rCBF studies was the possibility of performing functional activation investigations in normal subjects engaged in sensorimotor and cognitive tasks, and measuring the associated modifications in regional cerebral perfusion. These pioneering investigations in the field, of, for example, language, have given interesting and somewhat unexpected results, such as the presence of a bihemispheric activation with left hemispheric prevalence (see the chapter on the neurological

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foundations of language). A predominantly right hemispheric activation was found with visuospatial tasks, such as judgement of line orientation (Hannay, Falgout, Leli, Kathaly, Halsey, & Wills, 1987) or mental rotation (Deutsch, Bourhon, Papanicolaou, & Eisenberg, 1988). The activation paradigms could also be applied to patients. In aphasics, they have been used in order to investigate the neurological basis of recovery (still an open question). Knopman, Rubens, Klassen, and Meyer (1984) showed an activation of right frontal areas in patents with temporo-parietal strokes who had shown partial recovery. The patients with good recovery had spared left temporo-parietal areas, and showed right hemispheric activation only in the early phase; later, the activation was prevalent in the left temporo-parietal region. Demeurisse and Capon (1987) found that, during a naming task, aphasics subjects had a more bilateral activation than normal subjects. However, the patients with larger left hemispheric activation had a better prognosis. Although technological advances in the last decade have made these techniques obsolete, their importance remains to be underlined, not only for historical reasons. Their results have been largely confirmed and refined with newer functional imaging techniques, such as PET and fMR: in particular, the fact that all cognitive tasks do not engage a single brain area, but complex, differentiated networks of cerebral regions.

Single photon emission computerised tomography (SPECT) Technical aspects This technique represented a major methodological advance in rCBF measurements, allowing the tomographic assessment of cerebral perfusion and its representation according to axial, coronal, and sagittal slices. Clinical applications were developed by Kuhl and Edwards (1963): SPECT is based on the use of gamma emitters, which can be inserted in appropriate molecular complexes to produce radiotracers. The acquisition of emitted radioactivity is performed by a rotating gamma camera, in line with a dedicated computer, which reconstructs the collected data and computes the

tomographic images of tracer distribution. The ideal rCBF tracer should freely cross the blood-brain barrier, have a high cerebral extraction coefficient, and display a stable captation during the time of the exam. A group of molecules belonging to the family of lipophilic amines (IMP and HIPDM with 1231), and, more recently, 90mTc HMPAO have been widely used (Lucignani et al., 1987). The distribution of these tracers, in the absence of rediffusion from brain to blood, is proportional to regional cerebral blood flow. Inhaled 133Xe can also be used for SPECT (Stokely, Sveinsdottir, Lassen, & Romner, 1980): while the previous tracers allowed only steady state measurement, the Xe SPECT can also be used to perform activation studies (see, for example, Rezai, Andreasen, Alliger, Cohen, Swayze, & O’Leary, 1993). Neuropsychological applications SPECT with [1231] HIPDM has been used in particular in patients with cerebrovascular lesions, and has confirmed tomographically the presence of areas of hypoperfusion which are larger than the structural damage shown by CT (Perani et al., 1988): for example, subcortical lesions can be associated with hypoperfusion of the overlying undamaged cortex, and supratentorial lesions can be accompanied by hypoperfusion of the contralateral cerebellar hemisphere (crossed cerebellar diaschisis—Baron, Bousser, Comar, & Castaigne, 1981). These reductions of blood flow in structurally unaffected areas probably depend on different mechanisms: particularly interesting from the neuropsychological standpoint is the possibility that the decrease in flow might be the consequence of a reduction of local metabolism, due to a “deactivation” following on from the distant lesion (diaschisis). This deactivation might be responsible for clinical events: for example, patients with aphasia or hemineglect due to a subcortical lesion have been shown to have a more severe cortical hypoperfusion than patients with subcortical strokes unassociated with cognitive impairment (Perani, Vallar, Cappa, Messa, & Fazio, 1987). This finding has been confirmed by other studies (Okuda, Tanaka, Tachibana, Kawabata, & Sugita, 1994; Skyhoj Olsen et al., 1986; Weiller, Ringelstein, Reiche, Thron, & Buell, 1990). The

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follow-up study of the same patients showed a parallelism between the recovery of neuropsychological disorders and the regression of cortical hypoperfusion (Vallar et al., 1988). SPECT with [1231] HIPDM and with [90mTc] HM-PAO has been also extensively applied to the study of dementing conditions, in particular of AD, and has consistently shown a reduction of perfusion in temporo-parietal associative cortex (see Perani & Cappa, 1995, for a review). The results are in excellent agreement with PET (Messa et al., 1994) (Fig. 5.5), and indicate that SPECT has an important role in the early diagnosis of AD (Karbe, Kertesz, Davis, Kemp, Prato, & Nicholson, 1994). The reduction is usually bilateral, but can sometimes be asymmetric, with a good correlation with verbal/nonverbal asymmetries in neuropsychological impairment (Perani et al., 1988). A good correlation of the site of hypoperfusion with the neuropsychological presentation has also been found in progressive, selective neuropsychological impairments, such as progressive aphasia (Cappa et al., 1993; Snowden, Neary, Mann, Goulding, & Testa, 1992) and frontal lobe dementia (Elfgren, Ryding, & Passant, 1996; Miller et al., 1991).

Positron emission tomography (PET) Technical aspects Positron Emission Tomography (PET), the leading method for the investigation of brain physiological processes in vivo, is based at the most general level

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on three components (Powers & Raichle, 1985): (1) a positron tomograph which allows the precise measurement of regional radioactivity in vivo; (2) a positron emitting tracer which can be used for human studies; (3) a mathematical model of the tracer kinetics which establishes the quantitative relationship between the regional radioactivity measured by the tomograph and the physiological variable under investigation. These three aspects, rooted in different fields of science, from physics to chemistry to mathematics and computer science, are in continuous, rapid development. PET tomographs include a system of detectors that can take advantage of the fundamental property of positron emitters, i.e. the interaction of positrons with electrons, resulting in the creation of two gamma photons travelling in opposite directions. The registration of these coincidence events by two opposite detectors allows the precise determination of the spatial location of the annihilation. This basic mechanism, associated with absorption correction procedures, according to the general principles of tomographic techniques, allows the measurement of local radioactive tracer concentrations which can be represented as images of brain radioactivity. In this field the advances have been in particular from the point of view of improving spatial resolution and signal to noise ratio. The recent developments of 3-D data acquisition techniques, with the retraction of the septa used for collimation (septa out) have been extremely successful from this point of view (Townsend et al., 1991).

FIGURE 5.5

Comparison of MRI, PET, and SPECT in the same AD patient. Although the structural image is not characteristic of the condition, both PET and SPECT show the “typical” AD pattern of posterior (temporo-parietal) metabolic and perfusional reduction.

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PET tracers can be isotopes of biological elements (such as oxygen 15) or of nonbiological elements which can be combined to biological molecules as markers (such as fluorine 18 in the deoxyglucose molecule). All positron emitting isotopes have a short half-life, from less than a minute to a few hours: this characteristic dictates the necessity to have isotope production by cyclotron available in the proximity of the PET tomograph. The main development in this area is the availability of smaller, dedicated cyclotrons (baby cyclotrons), which are less costly (relatively speaking) and easier to operate and maintain. The third, non-hardware area of PET development, mathematical and statistical modelling, is in a state of continuous evolution. Although most of the following discussion will be limited to modelling aspects of metabolic and blood flow measurements, it must be underlined that the field of application of PET techniques to the in vivo study of brain physiology is much broader, including other parameters, such as protein turnover or neuroreceptor binding. Although these potentialities have not, with a few exceptions, been applied to the study of cognitive function, it appears likely that they will become more and more important as the field of cognitive neuroscience moves from the system to the cellular and molecular levels of investigation. When we wrote this chapter for the first Italian edition of this textbook (1988), we could be confident that we had reviewed all the PET literature devoted to the study of cognitive function. It is a matter of satisfaction for researchers in the field to note that now any effort to cover exhaustively even a single area, such as language or memory, would be doomed to certain failure: new PET studies appear continuously, not only in specialised journals, such as Neuroimage or Human Brain Mapping, but also in publications dealing with every other discipline related to the study of cognitive function. Our endeavour will thus be limited to providing the basic information about the main methods of PET investigation, including some technical aspects that we deem necessary for the appropriate interpretation and planning of cognitive experiments. The review of specific research will be limited to the exemplification of

different approaches. The discussion will cover resting state methods, i.e. the assessment of physiological parameters, such as cerebral blood flow, while the subjects are not engaged in a predetermined cognitive activity, as well as the now prevailing field of functional activation methodology. Resting state studies Methodologies. The 18-fluorodeoxy glucose method (18F-FDG) is based on a modification of the in vitro autoradiographic method originally described by Sokoloff et al. (1977). Deoxyglucose is transported to the brain and phosphorilated as glucose, but cannot enter further metabolic pathways and is trapped in the tissue. If marked with a positron emitter, its local concentration can be measured with PET. This is one of the variables that are entered in the equation to calculate the local glucose metabolic rate, together with three constants (influx, efflux, and phosphorilation) and a “correction” constant to account for kinetic differences between glucose and deoxyglucose (Reivich et al., 1985). The oxygen dynamic steady state method (Frackowiak, Lenzi, Jones, & Heather, 1980) allows the measurement of rCBF, of local oxygen consumption (rCMR02), and oxygen extraction ratio (OER). The assessment of rCBF requires the inhalation of C 02 labelled with 150. In the lungs carbonic anhydrase converts it to circulating water, [150] H20. After a few minutes a steady state is reached, which allows the calculation of regional cerebral blood flow. The measurement of oxygen consumption requires the inhalation of molecular oxygen marked with 150. The tracer binds to haemoglobin and enters the systemic circulation: in the brain part of the oxygen is extracted for normal aerobic processes, and is transformed in labelled water, whose regional concentration at steady state depends on the oxygen extraction ratio (rOER). The rCM R02 can be calculated by multiplying rOER with rCBF and blood oxygen concentration. Both the oxygen and the glucose steady state methods are characterised by an excellent spatial resolution. They are both based on steady state

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measurements (in the case of [18F] FDG, 60 minutes after intravenous injection of the tracer, in the case of oxygen 15,10 minutes after inhalation) that must be pursued until sufficient radioactivity counts have been collected. Given these characteristics, they are not suitable for the assessment of the fast and short-lived changes of regional blood flow and metabolism due to sensorimotor and cognitive activity, but only for the study of “resting” brain function in patients with cognitive disorders due to central nervous system impairment. They allow the measurement of lesioninduced “functional” derangement, which often does not coincide with the “structural” damage shown by CT or anatomical MRI. This is of course typical of conditions that are not associated with gross tissue necrosis, as most degenerative diseases; but can also be true of vascular lesions, as already discussed for other rCBF measurements (see previous section). Neuropsychological applications. The resting state PET studies in the field of aphasia are discussed in the chapter on the neurological foundations of language (Cappa & Vignolo, Chapter 8 this volume). Recent applications include the study of recovery. Metter, Jackson, Kempler, and Hanson (1992) have shown a significant positive correlation between changes in temporo-parietal metabolism and auditory comprehension recovery, while Heiss, Kessler, Karbe, Fink, and Pawlik (1993) have shown that the glucose metabolic rates in undamaged left hemispheric areas had the best predictive value on the recovery of auditory comprehension four months after stroke. In general, there is a positive correlation between the regression of functional depression in structurally undamaged areas in both hemispheres and aphasia recovery in the early period (from one to three months post stroke) after a left hemispheric stroke of limited extent (Cappa et al., 1997). The same phenomenon has been observed in right hemispheric lesion patients with unilateral neglect (Perani, Vallar, Paulesu, Alberoni, & Fazio, 1993; von Giesen, Schlaug, Steinmetz, Benecke, Freund, & Seitz, 1994). Recovery was associated with regression of functional impairment in areas not only in the ipsi-, but also in the contralateral hemisphere.

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Resting glucose metabolism has also been investigated in a group of amnesic patients who had lesions of different aetiologies, sometimes unassociated with any structural damage on MRI (anoxia, Korsakoff’s syndrome) (Fazio et al., 1992). This study showed a widespread metabolic depression which involved all structures connected in Papez’s circuit—hippocampal regions, thalamus, cingulate cortex, and fronto-basal areas— underlining the role of this network in episodic memory. Perhaps the most important area of application of resting state methods is the study of dementing conditions (see Perani & Cappa, 1995, for a review). The original observation of decreased temporo-parietal rCMR02 and rCBF, paralleling dementia severity (Frackowiak et al., 1981) has been confirmed and refined by many [18F] FDG studies, which have indicated that this pattern is “typical” of AD (Foster, Chase, Fedio, Patronas, Brooks, & Di Chiro, 1983; Haxby, Duara, Grady, Cutler, & Rapoport, 1985). The correlation between the pattern of metabolic impairment and the neuropsychological picture has been addressed by many investigations: an excellent concordance exists between right-left asymmetries and predominant “verbal” or “visuospatial” patterns of impairment (for a review, see Rapoport, 1991). Specific correlations between different aspects of memory in AD and local glucose metabolism have also been found (Perani et al., 1993) (Fig. 5.6). In particular, this study confirmed the association of episodic memory with the structures of Papez’s circuit, and showed correlations between, respectively, short-term and semantic memory and language areas, and procedural learning and a network including cerebellum, basal ganglia, and dorsolateral frontal cortex. PET is also useful to identify the pattern of metabolic impairment in other dementing conditions associated with mostly subcortical involvement, such as progressive supranuclear palsy (D’Antona, Baron, Samson, Serdaru, Viader, Agid, & Cambier, 1985; Leenders, Frackowiak, & Lees, 1988) and Huntington’s chorea (Young et al., 1986), as well as in other diseases that can be associated with cognitive decline, such as multiple sclerosis (Brooks, Leenders, Head, Marshall, Legg,

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& Jones, 1984; Paulesu et al., 1996), or the AIDS dementia complex (Rottenberg et al., 1987). In general, these investigations have confirmed the involvement of the frontal lobe in the so-called “subcortical” dementias. Activation studies The introduction of dynamic methods for the rapid measurement of regional cerebral blood flow while subjects were engaged in a specific task has played a crucial role in the development of cognitive activation studies. These methods require the intravenous injection of a bolus of water labelled with positron emitting 150, which has a half-life of 2.1 minutes (H2150) (Herscovitch, Markham, & Raichle, 1983), or the inhalation of C1502 (Lammertsma et al., 1990). Another tracer that has been used recently is 150-buthanol (Herscovitch, Raichle, Kilboum, & Welch, 1987). PET is used for the dynamic measurement of the cerebral uptake of the tracer, which will reflect the conditions of

cerebral activity, being proportional to blood flow (Fox & Mintun, 1989). Several different data analysis methods have been developed to identify the site and extent of the modifications in cerebral perfusion associated with specific, localised cerebral activation. They are based on different approaches to the same set of problems; that is, to detect and evaluate the significance of differences or modifications in the spatially extended maps of cerebral radioactivity reflecting genuine changes in function related to the experimental paradigm. These must be separated from the noise due to different confounds, and localised with reference to brain anatomy (Fox, Mintun, Reiman, & Raichle, 1988; Poline & Mazoyer, 1993; Roland, Levin, Kawashima, & Akerman,1993; Worsley, Evans, Marret, & Neelin, 1992). This is a field in constant evolution: while the details of the different procedures can be of considerable complexity, some basic understanding of the problems of data analysis, and of the possible

FIGURE 5.6

Images of regional cerebral metabolic rate for glucose for similar axial and coronal sections in a normal subject, an amnesic patient, and an AD subject. The axial image shows the reduction of thalamic and mesial temporal metabolism in the amnesic patient, and the “typical” temporo-parietal metabolic depression in AD. The coronal images show the mesial temporal hypometabolism in both amnesia and AD (see arrows).

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solutions, are mandatory for proper experimental design and results interpretation. In this chapter, the discussion will be limited to Statistical Parametric Mapping (SPM) a comprehensive and continuously evolving set of data analysis procedures developed by the Wellcome Department of Cognitive Neurology group (Friston et al., 1989; Friston et al., 1990; Friston, Frith, Liddle, & Frackowiak, 1991a, b; Friston et al., 1995b). The reason for this choice is that SPM is the most diffuse data analysis methodology in cognitive neuroscience. SPM takes into careful consideration all the problems summarised earlier, proposing an open set of solutions within the framework of statistical theory, from the general linear model (Friston et al., 1995), to nonparametric (Holmes, Blair, Watson, & Ford, 1996) and multivariate approaches (Friston, Poline, Holmes, Frith & Frackowiak, 1996). This general approach has been also fruitfully applied to fMR (see later). SPMs are spatially extended statistical processes, which are based on the following data analysis steps: 1. Stereotactic normalisation: PET data acquired for each subject are oriented according to the bicommissural line and transformed to the standard stereotaxic space (Talairach & Tournoux, 1988). With 2-D data acquisition techniques, normalisation was a necessary step for inter-subject averaging. The low signal to noise ratio resulted in signals of limited intensity: it was thus necessary to average data from multiple subjects studied in the same experimental conditions (Fox, Mintun, Reiman, & Raichle, 1988), making any direct correlation with the individual anatomy impossible. The new 3D tomographs allow single subject studies, which allow direct (within-subject) coregistration with anatomical MRI (Watson et al., 1993). However, multiple subjects are still generally used to improve statistical power, given the low magnitude differences elicited by most cognitive paradigms (for recent developments and a general approach to normalisation, see Friston et al., 1995a). 2. Smoothing, using a Gaussian filter, in order to suppress the effects of individual anatomical

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differences and to increase the signal to noise ratio. 3. Analysis o f covariance (ANCOVA): this preliminary normalisation procedure removes global variations of regional perfusion among individual subjects and among different conditions, which are independent from the local cerebral modifications induced by the experimental manipulations. 4. Hypothesis testing, which can be performed according to several experimental designs. The most widely used, and simplest, design, is the so-called subtraction method, based on Donders’ mental chronometry approach in experimental psychology (Donders, 1969). The subtraction method requires a baseline condition (usually rest), which can be compared to an “activated” condition. In the most basic form, the radioactivity images collected during baseline and activation conditions are subtracted, and the resulting differences submitted to some form of statistical test. Within SPM, the evaluation of significance is based on an estimate of error variance in each point (voxel). A typical PET study with a 10cm field of view in the axial direction, yields about 10,000 voxel measurements: the SPM procedure measures the differences in perfusion and the error variance for each voxel, and tests them against the null hypothesis (lack of differences between baseline and activation) using a known distribution, such as Student’s t, F, or chi square). The recent versions of the SPM include also a formal evaluation of the significance of the size of the activation in number of pixels, based on the theory of Gaussian fields (Friston, Worsley, Frackowiak, Mazziotta, & Evans, 1994). This “categorical” approach, which has been extensively used in cognitive PET research, is based on a large number of assumptions: in particular, it requires what has been called the “pure insertion hypothesis” (Friston et al., 1996), i.e. cognitive processing components are considered as separate and simply additive, not interacting with each other. Only this assumption allows the (now) classic decomposition of cognitive tasks into

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multiple components, which is the prerequisite of any subtraction. A prototypical example of this approach is the Petersen, Fox, Posner, Mintun, and Raichle (1988) word processing experiment, described in detail in another chapter (Cappa & Vignolo, Chapter 8 this volume). While this approach may be perfectly legitimate at a “functional” level of analysis, it appears extremely unlikely that the set of underlying assumptions apply to actual brain function. Other approaches are, within the general linear model, the parametric and the factorial (Friston et al., 1995b). The former is based on the computation of correlations between regional cerebral activity and continuous or graded stimulation parameters: for example, Grasby, Frith, Friston, Frackowiak, and Dolan (1993) found that the activation of the hippocampus was correlated with the increase in word list length that the patients had to memorise. Price, Wise, Ramsay, Friston, Howard, Patterson, and Frackowiak (1992) have reported a linear relationship between the regional perfusion in auditory areas, and the rate of word presentation (see Buechel, Wise, Mummery, Poline, & Friston, 1996, for the results of nonlinear correlations applied to a similar experimental paradigm). Factorial design allows the study of interactions: this has been applied to combined pharmacological-cognitive paradigms (Friston et al., 1992), but might prove a fruitful approach to cognitive processing (Friston et al., 1996). The most recent proposal within SPM is the multivariate method of data analysis, which does not require the probably untenable assumption of linearity in brain response (Friston et al., 1996), and seems to be ideally suitable for the study of functional connectivity, which previously could be approached only descriptively through principal component analysis (Friston, Frith, Liddle, & Frackowiak, 1993) Neuropsychological applications. The first PET activation studies in normal subjects were performed using the [18F] FDG method, which required a protracted presentation of repeating stimuli, and thus measured a brain response averaged over a long lapse of time, i.e. in totally unphysiological conditions. It was nevertheless possible using this method to show functional

asymmetry in the temporal cortex. Verbal stimuli activated the left fronto-temporal cortex and the thalamus, while nonverbal stimuli were associated with a predominant right hemispheric response (Mazziotta & Phelps, 1985). As already observed, the availability of dynamic methods, allowing the measurement of brain responses within a more adequate time range (in the order of a minute with standard activation techniques) has resulted in a real explosion of cognitive activation studies. All the domains of cognition have been explored: language (see Cappa & Vignolo, Chapter 8, this volume), attention (Corbetta, Miezin, Dobmeyer, Shulman & Petersen, 1990; Corbetta, Miezin, Shulman, & Petersen, 1993), mental imagery (Decety, Perani, Jeannerod, Bettinardi, Tadary, Woods, Mazziotta, & Fazio, 1994; Kosslyn, Alpert, Thompson, Chabris, Rauch, & Anderson, 1994), and some of the results can be found in the relative chapters. The following examples, taken from the study of memory, are not intended to provide a full review (see Vallar, Chapter 15 this volume), but only to illustrate different approaches. Working memory is an active field of PET investigation, and has been particularly focused on the role of the frontal lobe. An interesting integrative approach has been taken by the McGill group. This is based on the selection for PET studies of tasks that are known to be impaired in patients with frontal ablations, and which have “monkey” versions for which a link with specific lesion sites within the frontal lobe has been shown. These included a visual working memory task, requiring the continuous monitoring of the responses (self-ordered pointing task), and the learning of arbitrary associations (conditional task). PET showed distinct location of frontal activation, compatible with animal studies: Ba 9 and 46 for the former, Ba 8 for the latter, bilaterally with a left sided prevalence (Petrides, Alivisatos, Meyer, & Evans, 1993a). A verbal task similar to the one used in the visual working memory experiment activated the same areas in the left hemisphere, with the addition of a ventral frontal region (Ba 10) when monitoring of externally ordered stimuli was required (Petrides, Alivisatos, Meyer, & Evans, 1993b). The role of the latter area in working memory has been recently confirmed in another

5.

investigation with the Tower of London test (Owen, Doyon, Petrides, & Evans, 1996). A complementary approach to the PET study of working memory is based on Baddeley’s model (Baddeley, 1986). Paulesu, Frith, and Frackowiak (1993) have shown that an auditory-verbal working memory task was associated with a left peri sylvian activation pattern. Comparing this activation with the one observed during a letter rhyming judgement task, it was possible to separate the areas related to the rehearsal process (mainly Ba 44) from those involved with phonological storage (supramarginal gyrus—Ba 40). Visual working memory has been associated with the activation of a network of frontal, parietal, and occipital areas in the right hemisphere (Jonides et al., 1993). Another extremely active area of investigation has been the study of long-term retention. One of the leading research problems in this field has been the discrepancy between the well known role of hippocampal lesions in producing human amnesia (Squire & Zola-Morgan, 1991), and the relative difficulty of observing hippocampal activation during PET studies of normal subjects engaged in long-term memory tasks. The hippocampus was activated in an early study (Squire et al., 1992), which contrasted a cued recall condition of word lists with a priming (stem completion) task. During retrieval, a right frontal and hippocampal activation was observed with the former, while the latter was associated with a flow decrease in the right occipital lobe. Grasby et al. (1993) found that when the activation observed with digit sequences exceeding the span was compared with that associated with a digit span task, activations were found bilaterally in the dorsolateral frontal cortex, in the precuneus and in retrosplenial areas. Hippocampal activation could only be observed with a parametric design (see earlier), i.e. correlating the blood flow response with list length (Grasby et al., 1993). Subsequent studies have found that hippocampal activation is associated with high recall conditions, due to repeated exposure and deep encoding (Schacter, Alpert, Savage, Rauch, & Albert, 1996), and in general to successful recollection (Nyberg, McIntosh, Houle, Nilsson, & Tulving, 1996). Specific correlates have also been assigned to the multiple neocortical areas associated with memory

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tasks. There is ample evidence that left dorsolateral frontal cortex activation is related to semantic encoding (Kapur et al., 1994; Shallice et al., 1994; Tulving et al., 1994); the right prefrontal cortex has been shown to be related to intentional retrieval (Shallice et al., 1994), although it is still debated whether its activation increases with successful retrieval (Rugg, Fletcher, Frith, Frackowiak, & Dolan, 1997), or is simply related to retrieval attempt (Kapur et al., 1995). The precuneus is activated in high-imagery memory tasks (Fletcher, Shallice, Frith, Frackowiak, & Dolan, 1996). This set of results is remarkable, because it has suggested important roles in memory processing for several areas, which were not predicted on the basis of neuropsychological investigations in amnesic patients. In particular, the role of the frontal cortex in “strategic” or “cognitive mediation” (Warrington & Weiskrantz, 1982) aspects of memory seems to be amenable to empirical investigation with PET. It is noteworthy that a “reverse” approach (i.e. neuropsychological investigations in patients primed by PET results) is appearing in the neuropsychological literature (see, for example, Swick & Knight, 1996, for a partial failure to find encoding and retrieval defects in patients with frontal lesions). Although the results of this integrated approach may be sometimes difficult to reconcile (see Vallar, this volume), they clearly show that PET does not simply have a confirmatory role regarding the results of lesion-based neuropsychological investigations. Other interesting insights have been provided by the study of semantic memory. Perani et al. (1995) found that animal picture recognition activated the posterior visual areas, including the left inferior temporal gyrus. For artefact picture recognition, all activations were left hemispheric and dorsal through the temporal and frontal lobes, with the exception of ventral activation seen bilaterally in the inferior temporal/fusiform gyrus and left hippocampal gyri (Fig. 5.7). Similar results have been reported by Martin, Wiggs, Ungerleider, and Haxby (1996) for a picture discrimination task, supporting different anatomical activations depending on the category of picture (living or nonliving) presented. The neural corre-

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lates of access to semantic knowledge from pictorial or verbal material have been compared by Vandenberghe, Price, Wise, Josephs, and Frackowiak (1996) using a word and picture matching task: the main finding was an extensive area of common activation for words and pictures, which included several left hemispheric areas: the temporo-parietal junction, the fusiform gyrus, the middle temporal gyrus, and a left inferior frontal area. Damasio, Grabowski, Tranel, Hichwa, and Damasio (1996) reported activations from a PET study where subjects named from pictures, famous people, animals, and tools. Naming famous people activated an area in the left ventrolateral temporal pole, while naming animals and tools activated different areas in the left posterior inferotemporal and left temporal pole. Taken together, these studies have provided evidence for an important role of temporal lobe structures (in particular, for inferior temporal cortex) in semantic memory.

Another area of extreme interest for the clinical neuropsychologist is the PET activation study of patients. This approach has to date been limited by several technical problems, which have however been largely solved by the possibility of performing single subject experiments. Group studies have been performed using simple motor tasks in patients who have recovered from motor impairment, and have shown evidence of extensive brain reorganisation (Chollet, Di Piero, Wise, Brooks, Dolan, & Frackowiak, 1991), with large inter-individual variability (Weiller, Chollet, Friston, Wise, & Frackowiak, 1992). A group of patients who had recovered from Wernicke’s aphasia has been studied with single word repetition and controlled association tasks (Weiller et al., 1995). This study showed evidence of a recruitment of right hemispheric frontal and parietal areas, not activated by normal subjects during these tasks. Examples of the single case approach can be found in Engelien et al. (1995).

FIGURE 5.7

Areas of differential activation during the recognition of (A) living (animals) and (B) non-living (tools) entities.

5.

Functional magnetic resonance (fMR) The most important recent addition to the field of functional imaging is certainly functional magnetic resonance (fMR). From the discussion of the principles of MR image formation, it should be clear that any modification in the chemical milieu of the brain, as in the metabolic changes induced by neuronal activity, will affect water molecules and, consequently, the MR signal. The main source of these modifications is the variation in cerebral blood flow coupled with the regional increases in cerebral activity associated with motor, sensory, and cognitive tasks (Raichle, Grubb, Gado, Eichling, & Ter-Pogossian, 1976). The blood-flow changes, however, are short-lasting and are quantitatively modest. A crucial role in the development of functional imaging with MR has been played by the ultrafast image acquisition techniques called Echo-Planar Imaging (EPI) (Stehling, Turner, & Mansfield, 1991). In contrast with GRE sequences, EPI does not require the repetition of the application of the radiofrequency, as the whole image is acquired within the time frame of the decay of a single MR signal (about 50 milliseconds). The EPI technique, which is based on the ultrafast application of alternating magnetic gradients, requires specific hardware, which is not included in standard clinical machines. The first functional MR study (fMR) was performed using a paramagnetic contrast agent (gadolinium DPTA), given to the subjects intravenously; the activation condition was an intermittent visual stimulation (Belliveau et al., 1991). The local concentration of the contrast agent influences tissue T2*. Using a T2* sensitive EPI sequence it was possible to acquire a series of images showing the passage of the injected bolus during a 15-second period (blood volume maps). The comparison of resting state maps with the maps acquired during photic stimulation showed a localised increase in the primary visual areas. The general principle that the rate of T2* decay is influenced by local variation in magnetic field intensity caused by changes in magnetic sensibility was then extended to endogenous molecules, leading to totally noninvasive fMR methods. In particular, blood and brain tissue differ in magnetic susceptibility because of the

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paramagnetic properties of deoxyhemoglobin. The variation in the content of oxygenated and deoxygenated haemoglobin can thus be used to acquire different MR images (Fig. 5.8). Ogawa, Lee, Nayak, and Glynn (1990) were the first to show that a reduction in oxygen content increased the contrast between blood vessels and surrounding tissue. Turner, Le Bihan, Moonen, Depres, and Frank (1991) were able to detect the temporal variation in the level of oxygenation in the living animal. The first in vivo human studies based on the level of blood oxygenation were performed by Ogawa et al. (1992), and by Kwong et al. (1992). The increase in MR signal in the occipital areas associated with photic stimulation was interpreted as the consequence of the relative uncoupling between the increase in blood flow and the increase in oxygen consumption. Given that the flow increase exceeds the increase in oxygen use by the tissue, the venous blood draining from an activated cerebral region has more oxyhaemoglobin and less deoxyhaemoglobin, which thus can act as an endogenous contrast agent. Similar results were obtained by Bandettini et al. (1992) using a motor activation task.

FIGURE 5.8

The principles of functional MR imaging using the BOLD technique (explanation in the text).

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The BOLD technique is based on the modification of the T2* signal, most likely in the venous district. However, the influx of arterial blood can also affect the T1 signal (Kwong et al., 1992), and is at the basis of the EPISTAR technique (see Cohen & Bookheimer, 1994). The application of a preparatory radiofrequency stimulus or “saturation” to reduce the signal coming from a section is used for MR angiography. This allows the detection of incoming blood in the saturated region, which results in a signal increase, and can be used to measure the differences between a baseline and an activated condition. Several groups have attempted to perform functional imaging studies with less rapid, non-EPI, imaging techniques (based on GRE sequences) on clinical scanners. Convincing results have been obtained with high magnetic fields (4.0 Tesla: Ugurbil et al., 1993), or for sensory and motor activations (Cao et al., 1994; Schneider et al., 1994), while cognitive activations seem to be more difficult to detect. The impressive development of fMR has awakened great interest in the neuropsychological community: in comparison with PET, fMR is non invasive, less expensive and more widely available, and seems thus to be the ideal candidate for cognitive activation studies. However there are still several problems with data analysis and interpretation which remain to be solved. A few seconds (5 to 10) are necessary after stimulus presentation for the signal to reach its peak: this interval represents the limit of temporal resolution, which, although superior to PET, remains far from the time window of neurophysiological techniques. The ability to study the entire brain is still limited to a few centres: usually the acquisition is limited to a number of sections. The activation-induced modification of the MR signal is modest, in the order of 2-5% at 1.5 Tesla, and thus difficult to disentangle from noise and temporal fluctuations. The most serious problem is caused by the presence of artefacts. The high spatial resolution of the technique has a consequence that even minimal head movements produce huge variations in pixel intensities. In the case of image subtraction, these movement artefacts can produce false areas of activation. Image co-registration algorithms are

effective in reducing this risk (Woods, Cherry, & Mazziotta, 1992). Signal from venous vessel not related to the activation is another problem, which can be solved by preliminary MR angiography. Activation studies As in the case of PET, methods of data analysis are in constant evolution. The high spatial resolution and good signal-to-noise ratio are ideally suited for single subject studies, which are however usually associated with some form of group analysis As in the case of PET, the activation studies can be analysed with image subtraction (activation minus control), followed by some form of statistical testing. The areas of significant activation are then usually mapped on anatomical images from the same subject. fMRI allows another class of analyses, based on the time series of the activation. Each pixel response can be cross-correlated over time with a reference function representing the time course of the expected activation, taking into account the latency between the stimulation and the haemodynamic response. As most of the artefactual signal over time is due to events, such as head movements, blood pulsation, etc., which occur at random with respect with the time course of the activation, these methods can be useful to remove artefacts (Bandettini, Jesmanowicz, Wong, & Hyde, 1993). A similar approach, within the general SPM framework, is based on multiple regression analysis (Friston, Jezzard, & Turner, 1994; Friston et al., 1995). Nonparametric statistical approaches have also been recently proposed (see, for example, Stem et al., 1996). The anatomical location of the activations shown by fMRI have been “validated” with the comparison to those observed with PET using the same paradigm (auditory-verbal short-term memory: Paulesu et al., 1995; face matching: Clark et al., 1996). Neuropsychological applications The characteristics of the MR setting require the development of dedicated methods for stimulus presentation (for a discussion, see Cohen, Noll, & Schneider, 1993). It is thus not surprising that the first applications were devoted to simple motor

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tasks: for example, Kim et al. (1993) studied subjects while they were performing sequential thumb opposition movements. An asymmetry was observed in the primary motor cortex activation: left finger movements were associated with a strict contralateral cortical activation, while on the right side both ipsi- and contralateral activation could be observed, in particular in right-handers. Rao et al. (1993) have shown a contralateral activation for simple flexion-extension movements, while complex, sequential movements were associated with a more extensive activation, which included the somatosensory cortex, the supplementary motor area, as well as premotor areas bilaterally; the latter areas were also active during imagined execution of the movement. Visual perception and visual imagery have also been areas of intensive investigation (see Tootell, Dale, Sereno, & Malach, 1996, for a review). An exquisite specialisation has been shown to exist in the inferior temporal cortex, with a region in the fusiform gyrus selectively activated by faces and a nearby temporo-occipital area activated by letter strings (Puce, Allison, Asgari, Gore, & McCarthy, 1996). Visual cortex activation has been reported during visual imagery tasks (Le Bihan, Turner, Zeffiro, Cuenod, Jezzard, & Bonnerot, 1993). Language studies initially focused on word generation tasks (Hinke et al., 1993; McCarthy, Blamire, Rothman, Gruetter & Shulman, 1993;

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Rueckert et al., 1994). These were mainly confirmatory studies, which indicated a left hemispheric frontal opercular activation. A more complex pattern is shown by the comparison of letter and semantic fluency (Paulesu et al., 1997) (Fig. 5.9). In comparison with resting state, both tasks activated the anterior triangular portion of the left inferior frontal gyrus (IFG) and the left thalamus. There were also areas activated in one task but not in the other: the posterior opercular portion of the left IFG for phonemic fluency, and the left retrosplenial region for semantic fluency. The passive presentation of meaningful and meaningless verbal stimuli activates both superior temporal lobes, with an extension superior to that associated with nonverbal noise (Binder et al., 1994); the response amplitude was correlated with presentation rate (Binder, Rao, Hammeke, Frost, Bandettini & Hyde, 1994). Left-lateralised activation in the frontolateral and parieto-occipital cortex was associated with semantic monitoring of single words (animal names) (Binder et al., 1995). This activation was shown to be reliable across subjects and task repetitions, indicating that fMRI is a promising tool for the assessment of language dominance. The size of left hemispheric activation, elicited by a sentence comprehension task, has been suggested to be related to syntactic complexity (Just, Carpenter, Keller, Eddy, & Thulborn, 1996).

FIGURE 5.9

Brain activation during a word fluency task measured with fMRI: (A) phonemic verbal fluency; (B) semantic verbal fluency (adapted from Paulesu et al., 1997).

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In the memory field, Paulesu et al. (1995) have replicated the results of a PET study of auditory-verbal and visuo-spatial short-term memory with fMR, with a good correlation in two out of three subjects (Fig. 5.10). Prefrontal activation, with a right-sided prevalence, has been observed during a spatial working memory task (McCarthy et al., 1994). D’Esposito et al. (1995) have shown prefrontal cortex activation during dual task performance, but not during single working memory conditions, supporting the role of the frontal lobe in the central executive component of the working memory model. Stern et al. (1996) have been able to show bilateral hippocampal and parahippocampal activation during novel picture encoding in a recognition memory task. fMR studies have also shed new light on the functions of the cerebellum: rather unexpectedly, dentate nucleus activation has been observed during cutaneous stimulation and discrimination (Gao et al., 1996), and even during problem solving (Kim, Ugurbil, & Strick, 1994)

fMR has also been applied to the study of clinical populations. Hemiparetic subjects after a perinatal lesion showed a similar activation in the healthy hemisphere for both ipsi- and contralateral hand movements (Cao, Vikingstad, Huttenlocher, Tolwe & Levin, 1994). The V5/MT activation induced by visual motion (Tootell et al., 1996) was absent in developmental dyslexics (Eden et al., 1996).

Magnetic resonance spectroscopy (MRS) The modifications in cerebral metabolism induced by neural activity can also be assessed with in vivo magnetic resonance spectroscopy (MRS), using the 1H nucleus. In vivo spectroscopy allows the measurement of substances such as lactate, glutamate, and glucose, providing information on the glycolitic processes. The analysis is performed on regions of interest with a volume in the order of one cubic centimetre, and requires long acquisition times (several minutes) (Shulman, Blamire, Rothman, & McCarthy, 1993). Using this method, Chen, Novotny, Zhu, Rothman, and Shulman

FIGURE 5.10

Comparison of the regional activations during an auditory-verbal (a) and visuo-spatial (b) working memory task assessed with PET. Activation foci associated with phonological (c) and visuo-spatial (d) store. (Kindly provided by E. Paulesu.)

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(1993) have been able to measure variations in glucose metabolism induced by photic stimulation in the occipital cortex. Recent developments include multislice techniques, which have been already applied to clinical populations (Tedeschi et al., 1996).

CONCLUSIONS The application of neuroimaging methods to the study of cognitive functions has enjoyed an unprecedented development in the last few years, and is presently one of the cornerstones of cognitive neuroscience. This chapter has tried to provide an overview of the different research tools that are presently available to this field of research (with the exclusion of electrophysiological methods, which are described by Mecacci and Spinelli, Chapter 3 this volume). Our major aim has been to emphasise the strength and weaknesses of the different imaging tools from the point of view of the cognitive researcher or neurologist. To summarise, we can conclude that anatomical MRI represents at the moment the gold standard for in vivo lesion localisation and for studies of normal human anatomy. Methods for 3D reconstruction are now widely available; the areas of developments are automation of image segmentation and methods for cortical surface modelling (Loftus, Tramo, & Gazzaniga, 1995; Tootell et al., 1996). In the field of functional imaging, PET is the reference method. Recent methodological developments have remarkably simplified data analysis, and allow the activation study of single subjects, normal and lesioned. However, the high costs of the method are probably not going to decrease remarkably in the short term, and PET will remain the privilege of a few centres. Many cognitive researchers are entering the field of functional magnetic resonance, because of the wider availability and lower maintenance costs, and it appears possible that in the near future fMR will become the privileged method for cognitive activation studies. SPECT is widely available, and has been used in the neuropsychological field quite extensively. If used appropriately, it can provide important information

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supplementing structural imaging modalities, in particular in the study of dementing disorders. The relationship between the results of PET and fMRI imaging and the corpus of knowledge derived from anatomo-clinical and, more recently, clinicoradiological correlation study is not straightforward, and is the focus of a lively debate (see also Vallar, Chapter 6 this volume). The results of these different research methods are not directly comparable, but need to be integrated in a comprehensive framework that takes into account the strengths and weaknesses of each approach, and its unique contribution to the understanding of the neural basis of cognitive function. Functional imaging techniques allow the investigation of brain activity in normal, undamaged individuals, directly during the actual performance of a cognitive task that has been selected by the experimenter on the basis of a predicted relationship with brain function. It is hardly surprising that this type of investigation provides results that are not totally coincident with the findings of patient correlation studies, which are based on the observation of a lesion site, and of the accompanying modifications in cognitive processing (some examples have been discussed in relation to PET memory studies). In the first place, a total coincidence of the results between the two approaches would make the contribution of functional imaging largely trivial, and confine it to a confirmatory role. The reproducibility of PET results has been addressed experimentally. Although it is now well known that minimal modifications in the experimental paradigm, such as rate of stimulus presentation (Price et al., 1994), or practice with the stimuli (Raichle et al., 1994) can result in significant modification of the site and size of brain response, a recent European community study has shown excellent reproducibility across Centres, PET scanners, and cultures using a standardised experimental procedure (Poline, Vandenberghe, Holmes, Friston & Frackowiak, 1996). The main theoretical problem remains the interpretation of the regional patterns of activation or deactivation of brain areas. It must be underlined that the interpretative issue will remain crucial, even if all the technical limitations of functional imaging methods, such as spatial and temporal

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resolution, data analysis, and reliability, could be eliminated. Important advances can be expected from the integration of different imaging modalities in order to obtain optimal spatial and temporal resolution, for example by combining PET with neurophysiological techniques, such as MEG, which have exquisite temporal resolution (see, for an example of this approach, Heinze et al., 1994). The information processing models that have been prevalent in cognitive neuropsychology were typically compatible with the compositional analysis of PET tasks, and have informed a general approach to PET activation studies that tried to map

the boxes and arrows of cognitive models to specific brain regions. This type of approach has provided interesting results, but is not directly connected with any neurobiological theory of how the brain implements cognitive functions. The most influential alternative to this approach is related to connectionist (neural networks) modelling, and might find its PET methodological counterpart in nonlinear data analysis. Although it is too early to evaluate this approach, there is no doubt that the time is ripe to consider seriously the need for neural modelling as a necessary intermediate step between cognitive theory and behaviour.

6 The Methodological Foundations of Neuropsychology Giuseppe Vallar

Roger W. Sperry, who is well known to neuropsychologists for his seminal investigations of split-brain patients. A main feature of the recent developments of neuropsychological research, in addition to the production of a great deal of empirical data, has been a debate on the methodological foundations of the discipline. This chapter will discuss some main methodological issues, even though, when appropriate, reference will be made to specific historical periods in the development of neuropsychology. Neuropsychology, since its inception, has had two main aims. As a medical discipline, neuropsychology investigates the pathological modifications of cognitive and emotional processes, produced by brain damage or dysfunction, with diagnostic and therapeutic aims. Neuropsychology, however, has never been confined to this clinical dimension, developing instead a main heuristic component, which takes advantage of brain-damaged patients in whom mental processes are defective, treating them as experiments o f nature (see an early discussion of this method in Bernard, 1865).

In the last 30 years, a considerable development of human neuropsychology has been taking place. An indication of this is the number of journals specifically devoted to this discipline. In the 1960s, Neuropsychologia (1963) and Cortex (1964) were founded, in the following decade Brain and Language (1974), and in the 1980s Brain and Cognition (1982), Cognitive Neuropsychology (1984), Aphasiology (1987), the Journal o f Cognitive Neuroscience (1989), and Neuropsychology. In addition, neurological journals such as Annals o f Neurology, Archives o f Neurology, Brain, Journal o f Neurology, Journal o f Neurology Neurosurgery and Psychiatry, Neurology, and Revue Neurologique, still publish neuropsychological articles, which also appear in psychological journals (e.g. Cognition, Quarterly Journal o f Experimental Psychology, Journal fo r Experimental Psychology). This is also the case of neuroscience journals such as Behavioral and Brain Sciences, Experimental Brain Research, and Neuroreport. The role of neuropsychology within the human behavioural sciences is also witnessed by the Nobel Prize 1981 awarded to 95

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Two heuristic distinguished.

related

scopes

may

be

1. The investigation of the neural bases o f mental functions, through the anatomo-clinical correlation method, used since the early 19th century, and with the recent functional neuroimaging methods. 2. The investigation o f mental functions p erse; the study of patients with specific deficits may provide useful information to elucidate the functional architecture of mental processes, also independent of their neural correlates. The chapter comprises five sections.The first discusses the anatomo-clinical correlation method. A useful reading of this section presupposes a minimal knowledge of the basic technological foundations of the main neuroimaging techniques: Computerised Tomography (CT), Magnetic Resonance Imaging (MRI), Single Photon Emission Computerised Tomography (SPECT), Positron Emission Tomography (PET), functional Magnetic Resonance Imaging (fMRI) (see Perani and Cappa, this volume).The second section considers the contribution of connectionist modelling.The third is concerned with the method that, after World War II, replaced the traditional clinical assessment: group studies in braindamaged patients, whose performance on standardised tasks is compared with that of normal subjects, matched for relevant neurological and demographic variables. The fourth section considers the approach of cognitive neuropsychology, which has been very influential in the last 30 years. The fifth section discusses a number of specific controversial issues raised in the preceding sections: associations and dissociations among neuropsychological deficits, the concept o f syndrome, and group vs. single case studies.

THE NEURAL BASIS OF MENTAL ACTIVITY The anatomo-clinical correlation method The birth of scientific neuropsychology took place in the second half of the 19th century, as the

neuropsychology of aphasia (see also Gainotti, Chapter 7 this volume). In the early 19th century the anatomist Franz-Josef Gall (1758-1828) proposed a cerebral localisation of mental faculties (see ZolaMorgan, 1995). It was however the anatomoclinical correlational approach of the French physician Bouillaud (1825) and, most of all, of Paul Broca, which revealed a relationship between the damage to specific brain regions and dysphasia (see Hecaen & Dubois, 1969). The German neurologist Carl Wernicke (1874/1966-1968) then put forward an anatomo-functional model, in which the faculty of language was fractionated into discrete, though connected, components with different anatomical correlates. Wernicke drew a distinction between a centre for acoustic-verbal images, localised in the temporal lobe, and a centre for motor-verbal images, localised in the frontal lobe (Fig. 6.1). Many neurologists took the view that language was a multi-componential function. The most influential was Lichtheim (1885), who, following Kussmaul (1877), added to Wernicke’s model a component concerned with concepts, and accounted for the existence of reading and writing disorders, assuming the existence of specific centres for visual images and for the innervation of the peripheral organs involved in writing (Fig. 6.2).1 On the basis of models of this sort, in the second half of the 19th century the paradigmatic (Kuhn, 1970) research programme in neuropsychology aimed at localising different mental functions in specific brain areas or centres. The classical anatomo-clinical correlation method comprised these main steps. A behavioural analysis of the patient’s deficits (e.g. aphasia) was followed by a localisation of the cerebral lesion. The presence of an association between a specific behavioural deficit (i.e., the impairment of a given function) and the damage to a cerebral area allowed the inference that the neural basis of the function of interest was localised in that brain region (see discussion in Kosslyn & Van Kleek, 1990; Von Eckardt Klein, 1978). This kind of inference made use, since its inception, of the principle of dissociations between symptoms and signs. Bouillaud’s conclusion that the centre for words was localised in the frontal regions of the cerebral hemispheres was based on two related observations: patients with defective

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FIGURE 6.1 Wernicke’s (1874/1966-1968) anatomo-clinical model of language function.

FIGURE 6.2

An anatomo-clinical model of language function. A: centre of auditory images; M: centre of motor images; a: afferent branch; m: efferent branch; B: centre for the elaboration of concepts; 0: centre of visual representations; E: writing centre (redrawn from Lichtheim, 1885).

speech production had lesions in the frontal regions, that was spared in patients in whom the function was preserved. The inference from the pathological association (the abnormal behaviour, the symptoms or signs, manifestations of the impairment of function F, are associated with a lesion of brain region R) to the

normal state (F is localised in R) is not free from problems, however. The British neurologist Hughlings-Jackson (1879) pointed out that localising the lesion that disrupts a given function and localising the function are not the same thing. There may be different readings of this warning: 1. According to an holistic approach, in which all cerebral regions (at least as far as higher mental functions are concerned) are functionally equivalent, localising a specific mental function is simply meaningless. The investigation of the neural correlates of complex mental processes, such as language, spatial abilities, and memory, has clearly shown, however, that such nonlocalisationist positions (e.g. Lashley, 1929) are untenable, at least in their more extreme versions (see discussion in Benton, 1988; Phillips, Zeki, & Barlow, 1984). Many chapters of this book illustrate this conclusion. 2. A second problem derives from the fact that different brain regions are interconnected by white matter fibre tracts. A lesion of area A, therefore, might bring about a specific deficit disrupting the operation of brain circuit C, of which A is just one component. According to this view the correlation is to be, rather than with the damaged region only, with the whole circuit made dysfunctional by the focal lesion. The idea that a cerebral lesion may produce a functional impairment in far removed, but

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connected, regions is not novel (Monakow, 1914). Only in the last 20 years, however, has this concept of diaschisis been adequately specified, through functional neuroimaging techniques, which provide in vivo measures of the functional activity of the brain, in terms of regional blood flow and metabolism (see Perani & Cappa, Chapter 5 this volume). For more than a century the correlation has been based on methods such as post-mortem examination, surgical exploration, and, more recently, neuroradiological techniques with a higher and higher spatial resolution (brain scan, CT, MRI), which provide anatomo-pathological information, concerning the site, size, and aetiology of the cerebral lesion, but are unable to detect functional changes that do not produce neuronal death. Functional neuroimaging techniques (SPET, PET) have shown that cortical and subcortical lesions may bring about, in addition to the focal structural damage, a reduction of neural activity, without neuronal death, in far removed unaffected regions (at least at the current level of spatial resolution of CT and MRI) (see review in Feeney & Baron, 1986). Reductions of regional cerebral blood flow (rCBF) and metabolism are indexes of this pathological hypoactivation. This diaschisis is produced by the interruption of afferent projections from the damaged region to connected, far removed, areas. Mechanisms of this sort are, by and large, in line with the view that the neural basis of mental processes should be conceived in terms of complex neural circuits (e.g. Fazio, Perani, Gilardi et al., 1992; Mesulam, 1990; Metter, Riege, Kuhl et al., 1984). 3. Finally, it should be considered that the localisation of a given function in a specific cerebral region may imply an adequate neurobiological description (or reduction, according to physicalist materialism). The typical inference drawn from the anatomoclinical correlation studies discussed in this chapter is instead that specific cerebral regions are the neural basis of discrete mental functions.2 With these caveats in mind, the anatomo-clinical correlation method may be used independent of the

type of functional description of both the neuropsychological deficit and the normal mental function. Consider, for instance, aphasic disorders. According to research approaches using the Wemicke-Lichtheim model of the aphasias, the functional counterpart is a taxonomy of normal linguistic processes based on Wundt’s associationism (see Boring, 1950). The correlation may also be referred to more recent psycholinguistic models, which distinguish different levels of processing, such as phonological, syntactic, lexical-semantic. The functional description, finally, may be in terms of the box-andarrow information processing models of cognitive psychology, in which the dysfunction of specific components is correlated with the localisation of the lesion.3 Four anatomo-clinical studies illustrate these possibilities. Mazzocchi and Vignolo (1979) correlated the lesion sites of aphasic patients, as assessed by CT, with the traditional aphasic syndromes, confirming the classical localisations, even though relevant exceptions were found, such as the so-called subcortical aphasias (Vallar, Cappa, & Wallesch, 1992). Cappa et al. (1981) through a correlation between the type of error made by aphasic patients in a confrontation naming task, and the site of the lesion, suggested that the perisylvian regions of the left hemisphere are the neural basis of the phonological level of speech production, and the marginal ones (farther from the sylvian fissure) of the lexical-semantic level. Shallice and Vallar (1990), on the basis of a metaanalysis of the lesion sites of 10 patients with a selective impairment of auditory-verbal span, suggested that the inferior parietal lobule (supramarginal gyrus) of the left hemisphere was the neural correlate of the phonological short-term store component of verbal short-term memory. The anatomo-clinical correlation method has also been applied to non-verbal disorders, such as hemineglect. In humans, a lesion of the inferior parietal lobule (supramarginal gyrus) of the right hemisphere is the more frequent anatomical correlate of this disorder (Vallar, 1993). In principle, then, the anatomo-clinical correlation method may be applied within a given functional model, both to a series of single case

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studies, and to groups of patients. The significance of the correlation depends not only on the validity of the functional model, but also on both the adequate control of some neurological parameters (lesion aetiology, temporal interval between the onset of the disease and the correlation) and the specific imaging techniques (see Perani and Cappa, this volume) that are being used. The role of temporal parameters and of imaging techniques is illustrated by a study by Bosley et al. (1987), concerning a primary sensory deficit (lateral homonymous hemianopia), which may be produced by a contralateral lesion involving the occipital cortex. In a series of five stroke patients with hemianopia, CT showed in three a lesion in the occipital regions, which were spared in two cases. PET performed shortly after the ictus, by contrast, revealed occipital hypometabolism in all five patients. In the two patients in whom the lesion spared the occipital lobe, recovery from hemianopia paralleled a reduction of occipital hypometabolism. In the three patients with occipital damage no functional recovery took place. This study illustrates the role of two factors that may modify the interpretation of the anatomo-clinical correlation: the time of the correlation, and the imaging technique. First, had the correlation been done in the chronic phase only (at least one month after stroke onset) the erroneous conclusion would have been that only lesions involving the occipital lobe may bring about hemianopia. The study in the acute phase shows instead that extra-occipital lesions involving the afferent projections to the visual cortex may also produce a visual field disorder, which may recover over time. Second, PET revealed a functional derangement in the occipital regions, undetected by CT. The role of the factor aetiology is illustrated by the differential effects of neoplastic and vascular lesions. In the former, the natural evolution is one of progressive worsening of the deficit. In the latter some spontaneous recovery may occur. The factor length o f illness has, therefore, a very different role in the two types of deficits. In the case of neoplastic lesions, for instance, growth rate and type of tumour are relevant factors. Vallar and Perani (1987), reviewing published cases and personal observations, noted that hemineglect is more

frequently produced by rapidly growing malignant tumours, such as glioblastomas. By contrast, the association with slowly developing tumours, such as meningiomas, is less frequent. This difference might reflect the rapid growth of a tumour, which prevents the development of compensatory mechanisms by undamaged cerebral regions. Anderson et al. (1990) found that the association between visuo-perceptual deficits and right hemisphere damage was less systematic in the case of CT, or MRI-assessed tumours (gliomas, meningiomas), compared to stroke lesions with a similar localisation. Similarly, neoplastic lesions in the left hemisphere bring about aphasic deficits that are less severe than those produced by strokes. Qualitative differences also exist. Anomic aphasia is more frequently associated with tumours than with vascular lesions (Haas, Vogt, Schiemann et al., 1982; Miceli, Caltagirone, Gainotti et al., 1981). Autotopoagnosia in the pure form (i.e. the patients’ selective inability to indicate parts of their own body, to a verbal command, in the absence of aphasic disorders) is usually associated with left parietal neoplastic lesions (Denes, 1989). Finally, demographic factors such as sex, age, and socio-cultural differences (i.e. years of schooling) may affect the neuropsychological deficit, and, therefore, the anatomo-clinical correlation (see Basso & Cubelli, Chapter 9 this volume, for a review of the differences between fluent and nonfluent aphasia, related to age and sex differences). For instance, the mean age of patients with fluent aphasia has been found to be higher, compared with that of non-fluent aphasics (Basso, Capitani, Laiacona et al., 1980; De Renzi, Faglioni, & Ferrari, 1980; Miceli et al., 1981). Also the patients’ sex may influence the clinical manifestations of aphasia. The incidence of nonfluent aphasia has been reported to be higher in males (De Renzi et al., 1980), but the empirical evidence is not univocal (e.g. Basso et al., 1980), while recovery is better in females (Basso, 1992). These effects of sex may be related to differences in the anatomo-functional organisation of the brain (Kimura, 1983, Shaywitz et al., 1995; Witelson & Kigar, 1988). To summarise, anatomo-clinical correlation studies should take into account both neurological

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and demographic factors. The optimal strategy is to compare groups of patients, who differ only in the variable under investigation (e.g. the behavioural deficit, or the site and size of the lesion), all other parameters (e.g. age, sex, aetiology, and duration of the disease) being comparable.

Cerebral activation methods Even though pioneering investigations date back to the first half of the century (Fulton, 1928), and early rCBF activation studies were performed since the late 1960s (e.g. Lassen & Ingvar, 1990, for areview; Risberg & Ingvar, 1973), only in the last 15 years has the study of the neural basis of mental processes through activation methods undergone a major development, due to the availability of new functional imaging techniques (Frackowiak, Friston,Frithetal., 1997;Perani& Cappa,Chapter 5 this volume). The logic underlying this approach is complementary to that of the anatomo-clinical correlation method. The relevant correlation here is between the localisation of the variation (usually the increase, but also the decrease) of rCBF and the task performed by the subject, rather than between a defective performance and the site and size of the lesion. This method has been used mainly in normal individuals, but in a few studies the neural basis of functional recovery or residual performance has been assessed (e.g. Bottini, Paulesu, Sterzi et al., 1995). In PET studies, the conclusion that a given task is associated with the activation of one or more cerebral areas is based on the comparison between the experimental condition and an appropriate control condition, which differs from the former only in the process or task under investigation. This method was based on a procedure originally used in mental chronometry (Bonders’ subtraction method) (Meyer, Osman, Irwin et al., 1988; Posner, 1978). For example (Petersen, Fox, Posner et al., 1988), the cerebral areas activated during listening to words may be revealed by subtracting from the rCBF activation values of this condition the activation pattern of the control condition, in which subjects do not receive any stimulation, but just look at the fixation point, as in the experimental condition. As the two conditions differ only in the auditory-verbal stimulation, their difference gives the activation

pattern that is specific to word listening (see also Cappa & Vignolo, Chapter 8 this volume). More recent developments make use of nonsubtractive paradigms, which do not make the additivity assumption (see Frackowiak & Friston, 1994, for a review; Friston, Price, Fletcher et al., 1996). According to one procedure, the experimental tasks can be directly compared: the Task-1 minus Task-2 subtraction provides the pattern of activation associated with Task-1, the Task-2 minus Task-1 vice versa. The self-ordered and externally ordered working memory tasks of Petrides et al. (1993) provide an illustrative example. The amount of neural activity in specific cerebral regions may be correlated with a behavioural measure: for instance, hippocampal rCBF with a measure of long-term auditory-verbal memory, but not with a short-term memory score (Grasby, Frith, Friston et al., 1993), verbal episodic retrieval with activation of medial temporal structures (Nyberg, McIntosh, Houle et al., 1996b). The whole set of brain regions in which rCBF is positively and negatively (increased vs. decreased brain activity) correlated with a behavioural or physiological condition may be identified. Recent studies concerning human rapid-eye-movement sleep and dreaming (Maquet, Peters, Aerts et al., 1996) and episodic memory retrieval (Nyberg, McIntosh, Cabeza et al., 1996a) provide illustrative examples. Finally, interaction and factorial designs are also used. A study by Paulesu et al. (1996), who investigated the brain areas activated by a phonological short-term memory task in normal and dyslexic subjects, provides an illustrative example. Using these paradigms, the neural bases of functions such as verbal memory, language, and attention have been explored (Frackowiak, 1994; Petersen & Fiez, 1993; Posner & Raichle, 1994; Posner & Raichle, 1995). Over and above the specific results of different studies, and the discrepancies among them, the general emerging pattern is one of a high degree of functional specialisation in the brain, at the level of both sensory-motor processes and higher mental functions. Most activation experiments have provided results that confirm and extend findings from

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anatomo-clinical correlation studies in humans and animals. The lack of activation of a cerebral region, which, on the basis of correlation studies in braindamaged patients, has a specific functional role, raises interpretative problems, however. For instance, Shallice et al. (1994) did not detect activation in the hippocampal region during a verbal long-term memory task. This negative finding was unexpected on the basis of lesion studies, which have repeatedly shown that hippocampal damage produces anterograde amnesia (see Vallar, Chapter 15 this volume). On the basis of a negative result of this sort (“the ambiguity of a null result”, see Farah, 1994a), the conclusion that a given cerebral region does not participate in the operation of a specific function may be premature, if such a role is suggested by lesion studies. In the study mentioned earlier, Shallice et al. (1994) cautiously hypothesised that a comparatively low neuronal activity might account for their negative results (see Skaggs & McNaughton, 1992). Other studies have however revealed an association between specific long-term memory processes, such as successful recollection, and activation in the hippocampal region (Nyberg et al., 1996b; Schacter, Savage, Alpert et al., 1996). This type of difficulty does not apply to anatomo-clinical correlation studies. If the lesion of a specific cerebral region does not disrupt a given mental process, it is very unlikely that the damaged area plays a substantial role. Studies in brain-damaged patients, however, suffer from other problems, such as the patients’ selection (see Group and single case studies), and the size and the site of the lesion, which, being natural (e.g. a tumour, a stroke), may have effects that are not selective, but disrupt more than one function, producing multiple deficits (see an early discussion in Lichtheim, 1885). The observed impairments, therefore, may reflect damage to multiple components, making the pattern more complex and the interpretation more difficult. Patients with selective deficits (the so-called pure cases) are specially valuable in this respect. Since the early days of scientific neuropsychology, such cases, which show dissociated patterns of impairment (see Dissociations among symptoms), have been providing the main source of pathological evidence

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for a multi-componential organisation of mental processes and their neural bases. A final problem with activation studies is one opposite to the failure to detect the activation of a relevant cerebral area. Paulesu et al. (1996) have suggested that in normal subjects engaged in a given task, not only the critical or necessary areas may be activated, but also additional or incidental regions. In their study they teased apart the necessary and incidental regions by examining both normal subjects and a pathological population (developmental dyslexics), who were able to perform the critical task. To summarise, cerebral activation methods and anatomo-clinical correlation studies in braindamaged patients may provide complementary results, concerning the neural and functional architecture of mental processes.

A SIMULATION APPROACH: CONNECTIONIST MODELLING In the last 15 years, there has been a considerable development of an approach to the investigation of mental architecture, which—unlike its immediate predecessor, artificial intelligence (Newell, Rosenbloom, & Laird, 1989; Woodhouse, Johnstone, & McDougall, 1982)— aims at providing an abstract and general model of the computational organisation of the brain. This approach, like those developed in the past (mechanic and hydraulic, telephone central, and computer models) offers analogies and metaphors taken from the more advanced technologies of the time. As with artificial intelligence, connectionist modelling provides a computational simulation of mental processes. Its distinctive feature is however that the architecture differs from that of the present computer generation (von Neumann), but is broadly similar to the structure and function of the real brain. The computational activity of connectionist models is, then, neural-like, with the computer metaphor being replaced by the brain metaphor (Rumelhart, 1989). In connectionist neural networks, the basic processing unit is a sort of abstract neurone, which

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receives inputs and sends signals (numbers) to other neurones. Three main neurones may be distinguished: (1) input units, which receive signals from outer sources (sensory stimuli, other networks); (2) output units, which send signals out of the system, e.g. to motor effectors, or to other networks; (3) hidden units, with efferent and afferent projections internal to the system (e.g., from input to hidden units). Figure 6.3 shows an example of a connectionist network (Rumelhart, Hinton, & Williams, 1986). Other types of units (icontext or memory) may be useful under specific circumstances, such as learning of sequences (Elman, 1990; Nolfi, Parisi, Vallar et al., 1991). A representation of the state of activation of the different components of the network is also needed. Finally, the activation function of the units (identity, threshold, stochastic, non-linear, such as sigmoid), the organisation of the connections, and their weight (a positive weight indicates an excitatory connection, a negative an inhibitory one) should be specified. Each unit transforms the received inputs into an output signal, which is forwarded to connected units. The process has two components: each input signal is multiplied by the weight of the connection, and the sum of all signals is the total input, which, in turn, is converted into the output signal by the activation function.

FIGURE 6.3

An illustrative example of connectionist network, which includes input, hidden , and o u tput units (reproduced from Vallar, 1996, with permission of Zanichelli Editore).

The procedures whereby a neural net may learn a task, and become able to perform it on new stimuli (generalisation) are also to be defined. The training of the net (e.g. learning to recognise numbers or letters) is performed by sending appropriate signals to the input units, and by computing the discrepancy between the output signal and the target (in the example, correct recognition). On a trial-and-error basis, the weights of the connections are continuously modified, with the procedure (learning cycles) being repeated until the net becomes able to perform the task with a given level of accuracy. A widely used learning procedure is the back-propagation algorithm: a signal concerning the error made by the net in responding to a given stimulus is sent backwards from the output to the input units, modifying the weight of the connections. In this type of architecture, knowledge (long-term memory) is stored in the connections, whereas the activation of the units produced by a given stimulus may be considered as a temporary representation. To summarise, artificial networks are an abstract and relatively simplistic model of real neural circuits, constituted by dendrites and axons. The synaptic function is simulated by the changing weight associated with each connection. The output electric signal generated by each neurone is

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represented by a number, which denotes its activity (Hinton, 1992). Given their close reference to the real brain (Crick, 1989), connectionist models may be of interest to neuropsychologists more than the preceding analogies or metaphors. Neural networks have been used to simulate the activity of specific cortical neurones. For instance, neurophysiological studies in the monkey suggest that the inferior parietal lobule includes three types of neurones: cells with retinotopic receptive fields; cells that code eye position; cells with retinotopic receptive fields, in that the size of the response is modulated by eye position. The latter neurones generate a headcentred representation, as their response to stimuli in a given location with reference to retinotopic coordinates is maximal when the eyes have a specific position in the orbit. A representation of this sort is required for the execution of movements directed towards targets in personal and extrapersonal space (Andersen, 1989; Andersen, Snyder, Li et al., 1993). Zipser and Andersen (1988) trained a neural network to code visual targets according to head-centred coordinates, providing inputs concerning the retinotopic coordinates of the stimulus, and the position of the eyes. After learning through back-propagation, Zipser and Andersen (1988) found in the hidden units a pattern of activation similar to that of parietal neurones responding to both the visual stimulus and eye position. Within its receptive field, each unit had a maximal response when the eyes were in a specific position. Some aspects of the model could differ from the real brain, however. For instance, it is unclear whether or not in animals and humans head-centred coordinates are, wholly or in part, learned, and, if so, by backpropagation. In any case, the existence of similarities between neurophysiological and connectionist sets of data suggests that the model is a plausible architecture, and generates working hypotheses. Zipser and Andersen (1988) concluded their paper by noting that there was no empirical evidence for a head-centred spatial representation, independent of the position of the eyes. Such a representation would not exist in the brain, being instead a behavioural manifestation, when the animal fixates a target, or points to it. Some years later, however, neurones with non-retinocentric,

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eye-position independent, receptive fields, have been found in the premotor (area 6) (Fogassi, Gallese, di Pellegrino et al., 1992; Fogassi, Gallese, Fadiga et al., 1996; Graziano, Tian Hu, & Gross, 1997), and in the posterior parietal (Battaglini, Galletti, & Fattori, 1996; Galletti, Battaglini, & Fattori, 1993) cortex. These cells could constitute a neural basis of spatial egocentric (e.g. head-centred, arm-centred) representations of objects. A second use of neural networks is to study the effects of lesions after the learning of a specific ability. The performance of the damaged network may be compared with that of brain-damaged patients, who are impaired in that task, in terms of both accuracy, and qualitative patterns of errors. Relevant aspects of deficits such as optic aphasia (Plaut & Shallice, 1993b), and surface (Plaut, McClelland, Seidenberg et al., 1996), deep (Plaut & Shallice, 1993a), and neglect (Mozer & Behrmann, 1990) dyslexia have been successfully simulated, even though the correspondence with the patients’ behaviour may be not complete. The results of these simulations suggest that the network may be a plausible architecture of the system damaged in patients. The results of simulation studies may stimulate a critical reappraisal of the traditional box-andarrow models, which have been widely used by cognitive neuropsychologists in the last 25 years. Plaut et al. (1996), for instance, found that networks using a single procedure (orthographic and phonological representations) were able to learn to read both regular and irregular words, and non words. Lesions to these networks reproduced some aspects of the error pattern of patients with surface dyslexia; however a more successful simulation required the introduction of a semantic component. Both dual-route (Whitney, Berndt, & Reggia, 1996; Zorzi, Houghton, & Butterworth, in press) and one-route (Plaut et al., 1996) connectionist models of reading have been developed (review and discussion in Denes et al., this volume). The plausibility of these models is related to their ability to simulate successfully behavioural patterns in normal subjects, and pathological deficits after experimental lesions (in the examples discussed here, reading and the different varieties of dyslexias). A third relevant

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factor is the relationship between the architecture of the network and the organisation of the brain (see related discussion in Plaut, 1995). In this respect, it may be noted here that some PET activation studies have been interpreted in the light of an anatomo-functional dual-route model of reading (Petersen & Fiez, 1993; Petersen, Fox, Posner et al, 1989). A connectionist approach has been used by Farah (1994b) to challenge the view that the functional architecture of the mind is multicomponential, or modular, supporting instead an account in terms of distributed and interactive representations. Neural networks too, however, may have a multi-componential architecture: multiple, connected systems, each including input, inner and output units (see Schneider & Detweiler, 1987; Zorzi, 1994). Furthermore, the learning process may induce a functional specialisation of some units. For instance, in a model of reading, hidden units may become specialised for reading exception words (Zorzi et al., in press); in a model of visuo-spatial processing the retinotopic receptive fields of hidden units may be differentially modulated by specific eye positions (Zipser & Andersen, 1988). Connectionist models differ from computational models such as, for instance, production systems, in that the network is not programmed a priori, through explicit instructions, in order to be able to perform a given task. The network's skills, which are initially rather poor, progressively improve through learning. The observation that a neural network becomes able to reproduce specific features of the human behaviour may be taken as a strong case that its architecture is a plausible simulation of the human system. Similarly, in lesion experiments the network is damaged in a relatively nonspecific fashion, interrupting connections or removing different amounts of units, but, at least in some cases, the localisation of the lesion may be critical (e.g. the concreteness effect in deep dyslexia: Plaut & Shallice, 1993a, pp.456-460). In the traditional computer simulations, by contrast, the damage should be specified much more precisely

(Kimberg & Farah, 1993; Kosslyn, Flynn, Amsterdam et al., 1990). Also in the case of lesion studies, the finding that a quantitative damage to the network brings about patterns of performances (and of impairment) similar to those observed in brain-damaged patients would provide a greater support to the conclusion that the net is a plausible simulation of the human system under investigation. Connectionist models, however, cannot be regarded as entirely atheoretic, as the architecture of the virgin network (i.e. before training) is a priori defined (e.g., Burgess & Hitch, 1996; Mozer & Behrmann, 1990). This argument is even stronger in the case of modular connectionist systems, including more than one network. The relevant role of the architecture of the network is suggested by the finding that putatively minor variations may be associated with different deficits, when a lesion is made (Plaut & Shallice, 1993a). The precise relationships between the locus of the lesions within a network and the resulting pattern of impairment remains far from transparent, however (see the concreteness effect in reading: Plaut, 1995). Finally, the a priori definition of the architecture of the network, and of the connections among networks in the case of multiple systems, may be used to simulate innate or genetically determined aspects of the neural bases of mental processes. To summarise, simulation may provide useful suggestions, which should be evaluated in the context of the results of lesion and activation studies in humans and animals. If a connectionist network or a computational model successfully simulates human behaviour (and the deficits produced by a lesion) in a given domain, but its structure differs from that suggested by experiments performed in humans, it is the latter architecture that should be considered the real one; that is, actually implemented in the brain. For instance, the computational model of phonological memory of Brown and Hulme (1995) does not include a discrete rehearsal process, but neuropsychological findings support the view that the phonological short-term store and the articulatory rehearsal process are functionally and

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anatomically separate (see review in Vallar, Di Betta, & Silveri, 1997).

THE NEUROPSYCHOLOGICAL METHOD Clinical observation The anatomo-clinical correlation is a main feature of classical neuropsychology. The qualitative and nonsystematical psychological analysis of the patients’ pathological behaviour, often confined to clinical observation (e.g. Moutier, 1908), was however a main weakness of the traditional approach. This contrasts with the relatively high level of the post-mortem examination. A perusal of the series published by Henshen (1920-1922) and Nielsen (1946), which included both personal cases and previously reported observations, illustrates this dissociation between the psychological and neuropathological levels of analysis. The clinical method, based on qualitative and nonsystematic observations, may favour the selection of patients with severe and immediately apparent deficits. These observations constitute a series of single cases, who attracted the examiner’s attention due to the severity or the peculiar features of the neuropsychological disorder. The traditional clinical method has had a crucial role in the birth and early development of scientific neuropsychology. The discovery that cerebral lesions may produce selective cognitive deficits was based on clinical observations. This method has limitations too, however, being inadequate to elucidate the precise psychological features and anatomical correlates of the deficit, and its relationships with other disorders. As a result of the limits of the classical clinical descriptions, some clinical syndromes, such as constructional apraxia (Gainotti, 1985, see also Grossi & Trojano, Chapter 19 this volume), are not precisely defined. In the absence of a precise definition, furthermore, a given disorder may be investigated by different methods, which may involve different abilities. The long-standing controversies concerning the putative existence of some clinical syndromes (e.g. Gerstmann’s syndrome; see Denes, Chapter 22 this volume), and the basic

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nature of some deficits (e.g. visual agnosia) (Bay, 1953; Bender & Feldman, 1972; Humphreys & Riddoch, 1987; Lissauer, 1890) provide another indication of the limitations of the clinical method. Finally, clinical observations do not usually take into account relevant variables, such as sex, age, and education of the patients, which may affect their normal and pathological behaviour. The final result is often a pattern of contrasting observations, in which a comparative analysis is made difficult by a lack of precision and definition, which concerns both the clinical deficit, and the behavioural tasks, that should be used for its assessment.

Quantitative and standardised tasks A solution to the unsatisfactory state of affairs discussed in the previous section is the use of clearly defined and standardised methods. After World War II, since the late 1950s, many neuropsychologists (Benton, 1966; De Renzi, 1967; Poeck, 1969), well aware of the limitations of clinical methods, took the view that standardised and quantitative paradigms should be used. This approach differs from the clinical examination used by neurologists in the second half of the 19th century. It does not necessarily challenge the classic anatomo-clinical models, however. Such a critique may be done, provided the results of studies performed using standardised and quantitative methods differ from those obtained through the traditional clinical assessment. Benton’s (1961) critique of Gerstmann’s syndrome (Denes, Chapter 22 this volume) is an illustrative example. Ennio De Renzi (1967) clearly stated the main features of this new method, which may be summarised in three points. Studies are performed in groups o f patients According to the traditional anatomo-clinical method the conclusion that the lesion of cerebral region R brings about a deficit of function F, producing the symptom or sign X , is based on the existence of positive cases, namely patients in whom R is damaged and X is present. This approach, however, does not take into consideration both patients in whom X is present, but R is unaffected, and patients in whom X is absent, but

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R is damaged. The traditional method, which considers only the positive cases, is therefore unable to rule out the possibility that X is produced by a nonspecific effect of brain damage, independent of its localisation. A similar line of reasoning may be applied to the analysis of functional syndromes. Consider the hypothetical syndrome S (see also Group and single case studies), comprising the symptoms A, B, C, and D, produced by a deficit of function F, and possibly associated with left hemisphere damage. The study should not be confined to the positive cases; that is, to patients who show the four symptoms of S. The investigation should include a continuous series of left and right brain-damaged patients, looking for the association of the four symptoms of S. The conclusion that S indeed exists is possible only if the positive cases show the four symptoms, which are absent in the negative cases. In the case of an anatomo-functional syndrome, S should be associated with left hemisphere lesions only. Clinical observations in single cases may provide interesting suggestions. A scientific investigation, however, can be performed only in a series of brain-damaged patients, who enter the study simply because they have a cerebral lesion, independent of the presence or absence of the symptom or the syndrome of interest. Using this method, it becomes possible to verify whether or not the co-occurrence of a set of deficits, and, possibly, their association with a specific lesion site, is significant; that is to say, represents a syndrome. An implication of this approach is that large samples of patients should be tested, as they better represent the corresponding population. In these large series, the demographic (age, sex, education) and neurological variables (length of illness) should also be taken into consideration. The examination is standardised The traditional clinical examination is not specified in full detail. In different patients, therefore, the examiner (or different examiners) may inadvertently modify more or less relevant aspects of the assessment. In addition, the conclusions concerning the patients’ performance reflect qualitative observations, which are not analysed by

statistical methods. The clinical descriptions usually do not report in full detail the tasks used by the examiner. This prevents a proper replication of the study by another researcher. These problems can be overcome using tasks precisely defined in full detail: administration procedures, scoring of the responses, error analysis, etc. Brain-damaged patients should be compared with normal subjects The clinical approach considers the patients’ errors as an indication of defective function. This conclusion may be correct when the deficit is severe, or clinically apparent. Some errors, however, may be interpreted as pathological only because the patient has a brain lesion. On the other hand, milder deficits may not be detected through the clinical exam. Finally, it should be considered that in virtually all tasks normal subjects commit some errors. Their amount and type is affected by many factors, including age, education, and sex. The patients’ performance, therefore, must be compared, by means of adequate statistical methods, with that of a series of normal subjects (the so-called control group), similar in age, education, sex, handedness, etc. (see Capitani & Laiacona, Chapter 4 this volume). Many neuropsychological studies, which have used this approach, have been performed both in the United States and in Europe, since World War II up to the 1970s. This methodological programme for neuropsychological research is well illustrated by studies performed in Italy by Ennio De Renzi, and Luigi Amedeo Vignolo, in France by Henry Hecaen, in Germany by Claus Poeck, and in the United States by Morris Bender, Arthur Benton, Hans-Lukas Teuber, and their co-workers (De Renzi, 1982b; Mountcastle, 1962; Vignolo, 1982). The typical structure of this type of study was the following. A number of neurological patients was subdivided in different groups on the basis of the side (left, right) of the lesion, and often of its intra-hemispheric localisation (pre-, retro-rolandic, frontal, parietal, etc.). The performances of the different groups of patients in a number of tests were compared with those of a group of normal controls, matched for demographic variables.

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These studies aimed mainly at establishing a correlation between a defective pattern of performance and the lesion of one side of the brain, and, if possible, of a specific cerebral region within one hemisphere. The relationship with experimental psychology concerned the method used to assess the behavioural deficit, rather than the functional architecture of mental processes. The main aim was to establish an anatomoclinical correlation between the cerebral hemispheres and specific mental abilities, not to investigate, using brain-damaged patients as experimental tools, the functional architecture of mental processes. As the main focus of the studies concerned the anatomo-clinical correlation, it is not surprising that: (1) the psychological categories were relatively underspecified (e.g. verbal vs. nonverbal abilities, perceptual vs. memory processes); (2) reference was often made to the classic neurological models (e.g. Wernicke’s model of language; Lissauer’s model of object recognition); (3) the interaction with psychological research in normal subjects was limited. At least up to the 1970s, the results of neuropsychological studies were typically not quoted in textbooks and handbooks of psychology. This lack of interest in neuropsychology on the part of psychology was what one might expect, considering that the main aim of this approach was to investigate the neural basis of mental processes. In this respect, psychology was useful to neuropsychology, providing functional models of mental function, based on the behaviour of normal subjects. The advantage, however, was not mutual. The anatomo-clinical correlations, resulting from the neuropsychological studies, were of limited interest to the student of normal psychological processes.

COGNITIVE NEUROPSYCHOLOGY In the last 25 years a novel neuropsychological approach has undergone a remarkable development: the main aim of cognitive neuropsychology is to explore the functional architecture of normal mental processes, through

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the investigation of the abnormal behaviour of patients with brain damage or dysfunction. The early seminal studies in cognitive neuropsychology can be traced back to the late 1960s and early 1970s, when in Canada, in the United States, and in Great Britain, scientists such as Brenda Milner (1966), Drachman and Arbit (1966), Elizabeth Warrington, Tim Shallice, and Alan Baddeley (Baddeley & Warrington, 1970; Warrington & Shallice, 1969), John Marshall and Freda Newcombe (Marshall & Newcombe, 1973) investigated in single cases or in very homogeneous small series of patients the specific patterns of impairment of short- and long-term memory, and of reading processes (the dual-route model). In the following years, this approach rapidly became a relevant component of neuropsychological research. This is also witnessed by a journal (Cognitive Neuropsychology, 1984), which aims to publish experimental studies and theoretical papers, based on this paradigm. At present, an interim conclusion is that the cognitive approach has produced a remarkable amount of work, concerning all areas of neuropsychology. The cognitive neuropsychological approach has been based, since its inception, on the so-called information processing or flow-chart diagram types of models of the mind, developed by cognitive psychologists in the 1960s. Briefly, the mental faculties comprise a number of connected components, with specific functional properties. For instance, memory was subdivided into shortand long-term components (Vallar, Chapter 15 this volume), the reading skills into phonological, visual, and semantic pathways (Denes, et al., Chapter 14 this volume). If the mind is a multiple-component system with specific features and connections, some of them may be selectively affected by brain lesions. Brain-damaged patients, therefore, may be investigated with a two-fold aim: (1) interpreting their impairment in terms of the defective function of one or more components or connections of the system; (2) increasing knowledge concerning its functional architecture. The methods used by cognitive neuropsychologists derive largely from those used by experimental psychologists. As in the quantitative

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and standardised approach discussed in the preceding section, and unlike the traditional clinical method, cognitive neuropsychologists make use of tasks, in which the materials and the procedures are precisely defined, and the patient’s performance is compared with that of an appropriate control group (Shallice, 1979).

Three basic assumptions The cognitive neuropsychological approach makes three basic assumptions, which were also present in the diagrams proposed by clinical neurologists in the second half of the 19th century (see Figs. 6.1 and 6.2). Modularity Quoting Marr (1982, p.325): “... any large computation should be split up into a collection of small, nearly independent, specialised subprocesses.” The postulate that the mind is modular has been widely present in the neuropsychological approach, at least since Gall (Finger, 1994), both in the 19th-century anatomo-clinical (Figs. 6.1 and 6.2), and in the information processing models of the 1960s (e.g. Norman, 1970, and Fig. 6.11). Its precise features, however, were not clearly defined. The problem was reconsidered by Jerry Fodor (1983) in a brief essay, which, if anything, made neuropsychologists fully aware of the relevance of the problem. According to Fodor, the modules are genetically determined computational mechanisms, which have a specific representational domain and localised neural correlates. The operation of the modules is fast and automatic, and relatively unaffected by other components of the system (using Fodor’s terminology, they are informationally incapsulated). Their content has little access to conscious processes. These modules are domain-specific computational mechanisms, similar to reflexes, which may be referred to as vertical faculties. Examples of modular systems of this sort are some auditory, linguistic (the syntactic and phonological analysers), and visual perceptual processes. By contrast, central processes, such as memory, reasoning and problem-solving are nonmodular, and mediated by horizontal faculties. As such, these central processes are not domain-

specific, do not have localised neural correlates, and are bad candidates for scientific enquiry (see comments in Fodor, 1985). This view is similar to the one taken by Lichtheim (1885, p.436), who localised all perceptual and motor linguistic functions, but not “... the part where concepts are elaborated”. According to most neuropsychologists, however, not only the input perceptual analysers are modular, namely multiple-component systems, with localised neural correlates (see Marshall, 1984; Moscovitch & Umiltà, 1990; Shallice, 1984). Response-production systems (Paillard, 1982), and faculties, which in Fodor’s view are non-modular (memory, Vallar, Chapter 15 this volume, and control processes set up to attain a particular goal, Shallice, 1994) are also conceived as multicomponential. Finally, modules may be not innate, as in the different components of the reading processes (Coltheart, 1985). The modular architectures of different aspects of the mind are often depicted as flow-chart diagrams of information processing (Figs. 6.1, 6.2 and 6.11), with a non-hierarchical organisation of the different components. When a specific part of the system is damaged, e.g. the grapheme-tophoneme conversion process (Fig. 6.11), the patient will make use of the components spared by the lesion. The architecture may be also hierarchical. A classical example is the distinction between the automatic vs. voluntary or propositionising aspects of language (Hughlings-Jackson, 1915; Kennard & Swash, 1989). A more recent example of hierarchical model is Tulving’s (1985) tripartite distinction of memory processes, in which the systems have different kinds of consciousness, or noesis (Fig. 6.4). The existence of episodic memory implies, or presupposes, that of semantic memory, which, in turn, implies procedural memory. A feature of hierarchical architectures which is relevant to neuropsychologists is that a damage to the superordinate systems produces a selective dysfunction, which does not affect the subordinate components. The automatic/voluntary dissociation of Flughlings-Jackson and the interpretation of amnesia as a deficit of episodic memory in a system such as that shown in Fig. 6.4 (see also Vallar, Chapter 15 this volume) are illustrative examples.

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FIGURE 6.4

Hierarchic organisation of three memory systems and forms of consciousness (noesis). The arrows denote im ply (redrawn from Tulving, 1985).

Finally, in hierarchical systems a dysfunction of the subordinate components also produces a defective function of the superordinate ones. Correspondence between functional and neurological architectures If computationally independent processes were implemented, at least in part, in physically discrete structures (brain regions), a cerebral lesion might selectively damage one (or more) of them. If the correspondence assumption aims only at accounting for the observation that brain damage can selectively disrupt specific aspects of mental processes, the precise neural level at which the implementation takes place does not require any further specification (see chapter 1 in Ellis & Young, 1988; Shallice, 1981). If, however, the neural basis of mental processes is of interest, then this level of analysis becomes relevant. In the anatomo-clinical models of the 19th century, then the correspondence was between specific functional centres and regions of the cerebral hemispheres (Figs. 6.1 and 6.2). The neural correlates of mental process are likely to be better conceived in terms of complex cortico-subcortical neural circuits, which may include different cerebral regions (Crick, 1984; Mesulam, 1990). At a fine-grain level of analysis these neural correlates may be referred to as cell assemblies (Hebb, 1949). The correspondence may also be at the level of single neurones (Barlow, 1985). For instance, in the monkey some neurones in the region of the superior temporal sulcus exhibit selective responses to faces,

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or to parts of them (eyes, mouth), or to specific orientations of a face (profile, back), or to an individual face (e.g. the experimenter) independent of orientation, size, expression, etc. (Perret, Mistlin & Chitty, 1987). It is likely, however, that such a specific knowledge is not stored in a single neurone, but in networks or assemblies, of which the single cell is a component part. The only state of affairs in which the cognitive neuropsychological approach would be not practicable is that of a putative correspondence between a modular functional architecture and a non-modular neurological organisation. If this were the case, a brain lesion would not produce specific deficits, decreasing instead the overall level of performance of the system, and these effects would be proportional to the amount of brain damage (Lashley, 1929). Accordingly, the modular architecture of the mind could not be investigated in brain-damaged patients. However, little empirical evidence supports this hypothesis. Constancy A research programme, which aims at investigating the multi-componential organisation of the normal mind through brain-damaged patients, is possible only if, after a cerebral lesion, mental processes do not undergo a functional reorganisation that involves the generation of new components, or of new connections. If this were the case, the mental processes of a brain-damaged patient would be qualitatively different, in terms of functional architecture, from those of a normal subject. Accordingly, any inference from the pathological to the normal behaviour would be impossible. To summarise, if the experimental study suggests that the patients are making use of functional components that are not present in the normal subject, their behaviour may be relevant in order to understand how the system may cope with a pathological situation, through a modification of its organisation, but not to investigate the normal system per se. After damage to a specific component, patients may develop specific strategies, which are not typically used by normal subjects. Also in this case the constancy or transparency (Caramazza, 1986, 1988a) assumption remains valid, provided such strategies are a part of the behavioural repertoire

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Modularity, correspondence, and constancy: Their plausibility Neuropsychological research does not aim at a direct verification of these assumptions, which have been regarded as a basic core (Caramazza, 1984; Ellis & Young, 1988). The following paragraphs briefly discuss their plausibility.

modifications affecting the whole system. This may be an evolutional disadvantage. Ellis and Young (1988) put forward the analogy with current hi-fi systems, which comprise different components (turntable, CD player, integrated amplifier, loudspeakers). In these systems a new module (e.g. a tuner) can be added, a damaged component can be repaired or replaced, and upgrading is possible. These changes were not possible in the so-called radiograms, built in the 1950s, which were much less modular, including tuner, turntable, loudspeakers. Developing the hi-fi analogy, it is of interest to note that the higher the level of the system, the more modular is its architecture. Accordingly the integrated amplifier splits into the preamplifier and the power amplifier, the integrated CD player into the transport, responsible for disc handling and accessing the data, and the digital to analogue converter. Another analogy is provided by the architecture of ships’ holds, and of submarines’ bodies, which include many discrete modules. If a local lesion of the keel occurs, the water inundates only the nearby modules. By contrast, if the structure was nonmodular, the water would spread all over the hold. Many empirical observations concur to support the modular view. An anatomical example is the organisation of the efferent and afferent connections of the different regions of the occipital-temporal visual cortex (DeYoe, Felleman, Van Essen et al., 1994). Furthermore, neurophysiological studies suggest that discrete areas of the visual cortex are involved in processing different aspects of a complex visual pattern (shape, colour, movement) (Cowey, 1985; Lueck, Zeki, Friston et al., 1989; Zeki & Shipp, 1988). Finally, many studies in normal subjects argue for the functional independence of some mental abilities, for instance: some visuomotor processes (e.g. to hit an approaching ball with a bat: McLeod, McLaughlin, & Nimmo-Smith, 1985), speech perception and production (Shallice, McLeod, & Lewis, 1985), verbal short- and long-term memory processes (Baddeley, 1966a, 1966b; Kintsch & Buschke, 1969).

Modularity. Non-modular architectures undergo only global changes, with even minor local

Correspondence. The existence of some correspondence between the neurological and the

available to normal subjects; that is to say, they are based on components of the normal system spared by the lesion. An illustrative example of the compensatory use of strategies, that are also available to normal subjects was provided by patient PV, who suffered from a selective deficit of auditory-verbal shortterm memory (Vallar, Chapter 15 this volume). PV, in a task requiring the immediate free recall of supra-span lists of words, adopted a serial order strategy, producing first and best the initial items. These represent the output of verbal long-term memory processes, which were spared in the patient. Normal subjects, by contrast, recalled first the final stimuli, which are stored in auditoryverbal (phonological) short-term memory. Normal subjects probably use this strategy because the lability of the short-term memory trace makes it advantageous to recall the final items first, with a subsequent production of the material held in longterm memory. In PV’s case, conversely, due to the pathological reduction of the capacity of phonological memory, a strategy that assigns a recall priority to the final stimuli was unlikely to improve her memory performance. In line with this view, her performance remained defective even when she was explicitly required to recall the final items first. Finally, the normal repertoire includes both strategies: normal subjects are able to recall the initial items first (the strategy spontaneously used by PV), and PV was able to recall the final items first (the recall order preferred by normal subjects). Under these conditions, the assumption of constancy is not broken, and the inferences from the pathological behaviour to the organisation of the normal functional architecture are legitimate (Vallar & Papagno, 1986).

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functional architectures, both modular in nature, has been a main feature of human neuropsychology, which, since its inception, has been concerned with selective deficits of cognitive functions, associated with focal brain damage.4 The data mentioned in the previous section support this view. Constancy. The postulate that, at least in adult subjects5 , the reorganisation of the system after a brain lesion does not include qualitative changes, such as novel components or connections, cannot be easily verified. A variety of neurobiological mechanisms may participate in functional recovery, such as reduction of diaschisis, and new synaptic connections (Basso & Pizzamiglio, Chapter 35 this volume, see also Cappa & Vallar, 1992; Chollet & Weiller, 1994). In the case of sensory-motor functions, both sensory de-afferentation (Pons, Garraghty, Ommaya et al., 1991), and peripheral (Cohen, Bandinelli, Findley et al., 1991) and central (Weiller, Chollet, Friston et al., 1992) lesions may induce a reorganisation of cortical maps. Data of this sort indicate that some degree of plasticity is a feature of the central nervous system, in order to cope, at least in part, with the damage produced by a lesion (see Basso and Pizzamiglio, Chapter 35 this volume). This ability does not necessarily imply, however, that the post-lesional organisation is qualitatively different from the normal system. To summarise, the assumption that, after a cerebral lesion, mental processes do not undergo qualitative changes, which modify their architecture, is to be treated with caution and pondered in each specific case. The significance o f observations in brain-damaged patients Even if the three postulates just discussed (modularity, constancy, correspondence) are true, this does not necessarily imply that the pathological deficits produced by brain lesions can be interpreted in terms of the selective impairment of one, or more, components of the normal system. The possibility should be considered that the neuropsychological observations are contradictory, and cannot be analysed from this perspective (Postman, 1975). This is a plausible view, as the localisation of naturally occurring lesions is

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determined by factors such as the organisation of the vascular system (in the case of stroke lesions), which are not related to the functional architecture of interest. In addition, even if neuropsychological deficits can be interpreted in the light of the functional architecture of normal processes, this does not necessarily imply that the data from pathology are relevant to our knowledge of the normal system. Similarly, the best method for understanding the architecture of a man-made object such as a car, is probably to disassemble it in an orderly fashion, rather that to beat the car with a hammer, or to study it after a crash. If the latter approaches were used, the localisation of the damage would not be related to the functional properties of the object. Under these conditions, neuropsychology parasitises psychology, making use of models of mental function based on studies in normal subjects, without providing any heuristic information on their architecture and properties (Crowder, 1982, p.38). A perusal of neuropsychological studies performed in the last 30 years shows, however, that these reservations are unfounded. Not only the deficits of patients with brain lesions are interpreted in the light of models of normal processes. Such pathological studies have also contributed to settling controversies concerning their architecture. An illustrative example is the issue, discussed in the 1960s, as to whether or not memory was a single- or multi-componential process (Atkinson & Shiffrin, 1968; Melton, 1963). The observation that brain-damaged patients may display selective memory deficits lends support to the multiplesystems view (see Vallar, Chapter 15 this volume; Fodor, 1983, pp.99-100 for a related discussion of memory and amnesia—as a non-domain specific, horizontally organised faculty). A second example is the debate concerning the analogical vs. propositional features of mental images (Anderson, 1978; Bisiach & Luzzatti, 1978). The observation that brain-damaged patients may neglect the left side of mental images has been taken as evidence for the existence of analogical representations. A third example is the contribution provided by the investigation of amnesic patients to the elucidation of non-conscious memory processes (Vallar, Chapter 15 this volume). In amnesia, the selective

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damage of conscious, explicit memory, makes it possible to study unconscious, implicit memory in isolation, without interference from the former components. A final example concerns the putative distinction between the phonological short-term store and the rehearsal process components of phonological memory. On the basis of experiments in normal subjects and simulation modelling, interpretations in terms of a single component have been put forward (Brown & Hulme, 1995; Gupta & MacWhinney, 1995). However, experiments in brain-damaged patients and PET activation studies in normal subjects provide support to a bipartite architecture (see Vallar, Chapter 15 this volume). Evidence from patients with cerebral lesions may then provide a relevant contribution to our knowledge of the organisation of mental processes (Caramazza, 1992; Kosslyn & Intriligator, 1992).

Functional and neurological architectures The functional architecture of mental processes may be investigated, both in normal subjects and in brain-damaged patients, without any direct reference to the structures that constitute its neural basis, even though this issue may be relevant on its own. Seen from this perspective, investigation of the anatomical correlates of mental processes is not necessary to a research approach, which aims at expanding our knowledge as to “how the mind works” (Editorial: Cognitive Neuropsychology, 7: 1, 1984). One view, which has been popular among cognitive neuropsychologists, is that (taking for granted the postulate of correspondence, accounting for the existence of selective neuropsychological deficits produced by brain lesions) the neurological and neuropsychological levels of description are very different (see discussion in Mehler, Morton, & Jusczyk, 1984). Accordingly, it is unlikely that the investigation of the neural basis of mental processes provides data relevant to our understanding of their functional architecture. The limitations of a purely functional approach are apparent in a recent review concerning phonological dyslexia, of which the most prominent manifestation is a selective impairment of nonword reading. Coltheart (1996) discusses at length the case of patient LB (Dérouesné & Beauvois, 1985),

who does not show any associated phonological impairment, in a variety of tasks requiring the manipulation of phonemic constituents. By contrast, most patients with defective nonword reading have some phonological impairment in tasks not involving any orthographic processing. Although the latter cases suggest an interpretation of phonological dyslexia as a more global phonological deficit, the data from patient LB are not compatible with this view and have been explained by a specific dysfunction in the reading process itself, for instance at some orthographic level. After a long discussion concerning functional patterns of impairment and computational and connectionist models, Coltheart (1996, p.761) wonders whether the hypothesis of an anatomical contiguity of the brain areas involved in nonword reading and phonological processing might help to explain the observed dissociations, and “Should any significance be attached to the fact th a t...” patient LB was a right-handed individual who became aphasic after a lesion in the right hemisphere. The latter neurological fact raises in this patient the possibility of an idiosyncratic anatomo-functional organisation of the systems under investigation. Even though a strict functional approach remains possible in principle, the integration of neurological and psychological sets of results may have synergetic effects. The observation, in different patients, of a relationship between the site of the lesions and the patterns of behavioural deficit may be taken as evidence for a functional dissociation. This is the case, for instance, for the distinction between short- and long-term memory processes, drawn in the 1960s: patients with selective deficits of such systems differ both in the pattern of memory impairment, and in the site of the cerebral lesions. In the following years, the neurological analysis of the lesion sites of patients with memory disorders became more and more precise, localising the neural bases of specific components of short- and long-term memory systems (Vallar, Chapter 15 this volume). Another illustrative example is the association of perceptual hemineglect with parietal lesions, and of premotor neglect with frontal damage, which suggests a distinction between input and output processes in the stimulus-response chain (Vallar, 1993).

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A main reason for the relevance of behavioural experiments in brain-damaged patients and of cerebral activation studies in normal subjects (and in patients) is that data concerning the actual organisation of the neural bases of cognitive processes may help to eliminate possible alternative and plausible architectures, suggested by purely behavioural experiments in normal individuals, and by simulation studies. This procedure may in the end reduce the competing hypotheses to the single functional architecture implemented in the human brain. The lack of an adequate anatomical correlation between a specific deficit and lesion of a cerebral region does not, however, diminish the importance of a functional dissociation, revealed through behavioural experiments. For instance, in humans neglect may be confined to distant or to close extra-personal space, but this behavioural dissociation does not have a clearly defined anatomical counterpart at present (Vallar, 1993). These observations in humans are, however, in line with studies in the monkey, which have shown that experimental lesions of different cerebral areas may bring about selective forms of hemineglect for the distant, peripersonal, and peribuccal space (Graziano & Gross, 1995, for related evidence; Rizzolatti, Matelli & Pavesi, 1983). A cognitive neuroscience approach (see also Schacter, 1992), which integrates neural and behavioural data sets, may at present take advantage of three main methods: (1) the traditional anatomo-clinical correlation; (2) functional activation; (3) animal studies. The first and the second paradigm, have greatly benefited from the development of neuroimaging techniques (TC, MRI, SPET, PET, fMRI). The third approach provides relevant data concerning a variety of perceptual, mnestic, and motor functions, but cannot be used to investigate language and its disorders. These three sources, together with psychological experiments in different populations without brain damage (children, adults, elderly subjects) and simulation modelling, may provide evidence that, through converging operations,6 elucidates the functional and neural aspects of the mind’s architecture.

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SOME SPECIFIC METHODOLOGICAL PROBLEMS In this section some specific issues, which concern all the approaches previously discussed, are considered. In the last 20 years neuropsychologists have become more and more aware of the relevance of the assumptions that underlie their research work. These postulates and their implications have been extensively debated in specialised journals and books (Caramazza, 1988a; Ellis & Young, 1988; Shallice, 1988; Vallar, 1991).

Dissociations among symptoms Since its inception (see Bouillaud, 1825) neuropsychological research has made use of the paradigm of dissociations among deficits, in order to interpret sets of experimental data. Two forms of dissociation may be distinguished (Teuber, 1955; Weiskrantz, 1968). Simple dissociation The behavioural tasks A and B, which assess the functions F¡ and F 2 are given to a group of patients (or a single patient), selected according to the side or, the intra-hemispheric localisation of the lesion, or both features. The patients’ performance may be defective in A and, within the normal range in B. One interpretation of this result is that the damaged hemisphere or cerebral region is the neural correlate of function F 1 , which has been disrupted by the lesion. At a purely functional level, this pattern denotes the damage of Fi, while F2 is preserved. In the classical (strong) form of the simple dissociation, the patients’ level of performance is normal (presumably not different from the premorbid level, and, in any case, comparable with that of an appropriate control group) in one of the two tasks, and defective in the other (Fig. 6.5a). The simple dissociation may be less clear-cut (or weak). The patients’ performance may be more defective in one of the two tasks, even though they are impaired in both, compared with normal subjects (Fig. 6.5b). In this case the type of inference just mentioned should be treated more carefully: the defective performance in both tasks suggests a multiple-component disorder. The strength of a

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weak simple dissociation is related to two main factors: the difference between the levels of performance in the two tasks, and, in the task in which performance level is higher, the magnitude of the impairment in comparison with the control group. The greater is the difference, and the smaller is the impairment, the stronger is the dissociation. It remains possible, however, that a simple dissociation, both in the weak and in the strong form, is produced by a greater difficulty of task A, in comparison with B. Normal subjects might need to allocate a greater amount of resources in order to perform A (Norman & Bobrow, 1975). The cerebral lesion might have reduced the total level of available resources (e.g. attention, memory), so that only the easier task (B) may be performed at a normal level, or, in the case of a weak dissociation, below the normal level, but nevertheless better than A (Fig. 6.6). According to this view, a single function (e.g. Fi), is involved in the execution of both tasks, with B being easier than A. A parsimony criterion supports this conclusion, which requires a minor number of functional components (F7, but not F 2 ).

FIGURE 6.6

Resource/performance curves for two hypothetical tasks. A brain lesion may reduce the available amount of resources to a level R 1 , so that the patient’s performance is defective in the more difficult task, even though a single function is involved in both tasks (redrawn from Norman & Bobrow, 1975; Shallice, 1988).

FIGURE 6.5

Simple dissociation, (a) In the classic or strong form the level of performance is within the normal range in task B, defective in A. (b) In the weak form the levels of performance may be defective in both tasks, but there is nevertheless a difference between A and B (reproduced from Vallar, 1996, with permission of Zanichelli Editore).

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Double dissociation The problem of interpretation mentioned in the previous section is overcome by the existence of two groups of patients, or two single cases (Pi and P 2 ), who show this pattern of impairment. Compared with the performance of control subjects, Pi is impaired in task B, but not in task A, and P2 vice versa (Fig. 6.7a). This is the double dissociation in the classical or strong form. Under these conditions, the patterns of impairment cannot be interpreted in terms of task difficulty, and the conclusion may be drawn that two independent functions F 1 and F2 are involved in tasks A and B. This conclusion is tenable even when the patients’ levels of performance are below the normal range in both tasks (double dissociation in the weak form, Fig. 6.7b). In this case, the interpretation is more complex, however. It is likely that multiple deficits, a global impairment, or both types of disorders are also present, producing the general reduction of performance level (see also a discussion of double dissociations as cross-over interactions in Jones, 1983).

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The absence of significant differences in the severity of the dissociated deficits indicates both that the experimenter has used tasks with comparable sensitivity to the operation of the functions of interest, and that the overall severity of the neurological damage is similar in the two groups (Weiskrantz, 1968). This comparison may be easy when simple functions are assessed by psychophysical methods, such as sensory thresholds or discrimination skills (Teuber, 1955). In human neuropsychology more complex functions (e.g. language) are frequently investigated, however. The difficulty of the different tasks cannot be directly compared, even though raw scores can be converted into z or equivalent scores (see for example Albert, Goodglass, Helm et al., 1981; Spinnler & Tognoni, 1987). In the vast majority of studies in humans, levels of performance within the normal range vs. clearly defective are usually regarded as sufficient evidence to support a strong double dissociation.

FIGURE 6.7

Double dissociation, (a) In the classic or strong form patient or group P-j has a defective performance in task B, normal in A, P2 vice versa. With reference to the tasks, P-|’s performance level is higher than that of P2 in A, while an opposite pattern occurs in B. Finally, the levels of preserved and impaired performances are comparable across patients, (b) In the weak form the patients’ level of performance is below the normal range in both tasks (reproduced from Vallar, 1996, with permission of Zanichelli Editore).

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The inference suggesting the existence of discrete and independent components can be drawn only if the double dissociation is between patients. The level of performance of Pi is higher than that of P 2 in task A, lower in task B. Under these conditions, if only a single function were involved in both tasks, Rpi and R p2 being the resources available to the two patients, two contradictory inequalities would occur: task A: RPi > R P 2 task B : R P 2 > R pi The double dissociation, however, may take the form of complementary neuropsychological deficits, and occur between tasks and not between patients. As shown in Fig. 6.8, patient Pi has a higher level of performance in task A, compared with B, and patient P 2 vice versa. In both tasks, however, the level of performance of P 2 is higher. This pattern is compatible with an interpretation in terms of a single function, involved in both tasks, provided one performance/resource curve is steeper than the other (Shallice, 1988). The history of neuropsychology provides many instances of double dissociations. An illustrative example is the observation of De Renzi et al. (1969) that lesions in the left hemisphere are associated with agnosic disorders of the associative type, and right-sided lesions with apperceptive disorders. In Complementary double dissociation. The performance of patient or group P-| is better in task A compared to B. In P2 an opposite pattern is found. This dissociation, however, differs from the classical one in that it considers only the sign of the differences between tasks (dissociation between tasks), but does not require that each patient has a level of performance higher than the other in one task (dissociation between patients, see Fig. 6.7). It is therefore possible that P2’s performance is higher than that of Pi in both tasks, even though Pi performs A better than B, and P2 vice versa. This complementary pattern is compatible with the hypothesis that a unitary function is affected, but the two tasks have different resource/performance curves, and the two patients different amounts of resources available (redrawn from Shallice, 1988).

this study, apperceptive tasks, requiring a difficult visual discrimination (naming of overlapping figures, face identification, colour discrimination), and associative tasks, requiring the extraction of the meaning of the stimulus (object-figure matching) were given to a series of 168 brain-damaged patients with unilateral lesions. The performance of right brain-damaged patients with visual halffield deficits was defective in the three apperceptive tasks, compared with that of both right braindamaged patients without visual half-field deficits, and left brain-damaged patients. The latter group, by contrast, was impaired in the associative task. Faglioni et al. (1969) reported a similar double dissociation in the acoustic modality. The performance of right brain-damaged patients was defective in an apperceptive task requiring the discrimination of meaningless sounds, while left brain-damaged patients exhibited a deficit in an associative task requiring the identification of meaningful sounds (see Fig. 6.9). In the studies by De Renzi et al. (1969) and Faglioni et al. (1969) the behavioural double dissociation had an anatomical counterpart in terms of left vs. right latéralisation of the lesion. These results were confirmed by a study in which the site of the lesion was assessed by CT. Furthermore, in line with the conclusions mentioned earlier, patients with bilateral lesions displayed a defective performance in both tasks (Vignolo, 1982).

FIGURE 6.8

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FIGURE 6.9

An example of classical double dissociation: the performances of right (R) and left (L) brain-damaged patients and of control subjects (C) in two auditory tasks (APP: apperceptive; ASS: associative) (reproduced from Vallar, 1996, with permission of Zanichelli Editore; data from Vignolo, 1982, Table 1).

Another example of double dissociation is provided by the reading deficits of brain-damaged English speakers. Patients with phonological dyslexia are severely impaired in the case of pronounceable meaningless letter strings (nonwords, or novel words). They are however able to read both regular and irregular words with a higher level of performance, which, in some cases, may be nearly errorless. Patients with surface dyslexia, by contrast, are able to read non words, but their performance is defective in the case of irregular words (Denes et al., Chapter 14 this volume). This type of inference may be also drawn when the comparison is not between two tasks, but between the effects of two variables on the performances of two patients (method of the critical variable: Shallice, 1988). A crossover interaction for one of the two variables provides a classical double dissociation, which suggests the existence of independent functions. Also non-crossover interactions may allow a similar inference. An illustrative example is a study by Derouesne and Beauvois (1979), who investigated the effects of phonemic and graphemic variables. The reading

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performance of one patient with phonological dyslexia was affected by the graphemic variable, but not by the phonemic one. A second patient showed an opposite pattern: effects of the phonemic, but not of the graphemic variable (Fig. 6 . 10). In normal subjects, the paradigm of the concurrent tasks, which may selectively interfere with the operation of specific functional components, may provide results related to those obtained in brain-damaged patients (e.g. Shallice et al., 1985). The behavioural dissociations produced by brain damage are more clear-cut, however. In addition, concurrent tasks typically have global disruptive effects, which should be taken into consideration. To summarise, the double dissociation in its strong form is a powerful tool, which elucidates the multi-componential architecture of mental functions and their neural bases.

Associations among symptoms and signs The concept of syndrome (“a group of symptoms and signs of disordered function, related to one another by some anatomic, physiologic, or biochemical peculiarity”, Isselbacher, Braunwald, Wilson et al., 1994, p.3) is widely used in clinical medicine. A syndrome “embodies a hypothesis concerning the deranged function of an organ, organ system, or tissue ... A syndrome usually does not identify the precise cause of an illness, but it narrows the number of possibilities and often suggests certain special clinical and laboratory studies.” For instance, “in dementia, deterioration of memory, incoherent thinking, impaired language functions, visual-spatial disorientation, and faulty judgement are related to the destruction of the association areas of the cerebrum” (ibid, p.3). The associations among symptoms have had a main role in defining the taxonomy of the main neuropsychological disorders. A well known example is the traditional classification of language disorders, which defines entities such as Broca’s and Wernicke’s aphasias as the co-occurrence of a set of symptoms, signs, or both. The syndromic approach is not confined to language. Associations of deficits such as Gerstmann’s syndrome and

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Balint’s syndrome have a conspicuous position in the history of neuropsychology (Denes, Chapter 22 and Nichelli, Chapter 20 this volume). Deficits such as visuo-spatial hemineglect, extinction, anosognosia, which are often associated, constitute the clinical syndrome of spatial hemineglect (Heilman, Watson, & Valenstein, 1993; Vallar, 1998). In clinical practice, associations such as the aphasic and neglect syndromes have a diagnostic value, providing indications concerning the side and the site of the cerebral lesion (Adams & Victor, 1994; Mohr, 1994). Three different anatomo-clinical relationships may bring about an association of n symptoms and signs, giving rise to three different types of syndromes (Brain, 1964; Ellis & Young, 1988; Lichtheim, 1885;Poeck, 1983). Anatomical syndrome The cerebral regions or circuits A/, A2 , A 3 , A4 ..A n, in which the functions Fi, F2, F j, F4...Fn are localised, are anatomically contiguous. The

conjoint damage of these regions produces the association of symptoms Ni, N2, N3, N4..M1. This type of syndrome has an anatomical localising value, related to the probability (determined by neurological factors, such as the distribution of the vascular territories of the cerebral arteries) that adjacent cerebral areas are conjointly damaged by the lesion. The higher this probability, the higher the localising value. The anatomical syndrome allows for partial associations, or dissociations among deficits. These are produced by lesions confined to some of the contiguous regions. For instance, a lesion of Ai and A2 would bring about Ni and Afe, without N 3 and N 4 ; damage to A 3 and A 4 N 3 and N4, without Ni and N2. The anatomical syndrome may be considered weak, as its probabilistic features makes it compatible with incomplete or partial associations of deficits (for a discussion of the traditional aphasic syndromes as weak syndromes, see Benson, 1979; Poeck, 1983).

FIGURE 6.10

Performance of two patients in a task requiring reading aloud nonwords with different (a) graphemic and (b) phonemic complexity. The performance of patient A was affected by the graphemic variable. The patient made more errors in the complex grapheme-to-phoneme correspondence condition (a sound corresponds to two letters), compared with the simple condition (a one-to-one letter-to-sound correspondence). The phonemic variable (nonwords, homophones, or non-homophones of real words) did not influence A’s level of performance. In patient D, an opposite pattern was found: the phonemic, but not the graphemic variable affected the patient’s performance (reproduced from Vallar, 1996, with permission of Zanichelli Editore; data from Derouesne & Beauvois, 1979).

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Another example of an association of deficits produced by the anatomical contiguity of relevant cerebral areas is Gerstmann’s syndrome. The association of finger agnosia, left-right disorientation, acalculia, and agraphia has a localising value, suggesting a left parietal posterior-inferior lesion (Denes, Chapter 22 this volume). The syndrome, however, has no functional significance, as partial associations may occur. This indicates that these deficits are produced by the impairment of discrete functions, even though their neural correlates are contiguous. Functional syndrome The symptoms and signs Ni, Afc, N3, N4 ...Nn are associated because they are produced by the impairment of function F. Accordingly, the syndrome is always complete. Exceptions—that is, non-complete patterns—can be explained only in terms of individual variability: in some individuals the functional architecture of the mental processes of interest differs from that of the majority of the population. In this respect, the functional syndrome may be considered strong. Anatomo-functional syndrome The symptoms and signs N i, Afe, Afe, N4...Nn are associated because they are produced by the impairment of function F, localised in the cerebral area R , or in the neural circuit C. The anatomofunctional syndrome differs from the anatomical one in that F has a localised neural correlate. The patterns of aphasic deficits originally described by neurologists in the second half of the 19th century are illustrative examples (Lichtheim, 1885; Wernicke, 1874/1966-1968). The association among a given set of symptoms and signs is produced by the impairment of a specific function, localised in a cerebral area or circuit. Mixed syndrome The association among Ni N2, N3, and N4 reflects both anatomical and functional factors. Ni and N2 are produced by the impairment of function F/, and N3 and N4 of F 2 , giving rise to two discrete functional syndromes. The anatomical association is due to the contiguity of the neural correlates of

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Fi and F 2 , cerebral regions A; and A2 . A lesion involving both A; and A2 brings about the complete mixed syndrome. Lesions confined to either A; or A2 cause partial deficits. Interpretation o f associations The association among symptoms and signs may reflect, as discussed in the previous sections, three discrete patterns of anatomo-functional relationships: the anatomical contiguity of relevant brain regions affected by the lesion, the disorder of a unitary functional component, or both factors. Accordingly, the interpretation of an association is more complex than that of a double dissociation, in its classical or strong form. The study of associations, however, may provide useful insights concerning the pathological mechanisms underlying a neuropsychological deficit. An illustrative example is provided by a set of experiments by Baddeley et al. (1988). Their patient PV, who had a selective impairment of auditory-verbal short-term memory (reduced auditory-verbal span) was unable to learn new words. Two interpretations may account for this association of deficits (reduced span and defective acquisition of new words). The impairment of two independent functions brought about these disorders, and their association reflected the anatomical contiguity of their neural correlates. Alternatively, as suggested by Baddeley et al. (1988), the patient’s defective phonological memory caused an inability to learn new words, in addition to the reduction of auditory-verbal span, in other words: the impairment of a single function underlay both behavioural deficits. The original study by Baddeley et al. (1988) did not adjudicate between these two possible interpretations. However successive experiments in different populations—normal subjects (Papagno, Valentine, & Baddeley, 1991; Papagno & Vallar, 1992, 1995), children (Gathercole & Baddeley, 1989; Service, 1992) and patients with genetically determined cognitive disorders (Barisnikov, Van der Linden, & Poncelet, 1996; Vallar & Papagno, 1993)—have provided converging evidence to the effect that the two deficits reflect the impairment of a single function (phonological short-term memory).

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Another example is provided by a study by Caramazza et al. (1986). Their patient IGR was severely impaired in reading, writing to dictation, and repeating nonwords. The patient’s performance, by contrast, was substantially preserved in the case of words. Furthermore, error analysis revealed a phonological relationship between the stimulus and the response provided by the patient. Caramazza et al. interpreted this association of deficits in terms of the dysfunction of a short-term memory component, the output phonological buffer, which assembles phonological segments and transmits the output of its operation to the peripheral articulatory (for reading aloud and repetition) and graphemic (for writing) processes. These examples illustrate the heuristic role of associations. The presence of dissociations is also needed, however, in order to demonstrate that the conjoint failure in the tasks of interest can be traced back only to the impairment of a specific component. For instance, in patient PV, the inability to learn nonwords was not due to a general learning deficit, as her ability to learn words was preserved (Baddeley et al., 1988). In patient IGR, the repetition deficit was confined to nonwords, and could not be traced back to defective phonological analysis (Caramazza et al., 1986). The efficacy of the conjoint utilisation of associations and dissociations is illustrated by an experiment by Grossi et al. (1989). They studied a right brain-damaged patient with left hemineglect, and a left brain-damaged patient who was unable to generate mental images. The patients’ task was to compare the angles formed by the hour-hands of two clocks. In the perceptual task the clocks were printed on a card, one below the other. In the imagery task the patients had received instructions to generate the images of the two clocks, on the basis of a verbal command (e.g. “the time is five to three”). The patient with left neglect had a defective performance in both tasks, provided the angles to compare were in the left side of the clock-face. This patient showed a dissociation concerning the spatial position of the stimuli (left vs. right), but not the tasks (perception vs. imagery). The patient who was unable to generate mental images showed the opposite pattern of impairment: his performance

was defective in the imagery task, but not in the perceptual task, independent of the spatial position of the stimuli. Associations may be also used to evaluate the effects of a specific treatment (drugs, rehabilitation, physiological stimulations) on a neuropsychological deficit. For instance, if function Fi is involved in the execution of tasks A, F, and C, then its damage impairs the patients’ performances in all three tasks. Let us make the following two assumptions: (1) in patient P Fi is selectively impaired (i.e. P ’s defective performance in A, F, and C can be explained only by a deficit of Fj); (2) a treatment T (e.g. a specific rehabilitation procedure) selectively improves F /’s operation. If this is the case, T should improve P ’s performances in all three tasks. The improvement should also be selective. If in P component F 2 , involved in tasks D, F, and F, is also affected, the positive effects of T should not extend to these latter tasks. If F; was involved in tasks A and B only, but not in C, the effects of T should be confined to the first two tasks. In a situation of this sort, an association may be used to explore the architecture of mental processes, to test competing hypotheses. An illustrative example, which made use of a vestibular stimulation, is the study by Cappa et al. (1987), who aimed at assessing in right braindamaged patients whether this treatment induced the temporary remission of not only visuo-spatial extra-personal left hemineglect, but also of related disorders, such as anosognosia for left hemiplegia, and hemineglect for the left side of the body. According to their hypothesis, if these deficits were produced, at least in part, by the dysfunction of spatial processes modulated by the vestibular system, then the treatment should affect all of them in a similar fashion. In line with this prediction, vestibular stimulation improved both personal and extrapersonal hemineglect, and anosognosia.

Group and single case studies Neuropsychologists have made use of data from both individual patients and groups, selected on the basis of neurological (e.g. the side or the site of the lesion) or behavioural (the presence of a specific deficit) criteria. In different historical periods, one or the other approach has prevailed.

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In the 19th century, neuropsychological studies were performed in single cases, in whom the behavioural deficit, assessed through a clinical examination, was correlated with the localisation of the lesion. This method has a number of methodological flaws (see The neuropsychological method) and was replaced by studies performed in series of brain-damaged patients through standardised tests, which, after World War II, became the leading approach, even though relevant exceptions are on record, such as the noted patient HM (Vallar, Chapter 15 this volume). Since the late 1960s, with the development of the cognitive neuropsychological approach, single case studies again became a widely used experimental method. This modern single case paradigm differs from the 19th-century studies in important respects, however, making use of the methods of experimental psychology (Shallice, 1979). Standard tasks are used, and the patient’s performance is compared with that of matched control subjects, through statistical procedures. The dissociations in the patient’s performances in different tasks have to be statistically significant. The reliability of the patient’s performances may be assessed through repeated testing sessions7. A main reason that underlay this flourishing of single case studies in the 1970s and 1980s was the increasing awareness on the part of cognitive neuropsychologists that the functional architecture of mental processes is very complex, including many connected components. Consider for instance the simple model of the reading processes shown in Fig. 6.1 la. A cerebral lesion, the localisation and size of which reflect anatomo-physiological factors, may disrupt more than one component of the system. Accordingly, if a group of patients is selected on the basis of the side or site of the lesion, it remains possible that patients with heterogeneous behavioural deficits, and, by implication, damage to discrete functions, are pooled together. Also a selection on the basis of the presence or absence of a clinical syndrome (e.g. Broca’s aphasia, or spatial hemineglect) is open to this criticism, as patients with non-homogeneous cognitive disorders might be included. Consider, for instance, the functional model of repetition, reading and writing of single words and

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nonwords shown in Fig. 6.11b (Caramazza et al., 1986). These tasks are simple, compared with the complex analysis required by sentence and discourse processing. Nevertheless, they involve a number of discrete functional components, which may be selectively or conjointly damaged, giving rise to a variety of deficits. It seems then to be unlikely, at least a priori, that two brain-damaged patients show an identical functional impairment. This conclusion is even sounder, if one considers that some parts of the model (the perceptual and the more peripheral production components) are not specified in their full detail. Accordingly, the average behaviour of a group of brain-damaged patients might be a statistical artefact, which conceals heterogeneous patterns of impairment. Figure 6.12 illustrates such an hypothetical example in the case of a double dissociation. An experiment by Bisiach et al. (1983) showed how the group analysis of the performance of brain-damaged patients may cover different pathological patterns. In this study, 12 right braindamaged patients with hemineglect were required to set the mid-point of horizontal segments of varying length. A group analysis performed on the patients showed that the extent of the rightward displacement of the subjective mid-point was directly related to the length of the segment. This treatment of the data concealed some relevant differences among patients, however. An analysis in which the relevant parameter was the length of the represented segment (the part of the segment considered by each individual patient in order to compute the subjective mid-point) revealed two discrete patterns (Fig. 6.13). In one patient, RG, the longer the real segment, the greater was the rightward displacement of the left end of the represented segment. This pattern is compatible with the view that RG’s attention was pathologically focused towards the right end of the segment, so that longer segments produced a greater rightward bisection error (see a theoretical account of this behaviour in terms of opposite attentional vectors in Kinsboume, 1993). In another patient, CC, the longer the real segment, the greater was the leftward displacement of the represented segment. This pattern indicates that CC was, to some extent, taking into consideration the total

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FIGURE 6.11 Cognitive models of some mental abilities, (a) A simple dual-route model of reading (redrawn from Coltheart, 1985). (b) A more complex model for repetition, reading, and writing of words and nonwords (redrawn from Caramazza, Miceli & Villa, 1986).

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FIGURE 6.12

Example of double dissociation between groups, which conceals different patterns of impairment in individual patients. The behavioural pattern of group A patients is similar in all cases, while group B (a) includes sub-groups B-| and B2 (b); B-| does not show a double dissociation with respect to A (redrawn from Shallice, 1988).

length of the segments, and this conclusion might have been based on differences in their right sides. Two lessons can be learned through this example. First, the average performance of a group of patients may be misleading, concealing heterogeneous patterns of behaviour. Second, the theoretical model adopted by the experimenters has a crucial role in all the stages of the study (from the design of the experiment to the analysis of the data, see Caramazza, 1986). Previous researchers had made use of the bisection task (a test widely used for the clinical diagnosis of spatial hemineglect), but their theoretical model did not include the concept of representational space (Schenkenberg, Bradford, & Ajax, 1980). The complexity of the multi-componential architecture of mental processes and of their relationships with the neural correlates assigns a relevant role to single case studies. Natural cerebral lesions, in which the side and site of damage is determined by neurological parameters, usually disrupt multiple components of mental processes, and patients with selective (pure) disorders are comparatively rare.

Many relevant theoretical advances have been made possible by the study of patients who showed a dramatic dissociation between the severe and selective impairment of a specific functional component, and other processes, that were entirely preserved. In Broca’s patient the dissociation concerned a defective speech production vs. a preserved comprehension. The patients described by Anton (1899) and Babinski (1914) were anosognosic for a specific neurological deficit. Their lack of awareness for hemianopia or hemiplegia could not be easily interpreted in terms of defective general intelligence. The noted patient HM had a selective impairment of the explicit component of longterm memory (Vallar, Chapter 15 this volume). The investigation of patient PV revealed the role of phonological memory in vocabulary acquisition (Baddeley et al., 1988). The history of neuropsychology includes many examples of seminal single case studies. Single case studies, in addition, have some practical advantages, compared with group studies. There are no problems related to the selection of

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FIGURE 6.13 Average performance (short vertical dashed lines) of a group of 12 right brain-damaged patients with hemineglect, in a line bisection task (200,400, 600 mm). The lines were shown to the patients with their objective mid-point on the mid-sagittal plane of the patients’ trunk (long vertical dashed line). The performance of patient RG and CC (short vertical lines) are shown in the upper and lower halves of the figure. The dotted rectangles denote the “nonrepresented” portions of the segments, while the remaining part of each line indicates the extent considered by each patient in the bisection task (redrawn from Bisiach, Bulgarelli, Sterzi et al., 1983).

an homogeneous series of patients. The design is less rigid. The result of one experiment may immediately direct the successive investigations. In group studies, by contrast, the structure of the experiment cannot be modified, as this would produce noncomparable data. The only possible solution is to repeat the whole experiment, provided all patients are still available for study. Alternatively, a fresh series of patients may be tested. The greater flexibility of single case studies is based on the assumption that the deficit does not change over time. In the case of long-lasting studies, therefore, the stability of the deficit of interest should be assessed from time to time. The low flexibility of group studies can make data collection slower, but does not diminish, in principle, the value of this approach. The problem of patient selection is more complex. When a patient is assigned to a group on the basis of the presence of a behavioural deficit (e.g. neglect, or

aphasia) the potential role of neurological (site and size of the lesion, aetiology, handedness) and demographic variables, which could make the group non-homogeneous, should be taken into consideration (Vallar & Perani, 1987). If the selection criterion is neurological (e.g., side of the lesion) differences across patients in the pattern of behavioural impairment, which can affect their performance in the experimental task, can make meaningless any interpretation based on the average scores. One solution to these problems is statistical. If the patients’ performance (e.g., in an auditory latéralisation task) is affected by factors other than the investigated variable (e.g. the side and localisation of the lesion), the scores may be adjusted for the potentially confounding factors (e.g. age, schooling, overall neurological severity), through analyses of co-variance (Bisiach, Cornacchia, Sterzi et al., 1984). Alternatively the

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criteria of patient selection may be much more stringent. For instance, Vallar et al. (1988), in a study concerning deficits of verbal memory associated with left-sided lesions, set the absence of aphasia (assessed by a standard exam and the Token Test, a task sensitive to minor language disorders: Boiler & Vignolo, 1966) as selection criteria. In addition, each patient was matched with a control subject with a comparable age and educational level. A typical example of the problems of group studies concerns the possible biasing role of aphasia. When the experiment aims at assessing the incidence and the severity of a neuropsychological deficit after lesions of the left and of the right hemisphere, the percentage of patients who are unable to enter the study because they fail to comprehend the task’s instructions should be comparable in the two groups. In the study of the disorders of auditory latéralisation mentioned earlier, Bisiach et al. (1984) were able to verify that only three aphasies out of 107 patients did not take part in the experiment, due to their language deficit. In addition left and right brain-damaged patients with a visual field deficit had lesions with a similar localisation, but only the latter showed a disorder of auditory latéralisation. Another example is a study that aimed at assessing left-right asymmetries in the incidence of motor, somatosensory, and visual half-field deficits contralateral to a hemispheric lesion. Sterzi et al. (1993) examined retrospectively a large series of patients, taken from a community-based epidemiological survey, in which the two groups of patients were comparable as to all relevant neurological and demographic variables. The problems concerning patient selection frequently occur in group studies. De Renzi and Faglioni (1965) found that right brain-damaged patients had longer latencies in a visuomotor simple reaction time task. In order to account for this hemispheric difference in such a simple task, they suggested that patients with right brain damage had larger lesions. If the function involved in this task was represented in the brain in a diffuse, nonlocalised, fashion, the severity of the patients’ deficit would be directly related to the size of the lesion. The bias related to patient selection may be

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relevant: some left brain-damaged patients with extensive lesions could not have been tested, due to the presence of aphasia. By contrast, patients with right hemisphere lesions similar in size might have entered the study, as they were not aphasic and could comprehend the task. If this had been the case, in a series of patients selected for a behavioural study, right-sided lesions might be more extensive, and the deficit more severe. In a later study, Howes and Boiler (1975) investigated this problem through a volumetric measurement of lesion size, on the basis of a brain scan image. They confirmed that patients with right hemisphere lesions had longer latencies in visuomotor simple reaction times, but not that their lesions were larger. This study does not, therefore, support the view that the hemispheric difference found by De Renzi and Faglioni was produced by a selection bias, suggesting instead that the neural basis of the function of interest was, at least in part, lateralised to the right side of the brain (see related PET activation data in Pardo, Fox, & Raichle, 1991). To summarise, single case studies have a number of advantages, in comparison with group studies. The probability of producing significant theoretical advances is perhaps higher8. Single case studies are more flexible, and the problems related with patient selection are minimal. They are not adequate, however, to investigate hemispheric functional asymmetries, and the neural bases of mental functions. If the aim is to assess whether or not a specific brain region or circuit is (or is not) the neural correlate of a given function or set of functions, the study of a series of patients becomes necessary. The observation that an individual patient with a specific cognitive disorder has focal brain damage is compatible with a nonlocalisationist view of the functional organisation of the brain. If this was the case, the lesion, independent of its site, would produce a degradation of the level of performance, related instead to its extension. Let us assume that a patient P, with a cerebral lesion in area A, has a defective performance in task X , but not in tasks W, Y, and Z. On the basis of this single observation, the possibility that the cerebral regions involved in task X are not confined to A, including instead also B, C, and D, cannot be ruled out. In addition, this

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single dissociation does reject an interpretation in terms of allocation of the available resources: damage to A reduces the patient’s performance in task X , because this is easier than W, Y, and Z. Only the replication of the positive observation (a lesion of A affects the patient’s performance in task X), and a negative finding (a lesion involving cerebral area C, and sparing A, does not disrupt the patient’s performance in task X , affecting instead tasks W or Y) fully supports the conclusion that the brain region A is selectively involved in task X. Two examples will illustrate this pattern. In the first study a behavioural selection criterion was used, namely: the presence or absence of left extra-personal visuospatial hemineglect was subsequently correlated with the site of the cerebral lesion. The more frequent anatomical correlate of hemineglect (assessed by a visuomotor exploratory task) is a lesion of the right posterior-inferior parietal regions, which, in turn, are spared in patients without neglect (Vallar & Perani, 1986). In the second study (Risse, Rubens, & Jordan, 1984) the selection criterion was anatomical, namely: in two groups of patients with frontal and temporoparietal lesions, the pre- vs. post-rolandic site of the damage was subsequently correlated with the behavioural disorder. Risse et al. suggested that the main anatomical correlate of deficits of auditoryverbal short-term memory was a left-sided posterior-inferior parietal lesion. Patients with lesions involving this region had a defective auditory-verbal span, which was preserved in patients with damage involving the frontal lobe or the basal ganglia.

Critique of the concept of syndrome and of group studies Limits o f the concept o f syndrome In the last 20 years, the criteria (a specific pattern of behavioural deficits, the side and localisation of a cerebral lesion) that are used to select a sample of brain-damaged patients, who enter an experimental study, and whose performances are analysed as a group, have been widely criticised. The anatomical localisation value of the traditional neuropsychological syndromes has been

questioned. For instance, in the case of the aphasic syndromes (see Cappa and Vignolo, Chapter 8 this volume), TC and MRI studies have shown that lesions outside the classical language area (e.g. subcortical lesions) can bring about aphasic disorders (Vallar et al., 1992). Furthermore, with reference to the traditional syndromes, fluent aphasia may be associated with frontal lesions, and nonfluent aphasia with posterior damage (Basso, Lecours, Moraschini et al., 1985). Finally, relatively small lesions, localised outside the boundaries of the traditional language areas, may bring about global aphasia (Vignolo, Boccardi, & Caverni, 1986). Methods that provide a measurement of regional cerebral blood flow and metabolism have shown that the area of deranged function may involve regions that are structurally intact (Feeney & Baron, 1986; Metter, 1987; Vallar et al., 1992). On the basis of these observations the classical views on the relationships between neuropsychological syndromes and lesions of specific brain regions have been revisited. For instance, Metter et al. (1989) took the view that the traditional syndromes have little theoretical significance, because in both fluent and nonfluent aphasics metabolism was reduced in the temporal regions. Taken together, these findings suggest that the neural basis of mental processes should be conceived in terms of complex cortico-subcortical circuits, rather than as cortical areas connected by white matter fibre tracts (see Fig. 6.1) (Cappa & Vallar, 1992; Mesulam, 1990). Anatomo-clinical correlation studies of spatial hemineglect also support this conclusion (Vallar, 1993). The view that the neural correlates of mental functions are cortico-subcortical circuits modifies the anatomic part of the concept of neuropsychological syndrome, but not necessarily its functional aspects. These, too, have been impugned, however. In the case of aphasic syndromes, which first were challenged, the argument may be briefly summarised as follows (Saffran, 1982; Schwartz, 1984). The traditional syndromes are founded on a 19th-century model of the organisation of linguistic processes, which, of course, cannot take into consideration the advances that took place in the following decades. The study of mental

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processes, and of their pathological dysfunctions, should be based on current (information processing) models. If the traditional groups of symptoms and signs are analysed in these terms, it is clear that they are, at best, anatomical, probabilistic syndromes, useful in clinical practice, but with no functional significance. This is indeed a current clinical application of the concept of syndrome. The detailed study of the individual case, in addition, may reveal a remarkable lack of homogeneity among different patients, previously classified as belonging to a specific syndrome, through either an informal clinical exam, or standard neuropsychological batteries (the Aphasia Examination of the Neuropsychology Centre of Milano, the Boston Diagnostic Aphasia Test: Basso, Capitani, & Vignolo, 1979; Goodglass & Kaplan, 1972). Accordingly, syndromes such as Broca’s (Mohr, Pessin, Finkelstein et al., 1978; Sloan, Bemdt, & Caramazza, 1980) and conduction (Luria, 1977; Shallice & Butterworth, 1977) aphasias have been fractionated into more subsyndromes, in each of which the complex of symptoms and signs has been explained in terms of a specific functional deficit. Also the standard clinical batteries may disclose new associations, provided objective classification criteria are used. For instance, Kertesz and Phipps (1977, 1980) distinguished two subtypes (afferent and efferent) of the clinical syndrome of conduction aphasia, on the basis of differences in the patients’ performances in verbal fluency and comprehension tasks of the Western Aphasia Battery. Another indication of the limits of the traditional taxonomy is the high number of patients in whom a specific syndromic diagnosis cannot be made. When the assessment is standardised, but the classification is made by the examiner, and not, as in the Western Battery by an algorithm, a high percentage of patients end up not classified: over 40% of the patients on the Boston Diagnostic Aphasia Examination (Albert et al., 1981; Benson, 1979). Cognitive neuropsychologists, therefore, replaced the traditional anatomo-clinical syndromes with new associations, in which the complex of symptoms and signs is analysed in the light of the modem information processing models. In the 1970s and 1980s this revision has generated

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new syndromes, such as deep, phonological, and surface dyslexia (Denes et al., Chapter 14 this volume). More recently the syndrome of spatial hemineglect has been fractionated into a number of discrete components (Barbieri & De Renzi, 1989; Halligan & Marshall, 1992). However, cases classified according to these novel categories may also show relevant differences. This problem was already clear in a review on deep dyslexia, published in the late 1970s (Coltheart, 1980). These differences among patients indicate that any putative functional system, F (the lesion of which produces A7, N 2 , N 3 , and N 4 symptoms, signs or both) may in fact turn out to comprise n subsystems, which may give rise to a number of dissociations. This state of affairs reflects some basic principles of the anatomofunctional organisation of the central nervous system, which possesses a high degree of functional specialisation. An increasing tendency towards fractionation characterises not only the neuropsychological syndromes, but all neurological deficits (e.g. peripheral neuropathies) (see discussion in Vallar, 1994). Only single cases? A solution to these problems is to abandon the very concept of syndrome, which allows patient classification, studying each patient as an individual case (Caramazza, 1986; Ellis, 1987; Patterson, Marshall, & Coltheart, 1985). The alternative would be a multiplication of the syndromes. However, since virtually all skills are based on the cooperation among many functional components (see Fig. 6. lib), the possible defective syndromes produced by brain damage would become so numerous, as to be useless. In the case of dyslexia, for instance, over 16,000 are possible, according to Patterson et al. (1985, p .ll). The view that only the study of single cases provides data relevant to our understanding of the functional architecture of mental processes has been vigorously defended by Caramazza and his co-workers, who, in many papers, have developed this position in some detail (Caramazza, 1986; Caramazza, 1988a). Briefly, given the complex architecture of the cognitive system and the variability of the site and extent of naturally

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occurring lesions, it is very unlikely that two patients have similar functional deficits. It follows, therefore, that a homogeneous group of patients cannot be constituted. Furthermore, even if this were possible, the a priori criteria that define the group concern only the patient’s selection, not the results of the experiments that are to be performed. The functional deficit of each patient, therefore, can be established only a posteriori, after the experimental study (Caramazza, 1988b). Hence, studies in groups of patients which aim at elucidating the neurological and functional architecture of mental processes are useless and harmful, because they provide misleading results. The only appropriate method is to study individual patients, without the aid of any classical or modern syndrome. This extreme position (only single cases), which banishes group studies from the domain of neuropsychology and has been defined ultra (Shallice, 1988) and radical (Robertson, Knight, Rafal et al., 1993), encounters some problems, however. The study o f normal subjects. The arguments against the possibility of forming homogeneous groups of patients can also be applied to the case of normal subjects, showing that group analyses are unreliable, due to individual differences (Caplan, 1988; Shallice, 1988). This is nevertheless the current method of cognitive psychological research in normal subjects. McCloskey and Caramazza (1988) reply to this argument by assuming that normal subjects are homogeneous. Variability reflects a nonspecific background noise, and the behaviour of the majority of the subjects may therefore provide reliable indications as to the architecture of mental processes. Homogeneity, by contrast, can not be taken for granted in brain-damaged individuals, in whom, due to the reasons discussed earlier, it is likely that the functional deficits differ among patients. Differences among normal subjects cannot be accounted for entirely in terms of background noise, however. Let us suppose, for instance, that 10 out of 12 normal subjects show the detrimental effect of word length or of phonological similarity (immediate repetition span is higher for short or

phonologically dissimilar than for long or similar words: Baddeley, Lewis, & Vallar, 1984; Baddeley, Thomson, & Buchanan, 1975), but that in the remaining two subjects the effect is absent or reversed. This untypical behaviour might reflect background noise only, being therefore within the normal distribution of the observations, even though, on the mere basis of the effects of noise, the expected result might be a variability of the overall level of performance, without qualitative effects (i.e. absent or reversed effects). In the latter case, the performance of the two aberrant subjects should show the typical pattern, on repeated testing sessions. The untypical pattern could however be reliable. Such a result could reflect the utilisation by the two minority subjects of strategies different from those employed by the majority, even though the functional architecture of the systems involved is identical. In 251 adults Logie et al. (1996) have recently confirmed that word length and phonological similarity significantly influence the group means in the predicted direction. However 43% of the subjects failed to show at least one of the effects, and a notable number of subjects showed effects in the direction opposite from that of the majority. They also found variability in the presence of the effects on test-retest sessions. Span level was a predictor of the presence of the effects, but exceptions were found (i.e. subjects with high span who did not display the predicted effects). The subjects’ strategies were also relevant, and their effect was independent of span level.9 The untypical subjects might, for some reason, choose to use strategies different from those employed by the majority, but which nevertheless belong to the normal behavioural repertoire (see a related discussion of patient PV’s behaviour in the Constancy section). However, it remains possible that their functional architecture is qualitatively different. Were this the case, the homogeneity assumptions would not apply to normal subjects. That this may indeed be the case, at least for perceptual processes, is suggested by the behaviour of normal subjects in a number of tasks that require the organisation of part of the stimulus in the presence of a background or field. On the basis of their performance in tasks such as the Rod and Frame Test and the Embedded Figure Test, normal

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subjects may be classified along a continuum as relatively field-dependent or independent. These differences are, at least in part, genetically determined, and have been related to hemispheric functional asymmetries. For example, in a choice reaction time experiment, Zoccolotti and Oltman (1978) confirmed the well known superiority of the right visual half-field (left hemisphere) for letters and of the left visual half-field (right hemisphere) for faces in field-independent, but not in fielddependent male subjects. Using a similar paradigm, Pizzamiglio and Zoccolotti (1981) accounted for some hemispheric differences concerning verbal and nonverbal skills in terms of field effects, rather than sex. If group studies of brain-damaged patients must assume a complete homogeneity, in order to be performed, then experiments in normal subjects should also be done as single case studies. As noted earlier in the case of normal individuals, too, homogeneity can not be postulated. Group studies, however, are a current typical paradigm in cognitive psychology. This is because there is no assumption of homogeneity, but the results provided by the statistical treatment are taken as indexes of the behaviour, and of the organisation of the mental architecture, of the majority of the subjects examined. This approach is compatible with the existence of minority patterns. These may be the object of specific studies, and are very interesting in their own right; however, they do not undermine the significance of the conclusions concerning the majority pattern. To summarise, the argument that the selection of a group of patients implies the inclusion of functionally nonhomogeneous individuals (due to the effects of the lesion), applies also to groups of normal subjects. In both cases, the inferences concerning the deranged or normal functions are based on the majority behaviour. Replication. Replication of an observation is a distinctive feature of the scientific enterprise, in all its branches (Popper, 1959). The lack of replication of results (particularly if unexpected on the basis of current knowledge) casts serious doubts on their reliability and is taken as an indication of methodological flaws, or even fraud. The

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controversies (Maddox, Randi, & Stewart, 1988) concerning the reproducibility of the high-dilution experiments (memory of water) (Davenas, Beauvais, Amara et al., 1988) are a noted example. If replication across patients is impossible, as all patients are different from one another, are there alternative methods available to neuropsychologists devoted only to single case studies, in order to evaluate the reliability of an observation? First, replication in the same patient is relevant (Ellis, 1987, but see note 7). Second, the relationships of the new finding with the complete set of pre-existing data and with the theoretical models that have informed the study have an important role (Caramazza, 1986). The relative weight of each single case is therefore determined by the available knowledge in that specific field. In general, the larger the available set, the lower the relative weight of each single observation. A single result is crucial only if (within the context of a specific theoretical model) consistent with the vast majority of data available from other patients. Finally, the results in each single patient should be internally coherent, converging towards a single (the best) available model. The impossibility of replication across patients assigns a most relevant role to the corpus of preexisting experimental data, and to the theoretical models that have directed the study. This may have the effect of favouring studies that produce results in agreement with current knowledge and dominant theories. In other words, novel and unexpected observations, which break current paradigms, are implicitly discouraged. Observations that subsequently proved to be very important were often not based on an explicit project, with a detailed underlying theoretical model. This is the case in new areas, in which replication is the main means by which a novel finding becomes established knowledge. Illustrative neuropsychological examples are the observations that cerebral lesions may produce lack of awareness (anosognosia) for neuropsychological deficits such as cortical blindness, hemiplegia, and hemianopia (Anton, 1899; Babinski, 1914; Bisiach & Geminiani, 1991), and the discovery of the role of the right hemisphere in visuospatial processes (Brain, 1941; De Renzi, 1982a).

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Finally, the impossibility of replicating an experimental result in different patients makes unfeasible any anatomo-clinical correlation. This requires, as previously discussed, series of patients with homogeneous deficits. This limitation may be overcome by “... creating research consortia... This step will permit the accumulation of cases with the desired characteristics for the needed correlational analysis” (Caramazza, 1988b, p.417). This suggestion implies, however, that the difficulty with group studies is not theoretical, but practical, related to the problem of constituting groups of patients who are homogeneous with respect both to the selection criteria and to the results of the experimental study. Conclusion Over and above the specific problems discussed here, the view that only single case studies may be performed is based on the probabilistic assumptions that it is very unlikely that a group includes patients with homogeneous deficits. It is therefore legitimate to consider the results obtained through single case and group studies from the perspective of the advances of our knowledge of the functional and neural architecture of mental processes. A few examples. The view that some internal representations of objects in space have analogical rather than propositional features has been supported by studies in right brain-damaged patients, selected on the basis of the presence of left visuospatial hemineglect (Bisiach, Chapter 21 this volume). In amnesic patients, the study of the preserved and impaired components of long-term memory systems has been performed both in single case and in group studies (Vallar, Chapter 15 this volume). Finally, the selective deficit of phonological short-term memory constitutes an anatomo-functional syndrome, which has been replicated through many single case studies (Vallar, Chapter 15 this volume). To summarise, both single case and group studies contribute to our knowledge of the functional and neurological architecture of mental functions. There is no valid reason to banish one of the two paradigms from the neuropsychologist’s arsenal. Under specific circumstances, however, one approach may be more adequate than the other,

and the appropriate decision is to be taken pragmatically. Both approaches are integral components of neuropsychology.

ACKNOWLEDGEMENTS The author is grateful to Stefano Cappa and Marco Zorzi, who read the sections on the cerebral activation methods and on connectionism, for their helpful suggestions. Usual disclaimers apply.

NOTES 1. As to the centre for the elaboration of concepts, Lichtheim (1885, p.477) wrote: “I do not consider the function to be localised in one spot of the brain, but rather to result from the combined action of the whole sensorial sphere”. By contrast, the centres for motor and acoustic images (M and A in Fig. 6.2) were localised in Wernicke (Brodmann’s area 22) and Broca’s (Brodmann’s area 44) areas. 2. The brain-mind problem is not discussed in this chapter. The interested reader is referred to Bunge (1980), Smith Churchland (1986), Dennett (1991) and Chalmers (1996). 3. Both the 19th-century (see Figs. 6.1 and 6.2) and the contemporary information processing models conceive the human mind as a complex system, including a number of connected components. There is a relevant difference, however, The 19th-century models are anatomo-clinical in the strict sense of the term: any given functional component is (or should be) localised in a specific brain region, and the correspondence is an intrinsic part of the model. Information processing models do not necessarily imply such a correspondence. Their level of description concerns the functional architecture of the mind, rather than its neural correlates (Morton, 1984). Recent developments of cognitive neuroscience, however, are providing a fine-grain description of the neural architecture of a number of components of mental processes (see some illustrative examples concerning memory disorders in Vallar, Chapter 15 this volume). 4. The assumption of a correspondence between the neurological and functional architectures was also a main feature of the 19th-century models of language. By contrast, neurologists such as Pierre Marie, Henry

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Head, and, in the 1960s, Eberhard Bay, took the view that aphasia was a single deficit, and language a unitary process (see Lecours, Lhermitte, & Bryans, 1983; Lhermitte & Signoret, 1982). These positions have been revived by some recent PET studies in aphasic patients (Metter, Kempler, Jackson et al., 1989). 5. In patients suffering from developmental neuropsychological deficits the possibility should be entertained that neurological reorganisation processes take place, giving rise to systems qualitatively different from those of the normal adult subject. The value of extrapolations from data collected in developmental cases to the organisation of the normal system is therefore dubious (McCloskey, 1993; Vallar & Baddeley, 1989). 6. “Converging operations may be thought of as any set of two or more experimental operations which allow the selection or elimination of alternative hypotheses or concepts which could explain an experimental result. They are called converging operations because they are not perfectly correlated and thus can converge on a single concept... Ideally, converging operations would be orthogonal (completely independent), since such operations are the most efficient” (Garner, Hake, & Eriksen, 1956, pp. 150—151). 7. The inconsistency of the patients’ performances across experimental sessions may suggest unreliability, due to nonspecific factors, such as fatigue, lack of motivation, defective global attention, etc. Specific factors may also be involved, however.

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In tasks that assess semantic memory, the variability of the patient’s performance may indicate that the deficit concerns the access to representations, which are nevertheless stored and relatively preserved. By contrast, the repeated observation of a qualitatively and quantitatively stable performance suggests a degradation, more or less severe, of the stored material (Shallice, 1987; Warrington & Shallice, 1979). In psychophysical tasks, the variability of the detection threshold may reflect an attentional, rather than primary sensory, disorder (Tegner, 1989; Vallar, Bottini, Rusconi et al., 1993). 8. A comparative evaluation of the impact of single case and group studies should also consider some social rules of the scientific community. A scientist who makes a relevant discovery in an individual patient is willing to publish his or her finding as soon as possible. If the observation is reliable, replication typically follows. For instance, Bisiach and Luzzatti (1978) described two right brain-damaged patients with left hemineglect for internally generated visuospatial images. The finding was subsequently replicated in a larger series of right brain-damaged patients (Bisiach, Luzzatti, & Perani, 1979). Replication may also occur through a succession of single case studies (Shallice & Vallar, 1990). 9. A related analysis of agrammatic speech production may be found in Bates et al. (1991), who suggested that the patients’ variability may be accounted for by factors such as neurological status, education, and strategies.

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Part II

Language Disorders

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7 Development of the Concept of Aphasia Guido Gainotti

In most cases they were detected through clinical observation (or through congruence between clinical data and theoretical assumptions), based essentially on the systematic co-occurrence of a certain number of linguistic disorders and on the simultaneous integrity of other aspects of language. In other cases, instead, the theoretical model clearly oriented clinical observation, leading to prediction of the existence of clinical syndromes that had not yet been observed empirically. This was the case, for example, for conduction aphasia; its existence was logically predicted by Wernicke’s model even before it was observed on the anatomical-clinical plane (Wernicke, 1874). However, this double valence (classification and interpretation) of the aphasic syndrome construct has repeatedly and in various historicalcultural contexts given rise to a paradoxical situation. On one side, several aphasic syndromes—that is, anatomo-clinical pictures that identify rather well defined regularities in the chaotic data deriving from observation—have been consistently described by authors of various doctrinal orientations and universally used in clinical practice.

So as not to be completely extraneous to the topics in which contemporary researchers in aphasia are interested, it seems important to begin this chapter on the historical development of the concept of aphasia by referring to a construct that has stirred up great controversy throughout its entire history and which is still today at the centre of heated discussions, that is, the aphasic syndrome construct. Its central position probably depends on characteristics of polymorphism and the extreme complexity of aphasic symptomatology; characteristics that led Alajouanine, Ombredane, and Durand (1939, p.l) to say that “in the study of aphasia facts have so little independence from theories that not only their structure, but their very existence is debatable.” Now, the aphasic syndrome construct is probably the one in which facts and theories are most closely connected, as it was developed by associationist authors in the second half of the nineteenth century not only to better isolate clinical facts but also to provide a theoretical justification for isolated clinical pictures. The existence of a double valence (clinical and theoretical/nosographical and physiopathological) of the aphasic syndrome construct is obvious if we consider how the various syndromes were isolated. 135

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On the other side, the physiopathological significance or the existence of these syndromes was repeatedly contested by the authors of the Noetic School in the first half of the twentieth century and in recent years by the cognitivists. With regard to authors of the holistic/noetic approach, we need only think of a striking contradiction present in the work of Goldstein; in the general part of his monograph on language disorders (Goldstein, 1948) he negated the existence of aphasic syndromes on the basis of theoretical considerations and then ended up recognising these syndromes empirically in the special (clinical) part of the same volume. Criticisms of the aphasic syndrome construct by the cognitivists are more methodological and are, in any case, contrary to those of the holistic school. The latter hold that aphasia is one and indivisible and that it is not, therefore, possible to subdivide it into different syndrome pictures, each subserved by a different physiopathological mechanism. On the contrary, cognitivist authors hold that the functional architecture of the linguistic system is extremely complex and articulated into a large number of components. Thus, they do not negate the clinical utility of aphasic syndromes, but hold that they are nonhomogeneous symptomatological agglomerates and cannot be used to clarify the intrinsic organisation of language processing. Obviously, we cannot go into detail about this discussion of principle here, nor about more specific controversies regarding the single aphasic syndromes. Instead, we would just like to note that as the syndromes are the meeting place between facts and theories, different aphasic syndromes have been proposed by all streams of thought marking the development of aphasiology. Therefore, to run over the historical development of the concepts on aphasia means going over the making and unmaking of syndrome proposals in which the gathering of relevant data is oriented by a new reference model. For ease of presentation we will try to analyse this continuous flow by subdividing it into five distinct sections, dedicated respectively to: 1. the principle of localisation and the associationist model; 2. unitary interpretations of aphasic disintegration;

3. empirical classification and Geschwind’s neoassociationism; 4. Luria’s interpretative system and the theory of cortical analysers; 5. linguistic interpretations of aphasia.

THE PRINCIPLE OF LOCALISATION AND THE ASSOCIATIONISTIC MODEL Broca and the birth of scientific aphasiology The discovery that one of the highest functions and characteristics of the human species—language— is not generated by the brain as a whole, but is supported by well defined parts of it, marked the birth of aphasiology. As is well known, this discovery, made by the French neurologist Paul Broca, was not only due to this researcher’s anatomical knowledge and clinical shrewdness, but also to the great debate taking place at that time on the factors causing the emergence of the human “mind” over the course of the evolutionary process. Gall (1810) played an important role in this debate because his phrenological conception, in spite of its obvious arbitrariness, contained two important innovative factors: (a) an attempt to fragment the human mind into relatively autonomous functions, each having its own cerebral localisation; and (b) the recourse to pathology, as a source of empirical data able to confirm or invalidate the phrenological models. Bouillaud was the most eminent of the physicians who held Gall’s ideas in high esteem and tried to compare his theses with pathological data. Bouillaud (1825) was struck by Gall’s affirmation that the “sense of language” was located in the anterior parts of the brain and, as early as 1825, he reported data from clinical research “to demonstrate that the loss of speech corresponds with a lesion of the anterior lobes of the brain.” The clinical and anatomical data on which Bouillaud based his theses were judged as insufficient by his contemporaries and thus he did not influence the scientific thought of his time. However, the idea that the frontal lobes of the brain play a critical role in the development of intelligence and human language continued to stir up controversy in

7 DEVELOPMENT OF THE CONCEPT OF APHASIA

medical and anthropological circles of the epoch; and it was during a lively discussion on this topic that Broca’s main observation emerged. The discussion took place in 1861 at the Anthropology Society in Paris. The debate was between Auburtin (Bouillaud’s son-in-law and supporter of his ideas) and Gratiolet, an eminent neuroanatomist and supporter of the thesis that at least with regard to the higher nervous functions, the brain is an essentially homogeneous organ (see Ombrédane, 1951 and Hécaen & Lanteri-Laura, 1977 for a detailed illustration of the topic). Several days after this debate, Broca found a 51-year-old patient in his ward who from the age of 21 had lost the faculty of articulate speech (so much so that to every question he responded with the stereotype, “tantan”) even though he apparently understood what was said to him and demonstrated good intellectual ability. As the patient died several days later for extracranial reasons, his autopsy allowed Broca to make an extremely important check of the theses debated at the Anthropology Society. According to Broca, the autopsy report was clearly in favour of Auburtin because the major damage was in the frontal lobe, although the lesionai context also extended to the lower part of the parietal lobe and to the first temporal gyrus. Broca held that the lesion responsible for the loss of speech in his patient was the one that had destroyed the posterior part of the third frontal gyrus. Further, advancing a physiopathological hypothesis on the nature of his patient’s articulatory disorder, Broca (1861, p.237) held that it was due to the loss of “a particular type of memory, which is not memory for words, but for the movements necessary for articulating words.” In subsequent years, Broca reported other anatomical-clinical observations in support of his thesis and began to understand that not only the frontal location, but also the left hemispheric side of the lesion played an important role in the genesis of disorders of spoken language (Ombrédane, 1951; Hécaen & Lanteri-Laura, 1977). Actually, this latter affirmation was not entirely new, because similar observations had been reported several decades before by another French physician, M. Dax, who had gathered more than 150 cases in which, without exception, a language

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disorder accompanied a left hemispheric lesion (Dax, 1865). However, as these observations were made by a provincial doctor and communicated at a rather unimportant conference, they were completely ignored and even Broca did not know of their existence. On the wave of interest raised by Broca’s reports, this finding also rapidly became an accepted notion in the most qualified scientific community. Without going into the merits of Dax and Broca for the discovery of the relationships between language and the left hemisphere, I will conclude this part by outlining the essential points of Broca’s contribution: a lesion of the foot of the third frontal gyrus of the left hemisphere leads to a disorder in speech production, which Broca attributed to the loss of a particular type of memory, that is, memory of the movements necessary for articulating words.

The discoveries of experimental neurophysiology and the associationist model Several years after Broca’s anatomical-clinical observations, Fritsch and Hitzig (1870) provided for the first time experimental proof supporting the hypothesis that various functions are located in different parts of the cerebral cortex. In fact, these authors showed: (a) that the stimulation of anterior portions of the cerebral cortex of the dog provokes muscular contractions of the contralateral part of the body; (b) that analogous contractions are not obtained by the stimulation of posterior parts of the cortex; and (c) that a point-by-point correspondence exists between the area of cortical stimulation and localisation of the movement provoked by it. These same authors also showed that the destruction of the areas that provoked muscular contractions upon stimulation was followed by a paralysis of the corresponding muscle groups. In the following years, other experimental evidence favouring the principle of localisation was provided, for example by Ferrier (1878), who isolated an ocular-motor centre in the lower part of the frontal lobe; by Luciani & Tamburini (1879), who located the cortical areas of hearing in the temporal cortex of the monkey; and by Munk (1877-1880), who provoked “psychic blindness” in dogs by removing their occipital lobes.

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All of these data (discussed in detail by Hecaen & Lanteri-Laura, 1977) were combined in the model of cerebral functioning proposed by Meynert (1884). This author distinguished areas of projection and areas of association at the cortical level, hypothesising that the first served for analysing sensory information and for giving movement orders and that the second were, instead, a store of images (that is, storages where memories of previously analysed information or of commands given by the corresponding projection areas were grouped). We have already encountered this way of conceiving cerebral functioning in Broca’s hypothesis that lesions of the third frontal convolution destroy memory of the movements necessary for articulating words; and we will find it again in all the major models of aphasia formulated by Wernicke, Lichtheim, and other associationistic authors. Therefore, it seems important to explicitly recall the basic conceptions of associationist thought: 1. Thought is only a combination of images. 2. Images are just the faded trace of sensations received (or of movements executed) previously. 3. When a perceptual centre is again stimulated by a particular stimulus, an automatic evocation of the images formed previously by exposure to the same stimulus is produced. 4. As an object usually stimulates more than one sensory modality (for example, a musical instrument can stimulate sight and hearing simultaneously) the images that are evoked simultaneously in various sensory modalities tend to be associated. 5. An image (for example, the sound of a violin) could, therefore, be evoked not only by stimulation of the corresponding sensory centre, but also by another image associated with it (for example, the visual image of a violin). 6. Concepts of objects are just the corresponding associated images (for example, the concept of violin is just the sum of the visual, auditory, tactile, etc., images provoked by this instrument, and so forth). 7. Language is just a game of verbal images (auditory, visual, articulatory, and graphic)

stored in the associative areas adjacent to the corresponding sensory and motor centres; its reciprocal evocation is assured by the association fibres linking the various unimodal associative areas. 8. Therefore, language pathology depends on the destruction of centres where the verbal images relative to every sensory or motor modality are stored and/or on the destruction of the fibres connecting the various associative centres. According to this general conception, the term aphasia should be broken down into a multiplicity of sectorial disorders, due to the destruction of one or more image centres or to the dissociation of the areas in which these images are stored. These concepts constituted the reference system of all associationist authors and were at the root of the criticisms of those authors who proposed theses different from the associationist ones.

Wernicke’s first model and systematisation of the clinical forms of aphasia Wernicke, who was a disciple of Meynert, was greatly influenced not only by the model of cerebral functioning proposed by his teacher, but also by the notion that the central acoustic pathways terminate in the posterior part of the insula and are associated with an image centre containing auditory images of words. Wernicke clearly separated language from thought on the basis of his observation that deafmutes think, even though they do not know how to speak, and that, vice versa, in the first phases of language development, children repeat words whose meaning they do not know. On the contrary, Wernicke held that language is constructed starting from the auditory afferences and that, thanks to the child’s echolalic tendencies, from an early age important associations are established between auditory and motor images of words, allowing the control of one centre over the other. Combining his conceptions with Broca’s and Meynert’s observations suggesting the presence of a centre of articulatory images in the lower part of the frontal lobe and, respectively, a centre of auditory-verbal images in the posterior part of the insula and the first temporal gyrus, Wernicke

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constructed his first model, which was both simple and influential. According to this model (Wernicke, 1874), the critical structures for language processing are situated all around the left sylvian valley and are articulated into two centres, one frontal (verbalmotor) and one temporal (auditory-verbal) linked by bundles of associative fibres. Different clinical forms of aphasia are provoked by lesions selectively destroying the various parts of this audio-phonatory system. In particular: 1. The destruction of the auditory pathways, before they reach the auditory-verbal centre, causes deafness without aphasia. 2. The destruction of the centre containing the “auditory images of words” make the perceived sound lose all verbal value so that it is perceived as the “indistinct murmer of a foreign language.” Thus, the patient is unable to understand or repeat words. Further, having lost the possibility of controlling oral production with the auditoryverbal centre, the patient has a paraphasic language of which he is unaware. Wernicke named this form of aphasia “sensory aphasia”. 3. Destruction of the association fibres linking the auditory-verbal centre to the verbal-motor centre leaves both articulatory and auditory-verbal images intact. Thus, the patient does not have disorders of comprehension or expressive difficulties but presents disorders in transposing the auditory structure of a word into the corresponding articulatory form. Therefore, the basic deficit of these patients is a repetition defect. To be sure, some deformed words can also be observed in spontaneous language, but unlike what is observed in sensory aphasia, the patient is generally aware of this disorder (being able to control the operation of the verbal-motor centre with the auditory-verbal centre) and tries to correct him/herself. This form of aphasia, which still had no anatomo-clinical demonstration, but which Wernicke’s schemata predicted logically on the basis of the internal organisation of the model, was called “conduction aphasia.” 4. A lesion of the verbal-motor centre produces the clinical form of aphasia described by Broca and characterised by important deficits in verbal

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expression, in the absence of disorders in comprehension. In this form of aphasia, disorders in writing analogous to those seen at the level of oral expression are usually observed, because subjects accustomed to pronouncing the words they write find themselves in trouble because they lack this intermediate process of graphic activity. 5. Finally, a lesion in the fibres extending from the verbal-motor centre to the nuclei of the cranial nerves involved in articulatory activity brings about a primarily parethic type of dysarthria which leaves speech partially understandable.

Criticisms of Wernicke’s first model, and Lichtheim’s synthesis Without mentioning the conceptions of other authors of the associationist school (such as Bastian, 1869; Kussmaul, 1876; Exner, 1881, or Charcot, 1876), who developed models analogous to Wernicke’s, but who are only of historical interest today, in this final part of the section dedicated to the principle of localisation and the associationist model, only two points will be discussed: • the criticisms of Wernicke’s first model; • the schemata used by Lichtheim to try to respond to these criticisms, preserving what was essential in Wernicke’s model. The criticisms of Wernicke’s model were in part theoretical and in part purely empirical. The theoretical criticisms primarily regarded the conception of language proposed by Wernicke, because by considering language only in audiophonatory terms, he neglected the fact that the sounds of language are signs used by man to communicate his ideas and feelings to others (Finkelnburg, 1870; Kussmaul, 1887; Jackson, 1879). Empirical criticism concerned the fact that destruction of the motor and auditory images of the word (or disconnection of the corresponding centres) is not enough to explain the complex range of verbal disorders that can be observed in aphasic patients. For example, Wernicke’s model could not account for patients who repeat perfectly

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even though they show serious deficits in comprehension or serious difficulties in oral production. According to Wernicke’s model, destruction of the auditory images of words would produce linked disorders of comprehension and repetition, just as destruction of the verbal-motor images would provoke a parallel deficit of both spontaneous speech and repetition. To bypass these theoretical and empirical objections, Lichtheim (1885) incorporated Wernicke’s model in a more complex schema, that is, in a two-stage model; the lower level corresponded to the sensorimotor components of language, favoured by Wernicke’s model, and the upper level to the semantic-conceptual components of language, which Wernicke had ignored in his systematisation. Both Lichtheim’s schema and Wernicke’s model in a certain sense anticipated current cognitive models, as both had the following general characteristics: (a) a rather explicit and analytical basic theoretical interpretation of normal functioning; (b) in normal functioning, a series of functionally autonomous components were isolated, which could be destroyed individually by the pathological event; and (c) the changes following the destruction of each of these components could be predicted a priori on the basis of the function carried out by the component in question in normal language. Wernicke’s and Lichtheim’s schema also distinguished two types of functional deficits: • those resulting from the destruction of “centres” in which the functions in question were processed (analogous to what occurs in the “boxes” of the cognitive models); • those resulting from the interruption of “pathways” linking various centres (equivalent to the “arrows” linking the various boxes). Thus, Lichtheim’s model was extremely important for many reasons, which can be synthesised as follows: 1. It constituted the most thorough synthesis of associationist thought. 2. Its system of classification of aphasic disorders is still followed today by many schools of

aphasiology and it constitutes the reference schemata of the most well known test batteries for aphasia, such as the Boston Diagnostic Aphasia Examination (Goodglass & Kaplan, 1972), the Western Aphasia Battery (Kertesz, 1979) and the Aachen Aphasia Test (Huber, Poeck, Weniger, & Willmess, 1983).

3. Its “cognitive” approach is still extremely relevant today. 4. The basic criticism against it (that is, the existence and anatomical localisation of the socalled “centre of concepts”) can perhaps be resolved in light of current conceptions about the anatomical bases of specific semantic disorders by category.

For all of these reasons, it seemed important to dwell a little on this model, and in the following pages I will briefly illustrate: (a) Lichtheim’s model of the normal functioning of language; (b) the components this model is broken down into and the clinical forms of aphasia resulting from lesions of each of these components; (c) criticisms of this model and the possible responses and current conceptions about the anatomical bases of conceptual representations could counter them with. The model o f normal language functioning Lichtheim held that Wernicke’s conception, which reduced language to its audio-phonatory components, was valid only for the first phases of linguistic development, during which an activity of purely reflexive imitation made the acquisition of auditory and articulatory images of words possible. However, in successive phases, when the ability to understand the meaning of words and to produce language with communicative contents appears, it must be admitted that a “centre of concepts,” that is, of the meanings of words, is formed. This centre must be linked to both the “auditory-verbal” centre (to make possible the comprehension of word meanings) and the “verbal-motor” centre (to make possible the utterance of verbal messages able to communicate ideas). Further, with the development of written language, a visual-graphic centre (for reading) and grapho-motor centre (for writing) must be added to the auditory-verbal, verbal-motor,

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and conceptual centres. According to Lichtheim, these centres do not have direct access to the centre of concepts, as the visual information acquired from reading must pass through a phase of auditory-verbal recoding in order to be understood; while the passage from an idea to its graphic expression requires an intermediate oral formulation. For the sake of simplicity, we will not concern ourselves too much with the selective disorders of reading and writing and will focus our attention on the clinical forms of aphasia resulting from lesions of the pathways and centres involved in the various phases of oral language. Components o f the model and corresponding clinical forms o f aphasia In Fig. 7.1, I have tried to schematise the image centres and association pathways proposed by Lichtheim’s model as well as the clinical forms of aphasia that follow a lesion in these pathways and centres. The terminology used to indicate the clinical forms of aphasia is that proposed by Wernicke in his second conceptualisation, which essentially follows the schemata proposed by Lichtheim. This schemata includes seven clinical forms:

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1. Subcortical sensory aphasia (or pure verbal deafness), due to a lesion of the fibres linking the primary auditory areas with the auditoryverbal centre (Wernicke’s area), is characterised by a selective impairment of all linguistic performances (auditory-verbal comprehension, repetition, and writing on dictation), which are based on a correct analysis of the auditory afferences. On the contrary, linguistic performances, apart from the auditory afferences, remain correct, including spontaneous speech and writing, reading aloud, copying, and reading comprehension. 2. Cortical sensory aphasia (or Wernicke's aphasia), due to a lesion of the auditory-verbal centre, has the characteristics stated by Wernicke: disorders of auditory-verbal comprehension and repetition, with paraphasic speech of which the patient is unaware. Also, disorders in reading comprehension, due to the fact that the model does not predict a direct route from the visual areas to the centre of concepts, but holds, instead, that the written images must be first translated into the corresponding auditory-verbal images are present in this form of aphasia.

FIGURE 7.1 Image centres (represented within boxes), associationist pathways (represented with arrows connecting these boxes) and aphasic syndromes resulting from disruption of these centres or pathways according to Lichtheim’s model. ScSA= sub-cortical sensory aphasia; WA (CSA)= Wernicke’s Aphasia (cortical sensory aphasia); CdA= conduction aphasia; TcSA= transcortical sensory aphasia; TcMA= transcortical motor aphasia; BA (CMA)= Broca’s Aphasia (cortical motor aphasia); ScMA= sub-cortical motor aphasia.

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3. Conduction aphasia , due to lesions of fibre bundles linking the auditory-verbal centre with the verbal-motor centre (arcuate fasciculus); clinical characteristics are those thoroughly described by Wernicke. 4. Transcortical sensory aphasia, due to lesions of the fibres linking the auditory-verbal centre with the centre of concepts. In this form of aphasia, auditory-verbal and reading comprehension are impaired, but repetition is unimpaired. Spontaneous speech and writing are preserved but paraphasic, as disorders in comprehension impede the patient from adequately controlling verbal production. 5. Transcortical motor aphasia, due to an interruption of fibres linking the centre of concepts with the verbal-motor centre, is characterised by abolition of speech and spontaneous writing. Instead, both comprehension of oral and written language and repetition and the other forms of transcoding (copying, dictation, and reading aloud) are unimpaired as the relevant structures remain unimpaired. 6. Cortical motor aphasia (or Broca’s aphasia) is obviously due to the destruction of the verbalmotor centre and has the characteristics described by Broca. 7. Subcortical motor aphasia, due to lesions of the fibres linking the verbal-motor centre with the nuclei of cranial nerves involved in phonoarticulatory activity, is characterised by a selective impairment of oral expression and by a relative saving of written expression. This dissociation is due to the integrity of the “motor images of words” and to the selective interruption of the pathways linking the verbal-motor centre to structures carrying out the articulatory activity. Major criticisms o f Lichtheim’s model

There are two major criticisms of Lichtheim’s model: • the first is that it did not take into consideration a very common clinical form of aphasia— nominal aphasia; • the second is due to its hypothesis of the existence of a “centre of concepts”, without

being able to demonstrate that this centre really exists. As I will speak rather extensively about the problem of nominal aphasia later, in the sections of this chapter dedicated to Goldstein’s thought and to Geschwind’s neo-associationist conception, here I will only tackle the problem of the cerebral representation of concepts and their possible anatomical localisation. Actually, this is a rather ticklish problem for Lichtheim’s model, because, if you accept its assumption that anatomical connections exist which relate the auditory-verbal centre and the verbal-motor centre with the area of representation of concepts, then it becomes almost necessary to concede that this area has a rather precise location. However, even if some authors (for example Luria, 1974 and Heilman, Tucker, & Valenstein, 1976) hypothesised that the cortex of the angular gyrus may carry out a critical role in conceptual thought, no one has been able to demonstrate a selective disorder in the processing of concepts in patients affected by lesions in this area or in any other circumscribed portion of the cortex. Perhaps some current conceptions about the anatomical-functional bases of conceptual activity will allow us to approach this problem in a different way, indicating that the concepts are neither stored in a unique “centre”, as Lichtheim held, nor represented in a diffused way on the cortex, as his opponents held. Instead, they may be subserved by different but well-defined parts of the cortex, according to a rule that predicts that the critical zone for the representation of specific conceptual categories could be the same one that processed the most important information for the organisation of the categories in question. These concepts were recently elaborated by Warrington and colleagues (McCarthy & Warrington, 1990; Warrington, 1981; Warrington & McCarthy, 1987; Warrington and Shallice, 1984), who again took up and developed the associationist model of “associated images”, where an integration between different sensory information is at the base of conceptual thought. In fact, these authors point out that even if different information usually converges in the processing of

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a specific concept, the weight of this different information can be remarkably different in different categories. For example, some “biological” categories (such as animals, vegetables, flowers, fruit, etc.) could be primarily based on sensory information and, in particular, on visual information. For instance, the characteristic that best distinguishes a lion from a tiger or from a leopard is homogeneous appearance, stripes or spots. Instead, other categories of manufactured goods (for example, utensils or clothing) could be primarily based on functional information, that is, information relative to the precise function for which the object was made (a knife for cutting solid food, a spoon for bringing liquid foods to the mouth, etc.), besides proprioceptive information, linked to the manipulation of the object. Now, given that different types of information are transmitted by functional systems located in different parts of the brain, it is possible to hypothesise that lesions located in different parts of the cerebral cortex disorganise primarily those conceptual categories that are preferentially based on information processed in that part of the cortex. Anatomoclinical data consistent with this hypothesis have recently been reported by Damasio, Damasio, &

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Tranel (1990a) and by Gainotti, Silveri, Daniele, & Giustolisi (1995). These data seem to indicate that conceptual representations are associated with well defined areas of the cortex (and that anatomical connections may exist between language areas and cortical areas where the concepts are processed). However, they are not concentrated in a unique portion of the cortex, but represented in a multifocal way, in relation to the importance of various sources of information in the organization of different conceptual categories. Although this general conception creates a series of additional problems (which, however, are not important to discuss here) for Lichtheim’s schemata, it is in line with one of the basic assumptions of the connectionist models (see for example Ballard, 1986; Churchland & Sejnowski, 1988) that representations do not exist apart from the data that have contributed to their processing. According to this assumption, in fact, the representations must be considered as patterns of activation in the connections stabilized between the units that processed the information on which the “representations” are based. As Lichtheim’s model has been presented in detail, and can be considered as the most complete

FIGURE 7.2

Schématisation of the main language areas and of the cortical areas which could play a selective role in the representation of different conceptual/semantic categories.

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synthesis of associationist thought for interpreting aphasic disorders, it is now time to present the theses of those authors who proposed different interpretative schemes.

THE NOETIC SCHOOL AND THE UNITARY INTERPRETATION OF APHASIA While associationist thought was obtaining its most convincing results in interpreting aphasic disintegration, some authors were already expressing their dissent over several aspects of this interpretation. The most controversial aspects of the associationist approach were: (a) The importance attributed to sensory and motor components of the aphasic disorder. (b) The adoption of a mosaic conception of the principle of localization in which no distinction was made between basic sensorimotor functions and higher cortical ones, because both were considered to be associated with precise cortical areas. (c) The use of a purely horizontal model (at the cortico-cortical level) of information processing, with a serial treatment of input at the level of the areas of projection, of the associative areas relative to the stimulated modality and to the other sensory modalities, and with final involvement of the associative areas and motor executions. (d) The fragmentation of aphasia into a multiplicity of qualitatively different clinical forms, resulting from the destruction of one or more image centres and/or of one or more association pathways between these centres. Finkelnburg (1870) was among the authors who first contested the validity of the first point (a); he believed aphasia was due to a central disturbance of the symbolic function, that is, the function that permits representation of an idea or a concept (meaning) that is not immediately perceptible with a concrete and immediately perceptible signifier (such as a sound or an image). In Finkelnburg’s conception, the

sensorimotor components of aphasia concern only the system of signifiers, but aphasic disintegration goes much deeper, also impairing the signifier-meaning relationship, as well as the organisation of the meaning. Proof of this is the fact that aphasic patients not only have difficulty in verbal understanding or in verbal expression but also in understanding nonverbal signifiers (for example, symbolic gestures, signs, graphic symbols, etc.) or in nonverbal symbolic expression (for example, in the performance of a pantomime). (b) Gratiolet (1834), whom I mentioned as one of the participants in the discussion at the Paris Anthropology Society and who may have provoked Broca’s main observation, was one of the authors who criticised the extension of the principle of localisation from the study of basic sensorimotor functions, to that of higher cognitive and symbolic (such as language) functions. In fact, Gratiolet held that the principle of localisation was valid only for the basic sensorimotor functions, but not for the higher cortical ones, which were processed by the brain in a unitary way, in conformance with the principle of mass action (Flourens, 1824). (c) The horizontal model of the associationists, based primarily on cortico-cortical connections, was criticised by Baillarger (1865) and by Jackson (1878), who countered it with a vertical model, based on the connections between cortex and subcortical structures and on the theory of functional levels. As is known, this theory, profoundly rooted in evolutionistic thought, conceded that the higher nervous functions are formed progressively during the course of evolution and the concomitant process of telencephalisation. This process consists in the passage: • from the more simple to the more complex; • from lower rigidly organised structures underlying automatic and preprogrammed functional levels to higher structures, organised in a more plastic way, to allow for learned behaviours and behaviours adapted to the changeable needs of the external environment, intentionally processed by the subject.

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Integration has as its inverse phenomenon dissolution, consisting of the passage from the most complex to the simplest, from the most plastic to the most rigidly organised and from the most intentional to the most automatic. This regression from higher cortical levels towards more primitive ones is due to the fact that the higher cortical functions are the most fragile and are, therefore, preferentially stricken by the morbid process, while the more elementary ones are more resistant. Further, given that in normal conditions the higher functions keep the lower ones under control, in the disintegration of higher levels not only negative symptoms are obtained (due to the failure of more elaborate and intentional aspects of use of the function) but also positive symptoms (due to the re-emergence of the more primitive functional levels, which were inhibited by the activity of the higher centres). The aspects of aphasic disintegration that most clearly support this interpretative model consist of the dissociation, observed first by Baillarger (1865), between propositional and automatic uses of language, the former being habitually lost when the latter are preserved. Further, these observations pose problems that are difficult to solve with the doctrine of images, typical of associationist thought. For example, take the commonplace observation of a patient who is completely incapable of pronouncing the word “madonna” if he has to give the name to a religious image, but who immediately afterwards automatically utters the same word, cursing over the interpersonal difficulties caused by his illness. According to Jackson, this commonplace observation shows that there is no destruction of an image (which once destroyed would be lost for any type of linguistic use) at the basis of the aphasic deficit, but rather an inability to use the words to form propositions with communicative value. However, it was primarily the last point (d), that is, the fragmentation of aphasia into many qualitatively distinct syndromes, which provoked the most heated and passionate reactions. Many authors held that this fragmentation, dictated by theory, did not correspond to data from clinical observation and affirmed that, rather than presenting as an archipelago formed by clearly

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separated entities, aphasia presented in general with very similar characteristics from patient to patient. In opposition to the associationist authors, who had isolated different clinical forms of aphasia, underlining the aspects that differentiated one aphasic syndrome from another, authors following a unicistic approach emphasised the common aspects of aphasics classifiable in different syndromes, hypothesising that a common factor underlies most of the deficits of aphasic patients. This orientation is found with different emphasis and formulations in the so-called “Noetic School”, and took on different aspects as a function of the personality and cultural interests of the individual authors. Due to space limitations, here I will only examine the contributions of two of the most important authors of this school: P. Marie (1926), who attacked the associationist models starting primarily from empirical-type considerations, and K. Goldstein (1948), who brought the comparison to the theoretical plane, opposing associationistic models with interpretative schemata derived from “Gestalt Psychology”.

Pierre Marie and his interpretation of Broca’s aphasia The doctrine of mental images had already been criticised by Jackson (1932) and even before by Bergson (1896); the latter had negated their existence as entities which were preformed and deposited in image centres and had affirmed that aphasia was due to a disorder of the faculty of actualising memories of words. Descending from the philosophical plane to the empirical one, P. Marie (1926) attacked: (1) the “deductive” method of the schemata, countering them with the naive examination (without doctrinal preconceptions) of anatomical-clinical facts; (2) the doctrine of images (motor, sensory, etc.) of words, whose disorganisation would result in different forms of aphasia; (3) the conception that the centre of motor images of words was stored in the foot of F3. P. Marie opposed the doctrine of verbal images with a unitary conception of aphasia; that is, qualitatively different types of aphasia do not exist, only one true aphasia exists, which P. Marie identified as Wernicke s aphasia. At the basis of this

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prototypical form of aphasia is a disorder of intelligence (defined by P. Marie as “the set of notions and procedures learned through didactic routes”) not a disorder of auditory images of words. Besides the disintegration of previously learned notions (a disorder that corresponds more with the construct of “semantic memory” than with that of “intelligence”, if we wish to translate it into the terms of contemporary psychology), R Marie identified another characteristic typical of true aphasia in the disorganization of internal language. From aphasia in the strict sense of the word, P. Marie distinguished anarthria, considered a mechanical disorder of the articulation of speech, which leaves internal language and intelligence unimpaired and which, therefore, does not accompany disorders of comprehension, writing, reading, etc. According to P. Marie, anarthria rarely exists in its pure form, but is usually combined with an aphasia, giving rise to Broca’s aphasia, according to the formula: Broca's Aphasia = Wernicke's Aphasia + Anarthria. According to P. Marie, the anatomical structures responsible for anarthria are subcortical (basal ganglia, internal capsule, external capsule, etc.) not cortical and not necessarily involving the foot of the third frontal gyrus. Rather, Marie upheld that the foot of F3 did not carry out any particular role in linguistic function and provided concrete evidence in support of this affirmation. In fact, he re-examined the brains of the two main cases described by Broca and demonstrated that in the first one the lesion extended well beyond the foot of F3 and in the second, the foot of F3 was not lesioned. Further, re-examining more than 100 anatomical-clinical cases in the literature, P. Marie demonstrated that in no case did an isolated lesion in the foot of F3 give rise to Broca’s aphasia, and that in many cases a lesion of F3 had not provoked aphasic disorders. Therefore, P. Marie’s conclusions were very clear and simple: there is only one anatomical localisation of the lesions giving rise to aphasia and one aphasia under the clinical profile. This location coincides approximately with Wernicke’s area (posterior part of the first temporal convolution, supramarginal gyrus and angular gyrus). There are no important

dissociations between the various modalities inside this area, but the seriousness of the aphasia is proportional to the extent of the lesion striking Wernicke’s area.

Goldstein and the structure of the organism Although P. Marie’s conceptions, partly taken from Bergson’s criticisms of associationism, were not part of a general theoretical model of the functioning of the mind, Goldstein, on the contrary, countered theoretical model with theoretical model, bringing the concepts of Gestalt psychology to the study of aphasia. As is known, the theoretical conceptions of the Gestalt concerning the nature of cognitive processes differed radically from those of associationism. For the latter, knowledge derived from an association of elementary data (sensations) coming from the sense organs, whereas for Gestalt psychology perception could not be traced back to a simple sum or association of elementary sensory data. Perception responds above all to laws of internal organisation, which permit the forming of perceptual units (“figures”), that are stable and well differentiated from the surrounding “background”; These two characteristics: (1) identification of global units of knowledge, and (2) importance attributed to the processes of figure-background differentiation constitute the keystone of Goldstein’s interpretation of the behaviour of braindamaged patients. According to Goldstein, in fact, the significant unit the physician or psychologist must consider is the patient’s organism. In fact, the organism functions as a whole and cannot be explained on the basis of simple elements such as reflexes or feelings. Consequently, it would be wrong to think that cerebral lesions determine isolated disorganisations of particular functions, because they actually bring about modifications of the whole, involving the organism in its totality. On the other side, Goldstein recognised that the organism responds to every particular situation with a particular operation which constitutes the figure of the corresponding process, and the rest of the organism constitutes the background. In the same way, Goldstein conceded that different behavioural disorders arise from lesions in different parts of the

7. DEVELOPMENT OF THE CONCEPT OF APHASIA

cerebral cortex, but he interpreted this to be a consequence of the fact that in lesions of the “peripheral portions” of the cortex (motor and sensory areas, in direct relation with the external world) the loss of figure-background differentiation prevails in a sense or motor modality, in relation to the cerebral localisation of the lesion. On the contrary, in lesions of central portions o f the cortex (delegated to higher-order functions), the prevalent modification is more unitary and consists of a regression from the abstract attitude to a concrete one, with abandonment of operations requiring the use of abstract procedures and the tendency to seek refuge in short operations, based essentially on concrete procedures. Applied to the examination of aphasic patients, these general principles led Goldstein to distinguish: (a) forms in which disorders of the sensory functions predominate (due to poor figure-background differentiation); (b) forms in which motor disorders predominate (due to the inability to utter the appropriate sounds, detaching them like figures from the articulatory background); and (c) forms in which the deficit of abstract and categorical functions prevail. Typical of this is amnesic (or nominal) aphasia, in which the patient is unable to find the names of objects, even though he or she has no sensory and articulatory disorders. In fact, Goldstein held that as names are labels we use to outline classes or categories of objects, the categorical attitude towards the external world and the ability to use words to outline concepts are essentially the same thing. Therefore, a deficit in the categorical attitude usually implies a naming disorder. If we consider all of these statements critically, two general points emerge: • The first is that Goldstein actually ended up being much less unicistic than his theoretical conceptions would lead us to believe. Recognising the existence of a cortical “periphery”, anchored to sense and motor functions, Goldstein proposed a classification schemata of the aphasias that is very similar to the one proposed by the associationist authors. The major difference is the basic mechanism

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hypothesised (destruction of different types of images for the associationists, disorder of process of figure-background differentiation in different perceptual-motor areas for Goldstein), but, to a great extent, the clinical description overlaps. • The second is that, as prototypical expression of the disorganisation of the central processes of aphasia, Goldstein gave importance to word-finding disorders, independent from perturbations of the sense or motor functions, which are in first place in amnesic aphasia (anomia or nominal aphasia) and which were practically ignored by the associationist authors. These disorders, which constitute one of the most commonly observed clinical phenomena in aphasia, were interpreted by Goldstein in terms of deficit of abstract and categorical thought. The ambiguity of the term, or at least its polyvalence (as abstract and categorical are not synonyms, but refer back to different aspects of the higher cognitive functions), translates the difficulty of specifying the exact nature of the perturbations of the cognitive processes underlying disorders of naming activity in aphasics. Later, Bay (1962, 1964) examined the same problem, accepting the basic assumption that the inability to find names of objects is the essence of aphasic disintegration, and tried to interpret the nature of this disorder more precisely and on the basis of more controllable empirical data. His conclusion was that the naming disorders of aphasics depend on a more general defect in discriminating and actualising concepts (that is, in the ability to distinguish one concept from another that is correlated with it, and to intentionally evoke the verbal label corresponding to the concept in question). The affirmation that the naming disorders in aphasics are associated with a disorganisation of corresponding concepts is certainly drastic and debatable, but at least it has the advantage of being relatively simple and clear and, in any case, still today remains rather central to the debate on the nature of the cognitive deficit in aphasics (Gainotti, 1988; Vignolo, Chapter 13 this volume).

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EMPIRICAL CLASSIFICATIONS AND GESCHWIND’S NEO-ASSOCIATIONIST MODEL Towards the mid-1960s the unicistic schools of interpretation of aphasia had completely exhausted their initial innovative thrust. The basic theoretical model of Gestalt psychology showed its ambiguities and limits, data from clinical observation, although confirming the existence of a basic, essentially unitary nucleus of aphasic distintegration, also confirmed the existence of different clinical forms of aphasia; the intimate nature of the deficit underlying naming disorders was difficult to explain using the basic theoretical models available. Two tendencies emerged in the area of aphasiology, which were undoubtedly influential in successive years: • on one side, an effort was made to approach the problem of aphasia on a purely empirical basis, putting aside schemata and theoretical assumptions; • on the other side, Geschwind (1965) took another look at the associationist concepts and re-evaluated them, proposing a general theory of “disconnection syndromes”.

Empirical classifications A first attempt to point out objective investigation parameters able to differentiate between different subgroups of aphasic patients was made simultaneously by Howes and Geschwind (1964) and by Goodglass, Quadfasel, and Timberlake (1964). Howes and Geschwind (1964) proposed dividing aphasics into two groups, defined respectively “group A” and “group B” on the basis of verbal and extra-verbal criteria. Group A (approximately overlapping Broca’s aphasia) was characterised by: • a verbal utterance rate lower than the norm (100-175 words/minute); • more frequent verbal perseverations than controls;

• a tendency towards agrammatism; • a practically normal threshold of word perception; • a high incidence of hemiplegia (about 80%). Group B (approximately overlapping Wernicke’s aphasia), was characterised, instead, by: • • • • •

a verbal utterance rate equal to or higher than controls; paraphasias that, in most serious cases, reach jargon aphasia; a number of verbal perseverations equal to controls; a threshold of perception of words increased and, above all, variable from one moment to the next; a low incidence (about 20%) of hemiplegia.

Goodglass and colleagues (1964) and then Benson (1967) and others, instead, distinguished a “fluent” and a “nonfluent” form of aphasia, based only on the characteristics of verbal production of these two groups of patients. Among the characteristic parameters of nonfluent aphasia (overlapping Broca’s aphasia and Howes and Geschwind’s group A) these authors placed: • articulatory disorders; • disprody, that is, a disturbance in the rhythm and melody of language, which can give speech a “foreign accent”; • the effort, often important, shown at the beginning of every oral production; • the defect of incitation to speak; • the tendency to produce much shorter sentences than normal, mostly composed of nouns and verbs (that is, by the lexical units that are richest in semantic information); • the tendency to neglect grammatical particles (articles, prepositions, auxiliary verbs, etc.) and to not conjugate verbs; the latter are often used in the infinitive or in the past participle, giving an agrammatical quality to the verbal production of these patients. Among the parameters characterising fluent aphasia (overlapping Wernicke’s aphasia and

7 DEVELOPMENT OF THE CONCEPT OF APHASIA

Howes and Geschwind’s Group B), the same authors identified: • the absence of articulatory disorders and obvious effort at the beginning of verbal production; • the preservation of normal language melody; • the pressure to speak, which makes these patients verbose, and even logorrheic; • the tendency to produce sentences of the same length and syntactic complexity as the controls; • the high incidence of verbal and/or phonemic paraphasias and neologisms, making the verbal production of these patients scarcely understandable. Benson (1967) also showed that the dichotomisation of aphasia into fluent and nonfluent forms not only corresponds to characters intrinsic in the verbal production of aphasics, but also reflects a different localisation of the lesions within the left hemisphere. The lesions responsible for the fluent forms of aphasia tend to be concentrated in the posterior regions of the sylvian valleys, and those responsible for the nonfluent aphasias tend to be concentrated in the lower parts of the Rolandic fissure. These results agree with the anatomoclinical observations of the classical authors (Foix, 1928), who noted that the lesions responsible for Broca’s aphasia tend to encroach on the lower part of the rolandic region, and the lesions responsible for Wernicke’s aphasis are concentrated primarily along the posterior two-thirds of the sylvian fissure.

Geschwind’s neo-associationist conception When I presented Goldstein’s thought, I said that, from the clinical point of view, one of the most obvious limitations of the associationist conceptions was their difficulty in interpreting disorders in naming activity, one of the most important and ubiquitous components of aphasic disintegration. Geschwind, who made a great effort in the second half of the 1960s to repropose the associationist models, was aware of this limitation and took the anatomical bases of naming activity as the starting point for his theoretical model.

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He affirmed that one of the newest and most important characteristics of the human brain is the possibility of forming direct associations between somesthetic, auditory, and visual modalities of sensory processing. In fact, in all subhuman species the intermodal associations are made indirectly, through the limbic system, where the afferences of sensory modalities converge. Only in humans does the great development of the temporoparieto-occipital associative areas permit the flow of information relative to the various sensory attributes of objects into nonlimbic cortical areas. According to Geschwind, this polysensory convergence is the necessary prerequisite of naming activity for two main reasons: first, because it is at the basis of the formation of concepts, considered (analogously to the construct of “associated images” developed by associationist authors) as the organised set of perceptual attributes of objects; second, because the convergence of multimodal information permits association of concepts of objects with the corresponding verbal labels. In fact, Geschwind holds that naming ability depends above all on the possibility of “associating names heard to things seen”. This is why Geschwind identifies the region of the angular gyrus, considered “the associative area of the associative areas” the anatomical substrate of naming ability. Starting from these phylogenetic conceptions on the anatomical bases of naming activity, and from his own anatomical-clinical observations on the behaviour of patients stricken by anterior or posterior lesions of the corpus callosum (Geschwind & Fusillo, 1966; Geschwind & Kaplan, 1962) Geschwind looked again at the conceptions of the associationist authors, emphasizing, in particular, the mechanisms of disconnection both within language areas and in the relationships between these areas and other motor and sensory portions of the cortex. Here, I do not intend to go into Geschwind’s conceptions on the clinical forms of aphasia due to the destruction of pathways or nervous centres within language areas, as these conceptions are the same as those of the classicists; one exception is the description of a form of anomia due to a lesion of the angular gyrus, which naturally depends on the general conception

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I have insisted upon thus far in the relationships between angular gyrus and naming activity. Instead, I will briefly touch on his conceptions concerning extrinsic disconnection syndromes in language areas, in which the connections between the language area and other motor and sensory cortical areas are interrupted. According to Geschwind, the largest form of disconnection of this type is the s y n d r o m e o f is o la tio n o f la n g u a g e a r e a s , produced when the lesion, even though it leaves the connections between Broca’s and Wernicke’s area unimpaired, cuts all other association pathways linking the language area to the other cerebral structures (Geschwind, Quadfasel & Segarra, 1968). In these cases, the patients’ language is characterised by the absence of articulatory and repetition disorders, in the presence of serious deficits in comprehension, almost complete impossibility of naming objects, and a more or less marked tendency toward echolalic behaviours. If, instead, the disconnection is more limited and selectively involves the relationships between the language areas and areas of projection of a specific sensory modality, partial disconnection syndromes occur; essentially they involve the impossibility of translating the information coming from these specific sense pathways into linguistic terms. In this case, we might find: 1. T a c tile a n o m ia f o r o b je c ts p la c e d in th e le ft

h a n d , in the syndromes of anterior disconnection, where there is an interruption of the fibres linking the somesthetic areas of the right hemisphere with the language centres of the left hemisphere, passing through the anterior part of the corpus callosum. 2. Pure alexia and anomia fo r colours in the posterior disconnection syndromes, in which there is a joint lesion of the left occipital lobe (with right homonymous lateral hemianopsia) and the splenium of the corpus callosum. In this case, in fact, the visual afferences may be processed only by the occipital areas of the right hemisphere where they receive a thorough nonverbal treatment) and may not reach the language areas of the left hemisphere, because the commissural pathways relative to visual

information pass through the splenium of the corpus callosum. Therefore, tactile anomia and pure alexia and anomia for colours are due to the impossibility of processing the information contained in a given sensory modality in linguistic terms, because of an interruption in the pathways linking the areas of sensory projection of the right hemisphere with the language centres of the left hemisphere.

LURIA AND THE CONCEPT OF FUNCTIONAL SYSTEMS During the years in which, in the West, research on aphasia tried to overcome the impasse in which the “unicistic” approach found itself, in the East, the personality and interpretative system of Luria (1966, 1970) dominated. Luria repudiated both the rigidly localising conceptions of the associationist authors and the nonlocalising theses of the unicistic authors, countering them with the concept of “functional system”, introduced and developed by Anochin (1935) in the area of reflexological theory. According to this concept, a complex function, such as the execution of a linguistic task, cannot be localised in a circumscribed portion of the cerebral cortex, because it requires the joint work of more elementary functions, situated in different areas of the cortex, which collaborate in the processing of the function, each making a specific contribution. In part taking up Pavlov’s theses, but primarily based on Vygotsky’s (1962) notions concerning the relationships between thought and language, Luria considered language as the basic organiser of the human mind. In fact, language not only distances humans enormously from the other animals at the level of interpersonal communication, but it also permits them to organise their own thought activities and to intentionally regulate their behaviour. On the other side, this basic organiser of the human mind, this regulator and mediator of the higher nervous functions, is processed just like every other form of nervous activity, starting from the work carried out by basic

7. DEVELOPMENT OF THE CONCEPT OF APHASIA

sensorimotor functions at a relatively elementary level. Therefore, according to Luria, it is the diminished specific contribution the damaged cortical zone brings to the processing of verbal behaviour that determines the various clinical forms of aphasia. In identifying these contributions and their specificity, Luria made reference both to the theory of cortical analysers (with regard to the functional organisation of the cortex) and the linguistic conceptions of his time concerning the intrinsic organisation of linguistic codes. Luria isolated six clinical forms of aphasia: 1. A k in e s th e tic m o t o r a p h a s ia , in which the basic disorder is difficulty in pronouncing single sounds of the language, called “articulemes”. 2. A k in e t ic m o t o r a p h a s ia , in which the articulemes are intact, but the patient is unable to correctly organise the sequence of movements necessary to pass fluidly from one articúleme to another, thus damaging the kinetic melody of the language. The first of these forms of motor aphasia is due to a lesion of the post-rolandic cortex and depends on an impairment of the afferent (proprioceptive) branch of the sensorimotor circuit of articulation. The second is due to a lesion in the pre-rolandic cortex corresponds to Broca’s classical aphasia and is based on a more purely motor deficit. 3. A s e n s o ry a p h a s ia , due to a lesion of the “cortical nucleus of the acoustic analyser” situated in the first temporal convolution of the left hemisphere (corresponding to Wernicke’s area) which provokes a deficit in acoustic analysis and synthesis of phonemes, resulting in disorganisation of both phonemic structure and semantic-lexical organisation of the languages. 4. An a c o u s tic -a m n e s ic a p h a s ia , due to a lesion in the middle regions of the temporal lobe, which do not directly belong to the cortical nucleus of the acoustic analyser and in which the deficit would have more to do with memory retention of the auditory-verbal traces than with the difficulty in grasping the acoustic structure of the word.

5.

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A s e m a n tic a p h a s ia , due to lesions

in the parietal lobe, in which the basic deficit is not the inability to understand the meaning of isolated words, but the inability to understand complex grammatical constructions requiring a simultaneous operation of analysis and synthesis, in which a spatial component often intervenes. 6. A d y n a m ic a p h a s ia , due to frontal lesions, in which linguistic codes are preserved but cannot be used because of a deficit in the dynamic components of cognitive processes. In this form of aphasia there is also a loss of the language ability to guide and regulate action and a more general disorganisation of the ability to process, develop and control the execution of complex motor programs, both in the verbal and extraverbal area. Two basic points seem to emerge from this attempt at a very rapid synthesis of Luria’s extremely complex, original and articulated conceptual system: on one side, the effort made by Luria to formulate many of his ideas in linguistic terms and to look for models in linguistics which would allow him to interpret data acquired from his very rich clinical observation activity; on the other side, the importance that, in spite of this, conceptions of a neurophysiological order continued to play in his interpretative system. It is, in fact, true that Luria adopted Trubetskoy’s conceptions (1933) regarding the organisation of the phonological aspects of language and the relevance of the distinctive traits of phonemes as a means for differentiating the meaning of words. It is also true that he adopted the ideas of Jakobson (1956b) on the distinction between the paradigmatic and syntagmatic aspects of language (see the next section) to characterise the “motor” and “sensory” aphasias in linguistically pertinent terms. However, it must be acknowledged that the Pavlovian doctrine of cortical analysers always remained in the background, as the basic interpretative schemata, to which the single parts of the taxonomy proposed by Luria made constant reference. Thus, it seems that we can conclude by stating that theories and linguistic models are introduced by Luria above all to analyse and

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explain particular aspects of a disorganisation that finds its basic reference system at the neurophysiological level.

LINGUISTIC INTERPRETATIONS OF APHASIA This final section will deal with the conceptions that have attributed a much more important role to linguistics in the study of aphasic disintegration than Luria did. Thus, we will be concerned with interpretations or with authors who, considering aphasia as a real pathology of language, have looked for the cleavage planes of its pathological disorganisation in the organisational principles of normal language, without resorting to notions or to disciplines outside linguistics, such as neuroanatomy or neurophysiology. The first author who tried to interpret aphasic disintegration in this way was Jakobson, who emphasised the existence of two general processes at all levels of language processing: the selection process and the combination process (Jakobson & Halle, 1956). The selection process consists of choosing a linguistic unit from among all units belonging to a specific level of linguistic organisation (for example, choosing a phoneme from among all phonemes of the language or choosing a lexical unit from among those that form the vocabulary of a specific linguistic community). The combination process consists of combining the chosen unit with others belonging to the same level. Thus, the formation of a lexical unit results from a process of selection and combination of appropriate phonemes, and the formation of a phrase requires a selection of lexical units and their combination, following the grammatical rules of language. According to Jakobson and Halle (1956), all the perturbations in aphasics’ language are due to disorders in selection processes (disorders of similarity) and in combination processes (disorders of contiguity). The perturbations of similarity explain the semantic alterations of Wernicke’s aphasics (semantic paraphasias, tendency to substitute the correct word with a generic word) while perturbations in contiguity explain several

characteristics of Broca’s aphasia, such as agrammatism or several types of expressive disorders described by Luria, such as the inability to correctly organise the sequence of movements necessary to pass fluidly from one articúleme to another. This model of analysis of language functioning and dysfunctioning, although it allows for a linguistic interpretation of several of the main differences and basic characteristics of Broca’s and Wernicke’s aphasia, is actually too general to provide a thorough explanation of the complexity of the clinical aspects of aphasia. Therefore, Jakobson (1964) tried to give a more elaborate neuro-linguistic interpretation of the classification of the aphasias proposed by Luria, with the intervention of the “similarity disorders”/ “contiguity disorders” dichotomy as well as two other dichotomies. The first separates comprehension disorders from expression disorders, and the second opposes the aphasic symptoms due to an impairment in linguistic codes (“disintegration” aphasias) to those due to extralinguistic perturbations (“limitation” aphasias). The form of aphasia described by Luria under the name of “dynamic aphasia”, in which the patient is unable to use substantially unimpaired linguistic codes due to a deficit of the dynamic component of cognitive processes provides a good example of limitation aphasia. Besides the distinction proposed by Jakobson between selection and combination disorders (which are at the base of both Wernicke’s and Broca’s aphasia), another important contribution to the flowering of linguistic interpretations in aphasiology was provided by the distinction proposed by Chomsky (1957), in a much more general theoretical area, between linguistic competences and performances. First, we can consider competence as the linguistic knowledge of a subject, that is, as the implicit, intuitive knowledge (not necessarily reflexive) this subject has of the rules and processes of language. Instead, performance is the actual use the subject makes of linguistic competence in a concrete situation. As the concrete behaviour we observe is given by performance, competence cannot be observed directly, but can only be inferred starting from the total performances.

7.

Particularly important in aphasiology is the fact that a performance does not depend only on competence, but also depends on a whole series of other factors (perceptual, attentive, mnesic, emotional, etc.) that may interfere with competence in the execution of a performance. As a cerebral lesion can obviously impair one or more of these factors, the distinction between linguistic competence and performances induces us to pose the first problem, which can be formulated as follows: Do the perturbations we observe in aphasia depend only on an impairment of perceptual, motor, attentive, mnesic factors, etc. which make a linguistic performance possible, in spite of the substantial integrity of models of competence, as sustained, for example, by Weigl and Bierwisch (1970), or does aphasic disorganisation depend both on a perturbation of performance factors and on an impairment of models of competence? A second, equally important problem concerns the unitariness or multiplicity of models of competence. Thus, the problem is posed of evaluating whether the term “linguistic competence” denotes a unitary phenomenon or whether, instead, it is possible to distinguish different competences due to phonemic, semanticlexical, and syntactic-grammatical levels of linguistic articulation, as suggested, for example, by Lesser (1978). With regard to the first problem, all authors agree in recognising that many difficulties encountered by aphasics are due to motor, perceptual, mnesic, praxic, attentive, etc. disorders following a cerebral lesion and which can have repercussions at the level of linguistic performances. On the contrary, there is no agreement in also conceding a disintegration of models of competence as well as perturbation of performance factors. One of the most used methods for resolving this problem has been to study the correlations between different tests (for example, of comprehension and expression, or of comprehension in the auditory-verbal and written modality) that use different peripheral components, all requiring the intervention of the same models of competence (or the same central representations). If the model of competence is altered, its perturbation will be reflected in the performances obtained on all tests used. If, instead,

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the model of competence is unimpaired, and only several performance factors are impaired, then the performances obtained on the various tests will be remarkably heterogeneous, as only those that depend on impaired performance factors will be pathological. This research strategy was used, for example, to clarify the meaning of different types of expressive disorders observed in patients with different clinical forms of aphasia and which might suggest the possibility of a selective dissolution of different components of linguistic competence. For example, phonemic disorders at the expressive level are typically observed in the form of phonemic paraphasias, in conduction aphasia, in many cases of Wernicke’s aphasia, and in some cases of Broca’s aphasia. Analogously, lexical semantic disorders of the semantic paraphasia type can be observed primarily in transcortical sensory aphasia and in many cases of Wernicke’s aphasia, and also in several forms of nominal aphasia and Broca’s aphasia. Finally, morpho-syntactic expressive disorders can be typically observed in the agrammatism of Broca’s aphasics, but also in the paragrammatism of some Wernicke’s aphasics. Towards the end of the 1970s some authors posed the problem of evaluating whether the phonemic, lexical-semantics and morpho-syntactic disorders emerging in production tasks are due to impairment of peripheral factors, selectively involved in the selection, combination, and oral production of phonemes, in the selection, activation, and production of lexical-semantic units, and in the programming, holding in working memory, and production of phrasal units; or whether they are due to the disorganisation of central processors regarding phonology, the semantic-lexical system, or morpho-syntactic rules. Here, I do not intend to go into the details of research that has tackled this problem, as the results are thoroughly discussed in the chapters of this volume concerned with phonological, semanticlexical and morpho-syntactic disorders of aphasics. However, it seems important to briefly mention several of the general conclusions these results seem to suggest and the criticisms addressed to this research strategy.

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With regard to the phonological level of linguistic production, one of the first studies on the topic, conducted by Alajouanine, Lhermitte, Ledoux, Renaud, and Vignolo (1964) suggested the existence of a significant correlation between production of phonemic paraphasias on the expressive side and disorders of “phonemic hearing” on the receptive side. However, subsequent research, carried out in more controlled conditions by Gainotti, Caltagirone, and Ibba (1975), Blumstein, Cooper, Zurif, and Caramazza (1977a) and Miceli, Gainotti, Caltagirone, and Masullo (1980) showed that at the phonemic level disorders of production and comprehension are in large part independent. These data seem to indicate that the phonemic disorders in input or output are due more to a deficit in the processing of verbal sounds and respectively to a disorder in programming and articulatory production than to the perturbation of a central phonological processor. The situation regarding the lexical-semantic level seems different because, in almost all group studies conducted on the topic by Alajouanine and colleagues (1964), Gainotti and colleagues (1975), Gainotti, Miceli, Caltagirone, Silveri, and Masullo (1981), Butterworth, Howard, and McLaughlin (1984), and Gainotti, Silveri, Villa, and Miceli (1986), a highly significant simultaneous occurrence of disorders was documented at the level of naming and discrimination between units belonging to the same semantic field. Obviously, these results do not allow us to conclude that the presence of semantic paraphasias involves a central disorganisation of the semantic-lexical systems in every case. In fact, patients certainly exist who present semantic disorders limited to only one modality of linguistic production (for example see Caramazza & Hillis, 1990b and Hillis & Caramazza, 1995a for an illustration of patients presenting semantic paraphasias only in oral or written production); these cases are particularly important from the point of view of cognitive neuropsychology, because more thorough study of them may allow for better comprehension of the structure and functioning of the lexical-semantic system. However, the existence of rare cases of this type does not detract from the fact that in most patients the study of the associations and

dissociations between performances obtained in different modalities and linguistic tasks favours a central disorganisation of semantic systems. The situation seems rather similar when we consider the significance of the morpho-syntactic disorders observed at the expressive level in agrammatic patients. The majority of the group studies that have examined the ability of these patients to extract the morpho-syntactic information contained in sentences (Caramazza & Zurif, 1976; Heilman & Scholes, 1976; Schwartz, Saffran, & Marin, 1980a) have shown that agrammatic s are unable to extract the morphosyntactic indicators that denote the relations between the lexical constituents of sentences. Therefore, these authors postulated that agrammatism is due to the disorganisation of a central processor of morpho-syntactic information. However, in this case too the detailed study of single cases has shown that expressive agrammatical difficulties can also be observed in patients who do not present analogous difficulties in tasks of syntactic comprehension, and that dissociations can be observed in expressive agrammatical traits between reduction of syntactic complexity of utterances and omission of free grammatical morphemes (Bemdt, 1987; Miceli, Mazzucchi, Menn, & Goodglass, 1983). These data seem to indicate that, even if the expressive and receptive components of agrammatism usually tend to associate, they can do so according to different formulas and can, in some cases, present as clearly dissociated (see Miceli’s chapter for a more thorough examination of this problem). Passing from a synthetic presentation of the results obtained following this research strategy to the criticisms against it, we can say that the opposition between models of competence and performance factors (or between central processors and peripheral components) seems too rough and not explicit enough to increase our current state of knowledge. The much more articulated models offered by cognitive neuropsychology and the connectionist models still in the phase of development could make a more important contribution to a better understanding of the mechanisms responsible for aphasie disintegration.

8 The Neurological Foundations of Language Stefano F. Cappa and Luigi A. Vignolo

investigations, the data collected using the traditional anatomo-clinical approach will be presented in some detail in order to provide an adequate background for the comparison with new findings. The chapter is divided into four sections dealing with:

INTRODUCTION Until relatively recent years, the main source of information about the neurological basis of language was the anatomo-clinical study of aphasie patients. The quantitative and qualitative modifications of language behaviour, observed at the time of clinical evaluation, were correlated to the site of cerebral damage observed post-mortem. Following the introduction of computerised tomography (CT) in the early 1970s, and of magnetic resonance imaging (MRI) shortly afterwards, neuroradiological methods have provided the possibility of studying lesion site and size in vivo, at the same time as the clinical evaluation. A further development has been the introduction of functional imaging techniques, which allow the investigation of regional cerebral blood flow and metabolism in normal subjects and aphasie patients, both at rest and while engaged in linguistic tasks. This chapter will review some of the available evidence about the neurological foundations of language. While placing a particular emphasis on the results of recent functional imaging

• Lesion localisation in aphasic syndromes. • Anatomo-functional correlates of specific psycholinguistic aspects in aphasic patients. • Neurological correlates of aphasia in particular populations, such as acquired aphasia in childhood or aphasia in left-handers. • In vivo mapping of the cerebral organisation of language with functional imaging in normal subjects.

NEUROLOGICAL CORRELATES OF THE APHASIC SYNDROMES Aphasic syndromes are the consequence of left hemispheric lesions in right-handed subjects and in 155

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the majority of left-handers. The results of pharmacological deactivation studies (Wada test) indicate that the left hemisphere is language-dominant in about 70% of left-handers (Kimura, 1983). There is evidence for an anatomical counterpart of this functional dominance (see Perani & Cappa, Chapter 5 in this volume): the perisylvian areas of the left hemisphere are larger than the homologous region in the right hemisphere both macroscopically (Falzi, Perrone & Vignolo, 1982; Geschwind & Levitsky, 1968) and cytoarchitectonically (Eidelberg & Galaburda, 1984). Furthermore, the neurones in the left language areas are larger than on the contralateral side (Hayes & Lewis, 1993) and the dendritic synaptic morphology has features which suggest later ontogenic development (Jacobs, Batal, Lynch, Ojemann, Ojemann, & Scheibel, 1993; Simonds & Scheibel, 1989). The usefulness of the classification of aphasic syndromes following damage to the left hemisphere is controversial (for a discussion,see Caplan, 1987; Kohn & Smith, 1992). Traditional taxonomic labels, such as “Broca’s aphasia”, are of limited informative value, given the extensive variability in diagnostic criteria. Some cognitive neuropsychologists tend to deny the validity of the concept of “aphasic syndrome” itself (Marshall, 1986). Other authors advocate the usefulness of the concept of functional syndrome, due to the impairment of a specific component within an explicit model of the function under study (Vallar, this volume; see also Plaut & Shallice, 1993, for a discussion of the implications of connectionist modelling for the concept of functional syndrome). To what extent the traditional aphasic syndromes can be re-interpreted as functional syndromes is a matter of debate (Kohn & Smith, 1992). Taxonomic categories probably follow from the non-random localisation of cerebral vascular lesions within the brain (Foix, 1928; Poeck, 1983). In the following summary, we will refer to the traditional neurological classification (Goodglass & Kaplan, 1972; Vignolo, 1977). This choice is dictated by the wide diffusion of this taxonomy in clinical and rehabilitation settings. For a more detailed discussion of the clinical and linguistic aspects of the aphasic syndromes, see Chapter 9 by Basso and Cubelli.

One important factor that should be always given appropriate consideration when correlating the aphasic syndromes with the site of cerebral damage is the time elapsed between lesion onset and the moment of the examination. In the acute phase after a cerebral lesion, such as a stroke, perifocal oedema and other functional effects may contribute to the severity of the clinical picture, while compensation mechanisms are most likely to play a role in the chronic stage. It is thus a frequent observation that a patient may move from one taxonomic label to another with time post-onset. As a general rule, it must be underlined that the neuroimaging methods have different indications and specific limitations. Structural imaging techniques, such as CT and magnetic resonance imaging (MRI) require a localisation of the lesion according to a reference method (atlas, stereotactic localisation) (see Chapter 9, by Perani & Cappa). In the case of functional methods, such as positron emission tomography (PET) or single photon emission tomography (SPECT), the physiological data (regional blood flow and metabolism) must be correlated to the anatomical information (Fox & Woldroff, 1994; Roland & Zilles, 1994).

Broca’s aphasia Broca’s aphasia is characterised by nonfluent, often agrammatic speech with disorders of articulation. Repetition is impaired, while auditory comprehension is good or only moderately defective in most clinical tests. On the other hand, performance with syntactically complex material, such as reversible passive sentences (of the type “the boy is chased by the girl”) is typically impaired. The discussion about the site of lesions associated with Broca’s aphasia dates back to the beginning of the century, when the Broca’s “dogma” of a lesion in the posterior part of the left third frontal convolution (Déjerine, 1914), corresponding to Brodmann’s areas 44 and 45 (frontal operculum) (Fig. 8.1) was challenged by Pierre Marie (Marie, 1906). Marie denied any linguistic role for this area, claiming that the lesions associated with typical Broca’s aphasia always involve the posterior portion of the perisylvian language areas, plus the insulolenticular region (the “quadrilatère”: Fig. 8.2). A lesion limited to the insulo-lenticular region,

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FIGURE 8.1 The language areas of the left hemisphere according to Dejerine (1914).

FIGURE 8.2

Pierre Marie’s “quadrilatère”.

according to Marie, is associated only to an articulatory disorder, which he called “anarthria” (see later). CT studies (Alexander, Naeser, & Palumbo, 1990; Blunk, De Bleser, Willmes, & Zeumer, 1981; Mazzocchi & Vignolo, 1979; Mohr, Pessin, Finkelstein, Funkenstein, Duncan, & Davis, 1978) have, in general, supported, Dejerine’s position. The full syndrome of Broca’s aphasia is usually associated with a large anterior lesion involving, besides Broca’s area proper, the precentral gyrus, the anterior portion of the insula, the underlying white matter, and often reaching down to the basal ganglia. This is the vascular territory of the superior branches of the left middle cerebral artery. Smaller lesions are often observed in patients who show clinical components of the syndrome. Mohr et al. (1978) have described patients with lesions limited to Broca’s area proper: their language disorder was mild and transient. The rolandic region, with the underlying white matter, has been suggested to play a crucial role for articulation (Alexander, Naeser, & Palumbo, 1990; Lecours & Lhermitte, 1976; Tonkonogy & Goodglass, 1981; Mori, Yamadori, & Furumoto, 1989). If this region is spared by the lesion, a nonfluent aphasia without articulatory impairment and no associated hemiparesis is the rule (Tonkonogy & Goodglass, 1981; Masden &

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O’Hara, 1983; Henderson, 1985; Alexander, Naeser & Palumbo 1990). A transient Broca’s aphasia has been observed in a patient with a lesion limited to the insula (Shuren, 1993). Persistent alexia in Broca’s aphasia occurs in patients who have recovered from global aphasia, and hence harbour large lesions extending posteriorly (Boccardi, Bruzzone, & Vignolo, 1984). While these are the most frequent correlates, several “exceptions” have been reported in the literature, including entirely retrorolandic lesions (Basso, Lecours, Moraschini, & Vanier 1985; Willmes & Poeck, 1993). A possible hypothesis to account for these cases is that they represent instances of “atypical” cerebral dominance for language (Daffner, Schomer, Cosgrove, Rubin, & Mesulam, 1991; for a discussion of the concept of atypical dominance see Alexander, Fischette, & Fisher, 1989). A different prognosis may be associated with an atypical lesion location (Tramo, Baynes, & Volpe, 1988). The assessment of glucose metabolism in the resting state with 18 fluorodesoxyglucose (18FDG) and PET in patients with chronic Broca’s aphasia (Metter et al., 1987) has shown an extensive region of hypometabolism in the left hemisphere (frontal and parietal lobes, caudate, thalamus), which exceeded in extent the structural area of damage shown by CT. The metabolism was also severely depressed in the right cerebellar hemisphere. This “crossed cerebellar diaschisis” (Baron, Bousser, Comar, & Castaigne, 1981) was absent in other aphasic syndromes and was significantly correlated with the severity of both aphasia and motor impairment.

Wernicke’s aphasia The traditional correlation between a clinical picture characterised by fluent, paraphasic speech, disordered repetition, and impaired auditory comprehension, and a lesion that includes the posterior part of the left superior temporal gyrus (Wernicke’s area, area 22) has been confirmed by all CT studies (Kertesz, Harlock, & Coates, 1979; Mazzocchi & Vignolo, 1979; Naeser & Hayward, 1978). Exceptions to this anatomo-clinical correlation are rare (14% against the 43% of nonfluent aphasias in the series reported by Basso et al., 1985). Fluent aphasia with prerolandic lesions has been

found to be more frequent in old age (Basso, Bracchi, Capitani, Laiacona, & Zanobio, 1987). Embolism from the heart or the large vessels is a frequent pathogenetic mechanism of Wernicke’s aphasia (Knepper, Biller, Tranel, Adams, & Marsh, 1989). The linguistic characteristics of jargon seem to be related to lesion location: Kertesz (1983) found that in patients with neologistic jargon the lesion extended towards the parietal operculum, while cases with semantic jargon had lesions circumscribed to the temporal lobe. Patients with severe jargonagraphia have frequently multiple lesions (Cappa, Cavallotti, & Vignolo, 1987). The presence and severity of written language disorder is related to lesion site (Kirshner, Casey, Henson, & Heinrich, 1989). In patients who are more impaired in reading than in auditory comprehension the lesion usually spares part of the superior temporal gyrus and extends towards the parietal lobe, in particular to the angular gyrus. Lesions confined to the temporal lobe are associated with the reverse asymmetry in comprehension.

Global aphasia Global aphasia is the most severe aphasic syndrome, and is characterised by scarcely informative, nonfluent speech and severely impaired comprehension. The neuropathological substrate is compatible with the global features of the linguistic impairment: the responsible lesion in most cases destroys the entire vascular territory of the left middle cerebral artery, which includes most of the language areas of the left hemisphere. CT studies, while confirming this correlation, have brought to light several interesting exceptions. A persistent global aphasia has been observed in patients with prerolandic lesions, completely sparing Wernicke’s area, as well as in cases with posterior lesions or even in subcortical strokes (De Renzi, Colombo, & Scarpa, 1991; Vignolo, Boccardi, Caverni, & Frediani, 1986; Willmes & Poeck, 1993). The patients with unexpected lesion sites do not differ from “standard” global aphasics from the linguistic standpoint. Poeck, De Bleser, and Graf von Keiserlingk (1984) did not find any relationship between lesion characteristics and peculiar clinical aspects, such as the fluent production of syllabic stereotypies.

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Global aphasia without hemiparesis can be observed with two separate lesions of the anterior and posterior parts of the language areas (Legatt, Rubin, Kaplan, Healton, & Brust, 1987; Tranel, Biller, Damasio, Adams, & Cornell, 1987; Van Horn & Hawes, 1982). This clinical presentation is considered typical of embolic stroke, although exceptions are on record (Legatt et al., 1987).

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account for at least some features of the syndrome (Poncet, Habib, & Robillard, 1987; Tanabe, Sawada, Inone, Ogawa, Kuriyama, & Shirashi, 1987).

Transcortical aphasias The distinguishing feature of all transcortical aphasias is the preserved ability to repeat. Three different clinical forms can be observed.

Conduction aphasia This syndrome is characterised by fluent speech, with phonemic paraphasias, and by a disproportionate impairment of repetition in comparison with a relatively preserved auditory comprehension. The lesion damages the posterior sylvian region, usually involving the parietal operculum (supramarginal gyrus) and the underlying white matter. The latter includes the arcuate fasciculus, which connects temporal and frontal associative cortical areas (Benson et al., 1973). An involvement of the arcuate fasciculus has traditionally been considered responsible for conduction aphasia: this lesion is compatible with the traditional account of the syndrome. The interruption of a pathway connecting anterior and posterior language areas was supposed to explain the defective repetition, due to the impaired transmission between a “decoding” and an “encoding” centre. The results of a PET study with 18-FDG do not support the “disconnection” hypothesis, as the reduction of metabolism in the temporo-parietal areas was not constantly associated with frontal hypometabolism (Kempler et al., 1988). A more serious problem for the traditional hypothesis is that many patients have lesions involving Wernicke’s area only (Benson et al., 1973). CT studies have confirmed that both lesion sites can be observed (Kertesz et al., 1979; Mazzocchi & Vignolo, 1979). In some patients the lesion involves the insular region and underlying white matter (i.e. other association fibres linking the anterior and posterior language areas), or the angular gyrus and underlying white matter (Damasio & Damasio, 1980; Palumbo, Alexander, & Naeser, 1992). Mild conduction aphasia has also been observed in patients with small lesions limited to the white matter, suggesting that an isolated involvement of the connection pathways can

Transcortical motor aphasia is characterised by reduced, nonfluent, sometimes agrammatic speech; confrontation naming is usually preserved and auditory comprehension unimpaired. The different lesion locations that have been reported in association with this syndrome share the characteristic of interrupting the connections between the dorsolateral prefrontal cortex and the anterior portion of the language area. These include damage to the white matter anterolateral to the frontal horn of the left lateral ventricle (Damasio, 1981; Freedman, Alexander, & Naeser, 1984), or bilateral lesions of the centrum semiovale (Mazzocchi & Vignolo, 1979). When the damage involves the medial surface of the frontal lobe, as in strokes in the territory of the anterior cerebral artery, the supplementary motor area is destroyed. These cases are characterised by the severe reduction of spontaneous speech, without the other aspects of linguistic impairment (Bogousslavsky, Assal, & Regli, 1987; Masdeu & O’Hara, 1978; Tijssen, Tany, Hekster, Bots, & Endtz, 1984). An ataxic hemiparesis, with severe involvement of the leg, is frequently associated (Iragui, 1990). In “variant” forms (Freedman et al., 1984), the presence of articulatory disorders is related to lesion extension towards the white matter underlying the motor strip for the face in the precentral gyrus. A mild auditory comprehension impairment can be observed with lesions involving the capsulo-lenticular region (see later for a discussion of transcortical motor aphasia in subcortical strokes). Transcortical sensory aphasia is characterised by fluent speech with profuse verbal and semantic paraphasias and severely impaired auditory comprehension. This clinical syndrome has frequently been observed in the advanced stages of

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Alzheimer’s disease (Coslett, Roeltgen, GonzalezRothi, & Heilman, 1987; Whitaker, 1976); when it is due to vascular lesions, the temporo-parietooccipital junction, between the vascular territories of the middle and posterior cerebral artery, is usually involved (Heilman, Rothi, McFarling, & Rothmann, 1981). These lesions are usually due to a hemodynamic mechanism, such as severe hypotension (Howard, Trend, & Ross-Russel, 1987). In the series reported by Kertesz, Sheppard, and MacKenzie (1982) some patients had more posterior lesions, in the territory of the posterior cerebral artery. Similar cases have been reported by Damasio (1981) and Vignolo (1984). Alexander, Hiltbrunner and Fisher (1989), who reviewed the literature and described 12 new cases, suggest that a crucial role is played by damage to the left posterior paraventricular white matter. This is an area of convergence of fibres originating from visual associative areas and the thalamus, directed towards the temporal associative cortex and the temporo-parieto-occipital junction, which could be related to semantic processing.

1990) or the pharmacological deactivation of the right hemisphere with amobarbital (Berthier et al., 1991) abolished the preserved repetition abilities.

Mixed transcortical aphasia, or isolation of the language area, is characterised by nonfluent speech, severely impaired comprehension and echolalia; it is due to extensive cortical lesions, sparing the immediately perisylvian cortex (Geschwind, Quadfasel, & Segarra, 1968; Assal, Regli, Thuillard, Steck, Deruaz, & Perentes, 1983). It has also been observed in association with two separate lesions: an embolic stroke, involving the frontal cortex anterior to Broca’s area, and a watershed lesion in the borderzone between the territory of the middle and posterior cerebral artery (Bogousslavsky, Regli, & Assal, 1988). According to these authors, this combined lesion is typically associated to internal carotid artery occlusion. In the case of transcortical aphasias, unexpected lesions involving the perisylvian language areas have been reported (Berthier et al., 1991; Grossi et al., 1991; Rapcsak, Krupp, Rubens, & Reim, 1990). It has been suggested that in these unusual cases repetition may be subserved by the right hemisphere, possibly through a nonlexical route. This hypothesis is supported by the observations that a second, right-sided stroke (Rapcsak et al.,

Alexia with agraphia

Anomic aphasia Anomic aphasia has been considered for a long time as due to “diffuse” cerebral damage, as it is frequently observed in patients with Alzheimer’s disease, head trauma, or intracranial hypertension (Benson, 1979). Although an impairment of confrontation naming is present in most, if not all, aphasic patients, it is particularly severe when the lesions involve the left parieto-temporal cortex (Benson, 1977) or the left temporal lobe (Coughlan & Warrington, 1978; Newcombe, Oldfield, Ratcliff, & Wingfield, 1971). The label of anomic aphasia is reserved for patients in whom a severe disorder of word finding (amnesia nominum) is observed in the context of fluent speech, good repetition, and preserved comprehension. This clinical picture is infrequent, and is observed in patients with temporal lesions sparing Wernicke’s area proper (Fig. 8.3) (Miozzo, Soardi, & Cappa, 1994).

A selective impairment of written language was associated by Dejerine (1892) to lesions restricted to the left angular gyrus. Cases without any impairment of oral language (usually a mild fluent aphasia or anomia is associated) are extremely rare (Benson, 1979). Kawahata, Nagata, and Shishido (1988) have described three remarkably “pure” cases in Japanese patients: the lesion was localised with TC and PET to the left temporal lobe.

Pure forms The rare instances of selective disorders of one modality of language performance are called “pure forms”. Recent reports have by and large confirmed the traditional localisations associated with these unusual disorders (Geschwind, 1965). Anarthria (also called pure motor aphasia or cortical dysarthria) is characterised by a severe articulation disorder, in the absence of any other linguistic impairment. The responsible lesion involves the left precentral gyrus and the underlying white matter (Lecours & Lhermitte, 1976), and destroys the

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FIGURE 8.3 Coronal MRI sections showing a left temporal hemorrhage (due to the rupture of an arteriovenous malformation) associated with anomic aphasia.

motor area of the face (Bay, 1964). The opercular part of the inferior frontal gyrus is sometimes involved by the lesion (Pellat et al., 1991; Schiff, Alexander, Naeser, & Galaburda, 1983). A PET study has shown a similar localisation in a patient with a negative CT scan (Kushner et al., 1987). Partial lesions of the precentral gyrus may be associated with the “foreign accent” syndrome (Takayama, Sugishita, Kido, Ogawa, & Akiguchi, 1993). If the anarthria-producing lesion is associated with a mirror lesion in the right hemisphere, speech is completely suppressed (Cappa, Guidotti, Papagno, & Vignolo, 1987; Groswasser, Korn, Groswasser-Reider, & Solzi, 1988; Villa & Caltagirone, 1984). This clinical picture (the biopercular syndrome or Chavany-Foix-Marie syndrome) must be differentiated from mutism (Cummings, Benson, Houlihan, & Gosenfeld, 1983; David & Bone, 1984), which is due to a wide range of different conditions, from lesions in the anterior cerebral artery territory involving area 24 (Damasio & Damasio, 1989) to psychiatric

disorders, and is characterised by the total absence of vocalisation. Pure word deafness: Patients with pure word deafness are unable to understand what is said to them, while speech, reading, and writing are normal or only mildly impaired. The traditional neurological interpretation of this condition is that it is due to a lesion which disconnects both acoustic areas of Heschl from Wernicke’s area. Most patients have had two small strokes: typically, the disorder appears suddenly, after a left or right temporal lesion, in a patient with a previous lesion in a similar location in the opposite hemisphere (for a recent review, see Vignolo, 1995). In exceptional cases a single subcortical lesion in the left temporal lobe seems to be sufficient to produce pure word deafness (Gazzaniga, Glass, Sarno, & Posner, 1973). In several patients with CT or MRI documented lesions (Auerbach, Allard, Naeser, Alexander & Albert, 1982; Coslett, Brashear, & Heilman, 1984; Tanaka, Yamadori, & Mori, 1987), both Heschl’s primary acoustic areas and acoustic

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radiations were bilaterally involved by the lesions, with a prevalent right-sided extension. Two subcortical lesions, involving the medial geniculate body on the left and the internal capsule on the right, were shown by CT and MRI in a case with transient pure word deafness, but persistent auditory agnosia (Motomura, Yamadori, Mori, & Tamaru, 1986). Pure agraphia has been described with superior parietal lobule lesions (Basso, Taborelli, & Vignolo, 1978; Mazzocchi & Vignolo, 1979): an unilateral optic ataxia was associated in another case (Auerbach & Alexander, 1981). This is probably a form of apraxia relatively specific for writing movements (Alexander, Fischer, & Friedman, 1992). A selective disorder of writing has also been reported in association with a lesion in the left temporal lobe (Rosati & De Bastiani, 1979). Alexia without agraphia has been considered a typical disconnection syndrome, due to the interruption of the connections between visual cortex and the language areas of the left hemisphere, i.e. to a “visuo-verbal disconnection” (Dejerine, 1892). The responsible lesion is usually an ischemic stroke in the territory of the left posterior cerebral artery (De Renzi, Zambolin, & Crisi, 1987), or a hematoma (Greenblatt, 1983; Henderson,

Friedman, Teng, & Weiner, 1985) or a tumour (Turgman, Goldhammer, & Braham, 1979) involving the same areas. Typical lesions damage the calcarine fissure, the lingual gyrus, and the white matter around the occipital horn of the lateral ventricle (Fig. 8.4): this results in a right homonymous hemianopia and in an interruption of the fibres coming from the visual areas of the right hemisphere (Damasio & Damasio, 1983; De Renzi et al., 1987; Vignolo, 1983). Colour anomia is frequently associated, and indicates lesion extension towards the temporo-occipital areas (Damasio & Damasio, 1983). De Renzi etal. (1987) have shown that the visual naming disorder also extends, although with lesser severity, to other categories. The presence of verbal memory defects is due to the damage to the left hippocampal region (Damasio & Damasio, 1983; De Renzi etal., 1987). Pure alexia can also be observed in the absence of hemianopia. In these cases the visuo-verbal disconnection could be due to the interruption of the white matter pathways located immediately beneath the angular gyrus (Greenblatt, 1973); or at the occipito-temporal junction, at the level of the fusiform gyrus (Henderson et al., 1985; Weisberg & Wall, 1987). If the lesion extends towards the lingual gyrus, but spares the calcarine fissure and the optic radiations, hemichromatopsia can be observed instead of hemianopia (Damasio & Damasio, 1983).

FIGURE 8.4

Schematic drawing of the medial surface of the posterior part of the cerebral hemisphere, showing the main sulci and gyri.

8. NEUROLOGICAL FOUNDATIONS OF LANGUAGE

Subcortical aphasias The notion that aphasia can be observed in patients with subcortical lesions, sparing the cortical language areas, is not new (Henschen, 1922). These cases were often considered as instances of disconnection between cortical areas, due to the interruption of fibre pathways (see earlier), while the role of damage to grey nuclei, such as the thalamus and basal ganglia, was discounted (Nielsen 1946). The introduction of CT in clinical practice has resulted in increasing recognition of cases of subcortical aphasia. This renewed interest has led several authors to speculate about the possible linguistic function of subcortical structures (for an extensive review, see Cappa & Vallar, 1992). The studies of unselected samples of patients with subcortical stroke, identified with CT, have clearly indicated that only some patients with subcortical lesions present with a persisting aphasia (Vignolo, Macario, & Cappa, 1992). In the case of lesions involving the thalamus, a fairly typical clinical syndrome, similar to transcortical aphasia, has frequently been observed (Cappa & Vignolo, 1979; Puel et al., 1986). These patients usually have a reduced verbal output, with low vocal volume and frequent verbal paraphasias; repetition is preserved, and the impairment of auditory comprehension is usually moderate. Attempts at lesion localisation within the thalamic complex have indicated that in most patients with lesions of limited extent the anterior nuclei bear the brunt of damage (Bogousslavsky, Regli, & Assal, 1986; Davous et al., 1984; Graff-Radford, Damasio, Yamada, Eslinger, & Damasio, 1985). Patients with posterior thalamic lesions are frequently not aphasic (Cappa, Papagno, Vallar, & Vignolo, 1986), although some cases of aphasia due to pulvinar damage are on record (see, for example, the pathologically verified case of Crosson, Parker, Kim, Warren, Kepes, & Tully, 1986). These cases may be characterised by more fluent speech (Alexander & Loverme, 1980). The correlations are more muddled in the case of lesions involving the basal ganglia. Most clinical series (Basso, Della Sala, & Farabola, 1987; Cappa, Cavallotti, Guidotti, Papagno, & Vignolo, 1983;

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Puel et al., 1984) have failed to identify specific correlates of lesion site with the type, or even the presence of aphasia. Both “classical” and “atypical”, unclassifiable aphasic syndromes have been described in these patients (Damasio, Damasio, Rizzo, Varney, & Gersh, 1982; Puel et al., 1984) . A “core” syndrome of selective lexical impairment, in particular in controlled association tasks, has been suggested to be typical of capsulostriatal lesions (Mega & Alexander, 1994). Similar disorders are typical of transcortical motor aphasia, which has frequently been observed in patients with ischemic lesions in the territory of the anterior choroidal artery (pallidum, posterior limb of the internal capsule; Cappa & Sterzi, 1990; Decroix, Graveleau, Masson, & Cambier, 1986; Wallesch, 1985) . Subcortical aphasias are usually, but not invariably, associated with a fast recovery rate (Vallar et al., 1988), in particular if the lesion is of limited size and speech production is fluent (D’Esposito & Alexander, 1995; Mega & Alexander, 1994); residual lexical-semantic disorders are often present in the chronic stage (Kennedy & Murdoch, 1993). The physiopathological mechanisms underlying subcortical aphasia have been a focus of debate. PET and SPECT imaging studies of cortical metabolism and blood flow in patients with subcortical stroke and aphasia have shown a functional depression in the structually unaffected ipsilateral cortex, which is more severe and extensive in aphasic than in nonaphasic patients (Baron et al., 1986; Perani, Vallar, Cappa, Messa, & Fazio, 1987; Skyhoj Olsen, Bruhn, & Oeberg, 1986) . These effects have been interpreted by some authors as “diaschisis”, i.e. afunctional depression remote from a cerebral lesion. According to this interpretation, the reduction of neural activity is due to the interruption of synaptic connectivity from the area affected by the structural lesion (Feeney & Baron, 1986; Powers & Raichle, 1985). Weiller et al., (1993) suggested that in the cases associated with a reversible occlusion of the middle cerebral artery, a selective cortical neuronal loss may be due to an incomplete infarction. It must be underlined that sometimes patients with lesions limited to subcortical areas on CT are shown to have cortical

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damage on MRI (Godefroy, Rousseaux, Pruvo, Cabaret, & Leys, 1994). Lesion size appears to play a crucial role for the presence of aphasia (Perani et al., 1987; Skyhoy Olsen etal., 1986;Takanoetal., 1985; WeilleretaL, 1993). Lesion site is however also important. In cases with damage limited to the white matter, aphasia is infrequent (Perani et al., 1987; Skyhoy Olsen et al., 1986). This finding is in contradiction to the results of the study by Alexander, Naeser, and Palumbo (1987), where lesions limited to the putamen and caudate were associated only with mild anomia, while the site and extent of the white matter damage was related to specific aspects of linguistic impairment. The limited spatial resolution of CT, as well as heterogeneity in patients’ characteristics, may be responsible for the disagreements among reports. It is possible that MRI will be helpful to clarify these differences. In conclusion, the available data are compatible with a three-dimensional view of the language areas, which comprise multiple cortico-subcortical functional systems, related to specific aspects of linguistic processing. Some aspects of linguistic impairment in patients with subcortical lesions, such as articulatory disorders, may be related to damage to white matter pathways; however, lesion data support a participation of the thalamus in the neural substrates of lexical-semantic processing, together with the temporal and prefrontal cortex. The role of the basal ganglia remains unclear, and deserves further investigation.

NEUROLOGICAL CORRELATES OF APHASIC SYMPTOMS The previous section has summarised what can be called the traditional neurological approach, i.e. the correlation of aphasic syndromes with lesion site. Another possible method of investigation in clinical studies is the correlation of specific aspects of linguistic impairment, such as the individual symptoms that cluster in the aphasic syndromes, to lesion site. The introduction of psycholinguistic models to the study of aphasia (for an introduction, see Caplan, 1992) has been influential in this type

of approach, leading to a better definition of the aspects of linguistic impairment. These studies have been conducted both in clinical series and in individual patients. While group studies have usually addressed broadly defined clinical symptoms, such as disorders of naming or impairments in syntactic aspects of auditory comprehension, single case studies have tried to look for the neurological correlates of selective dysfunctions of a discrete component within a model of normal processing (for example, the inability to read non words). The first approach has been more successful: it is generally based on the comparison of a group of patients with a severe, or persistent, defect, with another sample of patients where the symptoms have been mild or transient. In the case of speech production, it has already been remarked that case studies suggest a crucial role of the precentral gyrus for articulation (Lecours & Lhermitte, 1976; Sugishita, Konno, Kabe, Yunoki Togashi, & Kawamura 1987). In a prospective study of 54 patients, this area was consistently involved in patients with persistent nonfluency at six months post-onset (Knopman, Seines, Niccum, Rubens, Yock, & Larson, 1983). Lesion extension towards the basal ganglia region (Ludlow, Rosenberg, Fair, Buck, Schesselman, & Salazar, 1986), and in particular the mesial frontal white matter (Naeser, Palumbo, Helm-Eastabrooks, Stiassny-Eder, & Albert, 1989) predicts poor recovery of fluency. Extensive involvement of deep fronto-parietal white matter seems to be associated with automatism in speech (syllabic, verbal, and phrasal stereotypies: Haas, Blanken, Mezger, & Wallesch, 1988). A recent study has reported a close association between articulatory impairment (“apraxia of speech”) and damage to the anterior part of the insula (Dronkers, 1996). A disorder of naming is observed in almost every patient in the acute phase. At six months it is persistent only in patients with extensive lesions, or damage to two critical regions: posterosuperior temporal-inferior parietal or insulo-lenticular (Knopman, Seines, Niccum, & Rubens, 1984). In the first instance the prevalent error type was semantic paraphasia, whereas phonological errors were conspicuous with the insulo-lenticular localisation. In a study devoted only to fluent

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aphasics, it was found that phonological errors in naming were associated with damage to the posterior perisylvian region, whereas semantic paraphasias were associated with lesions involving posterior temporo-parietal cortex (Cappa, Cavallotti, & Vignolo, 1981) (Fig. 8.5). In this study, patients with perisylvian involvement had a severe repetition impairment. Seines, Knopman, Niccum, and Rubens (1985) have shown that the disorder of repetition was persistent in fluent aphasics with lesions involving Wernicke’s area. A selective naming disorder can be observed with anterior temporal lesions, sparing Wernicke’s area (BA 20 and 21): these patients frequently show a grammatical category effect, with action naming superior to object naming (Damasio, 1992; Miozzo, Soardi, & Cappa, 1994); the opposite dissociation has been reported in patients with frontal lesions (see Daniele, Giustolisi, Silveri, Colosimo, & Gainotti, 1994, for a review). Damasio, Grabowski, Tranel, Hichwa, and Damasio (1996) have reported differential temporal lobe involvement in a large group of patients with category-specific lexical retrieval impairment. Proper name anomia was associated with lesions involving the left temporal pole, while animal naming was abnormal in patients with damage to anterior inferior temporal cortex (IT) damage; a disorder in retrieval of words for tools correlated with damage in posterolateral IT. The correlation for proper names was not supported by a meta-analysis of single case reports (Semenza, Mondini, &Zettin, 1995). On the receptive side, a group study of the identification and discrimination of consonants indicated inferior performance in patients with extensive damage to the white matter of both

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hemispheres, without a particular influence of left temporal lesions (Yeni-Komshian, Ludlov, Rosenberg, Fair, & Salazar, 1986). This finding is compatible with the results of a study of discrimination of synthetic consonants differing in sonority (Basso, Casati, & Vignolo, 1977), in which defective performance was not related to the fluency/nonflueney dimension. A recent investigation, using a more refined method (MRI morphometry) has found that involvement of a parietal region, centred on the left posterior supramarginal gyrus, was associated with defective phonemic discrimination and identification (Caplan, Gow, & Makris, 1995). A clinicoradiological investigation has indicated an important role of Wernicke’s area in vowel perception (Lund, Spliid, Andersen, & Moeller, 1986). Hart and Gordon (1990) have shown that lesions involving the posterior temporal-inferior parietal region are associated with severe single-word comprehension impairments. In unselected samples, a similar disorder is frequently present in the acute stage, but persists at six months only in patients with extensive cortical damage (Seines, Niccum, Knopman, & Rubens, 1984). Defective performance on sentence comprehension, as assessed with the Token test, is associated with lesions of Wernicke’s area and of the inferior parietal cortex (Seines, Knopman, Niccum & Rubens, 1983; Vignolo, 1979); these results have been confirmed by Naeser, Helm-Estabrooks, Haas, Auerbach, and Srinivasan (1987). In the latter study, lesion extent in the temporal, but not in the parietal, lobe correlated with the severity and persistence of the disorder. A conflicting finding has been reported

FIGURE 8.5

Schematic drawing of lesion overlap (mapped according to the method described by Mazzocchi & Vignolo) in patients with predominantly phonological (A) or lexical (B) errors in a picture naming task.

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by Kertesz, Lau, and Polk (1993), who found that only lack of damage to the inferior parietal region (supramarginal and angular gyri) predicted good comprehension recovery. Global aphasics show superior recovery of auditory comprehension if the lesion involves the temporal isthmus, rather than Wernicke’s area (Naeser, Gaddie, Palumbo, & Stiassny-Eder, 1990). No specific correlation emerged for the impairment on the test of syntactic comprehension (Caplan, Baker, & Dehaut, 1985), neither from the point of view of lesion location nor of lesion size within the left perisylvian language area (Caplan, Hildebrandt, & Makris, 1996). In the cases reported by Nadeau (1988) a relatively selective disorder of syntactic comprehension was associated with large frontal lesions. In a long-term follow-up study of veterans who had a nonfluent aphasia due to a cerebral wound 15 years before, a persistent syntactic impairment in production and in comprehension tests, both oral and written, was associated with posterior extension of the lesions towards Wernicke’s area (Ludlow et al., 1986). According to Naeser et al. (1987) Wernicke’s area involvement is associated with a qualitatively similar, but more severe impairment of syntactic comprehension, in comparison to other perisylvian locations of damage. In the area of written language, a psycholinguistic approach has largely superseded the anatomo-clinical classification, with which, however, it partially overlaps. The basic distinction is between disorders of the lexical route, which is required for irregular word reading, and disorders of the nonlexical mechanism, which performs grapheme-to-phoneme conversions and is necessary for reading unknown or nonexistent words (Coltheart, Patterson, & Marshall, 1980; Patterson, Marshall, & Coltheart, 1985). There have been some efforts to relate selective, or relatively selective, disorders of one of the two reading pathways to lesion location, which have met with limited success (Black & Behrmann, 1994; Roeltgen, 1994). In the case of deep dyslexia (in which a damage to the nonlexical route is associated with the production of semantic paralexias), the lesions are usually large, involving most of the left hemisphere language areas. This has led some

authors to postulate that the residual reading abilities of these patients may be mediated by the intact right hemisphere (Coltheart, 1980). Contrary to this hypothesis, in a case described by Roeltgen (1987), residual reading was totally abolished by a second, left hemispheric lesion. In surface dyslexia, where the lexical reading route is impaired, the lesion is usually smaller, and often circumscribed to the left temporal lobe (Vanier & Caplan 1987). Writing disorders compatible with the selective involvement of the different routes have also been observed. Phonological agraphia, characterised by poor nonword writing, has been observed with posterior perisylvian lesions (Alexander, Friedman, Loverso, & Fisher, 1992; Bolla-Wilson, Speedie, & Robinson, 1985; Roeltgen, Sevush, & Heilman, 1983), while the converse picture of lexical agraphia (poor irregular word writing) has been associated with different lesion sites, sparing the perisylvian region (Rapcsak, Arthur & Rubens, 1988; Roeltgen & Heilman, 1984).

APHASIA IN SPECIAL POPULATIONS Acquired aphasia in children The effects of damage to the left hemisphere have different consequences in children and adults, leading to a greater potential for plasticity and to better recovery in childhood aphasia (Lenneberg, 1967). The exact timing of brain damage is probably a crucial factor. Prenatal and early perinatal focal damage to the right or left hemisphere is associated only with mild delays in language acquisition (Bates et al., in press). A recent study of children evaluated for epilepsy surgery, in which the method of electrical stimulation through chronically implanted subdural electrodes was used to assess cerebral language representation (Dichowny et al., 1996) reported some unexpected results. No displacement to the right hemisphere was found in the case of developmental lesions, while lesions acquired before the age of 5, extensively damaging the language cortex, were associated with right hemispheric language dominance. The situation is different in the case of focal lesions occurring after language acquisition.

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Right-handed children then develop aphasia after left, but not right, hemispheric lesions (Cranberg, Filley, Hart, & Alexander, 1987; Woods & Teuber, 1978). Aphasia in children has been suggested to differ clinically from adult aphasia, because of the nonfluent production, independently from lesions site. This observation is in disagreement with reports of Wernicke’s (Van Dongen, Loonen, & Van Dongen, 1985), transcortical sensory (Cranberg et al., 1987), and anomic aphasia (Hynd, et al., 1995) in children. Similar clinical pictures seem to be associated with comparable lesion sites in children and adults (Aram, Rose, Rekate, & Whitaker, 1983; Van Dongen et al., 1985; Cranberg et al., 1987). It has been suggested that the high prevalence of subcortical lesions in children may account for some of the features considered typical of childhood aphasia, such as mutism and nonfluency (Martins & Ferro, 1993). This evidence suggests that the potentialities for language of the right hemisphere may be more limited in time than it was originally thought.

Aphasia in left-handers Naeser and Borod ( 1986) have shown that, when the site and extent of the cerebral lesion are matched, the clinical picture in right- and left-handers is comparable. Aphasia followed left hemispheric damage in 22 out of 31 left-handers. The patients who became aphasie after a right-sided stroke had atypical clinical features, such as good auditory comprehension in a case with extensive damage to Wernicke’s area. In these patients the pattern of cerebral hemispheric asymmetry shown by CT was characterised by a longer occipital lobe, suggesting left hemispheric dominance for some aspects of linguistic function. Lack of significant differences with right-handers has also been reported by Basso, Farabola, Grassi, Laiacona, and Zanobio (1990): in most cases the type and severity of aphasia, as well as the prevalence of associated symptoms, were comparable for similar lesion size and site in leftand right-handers. Moreover, recovery was not faster in a group of 15 left-handers, who were compared to a matched sample of right-handed aphasies participating to the same rehabilitation programme.

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Taken together, these findings confirm that only a minority of left-handers have a right hemispheric language representation, which appears to involve areas homotypical with those of the left hemisphere in right-handers.

Crossed aphasia The term “crossed aphasia” was first used by Bramwell in 1899 to designate, in a much broader sense than nowadays, both aphasia with right hemiplegia in a left-handed individual (Bramwell’s own case) and, by analogy, aphasia with left hemiplegia in a right-hander (which he stated he had never seen). Since the 1920s, however, the term has been restricted to purely right hemispheric lesions in an unmistakably right-handed individual. The syndrome, so defined, is comparatively rare (1 or 2% of right-handed aphasics), as the exacting demands of exclusively right hand preference, absence of left-handedness in the family, and intactness of the left hemisphere were seldom met in the older case reports. In a review of the literature from 1880 to 1988, Faglia and Vignolo (1989) found that only 26 out of the 87 published cases were satisfactorily documented. The review did not support the claim that the language disorder is qualitatively different from that due to left hemispheric damage; type and severity of aphasia and lesion size and site are similar to patients with comparable left hemispheric damage (Basso, Capitani, & Laiacona, 1985; Henderson, 1983). Similarly, the review failed to support the hypothesis that deep hemispheric lesions are particularly frequent in crossed aphasia (Habib, Joannette, Ali-Cherif, & Poncet, 1983), although several case reports of “subcortical” crossed aphasia are on record (see, for example, Perani, Papagno, Cappa, Gerundini, & Fazio, 1988). A clinical and metabolic follow-up study with PET in two crossed aphasics with subcortical lesions (Cappa, Perani, Bressi, Paulesu, Franceschi, & Fazio, 1993) has shown the presence of massive diaschisis in the ipsi- and contralateral cortex. Regression of these remote effects paralleled clinical recovery (Fig. 8.6). These findings indicate that the cerebral language areas in these patients mirror those usually present in the left hemisphere. If this is so, the

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FIGURE 8.6 Regional cerebral metabolic rate for glucose measured with PET and 18F-FDG in a patient with crossed aphasia due to a subcortical stroke. (A) Acute stage: widespread cortical metabolic depression, including both ipsilateral (right) and contralateral (left) cortex. (B) After clinical recovery: partial regression of the metabolic depression, in particular in the left hemisphere.

question of the division of competences arises. Some authors maintain that in these individuals, before stroke, there was a complete reversal of the normal representation of functions (language to the left hemisphere, spatial abilities to the right), while others argue that the right hemisphere has acquired language without losing its relative dominance for certain spatial skills. The presence of visuospatial neglect and the qualitative features of constructional apraxia in several cases (see Faglia, Rottoli, &

Vignolo, 1990; Faglia &Vignolo, 1990) favour the second possibility. Further thorough case studies are required.

Aphasia in deaf signers Sign-language aphasia has been reported after left hemispheric lesions in right-handers. In two lefthanded patients the lesion was left hemispheric in one, right in the other (Kimura, 1986). Clinical correlations have been reported in three right-

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handed aphasic signers in whom lesion localisation had been assessed with CT (Poizner et al., 1984). A lesion of the supramarginal gyrus was associated with a severe impairment in repeating linguistic gestures, suggesting a diagnosis of conduction aphasia. A nonfluent aphasia was observed in the patient with anterior cerebral damage, while the fluent patient had a subcortical lesion. A picture similar to Broca’s aphasia was observed in a signer with a left frontal opercular lesion (Hickok, Kritchevsky, Bellugi, & Klima, 1996). A striking dissociation between sign language aphasia and preserved nonverbal gestural communication has been observed in a deaf signer with a left hemispheric lesion (Corina et al., 1992). In a group study, comparing 13 left hemisphere-damaged signers to 10 signers with right hemispheric lesions, patients with left lesions had a significantly inferior performance on all linguistic tasks, and were unimpaired on visuospatial tests; the reverse dissociation was found in patients with right hemispheric lesions (Hickok, Bellugi, & Klima, 1996). These results indicate that sign language has a similar cerebral organisation as spoken language, and that hemispheric dominance is linked to language per se, rather than to processing mechanisms related to specific input-output modalities.

Aphasia in polyglots Many different variables, such as age at acquisition, level of proficiency, and affective resonance have been suggested to influence the clinical characteristics of aphasia in polyglots (Lambert & Fillenbaum, 1959). Several different patterns of impairment have been described in bilinguals who become aphasic. There are remarkable exceptions to the rule that the severity of impairment in each language should be proportional to the premorbid degree of mastery: for instance, selective aphasia for one of the languages, differential recovery, or even mixtures of the two languages, and different symptoms in each (see Paradis, 1995, for a review). An important role of subcortical structures in the cerebral organisation of the most frequently used language has been suggested on the basis of clinical evidence (Aglioti & Fabbro, 1993).

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Aphasia in speakers of non-indoeuropean languages The hypothesis of a different cerebral organisation of language in speakers of non-indoeuropean languages has been suggested on the basis of clinical observations. Crossed aphasia has been reported to be particularly prevalent in Chinese right-handers (15.5% in the study by Yu-huan, Ying-Guan, & Gui-quing, 1990). However, this does not seem to be the case in Japanese, in which crossed aphasia has a prevalence of about 1% (Sakurai et al., 1992). One of the factors that has been suggested to determine a difference in cerebral localisation for non-indoeuropean languages is the presence of an ideographic writing system (kanji). While dissociations between kanji and kana reading and writing are well documented in individual patients (Iwata, 1984), recent PET studies have indicated left hemispheric processing for both types of written language (Sakurai et al., 1992; see later, PET studies in normal subjects). The selective impairment of kanji, with preserved kana, is the characteristic feature of a syndrome known as Gogi aphasia in Japanese. This syndrome, which is similar to transcortical sensory aphasia and reminiscent of the pattern of linguistic impairment in the degenerative condition of semantic dementia (Hodges, Patterson, Oxbury, & Funnell, 1992), is associated with lesions of the postero-inferior part of the left temporal lobe (Jibiki & Yamaguchi, 1993).

FUNCTIONAL MAPPING OF THE CEREBRAL ORGANISATION OF LANGUAGE IN NORMAL SUBJECTS The possibility of investigating the cerebral organisation of language in normal subjects is relatively recent, and follows from the availability of methods that allow the in vivo measurement of parameters of cerebral function, such as regional blood flow, while subjects are engaged in linguistic processing tasks. The functional imaging era starts with the studies of regional cerebral blood flow, with the 133Xe method of the Scandinavian school. Ingvar and Schwartz (1974) and Larsen, Skinhoj,

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and Lassen (1978) were the first to show that automatic language (such as counting, or reciting the days of the week) activates multiple cerebral areas, in both hemispheres. The increase in blood flow was particularly large in the supplementary motor areas, anterior prefrontal cortex, sensorimotor area for the mouth, and auditory cortex. Listening to words (Nishizawa, Skyhoj Olsen, Larsen, & Lassen, 1982) was associated with a prevalent left hemispheric activation, in particular in the superior temporal lobe and in the prefrontal and orbitofrontal areas. Knopman, Rubens, Klassen, and Meyer (1982) confirmed the presence of a prevalent left hemispheric activation in the posterior sylvian region when the subjects were engaged in phonological tasks, such as rhyming judgements, but also in nonverbal auditory discrimination tasks. A left frontal activation was shown with lexical retrieval tasks, such as verbal fluency (Risberg, 1986). Object naming activated a wide network of cerebral areas, including the left temporo-parieto-occipital and frontal regions and the right parieto-occipital area (Demeurisse & Capon, 1987). Further progress came with the introduction of tomographic methods, such as single photon emission tomography (SPECT) with 133Xe, for activation studies. Using this method, Wallesch, Henriksen, Kornhuber, and Paulson (1985) have shown that verbal production increases blood flow in the left frontal and thalamo-pallidal region, while a bilateral activation is present in the caudate and retrorolandic cortex. The introduction of positron emission tomography (PET) marks the most important advancement for the investigation of language activation in normal subjects (see chapter by Perani & Cappa for a discussion of the technical aspects). It must be underlined that this field of investigation has been characterised by a continuous interaction with the theoretical developments in neuropsychology: more refined language activation paradigms have provided an ideal match for the hitherto unthinkable possibilities offered by PET. The inaugural study of this new era of research is the PET study of single word processing by the St. Louis group (Petersen, Fox, Posner, Mintun, & Raichle, 1988, 1989). This study will be reviewed

in some detail, as many of the methodological discussions related to this field of endeavour (Démonet, Wise, & Frackowiak, 1993; Perani, Gilardi, Cappa, & Fazio, 1992; Petersen & Fiez, 1993; Sergent, Zuck, Lévesque, & MacDonald, 1992) have made reference to this pioneering investigation (Fig. 8.7). The study provides a clear example of the application of the classical “subtractive” methodology to a lexical processing model (Posner & Raichle, 1994). It includes a control condition, in which cerebral perfusion was assessed while the subjects fixated a cross in the centre of a computer screen. The first “activation” step, according to the internal logic of the paradigm, was the auditory or visual presentation of words. The subjects had no task to perform during the presentation: they were simply asked to watch the screen where the words were presented. A further step was the condition in which the subjects had to read or repeat aloud the words. Finally, the subjects were required to produce a verb associated with the word presented on the screen (for example, “eat” for “cake”). Regional cerebral perfusion was measured with PET during each of these phases. The paradigm clearly entails the hypothesis of sequential stages in lexical processing. Subtraction of the scans collected during the control condition from those assocated with passive word presentation should then elucidate the areas involved in the perceptual analysis (including access to the word form). Subtraction of passive presentation from reading aloud or repetition should isolate the areas involved in encoding and articulatory programming. Finally, subtraction of the scans collected during the latter condition from verb generation should individuate the correlates of semantic processing. The results of the first two subtractions gave apparently uncontroversial results: modality-specific areas were activated by passive presentation (extrastriate cortex for visual words, superior temporal, more extensive in the left temporoparietal areas, for auditory words), while oral production was associated with frontal activation (precentral gyrus, supplementary motor area, Broca’s area). The third subtraction (generation minus reading or repetition) gave an unexpected result: semantic processing was associated not with left hemispheric temporal or

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FIGURE 8.7 The Petersen et al. (1988) single word processing PET activation experiment. The sensory stage corresponds to simple stimulus (word) presentation. The production stage is word reading or repetition. The associative stage is the retrieval of a verb which was semantically related to the stimulus word.

parietal activation, as predicted by neuropsychological investigations, but with the anterior cingulate area and the dorsolateral prefrontal cortex. The explicit and implicit assumptions of this paradigm have been the focus of an intensive debate. The “task decomposition”, which is mandatory for the application of the subtractive methodology, requires a strictly serial information processing model of the task under scrutiny. In the case of visual presentation, for example, the model assumes that when the subject is shown a word without instruction, the visual word form is accessed, without significant further processing of the meaning or activation of an output lexical representation. This is clearly implausible (Sergent, Zuck, Lévesque, & MacDonald, 1992). Even if serial, modular models might be internally coherent at the cognitive level, a further problem is that it is highly unlikely that they apply to neural processing, which is typically parallel and non linear (Friston et al., 1996; see chapter by Perani & Cappa for a

further discussion of cognitive subtraction). However, these and other criticisms directed to this study do not detract from its value in opening a new avenue of investigation. Any effort to provide an exhaustive review of what has been happening in the field of language activation studies since the paper just discussed is nowadays fatally doomed to rapid obsolescence. The following summary attempts to provide a selective review of the work that we consider most fruitful for future research approaches.

Acoustic-phonological processing Passive listening to linguistic material, both meaningful and nonmeaningful, in comparison to rest, results in a bilateral superior temporal activation (Wise, Chollet, Hadar, Friston, Hoffner, & Frackowiak, 1991). A linear increase in blood flow was observed in this area, including Heschl’s gyri, with increased rate of stimulus presentation. Only Wernicke’s area was insensitive to rate,

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showing a flat profile of activation which could be related to a categorical, stimulus-independent analysis of auditory input (Price et al., 1992; see Buechel, Wise, Mummery, Poline, & Friston, 1996, for nonlinear parametric analyses). A recent study with a non-subtractive methodology (Paus, Perry, Zatorre, Worsley, & Evans, 1996) has reported that a linear increase in superior temporal cortex blood flow could be observed also increasing the rate of silent syllable production by the subjects (whispering), suggesting a modulation of the auditory cortex by motor-tosensory (corollary) discharges. If the task requires the phonological analysis of acoustic material, a more extensive pattern of activation has been observed. Zatorre, Evans, Meyer, and Gjedde (1992) have reported an experiment in which the control condition was not rest, but the presentation of acoustic stimuli sharing the same physical characteristics of linguistic material. The activation measured during this condition was subtracted from the scans collected during phonetic discrimination (syllables ending with the same or a different consonant) and tonal discrimination (ascending or descending syllables). The main results of the subtraction were the activation of Broca’s area and the left superior parietal lobule for phonetic discrimination, while tonal discrimination was associated with a right prefrontal activation. A more difficult phonological discrimination task has been studied by Demonet et al. (1992). The subjects had to respond to the presence of the phoneme /b/ in nonwords only when it was preceeded by /d/. The comparison task was a tonal one (respond to ascending pure tones). The activated areas were not only posterior (the left superior temporal gyrus and, to a lesser degree, the homologous area on the right), but also frontal (left Ba 44 and 45). In a continuation of this study, Demonet, Price, Wise, and Frackowiak (1994) have further analysed the effect of sequential order and phonetic ambiguity, manipulating the stimuli used in the phonological discrimination task. In the nonsequential, unambiguous condition, the subject had to respond to nonwords beginning with /b/, which were intermixed with nonwords beginning with a phoneme that differed in more than one distinctive feature (i.e. to /bituval/, but not to /laritun/). The

nonsequential, ambiguous condition required a response to nonwords that contained a /b/, intermixed with words that contained a phoneme that was different for only one distinctive feature (i.e. to /livboki/, but not to /rokpamul/). The sequential, unambiguous required a response to ib/ only in nonwords if it was preceeded by /d/; the distractors were different in more than one distinctive feature (i.e. to /daboki/, but not to /donifal/ or /rinuban/). Finally, the sequential, ambiguous condition was based on nonwords where /b/ was preceeded by /d/; the distractors differed only for one distinctive feature (/odalubik/ but not /rotabig/ or /pidupan/). The main result was that the fusiform gyrus was activated only in the conditions with perceptual ambiguity (nonsequential tasks), while the Broca’s area activation was specific for the sequential conditions. The former activation was attributed to the need of orthographic encoding as a supplementary resource to disambiguate the stimuli, while articulatory rehearsal seems to be a plausible interpretation for Broca’s area activation. Fiez et al. (1995) reported activation of left frontal opercular areas when the phonological task required consonant detection, but not with vowels or with passive listening. Price et al. (1996) found that activation was greater with slower presentation rates, with a peak in Ba 45. Broca’s area has also been consistently activated in tasks requiring the phonological recoding of visual material. Sergent et al. (1992), using a rhyme judgement task for pairs of letters presented visually (i.e. T-B versus T-L) found an activation of Ba 45 and 46 and of the orbitofrontal cortex. Paulesu, Frith, and Frackowiak (1993) have confirmed the activation of Ba 44 during phonological recoding of visual material.

Lexical-semantic processing The first study of the visual processing of words and nonwords was reported by Petersen, Fox, Snyde, and Raichle (1990). The control task was central fixation, while the activation conditions were: visual presentation of sequences of abstract symbols similar to letters; unpronounceable strings of real letters, violating English orthographic rules; pronounceable non words; real words. The extrastriate occipital areas were activated by all four

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classes of stimuli. However, only real words and pronounceable (“legal”) nonwords activated a left medial extrastriate area, which was proposed as the substrate of the orthographic lexicon. The lack of difference between words and pseudowords is surprising, considering that real words might be expected to engage lexical-semantic processing. Price, Wise, and Frackowiak (1996) have shown that even if subjects are asked to perform a nonlinguistic task, such as visual feature detection, on words and nonwords, an extensive activation can be observed not only in extrastriate cortex bilaterally, but in all left hemispheric language areas. The activation is actually greater for nonwords than words, suggesting that all level of linguistic processing can be engaged by unfamiliar, but “language-like” stimuli. A fractionation between the different levels of linguistic processing must then be sought with more complex designs. For example, Howard et al. (1992) set out to investigate the cerebral correlates of the visual and auditory input lexicon. Two main subtractions were studied. In the first, the scans collected while the subjects listened to nonwords, while repeating (“shadowing”) continuously the same word (“crime”), were subtracted from a condition in which the subjects repeated real words. The second subtraction was the visual analogue: the scans obtained from the condition in which the subjects read non words while repeating continuously “crime” were subtracted from a condition in which they read aloud real words. The basic assmption underlying this complex design is that real-word processing is associated with automatic activation of all levels of lexical analysis, including access to word meaning, while the nonword and “shadowing” tasks engaged only the stages of perceptual analysis and production. The comparison of the results of the two subtractions should then allow the individuation of the areas associated with the phonological lexicon and the orthographic lexicon. The results were the following: the first subtraction (repetition) resulted in an area of activation which involved the middle part of the left superior and middle temporal gyri. The result of the second subtraction (reading) was unexpected, as the activation was centred on the posterior part of the

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left middle temporal gyrus. Also unexpected was the lack of any overlapping area of activation, which could be interpreted as the cerebral correlate of semantic access. The obvious discrepancy in the anatomical correlate of the visual input lexicon between this study and the results of Petersen et al. (1990) has prompted a further investigation (Price, Wise, Watson, Patterson, Howard, & Frackowiak, 1994), which tested the hypothesis that experimental parameters, such as the time of exposure of the stimuli and the type of task, may influence the pattern of cerebral activation during reading. The results indicate that these variables have clear effects not only on the intensity, but also on the topographic location of the response. A strict control of all the experimental variables is thus necessary to allow reproducibility and comparison of studies from different centres. If these factors are kept in appropriate consideration, the inter-centre agreement has been shown to be high (see, for example, Poline, Vandenberghe, Holmes, Friston, & Frackowiak, 1996). The difficulty of individuating activations related to semantic access has been attributed to the “distributed” nature of the semantic system, or to its automatic involvement in any aspect of linguistic processing. A possible role of the left prefrontal cortex was suggested by the results of Petersen et al. (1988). In a further study by the same group, the subjects were asked to respond to the names of dangerous animals, from a visually presented word list: the control condition was again “passive” presentation (Posner, Petersen, Fox, & Raichle, 1989). Here too the activation was localised to the anterior cingulus and left prefrontal cortex. Wise et al. (1991) suggested that semantic activation is present for all word-processing tasks (as suggested by Price et al., 1996), thus cancelling out in any subtraction condition, and that the left frontal activation is actually related to lexical retrieval. In their study, a semantic task requiring the matching of superordinate to subordinate nouns, and of actions with objects, showed only a bilateral superior temporal activation, identical to passive listening to nonwords, when compared to rest. Demonet et al. (1992) used a more attentional demanding semantic task, i.e. the monitoring of the names of small animals associated with positive

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adjectives (i.e. the subjects had to respond to “pretty mouse”, but not to “nasty mouse” or “gentle elephant”), compared to tone monitoring. An extensive area of activation related to semantic processing was observed in the left temporal lobe, fusiform gyrus, supramarginal gyrus, and Ba 39 and 40. Frontal activation was limited to Ba 47. A direct comparison between this task and the phonological monitoring condition described earlier, and vice versa, showed the areas of differential activation: the semantic task activated the left angular gyrus (Ba 39), the superior prefrontal cortex (Ba 8), the posterior cingulate cortex, and the middle temporal gyrus; only the angular gyrus was activated on the right. These results have been replicated, with different paradigms, by Vandenberghe, Price, Wise, Josephs, and Frackowiak (1996) and by Cappa et al. (in press) (see Fig. 8.8). Conversely, the phonological task was associated with left supramarginal activation (Ba 40) as well as with a small area of increased activity in the motor strip (Demonet, Price, & Frackowiak, 1994).

Word retrieval has been investigated with repetition (externally generated) and fluency (internally generated) tasks. Repetition is associated with greater activation of Broca’s area in comparison to passive listening, and the location of the peak is posterior, in Ba 44 proper (Price et al., 1996). There are many studies of word generation, starting from the Petersen et al. (1988) study, which required generation of verbs associated with nouns, and reported anterior cingulate and left dorsolateral frontal cortex activation. Wise et al. (1991), using the same task, found a more extensive pattern of activation, including left posterior temporal activation. In a replication of the same experiment, Raichle et al. (1994) confirmed the presence of a left posterior temporal activation. The difference with the results reported in the 1988 paper could be related to the different rate of presentation of the nouns, to which the subject had to associate an action (every second in 1988; every 1.5 seconds in 1994). A remarkable result of this second series of experiments was that the pattern of cerebral

FIGURE 8.8

Areas activated by lexical-semantic access (answering to questions about the referents of words, compared with pseudoword reading). After Cappa et al. (in press).

8. NEUROLOGICAL FOUNDATIONS OF LANGUAGE

activation was different according to the subjects’ practice with the task. The activation in the anterior cingulate, left prefrontal and posterior temporal cortex, and right cerebellar hemisphere, which was conspicuous in naive subjects, was substantially reduced if the subject had been trained on the task. In the latter subjects there was a bilateral activation of the sylvian-insular cortex, and of medial occipital extrastriate areas. This modification of the pattern of cerebral activation could be related to the learning of the task, which was executed in a more automatic fashion. A further systematic study of word generation tasks has indicated that temporo-parietal activation can be observed only in comparison with a resting state. The comparison with any other word processing task cancels the temporal activation (Warburton et al., 1996). This finding explains the observations of Frith and co-workers (Frith, Friston, Liddle, & Frackowiak, 1991a, b; Friston, Frith, Liddle, & Frackowiak, 1991) who, by directly comparing word generation (letter fluency) with word or letter repetition, confirmed the dorsolateral frontal cortex and anterior cingulate activation, which seems to be specific for task requiring spontaneous, intentional (willed) action, detached from the demands of the external environment, but consistently reported deactivations in the left temporal region. The comparison between letter and semantic fluency tasks has indicated significant differences. Mummery, Patterson, Hodges, & Wise (1996), with PET, found a selective left inferolateral and anteromedial temporal activation with category fluency, while the reverse comparison showed a peak in left Ba 44 and 6. Differential activations were observed in a similar study with fMR (Paulesu et al., 1997).

Sentence processing The studies reported earlier have mainly addressed single word processing tasks: sentence processing has been less investigated with functional imaging. Mazoyer et al. (1993) have studied the pattern of cerebral activation while the subjects listened to stories in an unknown language, to lists of words in their mother tongue, to meaningful stories, and to distorted stories. The main result of this study was that meaningful stories activated all the areas

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implicated in single word processing tasks, plus the middle temporal gyrus, an extensive portion of the left prefrontal cortex and the temporal poles bilaterally. The distortions, which mantained an unaltered syntax and prosody, but made the story unintelligible, abolished all these activations, with the exception of the temporal poles. A related paradigm was applied to study a group of Italian subjects with a fair knowledge of English: stories were presented in Italian, English, and Japanese (Perani et al., 1996): the Italian condition was associated with a similar pattern of extensive cerebral activation, included the temporal poles. A surprising result was the much more restricted pattern of cerebral activation not only with the Japanese stories, which the subjects did not understand, but also with the English ones, which were adequately understood (Fig. 8.9). Stroms wold, Caplan, Alpert, and Rauch (1996) have studied the cerebral correlates of acceptability judgement of sentences of different syntactic complexity which could contain semantic violations. An activation of Broca’s area was observed in the comparison of more complex (centre-embedded) with less complex (right-branching) relative sentences. Different results have been reported in a fMR study, where the subjects had to answer to questions of increasing syntactic complexity (Just, Carpenter, Keller, Eddy, & Thulborn, 1996): in this case, the volume of activated tissue increased with syntactic complexity not only in Broca’s, but also in Wernicke’s area and in their homologous right hemispheric areas. Extensive right hemispheric activation was observed in a study that examined the metaphorical interpretation of sentences (Bottini et al., 1994). The activation also included a superior frontal area (Ba 8), which has been shown to be engaged when subjects listened to stories requiring inferences about other people’s mental states (Fletcher et al., 1995).

Kana and Kanji Some PET studies have investigated the pattern of activation in Japanese subjects engaged in ideographic (kanji) or syllabographic (kana) reading. Kanji reading (Sakurai et al., 1992), when compared to fixation, activated bilaterally, with a

176 CAPPA AND ViGNOLO

FIGURE 8.9 .

Activations related to the processing of Italian language (mother tongue), the second language (English) and the unknown language (Japanese) in a group of Italian/English bilinguals with low proficiency for the second language (English). The figure shows cerebral areas activated by listening to a story in the maternal language (first row), in the second language (second row) and in the unknown language (third row), when compared with the attentive silence condition (baseline). The bottom row shows the activations related to listening to Japanese backwards when compared with the baseline condition. Zscores are displayed according to a linear colour scale (Zscore > 2.7; p run must be considered as the substitution of the inflection -s with the “zero” inflection. Myerson and Goodglass (1972) and Marin, Saffran, & Schwartz (1976) observed that agrammatic patients experience problems with verbs not only when producing inflections, but also when producing roots, as shown by the occurrence of verb omissions and nominalisations in spontaneous speech. Recent studies confirmed these observations and provided quantitative measures of the deficits (Kolk et al., 1985; Menn, & Obler, 1990; Miceli et al., 1989; Nespoulous et al., 1988; Saffran, Bemdt, & Schwartz, 1989). Another deficit reported in analyses of agrammatic speech is the difficulty with word order and, specifically, the inversion of thematic roles. This difficulty was described by Saffran et al.

12. GRAMMATICAL DEFICITS IN APHASIA

(1980), who observed the production of sentences like Man chasing woman in response to the picture of a woman chasing a man. These analyses allowed the formulation of a more complete description of agrammatic speech errors, but also underscored some relevant problems. First, with the single exception of the difficulties with grammatical morphemes, none of the symptoms considered as typical of agrammatism is observed in all the subjects classified as agrammatic (but see Note 3). One such symptom, the simplification of syntactic structures, is observed in most subjects, but some agrammatic speakers manage to produce fairly complex structures. The variability of this parameter is exemplified in Table 12.2, which reports sentences produced by three Italianspeaking agrammatic subjects. The first contains many subordinate clauses; the second consists of independent clauses linked by coordinate

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conjunctions; and the third results in a series of holophrastic utterances. Another classical symptom of agrammatism is reduced phrase length. However, analysis of the spontaneous speech of 20 Italian-speaking agrammatic subjects (Miceli et al., 1989) showed the average length of syntactic structures to range in various subjects from 3.1 to 10.5 words (the latter value does not differ from the average length observed in 10 cognitively unimpaired subjects). Yet another typical agrammatic disorder, difficulties with main verbs, may severely disrupt speech in some subjects, but may be completely absent in other cases (among the 20 subjects studied by Miceli, A.A. omitted 36.7% main verbs, whereas G.F. did not omit any). As a final example, the occurrence of word order problems is also extremely variable: it was found to be high in the subjects studied by Saffran et al. (1980), low in M.L. (Caramazza & Hillis, 1990), and was never observed by Miceli et al. (1989),

TABLE 12.2 Samples of spontaneous speech collected from three agrammatic speakers. a) Subject G.F.

Prendere [V ] anticoagulante e poi cambiare [le] cure e poi venire [il] nervoso perché io dice, dire sempre [che] morire, morire, morire, sempre impressionare che morire. To take [the] anticoagulant and then to change [the] medications and then to come [the] nervous because I says, to say always [that] to die, to die, to die, always to be scared that to die. Take anticoagulant and then change medications and then go berserk because I says, always to say die, die, die, always be scared that die.

b) Subject C.S.

Mi alzo ... lavo prima tutto quanto ... alla mattina metto [la] gonna ... poi dopo [faccio il] bagno ... poi dopo [mi] lavo ... quindi [faccio] gli esercizi, sempre ... e poi dopo mia figlia si va a scuola ... e poi dopo si fa tornare ... poi mangiamo ... e poi dopo si mette a dormire. I get up ... I wash first everything ... at the morning I put on [the] sk irt... then [I take the] bath ... then [myself] wash ... then [I do] the exercises, always ... and then my daughter goes herself to school... and then she makes herself come back ... then we e a t... and then one puts herself to sleep (target: then I/we go to sleep). I get up ... first I wash everything ... in the morning wear sk irt... then bath ... then wash ... then gymnastics, always ... and then my daughter goes herself to school... and then makes herself come back ... then we eat ... and then puts herself to sleep.

c) Subject G.D.C.

... il medico ... ospedale ... cervello ... ginnastica ... morto ... le m an i... niente. ... the doctor ... hospital... brain ... gymnastics ... dead ... the hands ... nothing

For each sample, the transcription of the subject’s output is reported first (omissions are in square parentheses; errors are underlined). It is followed by a verbatim English translation, and by an attempt at rendering what the transcript would sound like in English (only the subject’s output and the verbatim English translation are reported for subject G.D.C., who only produced holophrastic utterances).

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who found only one questionable instance of thematic role reversal in the speech of their 20 subjects. Second, pathological behaviours present in agrammatic patients may result from very different deficits, which sometimes do not involve grammar. Difficulties with main verbs and with word order can clarify this issue. Recent studies (McCarthy & Warrington, 1985, 1988; Miceli et al., 1984; Zingeser & Bemdt, 1988, 1990) demonstrate that difficulties in producing verbs may be observed not only in connected speech, but also in tasks like naming, reading aloud, and writing, that require the production of verbs as isolated words. In naming, agrammatic subjects tend to nominalise verbs (to pray —►the prayer), and sometimes are unable to provide any response to a pictured action. Selectively poor performance in spoken and in written naming of verbs may be observed in the absence of a comparable deficit with nouns (Caramazza & Hillis, 1990). Consideration of these results forces us to consider the possibility that difficulties with verbs in spontaneous speech derive, at least in part, from a lexical-semantic deficit, independent of disorders in the production of syntactic structures or grammatical morphemes. The interpretation of errors resulting in incorrect word order, and especially in apparent thematic role reversals, is even more problematic. As agrammatic speech is characterised by difficulties with grammatical morphemes (and sometimes with main verbs), errors that appear to be thematic role reversals may have different causes. Let us consider as an example the sentence Man chase woman, in response to the drawing of a woman chasing a man. The error may result from a genuine inversion of thematic roles in the presence of a difficulty with grammatical morphemes (the subjects tries to produce the sentence The man chases the woman, which contains a role reversal and, in addition, omits articles and produces the infinitive form of the verb). However, it may also derive entirely from a difficulty with grammatical morphemes (the subject attempts the production of The man is chased by the woman but fails in producing the morphology of the passive voice) or from difficulties with both grammatical morphemes and main verbs (the patient means to produce the

sentence The man precedes the woman, but has problems with grammatical morphemes and produces a substitution in lexicalising the verb— chase —► precede). Therefore, an error that surfaces as an inversion of thematic roles may result from very different deficits that may not even concern the grammatical level, such as a difficulty in verb lexicalisation or in thematic role assignment (see also sections later).

PARAGRAMMATIC PRODUCTION Paragrammatic speech has received far less attention than agrammatic speech. Nevertheless, even the results of the few studies on paragrammatism leave us with many puzzling questions. Kleist (1914) used the term paragrammatism to indicate a disorder, usually secondary to left temporal lesions, clinically characterised by errors in selecting and ordering words and grammatical forms. According to Kleist, this constellation of behaviours offers a sharp contrast with agrammatism, which is characterised by the impoverishment of syntactic structure, omissions of grammatical words and “telegraphic” style. The distinction between agrammatism and paragrammatism has remained in the literature, and is still accepted. However, the efforts to clearly define the phenomena distinguishing these two deficits have been less than successful. Goodglass and Mayer (1958) observed that omissions and substitutions of grammatical morphemes occur more frequently in agrammatic than in paragrammatic speech, but also underlined a large overlap between subjects of the two types. In an analysis of the grammatical structures produced by aphasic subjects, Goodglass and Hunt (1958) found that the agrammatic patients’ tendency to produce very short sentences is the only parameter that distinguishes these subjects from paragrammatic aphasics (and from subjects affected by other clinical forms of aphasia without grammatical errors). More recently, Butterworth and Howard (1987) analysed the spontaneous speech of control subjects and of five brain-damaged subjects,

12. GRAMMATICAL DEFICITS IN APHASIA

classified as paragrammatic because they produced grammatical errors in the context of fluent and neologistic speech. They analysed the production of content words, grammatical words, and inflections, as well as the production of syntactic structures. The errors observed in paragrammatic subjects were identical to (but more frequent than) those observed in normal controls, and all the errors typical of agrammatism were also found in paragrammatic speakers. Butterworth and Howard concluded that the errors observed in paragrammatic speech do not result from a grammatical disorder (as is the case of those produced by agrammatic speakers), but from damage to control mechanisms operating in the speech output system. Nevertheless, they admitted that it is not possible to clearly distinguish agrammatic from paragrammatic speakers based on the characteristics of spontaneous speech, and concluded that agrammatic and paragrammatic phenomena usually co-occur in the same subject. Their conclusion is very similar to that of Kleist (1934), who initially proposed a distinction between the two types of grammatical deficits, but after an analysis of his data came to the conclusion that the same subject usually produces agrammatic and paragrammatic sentences. To sum up, efforts to substantiate the claims advocating clear-cut empirical and theoretical differences between agrammatism and paragrammatism have largely failed to support the proposed distinctions.

PROBLEMS WITH RESEARCH ON CLINICALLY DEFINED GRAMMATICAL DISORDERS Hopes that detailed analyses of agrammatic (or paragrammatic) speech would allow a better definition of these disorders, and subsequently the development of articulated theories, were not fulfilled. Such analyses improved the description of grammatical disorders of production, but did not clarify their interpretation. This is very clear in the case of agrammatism. The analyses of agrammatic speech briefly reviewed so far, conducted on subjects classified

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on the basis of clinical criteria, yielded problematic results. First of all, none of the deficits considered to be typical of agrammatic speech was observed in all agrammatic speakers, with the exception of omissions of grammatical morphemes (but, as has already been said, the systematic occurrence of this phenomenon is only obvious, as the omission of function words is the criterion used to classify a subject as agrammatic). Second, all the phenomena that define agrammatic speech demonstrated great across-subject variability. Third, some of the phenomena reported in agrammatic speech result from true grammatical deficits (morphological or syntactic), but others can result also from phonological, lexical, or semantic disorders. Finally, the same, apparently grammatical, error may result from distinct impairments in different subjects. These results raise the possibility that agrammatic speakers are a heterogeneous group (Caramazza & Berndt, 1985; Goodglass & Menn, 1985), and that the difficulties in accounting for their speech disorder depend not only on inadequate theories, but also on methodological and metatheoretical problems resulting from the approach selected to analyse these deficits (Caramazza, 1986, 1988). Consideration of these issues has led different authors to take contrasting positions. Badecker and Caramazza (1985, 1986) underlined that in studies on agrammatism the neuropsychological deficit had been clinically defined, based on a small set of a priori criteria (the omission of grammatical morphemes, the simplification of syntactic structures, and the reduction of phrase length). These criteria, however, do not allow the identification of subjects affected by the same cognitive deficit. Consequently, the groups of agrammatic speakers selected on this basis include subjects with different cognitive lesions, whose average behaviour in a specific task results from impairments that differ across subjects. Therefore, the results of studies that use this methodology lead to uninterpretable results, and do not allow conclusions that are relevant for a theory of the cognitive processes involved in sentence production. Moreover, this approach does not permit one to deal in a principled way with the issue of across-subject variability of

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grammatical speech errors. In fact, the presupposition that a set of a priori criteria leads to the identification of cognitively homogeneous subjects amounts to the assumption that variations across subjects classified as agrammatic based on those criteria are random, and therefore theoretically irrelevant. According to Badecker and Caramazza, difficulties in the study of agrammatism result from these metatheoretical and methodological flaws. Efforts to define the disorder, based on empirical analyses, did not succeed; enlarging the database by collecting large speech corpora from subjects who were premorbidly speakers of a wide range of languages only confirmed the impossibility of providing an objective definition, and even identifying in a theoretically defensible way the types of empirical observations that were relevant for a correct interpretation. To overcome these problems, Badecker and Caramazza propose a different approach. Analyses of agrammatic speech should not be aimed primarily at an increasingly detailed description of the pathology of the linguistic system, or at formulating theories of agrammatism and paragrammatism. On the contrary, their main purpose should be to propose hypotheses about the structure of the normal cognitive system. Consequently, their starting point cannot be a clinical category identified a priori, but explicit hypotheses on the cognitive mechanisms that allow grammatically correct speech in normal subjects. Such hypotheses are necessary to identify the cognitive lesion responsible for the deviant speech observed in each subject. Due to the complexity of speech production mechanisms, the deficits that may result from damage to one or more components of these processes are so varied that they cannot be identified a priori. Therefore, the functional lesion responsible for agrammatic behaviour must be identified a posteriori, through theory-driven, detailed analyses of deviant linguistic behaviour. In addition, as the complexity of the system and the subsequent variety of possible deficits make it quite unlikely that groups of cognitively homogeneous subjects (i.e. of subjects affected by the same cognitive impairment) can be found, the most adequate strategy for the

investigation of agrammatic production (or of any other cognitive deficit, for that matter) is the study of single cases. Other authors (e.g. Caplan, 1986; Grodzinsky, 1987,1990,1991) took different positions. Caplan (1986) agrees with Badecker and Caramazza’s critique of the use of clinical categories. He, too, believes that empirical criteria and pretheoretical intuitions cannot lead to relevant conclusions about a theory of the organisation of normal language. However, Caplan does not consider these problems, nor the objections to the traditional approach, to be sufficient to abandon the use of a priori identified clinical categories in neuropsychological studies of the cognitive system. If the criterion selected for categorisation is based on a valid theory, clinical categories can still be used in research. In the case of grammatical disorders of production and comprehension, the use of the clinical category “agrammatism” is admissible, provided that this category is defined on the basis of a theory formulated independently from agrammatism. Caplan’s proposal starts from linguistic theory, which considers grammatical morphemes as a class of words distinct from the other words of a language. Because, on this account, grammatical morphemes constitute an autonomous category, selecting function word omissions as the criterion to classify a subject as agrammatic allows one to identify cognitively homogeneous subjects. According to Caplan, the term agrammatism should be used only to denote omissions of grammatical morphemes in spontaneous production; the other disorders often reported in agrammatic speech (syntactic simplification, reduced phrase length, difficulty with main verbs) should be disregarded. If the basic assumptions of this theory were correct, the study of groups of subjects classified as agrammatic based on the proposed criterion should yield results relevant for theories of the cognitive system. In order to evaluate these two positions based on empirical data, Miceli et al. (1989) analysed the spontaneous speech of 20 patients classified as agrammatic because they omitted grammatical morphemes (i.e. based on the criterion proposed by Caplan, 1986). They studied the errors of omission and substitution in the production of five free-

12. GRAMMATICAL DEFICITS IN APHASIA

standing grammatical morphemes (definite and indefinite articles, prepositions, clitics, and auxiliary verbs) and of three bound grammatical morphemes (nominal, adjectival, and verbal inflections). When all grammatical morphemes were lumped together, a large across-subject variability was observed for total errors, and for omissions and substitutions considered separately; in addition, the incidence of omission and substitution errors was not related (there were subjects with a comparable occurrence of omissions, but who presented with a very different occurrence of substitutions, and subjects with the reverse pattern). An even greater variability was observed when each of the five types of freestanding grammatical morphemes was considered separately (Table 12.3): both in the analysis of overall errors, and in the separate analyses of omissions and substitutions, the same morpheme may be the most spared in one subject and the most damaged in another. Moreover, the same patient

may present with only omissions in the production of a morpheme, and with omissions and substitutions in the production of another. The comparison of errors on free-standing and on bound grammatical morphemes also demonstrated a substantial across-subject variability: subjects with comparable numbers of errors on free-standing morphemes presented with very different numbers of errors on bound morphemes, and vice versa. Also the difficulties with nominal, adjectival, and verbal agreement were not homogeneous (Table 12.4): some subjects had problems with all types of agreement, whereas others only had problems with verb agreement (a similar observation is reported by Grodzinsky, 1990). Moreover, an analysis of verb agreement showed that errors almost always resulted in the citation form of the verb (infinitive and past participle) in some subjects, and in a finite but incorrect verb form in others. Thus, the results of this study are more consistent with the position taken by Badecker and

TABLE 12.3 Percent occurrence of omissions and substitutions in each category of free-standing grammatical morphemes. A rtic le s P rep o sitio n s

D e fin ite

Subject

Om

Subst

Om

A.A. F.A. F.B. C.D. F.D. C.D.A. G.D.C. E.D.U. G.F. T.F. F.G. G.G. M.L. A.M. M.M. B.P. C.S. F.S. L.S. M.U.

66.7 28.1 13.8 7.4 22.3 27.1 83.3 7.3 38.5 18.6 8.3 18.5 2.7 38.9 27.6 43.3

14.3 6.2 1.5 3.4 10.8 12.9

30.7 14.3 20.0

24.0 7.1 20.0

10.7 8.3 3.5 6.0 20.7 24.8 25.0 5.5 58.5 64.0 5.9 32.7 15.2 50.0 6.0 24.1 12.1 11.2 22.6 14.3

3.6 5.8 1.7 8.3 2.7 1.7 10.0

Subst

A rtic le s In d e fin ite Om

Subst

C litic s Om

46.7 1.5 5.4 5.0 8.9 7.3 2.0 1.9 3.0 6.8 5.0 3.4 3.3 24.5 16.1 2.0

257

12.5 33.3 25.0 33.3 33.3 37.5

12.5 9.5 33.3 5.3 7.1

33.3

10.0

7.0 16.1 53.8 22.2 10.0 36.4 100.0 14.3 15.4 8.3 80.0 14.3

15.0 50.0

50.0 20.0 33.3

A u x ilia rie s

Subst

Om

75.0

25.0 33.3 23.1 8.7 27.3 3.1 100.0 21.0 72.2 63.3

18.2 9.7 8.1 7.7 44.4 15.0

9.4 8.3 42.9 18.7 13.3 11.1

5.0 28.6 33.3 25.0 6.2 80.0 37.5

Subst

7.7 8.7 2.3 3.1 31.6 10.0 50.0 3.6 22.2 37.5 16.7 12.5

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TABLE 12.4 Occurrence and distribution of the violation of agreement phenomena (article-noun, noun-adjective and subject-verb). Subject

N

A.A. F.A. F.B. C.D. F.D. C.D.A. G.D.C. E.D.U. G.F. T.F. F.G. G.G. M.L. A.M. M.M. B.P. C.S. F.S. L.S. M.U.

25 71 63 ill

67 95 70 99 18 18 73 65 34 18 110 43 20 138 32 61

A r tic le -N o u n % V io la tio n s

8.0 5.6 0.8 1.5 4.2 5.7 2.0 5.6 1.4 2.9 11.1 4.5 9.3 14.5 12.5 3.3

Caramazza (1985) than with the hypothesis favoured by Caplan (1986) and Grodzinsky (1990). In fact, even though the items under analysis belong to the linguistically homogeneous category of grammatical morphemes, huge variations and dissociations are observed, both across subjects and in the same subject, in contrast with Caplan’s hypothesis.4

GRAMMATICAL PRODUCTION DEFICITS Analyses of the spontaneous speech of subjects classified as exemplars of two traditionally opposed clinical entities (agrammatism and paragrammatism) demonstrated more commonalities than differences—variability within category is at least as large as between categories (Badecker & Caramazza, 1985; Miceli et al., 1989). Therefore, it is not surprising that an approach based on the a priori classification of subjects cannot result in an objective and precise definition of the two deficits.

N

8 45 9 57 78 9 32 28 56 32 26 25 20 26 26 10 50 7 12

N o u n -A d je c tiv e % V io la tio n s

11.1 11.1 7.0 14.1 38 22.2 6.2 3.1 3.8 4.0 3.8 20.0 28.6 8.3

N

S u b je c t-V e rb % V io la tio n s

23 81 86 194 193 100 46 152 100 101 114 54 52 85 61 46 33 88 51 63

\

43.5 29.6 3.5 6.7 11.9 16.0 43.5 18.4 55.0 64.4 4.4 18.5 3.9 15.3 14.7 52.2 9.1 47.7 19.6 12.7

These facts have direct implications for the study of grammatical disorders in aphasia. The cognitive damage responsible for agrammatic production can be identified only a posteriori, because only explicit hypotheses on the functioning of normal processes allow the definition of the range of observations necessary to identify the cognitive lesion responsible for the observed behaviour, and to rule out all alternative accounts (Caramazza, 1986; Caramazza & McCloskey, 1988). Thus, the starting point of the analysis of aphasic speech must be a theory of the normal production system. In the scientific literature some production models, based on the analysis of speech errors produced by normal subjects during spontaneous conversation, have been presented (e.g. Bock, 1982; Dell, 1986; Garrett, 1980,1982,1984,1992; Lapointe & Dell, 1989; Stemberger, 1985): these models have begun to offer explicit hypotheses on the levels of representation involved in language production and on the mechanisms used to process these representations.

12. GRAMMATICAL DEFICITS IN APHASIA

Distinction among levels of representation in sentence production One of the best known production models is that proposed by Garrett in several papers (1980,1982, 1984, 1992). According to this author, sentence production requires several independent stages, corresponding to independent levels of representation. At the message level, which is sensitive to linguistic and extralinguistic factors, a conceptual syntax constructs complex utterances starting from a basic (but not small) repertoire of easy concepts. At this level, the message to be conveyed is decided (for example, that a woman is putting a bag on a chair). The message-level representation controls the phrasal processes that lead to the next level of representation: the functional level. This second level is based on the conceptual relationships specified at the message level. At the functional level, the lexical representations that will be used to communicate the content of the message are selected; the predicate-argument structure is organised and the thematic roles are assigned to the different arguments of the verb. Lexical representations are defined at this level only by their semantic and syntactic features, and do not have phonological or orthographic content. At the next stage, the positional-level representation is constructed, that involves three different processes. The first process consists of the organisation of a phrasal structure that includes the syntactic features needed to specify free-standing and bound grammatical words. The second process consists of the selection of the phonological forms corresponding to the major-class lexical items specified at the functional level and of their placement in the slot assigned by phrasal structure. The third process consists of assigning a phonological value to all the grammatical morphemes specified in the phrasal structure. Therefore, the representation created at the positional level consists of a string of phonologically specified elements, and is used in the following stages of production. A fundamental aspect of Garrett’s theory is the hypothesis that words are divided in two classes (open-class words and closed-class words), which are processed by distinct mechanisms. Open-class

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words are processed both at the functional level (where the semantic information generated at the message level activates lexical representations defined by their syntactic and semantic properties) and at the positional level (where a phonological value is assigned to the lexical representations activated at the functional level). By contrast, closed-class words are processed only at the positional level, where a phonological value is assigned to each grammatical morpheme on the basis of the information contained in phrasal structure, which is also constructed at this level.

Damage to morphosyntactic mechanisms as the cause of disorders in the production of grammatical morphemes The procedural distinction between open-class and closed-class words allows one to predict that a positional level deficit should selectively disrupt the production of grammatical morphemes in sentence production, but not as isolated words. Moreover, as the positional level is involved only in production, a deficit at this level should not affect comprehension. Two aphasie subjects, whose neuropsychological profile is consistent with positional-level damage have been described by Caramazza and Hillis (1989) and by Nespoulous et al. (1988). Both subjects presented with normal comprehension, in the presence of a severe deficit in the production of grammatical morphemes in a phrasal context. Their spontaneous output (both oral and written) was characterised by frequent omissions (and by infrequent substitutions) of freestanding grammatical morphemes, and by the production of the citation form of the verb (infinitive and participle) instead of the correctly inflected form. A narrative collected from M.L. (Caramazza & Hillis, 1989) contained 173 obligatory contexts for free-standing grammatical morphemes, 79 for bound grammatical morphemes, and 207 for open-class words. M.L. demonstrated substantial difficulties in the production of free-standing grammatical morphemes (62.4% omissions and 2.3% substitutions in obligatory contexts) and of bound grammatical morphemes (“omissions” of 18.5% of total inflections—remember that this subject is an

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English speaker), but very few problems with openclass words (major-class lexical items were omitted in 3.8% obligatory contexts, and word substitution errors never occurred on these items). Similar results were observed in other sentence production tasks (writing to dictation, reading aloud, repetition, sentence anagram). By stark contrast with performance in sentence production, M.L. flawlessly read aloud, repeated, and wrote to dictation morphologically complex words when these were presented in isolation. The performance reported for Mr Clermont (Nespoulous et al., 1988) is very similar to that reported for M.L. Mr Clermont flawlessly read all the words presented in isolation, irrespective of grammatical class and morphological structure, but made many morphological errors (omissions and substitutions of grammatical words) when reading sentences. An anecdote on this patient’s reading behaviour nicely exemplifies his contrasting behaviour when reading words as opposed to sentences. In a covert sentence reading task, words were presented each on a different page, but their sequence constituted a sentence. Mr Clermont read the first few words correctly, but as soon as he realised that they formed a sentence, he started to make errors on grammatical words, just as when reading sentences. That the production of grammatical morphemes can be spared at the single-word level, but selectively disrupted at the sentence level, is consistent with damage to the morphosyntactic mechanisms that, according to Garrett (1980,1982, 1984), act at the positional level5, by inserting grammatical morphemes in the slots specified by the phrasal structure. Garrett’s model argues that the positional-level representation is specified phonologically, but does not clarify its role in the different production tasks. In particular, it does not specify whether the same positional-level representation is shared by all production tasks, or distinct, modality-specific positional-level representations exist for speaking and for spelling. The performance reported for M.L. and for Mr Clermont, characterised by similar errors on grammatical words in both oral and written production, is compatible with the hypothesis of a modality-independent representation, used for both speech and writing. Other

observations, however, are more consistent with the alternative hypothesis that distinct positional-level representations are used for oral and written production. For example, subject P.B.S. (Rapp & Caramazza, 1997) had disorders of both oral and written output, but when asked to describe the same picture in speech or in writing he presented with very different behaviours. In speech, grammatical words were produced accurately, whereas attempts at producing content words resulted in many neologisms; in writing, grammatical words were often omitted, whereas content words were produced correctly. For example, when describing the drawing of a boy washing a car, RB.S. said “the/wVd/are rVzd/ the /md^/ with flWd/ and /tVv/ in a /rodld/” and wrote BOY WASHED CAR immediately afterwards. A related behaviour was observed in Case 1 (Miceli et al., 1983), who presented with agrammatic speech and grammatically correct writing. The results reported for these four subjects suggest that a production deficit may selectively preserve grammatical words in an output modality, while selectively disrupting them in the other. This pattern can be explained only by assuming that in the course of sentence production distinct positional-level representations are realised for speech and for writing6.

Damage to lexical morphology as the cause of difficulty in producing grammatical morphemes The cases discussed so far demonstrate that a positional-level deficit may result in a difficulty in producing grammatical morphemes in sentences. However, as other components of the output system are also involved in processing these morphemes, errors may result from damage other than to morphosyntactic processes. For example, difficulty with grammatical words may result from damage to the lexical-semantic system. Such a deficit may cause grammatical production errors, because morphological structure is one of the dimensions along which the lexical-semantic system is organised. The hypothesis that morphological structure plays a central role in language organisation has been repeatedly proposed in linguistic and neuropsychological studies of single-word

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processing and of sentence production (e.g. Anderson, 1982; Aronoff, 1976; Bock, 1982; Garrett, 1984; Mohanan, 1985; Scalise, 1984; Selkirk, 1982; Taft, 1985). Relevant neuropsychological evidence for the role of morphology in lexical organisation was collected, among others, from subject F.S. (Miceli & Caramazza, 1988). Just like the subjects described by Nespoulous et al. (1988) and by Caramazza and Hillis (1989), F.S. presented with grammatical difficulties in spontaneous speech, as shown by the frequent occurrence of errors in the production of freestanding and bound grammatical morphemes. F.S. made errors on 102/242 obligatory contexts for free-standing grammatical markers (42.1%, of which 22.3% were omissions and 19.8% were substitutions), and on 70/275 (25.5%) obligatory contexts for bound grammatical morphemes (19/138 for article-noun agreement, 13.8 %; 11/55 for noun-adjective agreement, 20%; and, 45/82 for subject-verb agreement, 54.9%). However, in contrast with the other two subjects, he also made very many errors in the production of morphologically complex nouns, adjectives, and verbs (which in Italian are virtually always inflected and sometimes derived) presented in isolation. In repetition tasks, 636/659 incorrect word responses (96.5%) could be classified as inflectional errors (chiamava, he was calling —► chiamare, to call) and 23/659 (3.5%) as derivational errors (passando, passing —► passaggio, passage). The dissociation between inflectional and derivational errors was also observed when the occurrence of the two error types was separately analysed in the repetition of words containing only a root and an inflection (fior/, flowers; cattiv-e, bad, f.pl.; sentiv-a, he was hearing) and of words consisting of a root, one or more derivational suffixes, and an inflection (parlatore, speaker; dolorosi, painful, m.pl.; utilizzazioni; utilisations). Of 511 morphological errors made in repeating words consisting of root + inflection, 492 (96.3%) were inflectional, 5(1%) were derivational, and 14 (2.7%) were ambiguous — e.g. the response ballo to the stimulus ballava may be interpreted both as an inflectional error (iballo, 1st sg. present indicative form of the verb ballare, to dance) and as a derivational error (ballo,

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noun, the dance). Of 109 morphological errors produced in the repetition of stimuli containing one or more derivations, 90 (82.6%) were inflectional, 12 (11%) were derivational, and 7 (6.4%) were ambiguous. In F.S.’s incorrect responses, therefore, a categorical dissociation was observed: errors to stimuli that did not contain derivational affixes only resulted in inflectional errors; and only errors to stimuli that contained one or more derivational affixes resulted in some derivational errors (in addition to many inflectional errors, of course). The analysis of the inflectional errors in the repetition of adjectival forms unambiguously demonstrated a deficit of lexical morphology (Table 12.5). In repeating four-ending adjectives, the masculine singular form was repeated more accurately than any other form, and was most frequently produced in the event of an inflectional error; in the repetition of two-ending adjectives, the singular form was produced much more accurately than the plural. Moreover, with four-ending adjectives most inflectional errors resulted in the production of the masculine singular form, even for those adjectives in which the male singular form is the least frequent in the language. That F.S. produced a very high number of morphological errors in repeating words presented in isolation (that is, out of a phrasal context) shows that morphological processes take place in the lexicon, and that morphology is one of the dimensions of lexical-semantic organisation. The dissociation between inflectional processes (severely damaged) and derivational processes (largely spared) also suggests that the two types of morphological processes take place in separate components of the lexicon. This separation is supported by both theoretical and empirical observations. Regarding the first, the distinction between inflectional and derivational processes is an important part of some linguistic theories (for review, see Bybee, 1985; Scalise, 1984). Moreover, a procedural distinction between inflectional and derivational processes is explicit in some psycholinguistic models of production. For example, according to Garrett, the base form of a derived word is inserted in the phrasal structure at the functional level, based on semantic information (like any other open-class word), whereas its

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TABLE 12.5 Stimulus-response relationships of the inflectional errors produced by F.S. in repeating four-way ending and two-way ending adjectives (percentages are in parentheses). (a)

4-way ending adjectives R esponse

Stim ulus

m.sg.

m .pl.

fs g -

fp l.

Total

m.sg. m.pl. f.sg. f.pl.

149 40 43 34

(94.9) (52.6) (48.9) (61.8)

8 (5.1) 26(34.2) 1 (1-1) 2 (3.6)

5 (6.6) 35 (39.8) 5 (9.1)

5 (6.6) 9 (10.2) 14 (25.5)

157 76 88 55

Total

266 (70.7)

37 (9.8)

45 (12.0)

28

376

-

-

(7.4)

(b) 2-way ending adjectives Response Stim ulus

sg-

pi

Total

pi-

sg-

56 (81.2) 36 (65.5)

13 19

(18.8) (34.5)

69 55

Total

92 (74.2)

32

(25.8)

124

inflection is selected at the positional level, based on phrasal structure information. Further empirical support to the hypothesis of a processing distinction between derivations and inflections comes from available transcripts of agrammatic speech: subjects demonstrate marked difficulty with inflectional, but not with derivational morphology. For example, M.L. (Caramazza & Hillis, 1989), who presented with a morphosyntactic deficit (but not with a morpholexical deficit), made errors on 18.5% inflectional suffixes, but never on derivational suffixes7. The contrasting behaviour observed in F.S., Mr Clermont, and M.L. is worth stressing. While the last two subjects had problems with grammatical morphemes only in a phrasal context, F.S. made morphological errors both when producing isolated words and when producing sentences. Therefore, it is likely that a morphosyntactic deficit was responsible for the performance observed in Mr Clermont and in M.L., whereas a morpholexical deficit was responsible for at least part of the errors on grammatical morphemes observed in F.S. In the case of this last subject, it would be desirable to unequivocally assign each error on grammatical morphemes in sentence production to a

morphosyntactic or to a morpholexical deficit. If this were feasible, an analysis of F.S.’s morphological errors across tasks could lead to a better understanding of the relative contribution of lexical and syntactic mechanisms to the processing of inflectional morphology in sentence production. However, a clear-cut conclusion cannot be drawn, for the time being. As neither linguistic theory nor available computational models of sentence production are sufficiently detailed with respect to the role of morpholexical and morphosyntactic mechanisms in language output, the relevant analyses cannot be decided. These uncertainties notwithstanding, the performance of F.S. clarifies at least one relevant aspect of the language output system: inflectional morphology is represented in the lexicon, and the correct production of inflections implies the ability to access the lexicalsemantic system both from semantic-lexical information (in the production of isolated words) and from syntactic representations (in sentence production). This hypothesis allows one to account for inflectional errors in sentence production both as the result of a lexical deficit (as in F.S., at least partially) and as a result of a syntactic deficit (as in Mr Clermont and M.L.).

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The independence of morphosyntactic mechanisms from the mechanisms that assign thematic roles In sentence production, information processed at the message level is used to assign thematic roles (agent, theme, beneficiary, etc.) to the lexical representations selected on the basis of conceptual information. Subsequently, grammatical roles are assigned on the basis of thematic roles. For example, for the sentence The mother gives the doll to the girl, the roles of subject, and direct and indirect object are assigned to the agent noun (mother), to the theme noun (doll), and to the beneficiary noun (girl). Neuropsychological observations show that a cerebral lesion may selectively disrupt thematic role assignment, sparing the production of grammatical morphemes. In a picture description task that required the oral or written production of simple declarative, semantically reversible sentences in the active or passive form, subject E.B. (Caramazza & Miceli, 1991) produced only seven errors (0.02%) out of 3600 contexts that offered the opportunity for morphological errors (omissions and substitutions of grammatical morphemes), but inverted thematic roles in 40/240 (16.7%) sentences (to the picture of a dog chased by a horse he said The dog chases the horse; to that of a boy kissing a woman he responded The boy is kissed by the woman). It is worth stressing that grammatical morphemes were produced accurately in essentially all the sentences that contained thematic role reversals. The errors produced by E.B. are not easily interpreted. The assignment of thematic roles is the final result of complex cognitive operations, and may take place correctly even in the presence of a severe semantic deficit (Saffran & Schwartz, 1994). It involves semantic-lexical mechanisms (knowledge of the object-verb structure, in order to establish which thematic roles are assigned by each verb) and syntactic mechanisms (in order to map syntactic roles like subject, direct object, dative object onto thematic roles like agent, theme, beneficiary). As the mechanisms involved in these operations are very complex, errors of thematic role assignment may result from various impairments. In the case of semantic-lexical damage, if conceptual information about the verb is spared but

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the argument-verb structure is unavailable, the mechanisms subservient to thematic role assignment, even though unimpaired, may assign roles inappropriately. In the case of syntactic impairment, information on single words (including the argument-verb structure) may be spared, but damage to the mechanisms that assign thematic roles will result in thematic role reversal errors. Irrespective of the specific cause (semanticlexical or syntactic) of their disorder, E.B. and other subjects with similar performance (Caramazza & Bemdt, 1985; Martin & BlossomStach, 1986) suggest two kinds of considerations. Their deficit (difficulty in thematic role assignment, without noticeable problems in the production of grammatical morphemes) is complementary to that observed in subjects like Mr Clermont (Nespoulous etal., 1988), Case 1 (Miceli et al., 1983), and P.B.S. (Rapp & Caramazza, 1997), who present with difficulties in the production of grammatical morphemes, but not in the assignment of thematic roles. This double dissociation supports the notion that in sentence production, morphosyntactic mechanisms are independent of the mechanisms that assign thematic roles. In the light of these results, the frequent co-occurrence of errors on grammatical words and of incorrect thematic role assignment in the same subject (Byng, 1988; Caramazza & Hillis, 1989; Saffran et al., 1980) cannot be interpreted as the result of one and the same deficit, and is better accounted for by assuming cognitive lesions involving distinct components of the production process. Furthermore, even if it is not possible to unequivocally establish the origin of the errors, the very fact that at least two alternative hypotheses can be entertained to explain thematic role assignment disorders suggests the possibility that the apparently homogeneous group of subjects who make errors in assigning thematic roles also comprises aphasies with very different cognitive disorders. Recent neuropsychological studies have resulted in relevant progress of our understanding of the disorders that underlie agrammatic production. Nevertheless, many problems raised by available empirical observations are as yet

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unsolved. Reliable answers to these problems will depend on the development of detailed cognitive models of language production. To mention but one example, current models cannot account for the dissociation between free-standing and bound grammatical morphemes (e.g. Caramazza & Hillis, 1989; Miceli et al., 1989), nor among different types of morphemes within each subset of items (Miceli et al., 1989) that are frequently observed in the same agrammatic speaker. Neither can they account for the modality-specific occurrence of agrammatic output disorders (Rapp & Caramazza, 1997). Unfortunately, in the absence of sufficiently explicit theories of language production, the experimental analyses necessary to evaluate the theoretical relevance or the irrelevance of these observations simply cannot be identified. Despite contingent limitations, however, the continuous interplay between theories of normal language and theory-based, experimental analyses of aphasic language disorders promises to lead to more detailed hypotheses of representations and procedures involved in speech production.

GRAMMATICAL COMPREHENSION DEFICITS Many of the studies mentioned in this section were conducted on groups of subjects, and set out to propose a unitary account of agrammatic comprehension. Therefore, for the reasons discussed earlier, they are difficult to interpret. By relative contrast with production studies, investigations of the disorders of grammatical comprehension helped to describe some general features of the comprehension processes, but did not result in sufficiently explicit models. Thus, the neuropsychological observations that follow are not presented in order to propose a coherent interpretation based on a specific theory, but rather to draw the reader’s attention to issues that are potentially relevant for normal comprehension processes. Difficulties of comprehension of grammatical structures have been hypothesised to result from phonological short-term memory deficits (Shallice, 1988; Vallar & Baddeley, 1984). This hypothesis

is based on the assumption that sentence understanding requires the construction of a veridical phonological representation, which is maintained active by a working memory component. The phonological string stored in this short-term memory system is processed by the syntactic parser, in order to build the syntactic representation needed for the subsequent stages of comprehension. On this account, normal phonological memory is necessary to construct a complete syntactic representation. When shortterm phonological memory is damaged, the parser can only work on shorter-than-normal phonological strings, which may at times result in poor comprehension. This interpretation of agrammatic comprehension is controversial (for a collection of different viewpoints, see Shallice & Vallar, 1990). It was suggested not on the basis of explicit theoretical models, but based on the empirical observation that in early descriptions of subjects with agrammatic comprehension, poor understanding of sentences co-occurred with poor performance on verbal span tasks. Thus, it cannot be ruled out that other, non-phonological memory systems play a role in sentence comprehension (for example, it would not be unreasonable to hypothesise that the syntactic parser works on information that, although abstract, is not phonologically coded; and, that this information is stored in a non-phonological short-term memory system). As a matter of fact, Martin (1987) and Waters, Caplan, and Hildebrandt (1991) showed that subjects with severe disorders of phonological short-term memory (as shown by major deficits in span tests) demonstrate a surprising ability in understanding complex syntactic structures. This result does not support the hypothesis of a causal relationship between damage to phonological short-term memory and asyntactic comprehension. Consequently, if the assumption that asyntactic comprehension results from a memory deficit is to be maintained, it must be assumed that the damaged short-term memory system is not one that stores veridical, phonologically coded strings, but a memory system that stores abstract representations of some other type. If a difficulty in the comprehension of grammatical structures may indeed result from a

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memory disorder (phonological or otherwise), it is also obvious that asyntactic comprehension may derive from a true syntactic deficit. Goodglass, Blumstein, Gleason, Hyde, Green, and Statlender (1979) presented a group of agrammatic subjects with a comprehension task that included two sets of stimuli, similar in length, but different in grammatical complexity. The first set consisted of two coordinate clauses (The man is greeted by the wife and is smoking the pipe), the second of a main clause and a subordinate clause (The man greeted by the wife is smoking the pipe). Agrammatic subjects performed much more accurately on the first type of sentence than on the second. Among the studies that tried to account for agrammatic comprehension in terms of the consequence of a specific inability to process syntactic structures, those by Caplan and Hildebrandt (Caplan & Hildebrandt, 1988; Hildebrandt, Caplan, & Evans, 1987) and by Grodzinsky (1987,1990) are of great interest. These studies reflect a strictly linguistic approach to the study of grammatical comprehension deficits, based on the theory of government and binding (Chomsky, 1981). The assumption of these papers is that poor grammatical comprehension results from the inability to process traces, i.e. the elements of a sentence that are not phonologically realised, but are present in the deep structure of the sentence8. Also relevant to the understanding of mechanisms that may disrupt sentence comprehension are the observations reported on by Linebarger, Schwartz & Saffran (1983), who submitted subjects with grammatical comprehension deficits to grammaticality judgement tasks that included structurally complex sentences. Some of these subjects, who in a previous study (Schwartz et al., 1980) had demonstrated very poor understanding of simple active declarative sentences presented auditorially, were reliably (even though not flawlessly) able to judge if a much more complex sentence presented in the same modality was grammatically correct or incorrect. Similar results were obtained also when the stimulus sentences were presented after completely eliminating prosody (Bemdt, Salasoo, Mitchum, & Blumstein, 1988). These observations show that in subjects with agrammatic comprehension, very

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poor comprehension may be associated to spared ability to judge the grammaticality of a sentence. Linebarger et al. (1985) interpreted this dissociation as support for the hypothesis that agrammatic comprehension does not result from a syntactic deficit, but from a difficulty in mapping grammatical roles onto semantic roles (Schwartz et al., 1980). Contrasting performance on grammaticality judgement and on sentence comprehension tasks may be accounted for by assuming that knowledge of syntax, enough spared as to allow judgement of whether grammatical rules are correctly applied, cannot be used to construct a sentence representation sufficiently accurate for comprehension. In Linebarger’s study, the sentences that proved to be the most difficult for agrammatic subjects were those in which the violation involved two words that appeared at very distant positions in the sentence. For example, subjects found it very difficult to judge the grammaticality of tag questions, which contain a long-distance noun-pronoun agreement (The little boy fell down, didn’t he?). These results raise the possibility that agrammatic patients are unable to build a global syntactic representation of the sentence, even though they still manage to build local syntactic representations. Consistent with this hypothesis, Blumstein, Goodglass, Statlender, and Biber (1979) reported that agrammatic subjects understand pronominal reference better when the pronoun and its referent are near (The boy watched the chef bandage himself) than when they are distant (The boy watching the chef bandaged himself). Results consistent with this hypothesis were reported in subject D.E. by Tyler (Tyler, 1985, 1989; Tyler & Warren, 1987). Poor comprehension may also result from the inability to process information carried by grammatical morphemes. The reasons for poor comprehension in this case are quite obvious. Utterances like The horse is chased by the cow, or My cousins nephew can be understood correctly only if grammatical morphemes are adequately processed. Problems with grammatical morphemes in comprehension have been repeatedly observed in subjects with asyntactic comprehension (Bradley et al., 1980; Caramazza & Zurif, 1976; Goodenough et al., 1977; Heilman & Scholes,

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1976; Zurif et al., 1972), and can affect various grammatical morphemes to a very different extent. For example, the same preposition may or may not be used by the same subject in comprehension tasks, as a function of the role it plays in a sentence (Friederici, 1982, 1985). In these studies, subjects with agrammatic comprehension had fewer problems in processing prepositions that are semantically loaded (in the sentence The book is under the box, the relationship between book and box is entirely expressed by the preposition under) than in processing semantically “empty” prepositions (as the preposition on in The vase fell on the floor). The possibility that an impairment of the ability to process grammatical morphemes results in asyntactic comprehension receives support from the results obtained by subject D.E. (Tyler & Cobb, 1988). In a task that required the ability to process auditorily presented words, this subject performed normally with derived words, but demonstrated severe difficulties on inflected words (note that these results duplicate, in an auditory input processing task, the dissociation between inflectional and derivational morphology reported in production by Miceli & Caramazza, 1988). Further observations relevant to the interpretation of grammatical comprehension disorders were gathered from studies focused on the comprehension of reversible sentences. Schwartz et al. (1980) demonstrated that agrammatic subjects present with a severe difficulty in comprehending active and passive reversible sentences, and attributed it to the inability to map grammatical roles onto thematic roles. Poor grammatical comprehension associated to difficulties in assigning thematic roles has been reported on repeatedly (e.g. Byng, 1988; Caplan & Futter, 1986; Caramazza & Berndt, 1985; Caramazza & Miceli, 1991; Martin & Blossom-Stach, 1986; Martin, Wetzel, Blossom-Stach, & Feher, 1991; Mitchum, Haendiges, & Berndt, 1995; Weinrich, McCall, & Weber, 1995). Understanding a sentence like The man is kissing the woman requires that the thematic roles of agent and theme be assigned to man and woman, respectively, starting from the grammatical roles of subject and direct object. A difficulty in establishing this correspondence

(resulting in the incorrect assignment of the role of theme to woman, and of that of agent to man) may result in poor comprehension. Schwartz et al.’s hypothesis is supported by the observation that subjects with agrammatic comprehension perform normally on grammaticality judgement tasks, even though they make many errors in understanding reversible sentences (Berndt et al., 1988; Linebarger et al., 1983). Possible problems for the account proposed by Schwartz et al. come from the fact that their subjects, in addition to being poor at thematic role assignment, suffered from other disorders that might result in asyntactic comprehension. For example, they presented with difficulties on grammatical morphemes; therefore, poor comprehension in some of these subjects may have resulted from inaccurate processing of grammatical words, and not from problems with thematic roles (in The man is chased by the woman, grammatical morphemes signal the passive voice, and are instrumental in establishing that the first noun is the theme and not the agent of the sentence). However, this possibility can be safely ruled out in other cases. Subject E.B. (Caramazza & Miceli, 1991; see also subjects in Martin & Blossom-Stach, 1986) correctly used grammatical morphemes in all comprehension and production tasks, and performed normally on grammaticality judgement tasks, but he made many errors in the comprehension of reversible sentences. When asked to match an auditorially or visually presented sentence (The men are chasing the women) to one of two pictures, E.B. almost systematically selected the correct picture when it was paired with a morphological foil (e.g. men chasing a woman) or a semantic foil (e.g. men pushing women), but frequently selected the inappropriate picture (40% incorrect responses out of 240 stimuli) when it represented an inversion of thematic roles (e.g., women chasing men). In this subject, agrammatic comprehension could not be attributed to a disorder of phonological short-term memory (E.B. repeated all sentences correctly, even those to which he produced an incorrect response), nor to difficulties with grammatical morphemes (E.B. demonstrated normal comprehension of nominal, adjectival, and verbal inflections). Therefore, it is reasonable to

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assume that his errors resulted from difficulties in thematic role assignment. As already discussed (see previous section), the nature of E.B.’s errors is not unambiguous. The assignment of thematic roles during sentence comprehension requires the integrity of semanticlexical mechanisms (which establish the thematic roles assigned by the verb, such as agent, theme, beneficiary, goal, instrument, etc.) and syntactic mechanisms (which parse the sentence into its grammatical constituents, assigning the correct thematic role to each). Thus, the errors in sentence comprehension reported for E.B. might result both from a semantic-lexical deficit and from a syntactic deficit. The first account is based on the fact that lexical verbs are characterised both by conceptual information (to kill means to cause someone’s death), and by a predicate-argument structure, which specifies the thematic roles assigned by the verb (to kill assigns the roles of agent, theme, and instrument). Thus, E.B.’s errors might be explained by assuming selective damage to verbs as a grammatical class in the semantic-lexical system9. As E.B. shows normal preservation of both nouns and verbs in word-picture matching tasks, he may still be able to correctly process conceptual information on all the words in the sentence, taken one by one. However, damage to the predicate-argument structure might prevent the correct assignment of thematic roles, even if the mechanism that assigns thematic roles to grammatical constituents is spared, thus resulting in poor comprehension of reversible sentences. As an alternative, it might be assumed that the deficit in E.B. is syntactic, and involves the mechanisms that map grammatical roles onto thematic roles. In a sentence like The lion is killed by the tiger, these mechanisms assign the roles of agent and theme to the nouns that occupy the grammatical roles of subject and agent (lion and tiger, respectively). In this case, even though conceptual information about individual words is preserved, and the predicate-argument structure is unimpaired, asyntactic comprehension may result from a deficit of the syntactic mechanisms that assign thematic roles. A firm decision between these alternative interpretations is not possible. As already stated in the section on production disorders, the very fact

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that thematic role assignment errors in comprehension admit to more than one account strongly suggests the possibility that subjects who have difficulty assigning thematic roles in comprehension are cognitively heterogeneous. This short survey of grammatical comprehension disorders in aphasia helps to make at least one important (albeit controversial) point. Despite many efforts, a unitary characterisation of asyntactic comprehension cannot be proposed. Traditionally, disorders of grammatical comprehension were attributed to an impairment of grammatical morpheme processing. It is obvious at this point that such a deficit is only one of many possible causes of asyntactic comprehension. For several subjects, flawless ability to process the surface structure of a sentence, in the presence of asyntactic comprehension due to poor thematic role assignment, was reported. In these cases, poor performance in comprehension tasks may result from distinct cognitive lesions (damage to the semantic representation of the main verb, to the predicate-argument structure of the verb, or to the mechanisms assigning thematic roles). In addition, even if very debated, the possibility that asyntactic comprehension results from short-term memory deficits must also be considered. Even though current research still does not allow us to draw a coherent picture of grammatical disorders of comprehension, at the very least the studies briefly reviewed here make it clear that many problems will ultimately be solved only when more detailed theoretical models are available. A typical example of a yet unsolved problem, often raised in this area of research, concerns the relationship between grammatical deficits of production and of comprehension. Available reports clearly demonstrate that the co-occurrence of the two deficits in the same subject, although statistically very likely, is by no means necessary— some subjects only present with a comprehension deficit, others only with a production deficit, yet others with an impairment of both production and comprehension. In the presence of the repeatedly reported double dissociation between asyntactic production and comprehension, the interpretation of the frequent co-occurrence of the two disorders relies on the hypotheses one is willing to entertain on the mech-

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anisms involved in sentence comprehension and production. On the account that these mechanisms do not overlap at all, the co-occurrence of agrammatic speech and comprehension in the same subject results from damage to distinct mechanisms (one or more involved only in production, one or more involved only in comprehension). Alternatively, it might be assumed that some mechanisms are shared by comprehension and production, whereas others are dedicated to one or to the other process. On this account, the co-occurrence of disorders of grammatical comprehension and production might result from damage to one or more components shared by comprehension and production; from damage to independent components, some involved only in comprehension and some only in production; or from damage to some shared mechanisms and to some dedicated mechanisms. Obviously, only a model that explicitly specifies which mechanisms are involved only in production or only in comprehension, and which mechanisms are shared by both processes, will allow us to carry out the relevant experimental analyses and to correctly evaluate the alternative hypotheses10. Also in research on sentence comprehension, the combination of theoretical developments and of theorydriven experimental analyses is necessary in order to improve our understanding of the mechanisms underlying grammatical disorders.

ANATOMO-CLINICAL CORRELATES OF GRAMMATICAL DISORDERS In the first half of the twentieth century, detailed reports of the lesions in some agrammatic subjects were reported. Two patients studied by Bonhoeffer (1902) presented with agrammatism and motor aphasia following surgery “in the vicinity of Broca’s area”. According to Pick (1913), the frontal areas of the left hemisphere are most frequently damaged in subjects with agrammatism (and especially in subjects affected by the so-called pseudoagrammatism, usually found in association with motor aphasia) and damage to the left temporal structures is responsible for “true” agrammatism. Also Kleist (1934) stressed the role

played by damage to the foot of the third frontal circumvolution in the pathogenesis of agrammatic speech, and that played by the impairment of the temporal structures (in particular of Brodmann’s area 22) in agrammatic comprehension. More recently, noninvasive imaging techniques have allowed the extenson of the analysis of the anatomo-clinical correlates of agrammatism to large numbers of subjects. Some studies (e.g. Benson, 1967; Kertesz, Harlock, & Coates, 1979; Naeser & Hayward, 1978) demonstrated a correlation between Broca’s aphasia with agrammatism and lesions located in the foot of the third frontal circumvolution of the left hemisphere. These results duplicate the historical report published by Broca (1861), and are the not unexpected result of the clinical observation that agrammatism is frequently observed in the context of Broca’s (nonfluent) aphasia. However, other investigations failed to demonstrate such a close correspondence between agrammatism or agrammatic Broca’s aphasia and Broca’s area. In a study of 18 subjects, Mohr, Pessin, Finkelnstein, Funkenstein, Duncan, and Davis (1978) concluded that permanent Broca’s aphasia with agrammatism is observed only following lesions that involve, in addition to Broca’s area, postrolandic and perisylvian structures as well. From the analysis of two subjects, Levine and Mohr (1979) concluded that a lesion restricted to Broca’s area, even if bilateral, is not sufficient to result in Broca’s aphasia with agrammatism. More recently, Lecours, Basso, Moraschini, and Vanier (1985) showed that as many as 13/52 patients affected by completely prerolandic lesions involving Broca’s area (25%) did not present with a clinical Broca’s aphasia, and that 8/82 subjects affected by completely postrolandic lesions (9.8%) could be classified as having Broca’s aphasia. Also when agrammatism was considered perse, and not merely as a symptom of Broca’s aphasia, very heterogeneous anatomo-clinical correlates emerged. In an analysis of 26 subjects, classified as agrammatic solely on the basis of their speech disorder (i.e. irrespective of other symptoms of Broca’s aphasia), who were premorbidly speakers of different languages (Vanier & Caplan, 1990), the structure most frequently lesioned was not Broca’s area but the insula—a region that usually

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is not included among the structures involved in language processing. Another study (Miceli et al., 1989), that included subjects selected on the basis of the linguistic criteria proposed by Caplan (1986) failed to identify more reliable anatomo-clinical correlates of agrammatic speech. Of 18 subjects with focal lesions of the left hemisphere, verified by CT-scan, classified as agrammatic because they omitted grammatical morphemes in spontaneous speech, 3 (16.7%) suffered from an entirely postrolandic lesion. Thus, investigations dealing with the anatomoclinical correlates of agrammatic disorders have led to very heterogeneous results. From these studies, it emerges that in right-handed subjects the left hemisphere structures that receive blood from the middle cerebral artery play a crucial role in processing the grammatical aspects of language and that, among these, prerolandic areas seem to play a more relevant role than postrolandic structures. Nevertheless, precise correlations are not yet possible, and the available reports demonstrate that grammatical disorders occur in subjects affected by disparate lesions. These contrasting results are not surprising. A survey of the studies focused on the anatomo-clinical correlates of agrammatism reveals that the criteria used to group subjects were inconsistent or unreliable. In some cases, Broca’s aphasia (and not agrammatism) was the target category. In other cases, subjects were classified as agrammatic on the basis of features of their spontaneous speech (omissions of grammatical morphemes and production of sentences with a pathologically simple structure) that allegedly do not allow the selection of cognitively homogeneous subjects. If “agrammatism” does not denote damage to one and the same component of the cognitive system, but rather a heterogeneous group of symptoms, it is not surprising that the anatomo-clinical correlations obtained from the study of subjects presenting with these symptoms and classified on this basis as agrammatic are also diverse. More detailed correlations between the neural substrate and the cognitive mechanisms that control the processing of grammatical production and comprehension will be forthcoming when more explicit hypotheses on the cognitive/linguistic mechanisms involved in

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sentence comprehension and production allow subjects with agrammatic disorders to be studied in detail at the level of both the cognitive deficit and the cerebral lesion (Caramazza, 1987; Miceli, 1989).

CONCLUSIONS The recent metatheoretical, methodological, and theoretical developments of neuropsychological research have profoundly changed the approach to the study of the deficits observed in brain-damaged subjects. Analyses of the grammatical disorders of production and comprehension briefly considered in this chapter have also been influenced. As in all the areas of the neuropsychology of language, the study of grammatical deficits was initially based on clinical categories, on the implicit assumption that a limited number of intuitively predefined criteria would allow the identification of cognitively homogeneous subjects. Driven by these assumptions, researchers clinically classified subjects as agrammatic or paragrammatic, and tried to understand and analyse their deficits. However, studies based on these presuppositions led to contrasting conclusions: agrammatism has been considered as a selective production deficit, or as the deficit of a “central” component (involved in both comprehension and production); the cognitive lesion responsible for agrammatism has been located at the phonological, at the lexical-semantic, and at the syntactic level; agrammatic production has been considered as the direct consequence of a cognitive disorder, but sometimes also as the result of a compensation mechanism. As metatheoretical considerations and empirical data suggested that use of the clinical category agrammatism (and paragrammatism) results in the inclusion of very heterogeneous subjects in the same experimental group, various attempts were made to remedy this situation. It was proposed to keep using a priori categories, based not on clinical intuitions but on a linguistic theory, but this approach does not allow the identification of cognitively homogeneous subjects either—briefly stated, the study of grammatical deficits cannot be based on a priori categories (whatever the theory used to

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define these categories), but must rely on explicit hypotheses of the mechanisms responsible for the production and the comprehension of the grammatical aspects of language. The cognitive neuropsychological approach has already provided encouraging results, resulting from detailed analyses of the behaviour of individual aphasic subjects. It is reasonable to expect that this approach will improve our knowledge in the relevant areas of research, which include the mechanisms involved in language production and comprehension, knowledge of the relationships between these mechanisms and the anatomical substrate, the correct interpretation of language deficits in aphasia, and their rehabilitation.

ACKNOWLEDGEMENTS Preparation of this chapter was supported in part by grants from MURST and from CNR. This support is gratefully acknowledged.

NOTES 1. The two vocabulary classes have been given several other names, which stress various features that distinguish items belonging to the two groups. Major-class lexical items (nouns, adjectives, verbs) have also been called “content words”, to stress the fact that they convey most of the meaning of the sentence, and “open-class words”, to indicate that they are part of a vocabulary that allows the inclusion of new entries (consider terms like “Internet”, “fax”, etc.). Grammatical morphemes have also been called “function words”, because they specify the relationships among the content words that comprise a sentence and the role these play in the grammatical sentence structure, or “closed-class words”, because they form a subset of the vocabulary, to which new items are not added. This vocabulary class distinction reflects much more than a terminological detail. It results from the assumption, proposed by several authors (e.g. Bradley, Garrett & Zurif, 1980; Garrett, 1980), that there is a computational distinction between words belonging to the two classes; i.e. that words of the two

types are processed by distinct mechanisms. In the present chapter, the labels “major-class lexical items”, “content words” and “open-class items”, and the labels “grammatical morphemes”, “grammatical words”, “function words”, and “closed-class items” will be used as synonyms. 2. In the transcripts of agrammatic speech reported in this chapter, the following notations are used: substitutions of grammatical morphemes are underlined, and omissions of grammatical morphemes and of major-class lexical items are marked by square parentheses [ ]. Omitted items are reported in parentheses when the available narrative allows an unequivocal guess; otherwise, the omitted word is reported as [...]. Long pauses in the speech flow are indicated by ... A full stop indicates a short pause, or the end of an utterance (in this case, the following word starts with a capital letter). 3. Note that this is hardly surprising. As omission of grammatical words is the criterion for the clinical diagnosis of agrammatism, it is obvious that all agrammatic subjects will present with this deficit. 4. The study by Miceli et al. (1989) has been criticised by Bates, Applebaum, & Allard (1991) and by Grodzinsky (1991). Bates et al. objected that the reported differences across subjects can be fully accounted for by statistical variability, associated to the effect of other cognitive, linguistic, and neurological variables. On this account, the results reported by Miceli et al. could be explained by assuming random variation in a population of subjects in whom the cognitive system suffers from a high level of noise and/or a reduced processing capacity, which render the production of grammatical words particularly difficult (Bates et al., 1987). Because on this view across-subject variability results from variables independent from a grammatical deficit, agrammatism can be legitimately studied by using clinically identified groups of subjects (a similar position has been taken by Miyake, Carpenter, & Just, 1994). Grodzinsky (1991) objected that the results reported by Miceli et al. are not relevant because, however large, the quantitative differences observed in a group of subjects who suffer from a deficit that can be defined on a linguistic parameter do not license the conclusion that those subjects are heterogeneous. Therefore, agrammatism can be legitimately studied on the assumption that agrammatic speakers constitute a homogeneous group, and that across-subject variations are theoretically irrelevant, and as such can be legitimately neglected.

12. GRAMMATICAL DEFICITS ¡N APHASIA

In response to these objections, it should be stressed that Miceli et al. never argued that each and every discrepancy in grammatical morpheme production observed in their sample (either across or within subjects) results from theoretically relevant distinctions. They merely argued that, even when a linguistically defensible criterion is chosen, variability and dissociations across subjects are so evident as to make the idea that a p r io r i criteria (be they clinical or linguistic) allow one to identify cognitively homogeneous patients rather implausible. It is obvious that firm conclusions on the theoretical relevance (or irrelevance) of a particular dissociation cannot be based merely on an error distribution analysis (but again, that position was never taken by Miceli et al.); however, it is just as obvious that similar conclusions cannot be drawn on the basis of a statistical analysis (Bates et al., 1991) or of a linguistic hypothesis (Grodzinsky, 1991). Only investigations based on an explicit model of speech production will ultimately lead to motivated conclusions on the pathological mechanisms that result in agrammatic speech in each subject. 5. In addition, the dissociation that complements that observed in M.L. and in Mr Clermont (i.e. preservation of function words in the presence of damage to content words) has been reported several times, in at least two contexts. Subjects with the so-called “pure anomia” syndrome make normal use of grammatical morphemes in spontaneous speech, but demonstrate severe difficulty with open-class words (e.g, Kay & Ellis, 1987; Miceli, Giustolisi, & Caramazza, 1991). In addition, analyses of the spontaneous speech in neologistic jargonaphasia have repeatedly demonstrated the occurrence of pseudowords consisting of a neologistic root paired with a real suffix (e.g. Caplan, Kellar, & Locke, 1972; Semenza, Butterworth, Panzeri, & Ferreri, 1990). For example, spared agreement phenomena in the presence of damage to major-class lexical items were observed in the subject described by Caplan et al. (1972), who produced utterances like B ecause I ’m ju s t persessing to o n e ..., in which persess- is not a real root, but -in g is an inflection, used appropriately in the target sentence frame. These observations provide further support for the procedural distinction between closed-class and open-class words proposed by Garrett. 6. With reference to the problems discussed in the previous section, it seems unlikely that the four agrammatic subjects just described are affected by the same cognitive deficit, and that the observed discrepancy in performance can be accounted for by random

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(Bates et al., 1991) or theoretically irrelevant (Grodzinsky, 1990) across-subject variation. Subject M.L. and Mr Clermont present with agrammatic production both in speaking and in spelling; Case 1 in Miceli et al. (1983) shows agrammatic speech but not writing, and subject P.B.S. suffers from agrammatism in writing but not in speech. These contrasts are very difficult to interpret in the context of linguistic theories, which try to account for agrammatic output in terms of damage to a modality-independent level of representation, without considering the computational demands of each output task (e.g. Caplan, 1986; Grodzinsky, 1987, 1990, 1991). These theories cannot accommodate the observation that in the same subject production may be agrammatic in speech, but not in writing, or agrammatic in writing and neologistic in speech. Also theories that consider agrammatic output as the result of reduced capacity of the cognitive system or of noise (Bates et al., 1987, 1991; Miyake et al., 1994) have a hard time accounting for such diverse patterns of output disorders. Leaving aside that notions like “reduced capability” or “noise” have no explanatory value unless they are qualified in at least some detail, it is not clear how reduced capability or noise could selectively disrupt the ability to produce grammatical words in one modality while sparing the other (Case 1), or the ability to produce grammatical words in one modality, and that to produce content words in another (P.B.S.). Also theories that consider agrammatic production to be the result of an adaptive strategy (e.g. Kolk & Heeschen, 1990) can hardly explain these dissociations, as the same adaptive strategy would have to result in neologistic speech and in agrammatic writing. The dissociations reported in the subjects we have just discussed can be adequately interpreted only in the context of theories that include explicit hypotheses about computational demands, processes, and representations involved in each cognitive task. 7. The results reported for F. S. also speak to another relevant aspect of the organisation of the cognitive system. In particular, they converge with those obtained from Italian-speaking normal subjects (e.g. Burani & Caramazza, 1987; Caramazza, Laudanna, & Romani, 1987; Laudanna, Badecker, & Caramazza, 1992) and from other Italian-speaking aphasics (e.g. Job & Sartori, 1984; Caramazza, Miceli, Silveri, & Laudanna, 1985; Semenza, Butterworth, Panzeri, & Ferreri, 1990), in supporting the hypothesis that morphologically complex words are represented in the lexicon in a morphologically decomposed form. The

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hypothesis here is that roots (in Italian, items like do lo r-, sol-, gioc- for the words dolore; solo, giocare— pain, high, to play, respectively) and base forms (in Italian, items like d o lo ro s -, s o litu d in , g io c - for the words doloroso, solitudine, giocatore—painful, loneliness, player, respectively) are represented in a lexical component distinct from that in which inflections are represented. Contrary to this hypothesis, Taft has argued in several papers (e.g. 1985) that morphological decomposition plays a role during access to lexical representations, but that the latter are not themselves morphologically decomposed. For a more extensive discussion on the issue of the morphological organisation of the lexicon, the reader is referred to Chapter 11 in this handbook, where subjects who make morphological errors in strictly lexical tasks (e.g. Badecker & Caramazza, 1987; Badecker, Hillis, & Caramazza, 1991; Patterson, 1980) are discussed. 8. There is not enough room for an extensive discussion of Chomsky’s theory and of all the investigations it has inspired. Nonetheless, it is important to stress that, even though these studies are extremely stimulating, the same objections apply that were raised earlier to studies of asyntactic comprehension based on the analysis of subject groups and to investigations of agrammatism that have sought a unitary account of the disorder. It is entirely possible that in some subjects agrammatic comprehension results from a difficulty in processing traces (or from whatever deficit is appropriately described in linguistic terms). However, even if this turned out to be true in some

subjects, it cannot be argued from these observations that in all subjects with poor grammatical comprehension the deficit results from an impaired processing of traces. And in fact, the study of sentence comprehension abilities in F.M. (Badecker, Nathan, & Caramazza, 1991), E.B. (Caramazza & Miceli, 1991) and in the subjects studied by Martin et al. (1991) shows that poor grammatical comprehension may result from different disorders, and cannot be due (at least in these cases) to the deficit proposed by Grodzinsky (1991). 9. Selective disorders of verb comprehension have been already described (Miceli et al., 1988), and the possibility that these disorders cause difficulty in comprehending semantically reversible sentences has been demonstrated by McCarthy and Warrington (1985) in a subject whose deficit involves the conceptual representations of verbs. 10. This problem is exemplified by disorders of thematic role assignment. All the subjects who present with this disorder make errors both in comprehension and in production. When such errors are qualitatively and quantitatively comparable in comprehension and production tasks, in the oral and in the written modality, the simplest explanation is that they result from damage to a single, “central” component, shared by all the tasks administered to the subject. Nonetheless, such a conclusion is not justified, due to the lack of explicit hypotheses about modality-independent and modality-specific mechanisms involved in thematic role assignment (Caramazza & Miceli, 1991; Mitchum et al., 1995; Weinrich et al., 1995).

13 Disorders of Conceptual Thinking in Aphasia Luigi Amedeo Vignolo

ongoing debates about the inner structure of the semantic system and the category specificity in semantic loss (see Saffran & Schwartz, 1992, for an update on this problem). Several widely overlapping terms have been employed through the years to denote the impaired ability, and they are often used loosely as synonymous. Their different shades of meaning are briefly recalled here. Concept may be tentatively defined as a representation formed in the mind by generalising from particulars, and conceptual thinking as the process of performing the operations required to form and handle concepts. Abstraction is used here in two ways, first, as the process by which a concept is obtained, and second, as a general idea, considered apart from the particulars perceived by the senses. Abstract thinking is opposed to concrete thinking, while abstract attitude underlines the intentionality of the conceptual operation. Categorical (or “categoreal”) thinking belongs to the wider sphere of conceptual thinking, stressing, however, the classificatory activity. Finally, symbol is used here in its broadest meaning, including both one thing representing another and, improperly, an arbitrary

INTRODUCTION The neurological and neuropsychological literature of the past 150 years provides evidence that the language disturbances due to focal lesions of the brain are sometimes associated with disorders of conceptual thought. This fact is interesting as it can perhaps shed some light on the relationships between language, conceptual thinking, and the brain. The purpose of this chapter is to review both the older studies based on clinical observation alone and the subsequent ones based on the systematic administration of nonverbal standardised tests. The data discussed here are relevant to other areas of neuropsychology, such as the associative agnosias (see De Renzi, Chapter 16) and the semantic-lexical aspects of aphasia (see Semenza, Chapter 11). They may also be viewed in an historical perspective as the contribution of the lesion studies, from classical to contemporary aphasiology, to our knowledge of the semantic memory impairment following circumscribed cerebrovascular damage of the left hemisphere, although they provide no useful evidence for the 273

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sign such as a word. Symbols thus defined constitute an essential instrument of conceptual thinking. It is important to stress that all such terms designate only some aspects of the broader notions of “general intelligence” and “cognition”, and, in particular, they do not include the purely spatial organisational abilities. Among the reviews of disorders of general intelligence and cognition in aphasia are the earlier works of Isserlin (1936), Weisenburg and McBride (1935), Ombredane (1951), and Ajuriaguerra and Hecaen (1959), and the more recent studies by Hamsher (1981) and Gainotti (1988). The present review, like a previous one (Vignolo, 1989), focuses on the nonverbal, nonspatial conceptual impairment in post-stroke aphasia.

HISTORY Early clinical observations As early as 1869 the pioneer Broca recognised some sort of intellectual defect in aphasia, and since the late nineteenth century a number of clinicians have studied it. The evidence used in these studies, based as it was mostly on either one or a few case-reports and heavily loaded with theoretical assumptions, was of questionable worth, and only a few examples need to be mentioned here. Trousseau (1864,1865) stressed the fact that reading, writing, and sometimes the imitation of gestures were as impaired as oral expression, and on this fragile basis he argued that aphasic patients suffer from a partial, but significant, loss of intelligence. Finkelnburg (1870) noticing an inability to recognise pantomimed actions and various conventional symbols (such as coins and military signs of rank) in aphasics, suggested the comprehensive concept of “asymbolia” i.e. impairment of the symbolic function, to encompass both these nonverbal disorders and those of oral and written language. On the basis of two post-mortem cases, he indicated that the lesion was in the left insula and neighbouring temporal and parietal lobes. Jackson (1878) is credited with being the first in the English literature to suggest that aphasia involves an intellectual

element. He observed that pantomime may be impaired and stated that aphasics are “lame in thinking”, in as much as “speech is a part of thought” and that they often suffer from a “loss or defect in symbolizing relations of things in any way”. These now oft-quoted statements were virtually ignored until Head revived Jackson’s work in 1915 and developed it in his comprehensive book of 1926. Head observed that patients were often unable to carry out a number of partially nonverbal tasks, such as pointing to their eye and ear both on command and on imitation, setting the hands of a clock, performing simple arithmetical calculations, assessing the comparative value of coins, and executing what would now be called “constructional” tasks. He concluded that aphasia is a defect of “symbolic formulation and expression”, which to some extent transcends the linguistic sphere— a definition that enjoyed great success until the mid 1960s, especially among Anglo-saxon researchers. The Continental counterparts of the Jackson-Head line of thought were Marie’s views in France and Goldstein’s and Bay’s in Germany. Marie (1906, 1926), based on his clinical observation of about 100 cases, undertook in 1906 an epoch-making “revision of the question of aphasia”, and he emphatically concluded that “true aphasia” is an intellectual impairment. By “true” aphasia he meant Wernicke’s aphasia (including, in a unified way, all forms that are nowadays subsumed under the heading of “fluent” aphasia), while Broca’s aphasia (corresponding to all “nonfluent aphasia” forms, including global aphasia) also had an essential intellectual element in it, being merely a combination of “true aphasia” and an articulatory defect (“anarthria”). Marie maintained that the intellectual impairment of aphasics, unlike that of demented patients, is confined to “didactically acquired procedures”. It is both general (affecting the association of ideas, memory, professional knowledge, and conventional and descriptive mimicry) and specific to language (affecting the comprehension of oral and written language, reading, and writing). A well known example of what Marie regarded as an intellectual deficit is

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the description of the striking errors made by an aphasic patient, a cook by profession, in the simple tasks of frying an egg—a grossly defective behaviour which would now be diagnosed as a severe ideational apraxia. The idea that the aphasic’s disorder of thinking may reflect a specific conceptual impairment did not arise until the work of Goldstein, whose often intricate arguments leading to this conclusion are found in a number of papers spanning several decades (e.g. Goldstein, 1919, 1927, 1942, 1948). This author’s distinction between a concrete and abstract (categorical, conceptual) attitude is central to our topic, and it is clearly stated in his book of 1942 (p.89): We can distinguish normally two different kinds of attitudes toward the world: a concrete and an abstract one. In the concrete attitude we are given over and bound to the immediate experience of a given thing or situation in its uniqueness. Our thinking and acting are directed by the immediate claims that one particular aspect of the object or situation in the environment makes. [...] We respond unreflectively to these claims. In the abstract attitude we transcend the immediately given, or sense impression; we abstract from particular properties. We are oriented in our actions by a conceptual point of view, be it the conception of a category, a class, or a general meaning under which the particular object before us falls. Our actions are determined not so much by the objects before us as by what we think about them. We detach ourselves from the immediate impression, and the individual thing becomes an accidental example or representative of a category. Therefore, we also call this attitude the categorical or conceptual attitude. According to Goldstein, the loss of abstract attitude is not only an accompaniment but a basic ingredient of aphasia, which entails (a) language disruption, particularly in amnesic aphasia (Goldstein, 1924), and (b) inability to perform nonverbal tasks requiring the patient to pick out (in

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Gestalt terms) the essential in a field, to hold the figure clearly against the ground and, if necessary, to shift intentionally from a concept-directed classification to another (Goldstein & Scheerer, 1941). Two such tasks are, for example, Weigl’s (1927) Colour-Form Sorting Test, in which the patient classifies different cuts of wood according to colour and form, and Gottschaldt’s (1926, 1929) Hidden Figures Test, which evaluates the ability to disengage a geometrical figure from a distracting background which has been constructed using known field factors to produce maximal concealment. Bay’s theory (1962, 1963, 1964, 1974) incorporated both Marie’s view of the true aphasia and Goldstein’s contention of the primary role played by categorical impairment in the disruption of language. He stressed that the intellectual defect in aphasia can be traced back to a specific disorder of “concept formation” and actualisation. As nonverbal evidence of such a disorder, he described the remarkable errors made by some aphasics when requested to shape a plastic substance into threedimensional models of common animals or objects. For example, when asked to reproduce a giraffe, a patient modelled an animal with a short neck but a very long tail, thereby showing that he was unable to form the exact concept of the giraffe, although he still had a vague idea that a salient feature of this animal was a long body part attached at one extremity of the trunk. Likewise, a tea-cup became, in the patient’s reproduction, a much wider and flatter container, endowed, however, with a handle. Unfortunately, Bay provided no norms for such tasks, nor did he rule out the possibility that his patient’s errors were due to constructional apraxia — a disorder that cannot be considered a good marker of defective “concept formation”. The same criticism applies to similar tasks, such as spontaneous drawing and drawing to command. Most of these authors not only believed that aphasia entails an intellectual defect, they further maintained that the language disorder is merely one component of a more comprehensive and basic cognitive disorder of thinking. The opposite view was upheld by other workers, such as Wernicke (1874), Kleist (1934),

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Ajuriaguerra and Hecaen (1959), and Geschwind (1974) among others, all of whom minimised the importance of the cognitive impairment and maintained that disruption of the language mechanisms is an independent disorder. Wernicke, for example (1874, p.33), though well aware that aphasics did in fact sometimes show some intellectual deficits, explicitly warned that “nothing could be worse for the study of aphasia than to consider the intellectual disturbance associated with aphasia as an essential part of the disease picture”. This lengthy controversy, sometimes referred to, in the French literature, as the “noeticians vs. antinoeticians” debate, was inconclusive and indeed, as Benton (1985) rightly observed, proved to be “a rather fruitless exercise”. Nevertheless, it is both interesting and relevant for the present state of knowledge, because it contains some issues that are revived in more cautious terms in current hypotheses about the role of the conceptual impairment in aphasia.

First experimental studies 1930-1960 The main drawbacks of the research reviewed so far were the lack of a clear differentiation between verbal and nonverbal performances, the undue generalisation from single cases, and the absence of normative values for the tests employed to assess cognitive impairment. Substantial progress in this respect was made by Weisenburg and McBride (1935), who were the first to administer a standard battery, including nonverbal as well as verbal tasks, to representative samples of aphasics, nonaphasic brain-damaged patients, and “normal” controls. They found that not only the verbal but also the nonverbal tests were performed more poorly by aphasics as a group than by the controls. Unfortunately their nonverbal battery included form-boards, mosaics, picture completion, and drawing tests, which involved first and foremost a visual constructional element, and this is spatial rather than conceptual in nature. As Zangwill (1964) rightly observed, estimates of intelligence in aphasic patients should be based on performance tests only ¿/constructional apraxia has been satisfactorily excluded—which does not apply to Weisenburg and McBride’s study.

Further experimental research was carried out by Teuber and Weinstein (1956), who, setting out to investigate perceptual selectivity in brain-damaged patients, did in fact contribute to our knowledge of the abstraction deficit in aphasics. They gave Gottschaldt’s Hidden Figures Test to controls and brain-damaged patients who had suffered penetrating missile wounds about 10 years before the testing. Brain-damaged patients were found to perform consistently worse than controls. Within the brain-damaged sample, aphasics as a group, irrespective of presence or absence of visual field defects and/or somatosensory symptoms, were significantly more defective than the other patients. This difference also persisted when the influence of “general intelligence” (expressed by the Army General Classification Test score) on Gottschaldt’s scores was ruled out by covariance. These findings led Teuber and Weinstein to conclude that the disorder disclosed by Gottschaldt’s test was intellectual rather than sensory-specific in nature, but could not be identified sic et simpliciter with general intellectual deterioration: it was rather, a disorder of abstraction, conceived in its original meaning of mentally “isolating from” (abstraite re). Dissenting evidence came from the work of Meyers (1948) and Bauer and Beck (1954), who found no significant inferiority in aphasics as compared to controls. Zangwill (1964), stressing the importance of these negative contributions, added quasi-anecdotal evidence of his own that pointed to the poor correspondence between severity of aphasia and number of errors in the Progressive Matrices Test (Raven, 1962) and concluded by taking a sceptical stand on the alleged cooccurrence of abstract thinking impairment and aphasia. It should be noted, however, that the Progressive Matrices were subsequently shown to be performed significantly worse by aphasics (although not selectively so) in carefully controlled experimental studies (see review in Gainotti, 1986). The intrinsic difficulty of the topic, the too often contrasting results, and the admixture of empirical evidence with theoretical dogmas brought about a certain disaffection for the problem (cf. Zangwill, 1969,1975).

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REVIVAL OF RESEARCH IN THE 1960s Nonverbal association tasks Indirect (and unexpected) evidence of a nonverbal conceptual disorder in aphasia came from a number of quantitative studies in the 1960s and early 1970s, most of which were originally aimed at investigating the possible concomitance of aphasia and the hemispheric side of the lesion with the classical agnosias, i.e. the nonverbal recognition defects. The mechanism of the agnosias, like that of the apraxias, is an obscure problem in clinical neurology, and it is not surprising, therefore, that this line of research was started off experimentally by the Milan group of neuropsychology, which at the time was entirely made up of neurologists. Nonverbal recognition in various modalities (such as audition and vision of different types of stimulus) was assessed by means of ad hoc quantitative tests, administered to large unselected samples of right-handed patients, either without cerebral lesions (“controls”) or with stabilised lesions confined to one hemisphere. The latter were further subdivided according to presence/absence of aphasia, as assessed by standard language batteries, and often also by the presence/absence of a visual field defect (VFD), which was considered evidence of postrolandic extensions of the lesion. Auditory verbal comprehension scores were usually chosen as a measure of the severity of language disruption in the broader sense, as oral expression measures could be biased by concomitant articulatory difficulties. The control group scores were used to establish norms, i.e. to determine to what extent the imperfect performance of any given hemisphere-damaged patient could still be considered to fall within normal limits, or had to be defined as “abnormal”. In spite of variations in recognition modality, test construction, and scoring criteria, the common and crucial aspect of such nonverbal tasks is that they involved the association or matching of meaningful items (e.g. braying noise with donkey, red colour with cherry, etc.). Results were often compared with those of another type of tasks, entailing the perceptual discrimination of meaningless items (e.g. nondescript noises, different shades of the same colour etc.). It was

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observed from the beginning of these studies that the association tasks were selectively impaired in aphasics, even in the presence of good perceptual discrimination, and this led to the hypothesis that failure on these tasks betrayed a “high-level” disorder of recognition of meaning rather than of formal differentiation of perceptual characteristics. This possibility fuelled new interest in the problem of conceptual impairment in aphasia. The main pertinent studies will be discussed in some detail. Sound-to-picture association In an investigation of auditory agnosia, Spinnler and Vignolo (1966) examined three samples of patients with unilateral hemispheric damage (aphasic, nonaphasic left-brain-damaged, right-braindamaged, and “normal” controls) by means of a sound-recognition test requiring the identification of meaningful sounds or noises. The subjects were asked to indicate which of four pictures shown to them represented the natural source of the sound they had just heard. The picture corresponding to a given sound (e.g. the song of a canary) represented respectively (1) the correct natural source of the song (e.g. a canary singing); (2) the natural source of a sound acoustically very similar to the presented sound (e.g. a boy whistling); (3) a sound-producing event or object belonging to the same semantic category of the natural source of the presented sound, but producing a sound completely different from the presented one from an acoustic standpoint (e.g. a cock crowing); and (4) a sound-producing event or object unrelated to the presented sound either acoustically or semantically (e.g. a train in motion). Thus, three types of error were possible; acoustic errors, when the patient pointed to picture 2; semantic errors when he or she pointed to picture 3; odd errors, when he or she pointed to picture 4. About one fourth of aphasics (26%) fell below the normal cut-off score, while left nonaphasic and right brain-damaged patients performed virtually the same as normal controls. Moreover, aphasics made significantly more semantic than acoustic errors, while the reverse trend occurred in the remaining groups. These results were confirmed by Faglioni et al. (1969), employing two ad hoc tests,

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one similar to that used in the preceding study and intended to test the ability to identify the exact meaning of sounds, and the other intended to test the ability to accurately discriminate the acoustic patterns of sounds: the patients heard two successive nondescript noises and had to say whether they were the same or different. Aphasics, while specifically failing on the first test, were unimpaired on the second, which, by contrast, was particularly vulnerable to lesions of the right hemisphere. This double dissociation was later confirmed by Vignolo (1982), who checked the hemispheric side of the lesion by means of a CT scan, while Varney and Damasio (1986) showed that the associative defect may be concomitant with several lesion sites within the left hemisphere. The aphasics’ inability to match meaningful sounds and noises with their meaning is now well established (see also Doehringetal., 1967; Strohneretal., 1978; Varney, 1980, 1982a). The percentage of aphasics selectively impaired varies according to the testing techniques and experimental design from 26% (Spinnler & Vignolo, 1966) to 45% (Faglioni et al., 1969; Varney, 1980) and 43% (Varney, 1982a). On the whole, global and Wernicke’s aphasia patients do worse than the other aphasics. All these findings are rather consistent and show that the impaired sound recognition, which is found in aphasics, is due mainly to the inability to associate the perceived sound with its correct meaning, rather than to a defect of acoustic discrimination. Colour-to-picture association In a study of colour agnosia, De Renzi and Spinnler (1967) found that aphasics, in contrast with other groups of brain-damaged patients and controls, were specifically impaired on a test requiring the subject to choose the typical colour of a given object. The patient was given a set of coloured pencils and a sheet of paper with a number of black-and-white line drawings of common objects having a typical colour (such as a banana, a cherry, a cigar, etc.) and was asked to colour each drawing with a few strokes, choosing the appropriate pencil. On the other hand, Scotti and Spinnler (1970) found that aphasics had no difficulty in carrying out

tasks such as Farnsworth’s (1943) 100 Hues Test, requiring subtle chromatic perception and discrimination. Failure on this test was specific for the right brain-damaged patients with posterior lesions. These data were confirmed by De Renzi et al. (1972a), who concluded that the aphasics’ poor performance in the colour-to-picture tasks may be, at least in part, contingent upon a more general disorder of cognition, associated with, but not directly dependent on, the language derangement. This defect, which, whenever reported, was found in about one-third of the aphasic samples under study, has been confirmed by a number of investigations (Assal & Buttet, 1976; Basso et al., 1976, 1985; Cohen & Kelter, 1979; Varney, 1982b). It should be also noted, however, that colour-to-picture impairment in the absence of a major aphasic syndrome (though associated with colour anomia and alexia) has been described in single case reports by Stengel (1948), Kinsboume and Warrington (1964), and Varney and Digre (1983). Object-to-picture association A study of visual agnosia, carried out by De Renzi et al. (1969), showed that aphasics, in contrast to other samples of brain-damaged patients and controls, were selectively impaired in tasks requiring the subject to match a picture with the corresponding object. The test was so designed that the picture was not an exact copy of the corresponding real object, but belonged to a different type of the same category. For example, the real key was a small, flat, whitemetal car key, while the pictured one was a big, thick, black iron, old-fashioned gate key. As a consequence, a correct matching could rely very little (or, most often, not at all) on the mere perceptual features of the two items, while it implied a categorisation of the matched objects, leading to the awareness that both the real and the depicted object were subsumed under the same concept, e.g. the concept “key”. The poor performances of aphasics in this associative test (later confirmed by Della Sala, 1987) contrasted with their good performance on perceptual tasks such as the Overlapping

13.

Figures Test (Poppelreuter, 1917) and a Face Recognition Test, which were specifically vulnerable in patients with right posterior hemispheric lesions. Object-to-gesture and gesture-to-picture association In a study of so-called “agnosia of use” (Morlaas, 1928) or “apraxia of use”, which belongs to the wider category of ideational apraxia (De Renzi et al., 1968), the patient was given, successively, a number of objects frequently employed in everyday life, such as a hammer, and was asked to take the object into his or her hands and show how he or she would use it. This simple task was performed well by all experimental groups, except 34% of aphasics, and the deficit tended to be both more frequent and more conspicuous in global (80%) and severe Wernicke’s aphasia (50% affected). Comparison with the scores obtained on a parallel test of imitation of gestures ruled out the possibility that the poor performances were due to ideomotor apraxia, and indicated that the low scores resulted from inability to choose the gesture normally associated with the appropriate use o f the object. Here again, the basic disturbance of aphasic patients was associative rather than psychomotor, and it could be tentatively described as the failure to synthesise two different aspects of the same concept —a definition reminiscent of Bay’s (1964) view of impaired concept formation. Conversely, when gestures were demonstrated for the patients, rather than requested of them, the results were quite similar. The association of seen gestures with the correct picture presented in a multiple-choice array was significantly impaired in aphasics, from 41% (Varney, 1982a) to 62% (Gainotti & Lemmo, 1976) of the examined sample, but not in nonaphasic brain-damaged patients (see also Duffy & Duffy, 1981; Duffy & Watkins, 1984; Daniloff et al., 1982 and reviews by Peterson & Kirshner, 1981, and by Christopoulou & Bonvillian, 1985). When the type of mismatch was specifically investigated (Varney & Benton, 1982), semantic errors were found to be predominant, representing 80-100% of the total errors of aphasics, parallel to what had been observed with the identification of meaningful sounds.

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Tactile object-to-object association It is appropriate to insert here the results of research carried out several years later, in order to verify the possibility of isolating an associativesemantic aspect of recognition, as distinct from an apperceptual-discriminative one, even in the field of somesthetic (tactile) recognition. Bottini et al. (1995) gave two somesthetic tests to groups of aphasic, left hemisphere-damaged nonaphasic, right hemisphere-damaged and control patients. In the first test the patient had to tactually explore, with the hand ipsilateral to the lesion and blindfolded, a small stimulus object (e.g. a ring) and identify it tactually among four foils. These consisted, for example, of a ring of a different type from that of the stimulus ring (correct response), an earring, a brooch (semantic responses), and a rubber band (unrelated response). In the second test, which was identical to the first as far as structure and procedure were concerned, small three dimensional meaningless shapes were used, and the patient had to tactually discriminate among them. The aphasic group significantly failed on the first (associative or semantic) task, but not on the second (apperceptual or discriminative); performance on the latter was specifically impaired in right braindamaged patients. When individual patients with a severe deficit strictly confined to one test were singled out, it was found that all the three patients specifically impaired on the associative test were left brain-damaged (and one of them was aphasic), while all the three patients specifically impaired on the apperceptual test were right brain-damaged. This double dissociation confirmed the results of a preceding study of tactile-visual matching (Bottini et al., 1991) and extended to the purely haptic recognition the notion of a semantic-conceptual disorder, linked to left hemisphere damage and, to a certain extent, to aphasia. This evidence clearly indicates a preferential concomitance of aphasia in general with failure on nonverbal association tasks. This constitutes the socalled associative-semantic level of agnosia (consisting of faulty identification of the meaning of percepts), as opposed to the purely perceptualdiscriminative level (consisting of impaired

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discrimination of the form of percepts) (Vignolo, 1972). This isolation of the semantic-conceptual level of the nonverbal recognition disorder can be traced back to earlier theories. Finkelnburg’s (1870) view that defective pantomime recognition reflected a higher, symbolic disorder has already been mentioned. Lissauer (1890) isolated an “associative” form of visual object agnosia, to be distinguished from an “apperceptual” form. Lewandowski (1907) described a specific inability to connect the appropriate colour with the corresponding line drawings. Kleist (1928) discussed agnosia for nonverbal noises by contrasting the “deafness for the meaning of noises” (Gerauschsinntaubheit) with other types of deafness, such as that for isolated sounds or noises (perceptive Gerauschtaubheit) and for sequences of noises (Gerauschfolgetaubheit) The experimental findings reviewed so far add to the theoretical autonomy of these “higher-level” nonverbal disorders the important qualification that they are specifically associated with lefthemisphere lesions and aphasia. Why should these matching defects be considered conceptual in nature? The main argument is that, in spite of their seeming differences, they all require basically similar conceptual operations, as they all essentially test the ability to grasp and handle the meaning of the presented stimuli. To correctly match stimuli that are perceptually very different, such as a miaowing sound and the picture of a cat, a blue pencil and a line drawing of waves, a realistic picture of a big, old-fashioned black iron key and a small, whitemetal flat car key, etc., one must realise that the members of each pair signify the same thing. In other words, one must recognise them, beyond the appearances, as representative of the same concept and thus associate them. Likewise, as the gesture of hammering is a constituent element of the concept of hammer (as are the object itself, its typical shape, the sound of the blows, etc.), it is difficult not to see in the so-called “apraxia of use” still another instance of the same conceptual disorder. This analogy also applies to the whole series of tasks requiring gesture-to-figure matching, investigated on the receptive rather than the expressive side. Therefore, it is not surprising that even pantomime

recognition, like all association tasks, is specifically impaired in aphasic patients.

Weigl’s test The conceptual disorder revealed by the failure of a sizeable proportion of aphasic patients on nonverbal association tasks can be examined more directly by means of a classic test of categoreal thinking, such as the Colour-Form Sorting Test, devised by Weigl in 1927 and included in Goldstein’s battery (Goldstein, 1948). In the modified version adopted by De Renzi et al. (1966) the patient was given 12 pieces of wood which, although all different from one another, could be sorted according to five discrete categories, i.e. colour, form, suit (symbol), thickness, and size. The patient was then asked to group them by putting together all the blocks that had “something in common”. The ability to sort out, one at a time, each single feature of the blocks (e.g. form), leaving aside the other features implied an ability akin to that involved in the matching tests, as, in order to sort and group together all round blocks, for example, it is necessary to realise that they all belong to the same concept, the concept of circle. Results indicated that impairment on Weigl’s test is specifically associated with lesions that also produce aphasia, and not merely with lesions anywhere in the left hemisphere, as maintained by McFie and Piercy (1952). In addition, they failed to establish a poorer performance by amnesic aphasics (contrary to Goldstein, 1924), probably because the authors chose only patients with very pure, hence rather mild, amnesic aphasia. Not all nonverbal tasks proposed by Goldstein (1948) as specific tests of abstract thinking proved to be equally adequate to the intended purpose, probably because they also involve nonconceptual abilities. This is the case with Holmgren’s (1877) Skein Test and Gottschaldt’s (1926, 1929) Hidden Figures Test, among others. The former requires primarily the capacity to perform subtle perceptual discriminations (as pointed out by De Renzi et al., 1972b) while the latter is heavily loaded with a visuospatial component (as stressed by Russo & Vignolo, 1967). Finally, mention should be made of the studies performed on hemisphere-damaged patients (but

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not specifically on aphasics) with the Wisconsin Card Sorting Test (WCST), a “Weigl-type test” developed in 1948 by Grant and Berg. This test assesses not only abstract reasoning but several other cognitive abilities as well, such as working memory and the ability to shift conceptual sets according to changing feed-back. Therefore, the evidence gathered with the WCST lesion studies and pointing mainly to frontal lobe damage, with a dubious prevalence of the left hemisphere (see Mountain & Snow, 1993, for a recent review), adds little to the present discussion. In summary, the isolation of the associative or semantic level of agnosia alerted the investigators to the possibility of a nonverbal conceptual impairment in aphasia, and this hypothesis was confirmed by the use of Weigl’s Test. Whenever other intellectual tests, implying subtle perceptual discrimination or visuospatial analysis, were employed, right-brain-damaged patients also performed poorly.

TENTATIVE HYPOTHESES AND RECENT RESEARCH The evidence reviewed so far indicates that disorders of nonverbal conceptual thinking were more severe and more frequent in aphasics, as a group, than in left and right nonaphasic braindamaged patients and controls. However, closer scrutiny of the findings pointed to the need for further clarification of two problems, i.e. (a) the unity or multiplicity of the nonverbal conceptual impairment, and (b) its relationship to the language defect. Are we dealing here with one single basic Grundstôrungl This is the more economical

interpretation of the data, but it requires that the performances of aphasics as a group on these tasks should correlate with one another to a highly significant degree. This, however, is not the case. Vignolo (1972) computed the correlations between sound-to-picture, colour-to-picture, and object-topicture matching in 99 focal brain-damaged patients who had been administered the three tests together, and found that, while correlations were indeed significant only among the 57 left brain-damaged patients (virtually all of whom were aphasics), the degree of such correlations was not sufficiently high to point to one single underlying disorder (see Table 13.1). The unitary nature of the conceptual impairment was also questioned by Varney (1982a) who failed to find a close correlation between sound-to-picture and gesture-to-picture matching. Inquiry into the relationship of the nonverbal conceptual defect and the language disorder immediately meets with a perplexing finding: conceptual thinking was impaired only in a fraction of the aphasic groups, ranging approximately from one-third to two-thirds, according to different samplings, tasks, and experimental designs. Some severe aphasics did not show the defect, which, in contrast, was occasionally present, though to a less severe degree, in a few left-brain-damaged patients without aphasia. Moreover, the attempt to quantify the correlation is hampered by the difficulty in finding an adequate behavioural parameter of the severity of aphasia. As previously mentioned, auditory verbal comprehension scores were chosen as the least inadequate measure of the overall degree of language impairment, as in all aphasics except the so-called “word-deaf’ this modality is relatively independent of the lower-level sensorimotor mechanisms involved in communication. The correlations between the conceptual defect and comprehension of words and sentences were not as

TABLE 13.1 Correlation among matching tasks in 57 aphasic patients.

Sound to picture Colour to picture

C o lo u r to p ic tu re

P ic tu re to o b ject

0.48 PcO.OOl -

0.36 Pmammillo-thalamic tract—►anterior thalamus—►cingulate gyrus (Fig. 15.6). According to Papez’s original view, this circuit was concerned with emotion, rather than with memory. The afferent and efferent connections of the medial temporal region, shown in Fig. 15.7, are more complex, however. The present chapter takes into consideration data from human amnesia (reviews of animal studies may be found in Aggleton & Sahgal, 1993; Squire, 1992b; ZolaMorgan & Squire, 1993). Medial temporal region and hippocampus Even though early observations date back to the beginning of the twentieth century (von Bechterew, 1900, reviews in Angelergues, 1969; Victor & Agamanolis, 1990), the association between lesions of the hippocampal formation and amnesia was definitely established in the 1950s in epileptic patients, such as the noted case HM, who underwent a bilateral medial temporal lobectomy, that removed the amygdaloid nucleus, the uncus, the anterior two-thirds of the hippocampus, and the hippocampal gyrus (Fig. 15.8). Removals confined to the uncus or the amygdala did not bring about persistent memory deficits, which were related to the extent of the hippocampal damage (Scoville, 1954; Scoville & Milner, 1957; Terzian & Dalle Ore, 1955). These observations were complemented by the finding of transient memory deficits after bilateral temporal lobectomies sparing the hippocampal region (Petit-Dutaillis, Christophe, Pertuiset et al., 1954). A recent MRI study in patient HM showed a bilateral medial temporal lobe lesion including most of the amygdaloid complex, the entorhinal cortex, and the anterior part of the hippocampal formation, with partial damage to the parahippocampal gyrus (Corkin, Amaral, González et al., 1997). Unilateral and bilateral lesions of the amygdaloid complex do not disrupt verbal acquisition (Andersen, 1978; Jurko & Andy, 1977), but deficits of visual learning have been reported (Tranel & Hyman, 1990). The amygdaloid complex

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FIGURE 15.6

Papez’s (1937) circuit (a) A medial view of the right cerebral hemisphere, showing the hippocampal formation, and its connections with the mammillary bodies through the fornix, the mammillo-thalamic tract, which projects to the anterior thalamic nuclei, and the cingulate gyrus; cc: corpus callosum, eg: cingulate gyrus, cp: posterior part of the cingulate gyrus (retro-splenial cortex), f: fornix, a: anterior thalamic nucleus, mt: mammillo-thalamic tract, m: mammillary nucleus, u: uncus, h: hippocampus, d: dentate gyrus, hg: hippocampal gyrus, (b) A schematic representation of the circuit.

FIGURE 15.7

Hippocampal formation (hippocampus or Ammon’s horn, subicular complex, dentate gyrus, entorhinal cortex). A schematic representation of the main connections; the dashed lines indicate connections with subcortical structures (source: Amaral & Insausti, 1990; Squire, 1992).

may however participate in the emotional aspects of learning (Babinsky, Calabrese, Durwen et al., 1993; LeDoux, 1992). Bilateral extensive medial temporal lesions, including the hippocampal formation and the amygdaloid complex, do not disrupt the implicit acquisition of emotional material (Tranel & Damasio, 1993). The seminal observation of Scoville and Milner (1957) was confirmed by successive reports of amnesia associated with bilateral infarctions (DeJong et al., 1969; Victor, Angevine, Mancall et al., 1961; Woods et al., 1982) and anoxic atrophy

(Cummings, Tomiyasu, Read et al., 1984; Duyckaerts, Derouesne, Signoret et al., 1985; Muramoto, Kuru, Sugishita et al., 1979) of the hippocampal formation. In some of these patients the amygdaloid complex and the uncus were preserved. MRI studies have revealed a 50% reduction of the volume of the hippocampal formation in amnesic patients, compared with control subjects (Press, Amaral, & Squire, 1989; Squire, Amaral, & Press, 1990). The patient of Kartsounis et al. (1995), with a severe anterograde and retrograde amnesia, had a MRI-assessed

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FIGURE 15.8 Bilateral medial temporal lobectomy in patient HM (redrawn from Scovilie & Milner, 1957). A recent MRI study suggests a minor rostrocaudal (5cm) and lateral extent of the lesion (Corkin, Amaral, González et al., 1997).

ischaemic bilateral damage confined to fields CA1 and CA2 of the hippocampus. A number of post-mortem examinations have provided additional and more precise evidence for a crucial role of the hippocampal formation. In the patient of Cummings et al. (1984) the bilateral lesions were confined to the hippocampus, in which the number of pyramidal cells was dramatically reduced; the subicular complex, the dentate gyrus, the parahippocampal gyrus and the adjacent white

matter were preserved. In the patient of Duyckaerts et al. (1985) a complete neuronal loss in fields CA2 and CA3 was found. Also in the patient of Victor and Agamanolis (1990) the lesion was confined to the hippocampus with a virtually complete loss of the pyramidal cells (fields CA1-CA4). In patient RB the loss of pyramidal cells was confined to field CAI (Zola-Morgan et al., 1986). Patient RB has been described as a relatively mild amnesic, compared, for instance to patient HM; his

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retrograde deficit was minor, confined to a few years before the onset of the disease. The hypothesis that structures other than the hippocampal formation play a relevant role in amnesia (the temporal stem, which includes bidirectional connections of the temporal cortex and the amygdaloid complex, but not of the hippocampal formation: Horel, 1978) is not supported by these findings. The memory deficit of patients such as RB may be comparatively mild, as some temporal structures, such as the entorhinal, perirhinal, and parahippocampal cortices were spared. Damage to the entorhinal cortex may disrupt bidirectional connections between the hippocampal formation and other areas of the brain (Hyman, Van Hoesen, Damasio et al., 1984; Hyman, Van Hoesen, Kromer et al., 1986). In a recent neuropathological study Rempel-Clower et al. (1996) found damage confined to the CA1 field of the hippocampal formation in a patient with anterograde amnesia but no retrograde amnesia for autobiographical events; by contrast, two patients, with more extensive damage to the CA1, CA2, CA3 fields, the dentate gyrus and the entorhinal cortex, exhibited both anterograde and temporally graded retrograde amnesia. Diencephalon It has long been known that lesions of midline structures, such as tumours near the third ventricle may be associated with amnesia (Brierley, 1977, for review; Ignelzi & Squire, 1976; Kahn & Crosby,

1972; McEntee et al., 1976; Williams & Pennybacker, 1954). Some grey nuclei and white matter fibre tracts play a relevant role in memory processes: the mammillary nuclei, the mammillo-thalamic tracts, and the anterior and dorso-medial thalamic nuclei. The main connections between the anterior thalamus, the cingulate gyrus, and the hippocampal formation are shown in Fig. 15.9. Mammillary nuclei. Bilateral lesions of these structures have been described in patients with alcoholic Korsakoff’s syndrome (Barbizet, 1963; Delay & Brion, 1954; Delay, Brion, & Elissalde, 1958a; Delay, Brion, & Elissalde, 1958b; Malamud & Skillicorn, 1956; Remy, 1942). In four such patients, in whom the memory deficit had been documented through quantitative tests, a pathological examination showed neuronal loss in the mammillary nuclei, and gliosis in a region localised between the third ventricle and the dorsomedial thalamic nucleus (Mair et al., 1979; Mayes, Meudell, Mann et al., 1988). In some patients, however, the mammillary nuclei were spared: three out of 70 patients in the series of Malamud and Skillicorn (1956), and in case VIII of Delay et al. (1956); in these early studies the pathological examination may have failed to detect minor abnormalities, revealed by the more recent assessments. Mammillo-thalamic tracts, dorso-medial and anterior thalamic nuclei. The dorso-medial

FIGURE 15.9

Hippocampal formation, anterior thalamic nuclei, and the cingulate gyrus. A schematic representation of the main connections; the thicker lines denote the quantitatively more relevant projections (source: Aggleton & Sahgal, 1993).

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thalamic nucleus, which is not a component part of the circuit described by Papez (1937), is frequently damaged in amnesic patients. This nucleus was damaged in 53% of the 70 patients with alcoholic Korsakoff’s syndrome reported by Malamud and Skillikorn (1956). Victor et al. (1971) described five patients without amnesia, who showed lesions of the dorso-medial thalamic nuclei, but not of the mammillary nuclei; by contrast, in amnesic patients both nuclei were damaged. On the basis of these findings they concluded that damage to the dorso-medial nuclei was a main correlate of amnesia (see also Victor, 1976, pp.264-66). In the patient of McEntee et al. (1976) a postmortem examination showed a bilateral neoplastic lesion of the dorso-medial thalamic nuclei, while the mammillary nuclei, the mammillo-thalamic tracts, and the anterior thalamus were spared. Other structures such as the septum pellucidum (see section Fronto-basal region) were damaged, however. Other single case studies have confirmed the association between amnesia and CT-assessed bilateral lesions of the dorso-medial thalamic nuclei (Schott et al., 1980; Winocur et al., 1984). Von Cramon et al. (1985) localised the CTassessed intra-thalamic vascular lesions of a number of patients with and without amnesia. They suggested an association between amnesia and lesions of the mammillo-thalamic tracts and of the internal medullary lamina, a white matter fibre tract which includes connections between the thalamus and the amygdaloid complex, and between the dorso-medial thalamic nucleus and the cortex. In line with this view, in the two patients without amnesia (#5 and #6) the lesions were confined to the dorso-medial and ventro-oral nuclei. In line with von Cramon et al.’s (1985) conclusions, in other patients not just the dorsomedial thalamic nuclei, but also the mammillothalamic tracts were damaged. In the patient of Nichelli et al. (1988) the CT-assessed bilateral lesion involved the internal medullary lamina, and the dorso-medial thalamic nucleus; also the right mammillo-thalamic tract was damaged. In the patient of Barbizet et al. (1981) the CT-assessed bilateral damage involved the mammillo-thalamic tracts, with a relative sparing of the dorso-medial

thalamic nuclei. In the series of eight patients with bilateral thalamic infarctions described by Gentilini et al. (1987), only patient #3 exhibited a severe and persistent amnesia: the lesion was confined to the mammillo-thalamic tracts, while both the dorsomedial nucleus and the internal medullary lamina were preserved. In the patient of Hankey and Stewart-Wynne (1988) post-mortem examination revealed a haemorrhagic lesion of the left anterior thalamic nucleus at the termination of the mammillo-thalamic tract. In the series of GraffRadford et al. (1990) the two patients (cases #1 and #2) with severe global amnesia had bilateral lesions involving the mammillo-thalamic tracts and the anterior nuclei. Two patients (cases #3 and #4) had a milder deficit, revealed by psychometric testing: in patient #3 the mammillo-thalamic tracts were spared, while the bilateral lesion involved the dorso-medial thalamic nuclei; in patient #4 the lesions were small and involved fibres from the inferior thalamic peduncle. Also the amnesic patient of Malamut et al. (1992) had bilateral MRIassessed lesions of the mammillo-thalamic tracts, while the dorso-medial nucleus was spared. In patient #2 of Kritchewski et al. (1987), who did not show amnesia, a pattern complementary to that of the patients of Barbizet et al. (1981), and Malamut et al. (1992) was found: two small bilateral MRI-assessed lesions of the dorso-medial thalamic nuclei, with preserved mammillary nuclei, and mammillo-thalamic tracts. It remains possible, however, that these lesions, which involved about 10% of the dorso-medial nuclei, were too small to bring about memory deficits. To summarise, the observations discussed here suggest that a lesion of the mammillo-thalamic tracts plays a relevant role, disconnecting the thalamus from the hippocampal formation. Furthermore, the baso-lateral limbic circuit (dorso-medial thalamic nucleus, subcallosal area, amygdaloid complex) may be a component of the neural basis of LTM processes (discussion in von Cramon, 1992). The empirical observations that support this view come from patients with small infarctions of the left internal capsule, assessed by CT (Kooistra & Heilman, 1988, posterior limb) and MRI (Markowitsch, von Cramon, Hofmann et al., 1990, genu), who had deficits concerning mainly

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verbal memory. The lesions, involving the inferior thalamic peduncle, may disconnect the dorsomedial thalamic nucleus from the subcallosal area and the amygdaloid complex (through a lesion of the ventral amygdalofugal fibres). Lesions of the amygdaloid complex do not produce relevant memory deficits, however. Cingulate gyrus In psychiatric patients, Whitty and Lewin (1960) reported that bilateral anterior cingulectomy produced a transient confusional state and a memory disorder, characterised by a defective temporal localisation of events. This clinical observation, however, was not confirmed by a study of Long et al. (1978). Using an extensive neuropsychological battery in a series of 19 psychiatric patients they were unable to detect memory deficits both before the surgical operation and 3 to 12 months later. Valenstein et al. (1987) described a patient with amnesia associated with a left-sided lesion of the splenium of the corpus callosum, of the posterior part of the cingulate gyrus, posterior to the splenium, and possibly of the fornix and of the hippocampal commissure. The patient, TR, suffered a severe amnesia: for instance at noon he did not remember what he had done in the morning, even though the psychometric assessment showed an anterograde deficit involving mainly verbal memory, and a retrograde amnesia for about four years. Valenstein et al. (1987) ascribed this retrosplenial amnesia to a disconnection between the anterior thalamus and the hippocampal formation, as the retrosplenial cortex is a component part of a pathway, different from Papez’s (1937) circuit, which connects these two brain regions. In patient TR a PET study showed hypometabolism in the ipsilesional left thalamus, and increased metabolic activity in the left frontal cortex (Heilman, Bowers, Watson et al., 1990). Also in patients suffering from tumours of the splenium of the corpus callosum, the memory deficit may be attributed to damage of the posterior part of the cingulate gyrus (retro-splenial cortex), and of the fornix (Rudge & Warrington, 1991). The different effects of anterior vs. posterior lesions of the cingulate cortex (minor vs. severe

memory deficits) may reflect major damage to the connections between the anterior thalamus and the hippocampal formation, produced by a lesion of the retrosplenial cortex (Aggleton & Sahgal, 1993). Fornix Clinical observations in epileptic patients who underwent a surgical section of the fornix suggest that this white matter tract does not play a main role in LTM processes (review in Garcia-Bengochea & Friedman, 1987). Woosley and Nelson (1975) did not detect clinically relevant memory deficits in a patient with bilateral severe neoplastic damage to the fornix, and preserved hippocampal formation and dorso-medial thalamic nuclei. In other patients, however, damage to the fornix was associated to memory deficits. The patient of Brion et al. (1969) had anterograde and retrograde amnesia, and a bilateral ischaemic lesion of the fornix, with secondary atrophy of the mammillary nuclei. In the patient of Heilman and Sypert (1977) the surgical ablation of a tumour involving the posterior part of the fornix brought about an anterograde deficit, assessed through psychometric testing, and a clinically relevant retrograde amnesia. During the Vietnam war, the patient of Grafman et al. (1985) suffered a bilateral traumatic lesion of the fornix, and of other cortical and subcortical structures, including the anterior thalamic nuclei. The patient had a mild learning deficit for both verbal and spatial material, without retrograde amnesia, was able to live on his own, to work in a clerical position, and was aware of the memory impairment. Patient KW, who had a neoplastic lesion of the left fornix, exhibited a verbal memory deficit (Tucker, Roeltgen, Tully et al., 1988). Hodges and Carpenter (1991) reported two patients, with fornix damage after the removal of third ventricle colloid cysts, who had an anterograde deficit and a mild retrograde amnesia (less than one year) (Gaffan & Gaffan, 1991, for review; Gaffan, Gaffan, & Hodges, 1991). Also the patient of D’Esposito et al. (1995b) showed no retrograde deficits. To summarise, at least in some patients, there is evidence that damage to the fornix may produce an anterograde deficit, with a relative sparing of memory for past events.

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Fronto-basal region The rupture or surgical repair of aneurysms of the anterior communicating artery may produce severe memory deficits, associated with personality changes, anosognosia, and confabulation (Alexander & Freedman, 1984; Damasio, GraffRadford, Eslinger et al., 1985; Irle, Wowra, Kunert et al., 1992; Lindqvist & Norlen, 1966; Phillips, Sangalang, & Sterns, 1987; Talland et al., 1967; Vilkki, 1985; Volpe & Hirst, 1983). The damage associated with amnesia involves the median and para-median basal forebrain. This region, whose boundaries are not precisely defined, includes the septal area, the substantia innominata, and parts of the amygdaloid complex. The septal nuclei have bi-directional connections with the hippocampal formation, mainly through the fornix (Goldberg, 1984; Phillips etal., 1987;Taren, 1965). In one patient the removal of a tumour of the septum pellucidum produced amnesia (Berti, Arienta, & Papagno, 1990). In two other patients the memory deficit has been attributed to a lesion of the septal nuclei (von Cramon, Markowitsch, & Schuri, 1993), and to a septo-hippocampal disconnection, produced by damage to a dorsal septo-hippocampal pathway, different from the fornix (von Cramon & Schuri, 1992). From structures to circuits The anatomo-clinical correlation studies discussed in the previous sections suggest that damage to a number of connected cerebral areas may produce amnesia. Seen in this perspective, amnesia may be considered as a disconnection syndrome, in which the deficit is produced not only by the focal lesion, but also by the dysfunction of a circuit of which the damaged area is a component part (von Cramon, 1992; Warrington & Weiskrantz, 1982; Weiskrantz, 1985). In line with this view, in 11 patients with mixed aetiology (alcoholic Korsakoff’s syndrome, anoxia, cerebrovascular attacks, aneurysms of the anterior communicating artery) with diencephalic (thalamus, mammillary nuclei), or no detectable damage, as assessed by MRI, Fazio et al. (1992) showed through PET a bilateral reduction of metabolic activity in the fronto-basal and medial temporal regions, in the thalamus and in the cingulate cortex. In a patient with a predominantly

verbal memory deficit and a left thalamic infarction (anterior nuclei, mammillo-thalamic tracts, internal medullary lamina) PET showed hypometabolism not only in the anterior thalamus, but also in the posterior part of the ipsilateral cingulate gyrus (Clarke, Assal, Bogousslavsky et a l., 1994). In the patient of Markowitsch et al. (1997), who become amnesic after a heart attack, MRI showed no focal damage, while PET revealed bilateral general hypometabolism, more pronounced in the thalamus and in the mesial and polar temporal regions. In patients with alcoholic Korsakoff’s syndrome Paller et al. (1997) found hypometabolism in the middle and inferior frontal cortex, and in the cingulate gyrus. In the thalamic and hippocampal regions, however, glucose metabolism was comparable to that of the alcoholic control group (but see the different findings of Fazio et al., 1992), and no significant correlation was found between delayed memory performance and metabolism in these structures. The few published studies assessing regional metabolism in amnesic patients concur in suggesting that the cerebral dysfunction may involve a number of connected regions, in addition to the areas in which structural damage is present. However, the pattern of dysfunction may differ according to the aetiology of amnesia, and, perhaps, to the site of the lesion. The neural correlates o f implicit memory The investigation of the performance of braindamaged patients with lesions different from those of amnesics has provided relevant data concerning the neural correlates of implicit memory. Patients with Huntington’s disease, a disorder producing a progressive degeneration of the caudate nucleus, exhibited defective learning of a number of visuo-motor and visuo-perceptual tasks (pursuitrotor, reading mirror-reversed text) and did not show the adaptation-level effect. Stem-completion, by contrast, was preserved. Patients with senile dementia of the Alzheimer type showed an opposite pattern of impairment (Heindel, Butters, & Salmon, 1988; Heindel, Salmon & Butters, 1991; Heindel, Salmon, Shults et al., 1989; Martone et al., 1984; Shimamura et al., 1987). Patients with Huntington’s disease are also impaired in problem-

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solving tasks, such as the Tower of Hanoi puzzle (Butters et al., 1985). Visual repetition priming for words and nonwords is disrupted by temporo-occipital lesions, in the vascular territory of the posterior cerebral artery (Carlesimo, Fadda, Sabbadini et al., 1994; Swick & Knight, 1995). In a patient with bilateral occipital damage visuoperceptual, but not conceptual (meaning-based), priming was defective, visual recognition (explicit) memory being preserved; a patient with bilateral medial-temporal lesions (HM) showed the opposite dissociation (Keane, Gabrieli, Mapstone et al., 1995). Habit learning (the formation of associations in which a neutral stimulus comes to elicit a certain response as a function of repeated reinforcement) is defective in patients with Parkinson’s disease (a degenerative disorder producing atrophy of the substantia nigra and a consequent major reduction of the dopaminergic projection to the basal ganglia) but preserved in amnesic patients. The two groups showed an opposite pattern for declarative memory for facts about the testing episode, which was preserved in patients with Parkinson’s disease, and defective in amnesics (Knowlton, Mangels, & Squire, 1996). These results provide evidence to the effect that the neural correlates of implicit memory are different from those of the explicit systems, impaired in amnesia, and include structures such as the basal ganglia, the cerebellum, and the sensory and motor cortices (reviews in Salmon & Butters, 1995; Ungerleider, 1995). Activation studies In the last few years the neural correlates of memory function have been extensively explored in normal subjects by functional neuroimaging methods. The present section summarises the main findings, with the cautionary note that this is a rapidly developing field. A general pattern emerging from these studies is the association between specific tasks and the activation of sets of discrete cerebral regions. These neurocognitive networks, which overlap in part across different tasks, may be currently conceived as the neural bases of mental activities. A number of studies have investigated the neural structures active during encoding and

retrieval processes in LTM. In the experiment by Shallice et al. (1994), who used a verbal learning task, encoding was associated with activation in the left pre-frontal and retro-splenial cortices, retrieval with activation in the right pre-frontal cortex, and in the precuneus, on both sides. This hemispheric asymmetry has been found also by Tulving, Kapur, and their co-workers (review in Tulving, Kapur, Craik et al., 1994a). A “deep” encoding (a “living/nonliving” decision about a word) produced a higher recognition performance, compared to a “shallow” encoding (deciding whether or not a word included the letter “a”), and was associated to activation in the left inferior prefrontal cortex (Kapur, Craik, Tulving et al., 1994). Retrieval of verbal material activated the right dorso-lateral prefrontal cortex, the parietal cortex on both sides, and the anterior part of the left cingulate gyrus (Tulving, Kapur, Markowitsch et al., 1994b). This left (encoding and retrieval from semantic memory: Cabeza & Nyberg, 1997, for review) vs. right (retrieval) hemispheric asymmetry has been confirmed by a number of studies (Buckner, Petersen, Ojemann et al., 1995; Demb, Desmond, Wagner et al., 1995; Nyberg, McIntosh, Cabeza et al., 1996a). The role of the prefrontal cortex, with the right/left asymmetry mentioned earlier, appears to be related more to retrieval attempt or mode than to the actual successful recovery (ecphory) of stored material (Kapur, Craik, Jones et al., 1995; Nyberg, Tulving, Habib et al., 1995; Rugg, Fletcher, Frith et al., 1996). In the study by Nyberg et al. (1995) successful retrieval was associated with activation of a large set of frontal, temporal, and subcortical regions. Finally, an association between autobiographical memory and activation in the temporal, insular, and posterior cingulate regions of the right hemisphere has been reported (Fink, Markowitsch, Reinkemeier et al., 1996). The lack of hippocampal activation in the encoding and retrieval stages is remarkable, in the light of the well known association between medial temporal damage and amnesia (discussion in Haxby, 1996). Some recent studies have however provided evidence for a role of the medial temporal region in conscious recollection. In a task requiring the recall of supraspan lists of words, Grasby et al. (1993a) found a correlation between performance

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level in the central part of the list (which is based on LTM processes) and rCBF in the hippocampal region, more on the left side; recall of within-span lists showed no correlation with hippocampal activation (but see Grasby, Frith, Friston et al., 1993b). Nyberg et al. (1996b) showed a correlation between performance level in an episodic memory task (proportion of recognised auditory words) and rCBF in the left medial temporal lobe. Schacter et al. (1996) found activation of the right hippocampal region during successful recall of visually presented words. Activation of the hippocampal formation during object recognition has also been reported (Schacter, Reiman, Uecker et al., 1995).Owen et al. (1996) found activation of the right parahippocampal gyrus in the retrieval of object location. In a recent fMRI study Gabrieli et al. (1997) showed activation of discrete medial temporal lobe regions during retrieval (subiculum) and encoding (parahippocampal cortex) of meaningful material (line drawings). The hippocampal region, furthermore, seems to be also involved in other and more general aspects of stimulus processing, such as novelty detection (Stern, Corkin, González et al., 1996; Tulving, Markowitsch, Kapur et al., 1994c). The neural correlates of the facilitation effects of visual priming (stem completion) include a reduction of activation in the visual and temporal cortices, mainly in the right hemisphere (Buckner et al., 1995; Schacter et al., 1996; Squire, Ojemann, Miezin et al., 1992). In line with these findings Marsolek et al. (1992) found in normal subjects a left visual half-field (right hemisphere) superiority in stem completion. Finally, a number of studies have explored the neural correlates of working memory, a complex system involved in the temporary retention of verbal or nonverbal material, prior to and during the application of procedures, strategies, and analyses (see Baddeley, 1992, 1996). The concurrent performance of two tasks (D’Esposito, Detre, Alsop et al., 1995a), self-ordered and conditional memory tasks (Petrides, Alivisatos, Evans et al., 1993a; Petrides, Alivisatos, Meyer et al., 1993b) activate the dorso-lateral prefrontal cortex (review in Fiez, Raife, Balota et al., 1996).

Unilateral lesions o f Papezs circuit and o f related areas Unilateral lesions and global amnesia. Global amnesia is typically associated with bilateral diencephalic or medial temporal damage. Unilateral lesions do not usually produce amnesia, and, if this is the case, the damage more frequently involves the left hemisphere. In a series of 90 patients who underwent unilateral mesial temporal lobectomies, Penfield and Milner (1958) found a global memory disorder, concerning both verbal and nonverbal material, only in two cases, with a left-sided ablation of the amygdala, the uncus, and the hippocampal formation. On the basis of EEG recordings, they suggested however that the global amnesia was produced by the presence of additional contralateral damage. In one of these patients a post-mortem exam confirmed this hypothesis, showing atrophy of the right hippocampal formation (Penfield & Mathieson, 1974). Also in the patient of Dimsdale et al. (1964), who had a global and persistent amnesia produced by a right-sided medial temporal lobectomy, a sclerosis of the contralateral left hippocampal formation was subsequently found (Warrington & Duchen, 1992). In the patient of Mohr etal. (1971), who had a persistent and severe memory deficit, the post-mortem exam showed an ischaemic lesion confined to the left hippocampal formation, and a small right thalamic infarction. Left thalamic lesions may also produce an amnesic syndrome (Speedie & Heilman, 1982; Teuber et al., 1968, patient NA; von Cramon et al., 1985, patient #4). In these patients the retrograde deficit was mild (NA, the patient of Speedie & Heilman) or absent (the patient of von Cramon et al.). In the patient of Speedie and Heilman (1982) the anterograde deficit was more severe for verbal material. In patient NA, MRI showed a lesion of the left thalamus (internal medullary lamina, intralaminar, dorso-medial, ventral-anterior, and lateral nuclei), the mammillo-thalamic tract, and the post-commissural fornix; the mammillary nuclei were damaged on both sides (Squire et al., 1989a). To summarise, in some patients with global amnesia and unilateral lesions, a contralateral

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damage has subsequently been shown (Penfield & Mathieson, 1974; Squire et al., 1989a; Warrington & Duchen, 1992). In the PET study of Fazio et al. (1992) patients #10 and #11 had unilateral right-sided lesions (thalamus, fronto-basal region), but the reduction of regional metabolism was bilateral. To summarise, severe and persistent global amnesia is associated in many patients with bilateral damage or dysfunction. Minor memory deficits associated with unilateral damage. Even though unilateral cerebral lesions may, as noted earlier, produce a global amnesia, this is not the most frequent pattern of impairment. More frequently, unilateral damage brings about mild memory deficits, which may be revealed through psychometric testing. Unilateral temporal lobectomies in the hemisphere dominant for language (the left in the majority of patients) selectively disrupt learning and retention of verbal material, sparing nonverbal stimuli, such as spatial positions, faces, melodies, or meaningless patterns. Temporal lobectomies in the right, non-dominant, hemisphere produce an opposite pattern of impairment (Iversen, 1977; Milner, 1967, 1971, 1972; Paivio & te Linde, 1982). The relevant role of the left medial temporal regions has been confirmed by the finding that verbal LTM is defective in patients with ischaemic lesions in the vascular territory of the left posterior cerebral artery, which frequently involve the hippocampal formation (De Renzi, Zambolin, & Crisi, 1987b; Vallar, Papagno, & Cappa, 1988). In the series of patients with pure alexia of Damasio and Damasio (1983), the two patients with defective verbal LTM (cases #5 and #6) had vascular lesions involving the mesial temporal region (hippocampal formation, parahippocampal gyrus). Von Cramon et al. (1988) reported a series of 30 patients with ischaemic lesions in the vascular territory of the left posterior cerebral artery. In all patients auditory-verbal span was normal. The 12 patients with defective learning and retention had lesions involving the posterior parahippocampal gyrus and its afferent and efferent connections in the collateral isthmus (related discussion in Squire, 1992b); in three such patients the hippocampal formation was also damaged. By contrast, both left-sided lesions

sparing these areas and right-sided lesions did not affect verbal LTM. Unilateral thalamic lesions may also produce a similar pattern of impairment. In a patient with ischaemic damage to the right dorso-medial thalamic nucleus, learning of visuospatial material was defective, while memory for verbal material and past events was preserved; perceptual processes were also affected, however (Speedie & Heilman, 1983). Conversely, left dorso-medial thalamic lesions may selectively affect verbal LTM, sparing verbal STM and learning of nonverbal material (Michel, Laurent, Foyatier et al., 1982; Mori, Yamadori & Mitani, 1986). A clinical exam may be unable to detect these mild deficits of long-term learning and retention. Patients with posterior lesions of the right hemisphere, however, in addition to a defective performance in visuospatial learning tasks (e.g. a maze) may show anterograde and retrograde topographical amnesia. The cardinal feature of the disorder is the patients’ defective spatial orientation in both unfamiliar (e.g., the hospital’s wards) and familiar environments (De Renzi, 1982; De Renzi, Faglioni, & Villa, 1977b). Selective retrograde amnesia In some patients, electrophysiological and neuroimaging assessments (e.g. EEG, CT, MRI, PET) did not show any definite structural lesions or functional disorder (Andrews et al., 1982; De Renzi et al., 1995; Stracciari et al., 1994). In other patients CT or MRI did not show structural lesions, but EEG suggested a left temporal dysfunction (Damasio et al., 1983; Kapur et al., 1986; Kapur et al., 1989; Roman-Campos et al., 1980). In two such patients the initial memory deficit was a transient amnesia, global (RomanCampos et al., 1980) and epileptic (Kapur, 1993b). Patient JV (Stuss & Guzman, 1988), who exhibited a severe retrograde deficit (mainly autobiographical, but also for public events), and a mild anterograde deficit, had a left anterior temporal dysfunction, assessed by MRI and PET. In patient MM (Lucchelli et al., 1995) PET showed a bilateral reduction of metabolic activity in the posterior part of the cingulate gyrus. In the patient of Mattioli et al. (1996) PET revealed bilateral hypometabolism

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in the temporal regions, including the hippocampal formation. Other patients had focal structural lesions. In the case of Goldberg et al. (1981) CT showed bilateral post-traumatic temporal lesions and a mesencephalic damage (median and left paramedian zones, ventral tegmental area). In patient LD (Eslinger et al., 1993; O’Connor et al., 1992) MRI showed extensive post-encephalitic lesions in the right hemisphere (temporal pole, lateral and medial temporal regions, infero-medial frontal lobe, insula, inferior parietal lobule), and very limited damage to the left hemisphere (region of the collateral sulcus, insula, posterior ventromedial frontal cortex). In the patient of Markowitsch et al. (1993a,b) the post-traumatic lesion (more extensive on the right side) involved the temporal poles, the fronto-basal cortex, the right basal and lateral temporal areas, and the left temporo-parietal regions; the hippocampal formation was spared. In the post-encephalitic patient Felicia (De Renzi & Lucchelli, 1994) MRI showed bilateral temporal lesions, including both the temporal pole and the hippocampal region, more extensive on the left side. These three patients, however, had also mildto-moderate anterograde deficits, reported as less severe than retrograde amnesia. LD (O’Connor et al., 1992) had additional severe visuo-perceptual and constructional deficits, and Felicia (De Renzi & Lucchelli, 1994) had a category-specific semantic disorder. In patient LT (Kapur et al., 1992) the MRI-assessed post-traumatic bilateral lesion involved the anterior part of the temporal lobes, while the hippocampal formation was spared. A patient described by Calabrese et al. (1996) had right-sided inferior lateral prefrontal and temporal lesions, also involving the amygdalohippocampal region; minor left-sided frontotemporal damage was also present. To summarise, the available anatomical data suggest an association between bilateral temporal lesions and retrograde amnesia, with minor, or absent, anterograde deficits (see also the recent cases of Kroll, Markowitsch, Knight et al., 1997). The study of Barr et al. (1990) suggests a more prominent role of the left hemisphere: left, but not right, temporal lobectomies produced retrograde amnesia for public (verbal identification of famous

faces, knowledge of TV programmes) and autobiographical events, even though the latter deficit was less severe. The lesions were extensive, involving the hippocampal formation, part of the lateral temporal cortex, the amygdaloid complex and the uncus. The left and the right hemisphere may contribute to different aspects of memory for past events. Suggestions have been made that visuospatial processes and the right hemisphere may play a relevant, though not exclusive, role in recalling autobiographical episodic events (Markowitsch, 1995; O’Connor et al., 1992; Ogden, 1993, patient MH with autobiographical amnesia). The left hemisphere, by contrast may be more specifically involved in memory for semantic facts and public events (De Renzi et al., 1987a; Grossi et al., 1988; Markowitsch, 1995).

DEFICITS OF SHORT-TERM MEMORY Since the late 1960s patients have been described with selective, material-specific, STM impairments, concerning auditory-verbal or visuospatial material. The anatomical correlates of these disorders are focal cortical lesions.

Deficits of visual and spatial STM In brain damaged patients with focal lesions Warrington and Rabin (1971) assessed immediate memory for sequences of five stimuli (digits, letters, lines) simultaneously presented through a tachistoscope. Left brain-damaged patients had a level of performance lower than that of right braindamaged patients, who, in turn, were comparable to normal subjects. Patients with left posterior (parietal, occipital, temporo-parietal) damage were most severely impaired. These patients had also a disproportionately low auditory-verbal span, but its correlation with visual span and with performance on the Vocabulary subtest of the Wechsler Adult Intelligence Scale was low. This makes unlikely an interpretation of the visual memory deficit in terms of a co-occurring aphasic disorder. Similarly, a visual half-field deficit cannot account for this impairment: a

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comparable proportion of right brain-damaged patients with posterior lesions had eontralesional hemianopia, with no impairment of visual immediate memory. Finally the memory disorder cannot be attributed to a perceptual deficit. In a comparable series, left brain-damaged patients were not disproportionately impaired in dot detection and letter recognition tasks (Warrington & Rabin, 1970), and had a normal performance in a number estimation task (Warrington & James, 1967), in which, conversely, right brain-damaged patients were defective. The visual memory deficit of left brain-damaged patients with posterior lesions may reflect therefore the impairment of a visual STS. The patients’ preserved ability to make numerosity judgements makes unlikely an interpretation in terms of defective iconic memory. De Renzi and Nichelli (1975) investigated visuospatial memory using the block-tapping test devised by R Corsi (quoted by Milner, 1971). In this task the subject is presented with nine cubes, arranged in nonsymmetric positions on a board, and receives instructions to reproduce the sequence of blocks touched by the examiner. Using sequences of increasing length, a measure of visuospatial STM may be obtained. Right brain-damaged patients with left visual half-field deficits, and presumably posterior lesions, were disproportionately impaired, compared to both control subjects and left braindamaged patients without hemianopia. Patients with left hemisphere lesions and hemianopia scored worse than control subjects, but did not differ from the other patient groups. Finally, the auditory-verbal span of patients with right-sided lesions and hemianopia was normal. These results suggest that the posterior regions of the cerebral hemispheres, with a more relevant role of the right side, are involved in the short-term retention of visuospatial material. All patients were able to reach single cubes touched by the examiner, using the ipsilesional hand. Perceptual or motor impairments cannot therefore account for the span deficit, which may be interpreted in terms of defective visuospatial STS. The pattern of impairment of some patients may be explained in the light of a two-component view of memory processes. In the series of De Renzi and Nichelli (1975) two right brain-damaged patients with left visual half-field deficits had a low

visuospatial span, without visuo-perceptual deficits and hemineglect. These patients were able to learn the path of a visual maze, and showed no evidence of topographical amnesia. Another right braindamaged patient exhibited the opposite dissociation: Preserved visuospatial span, topographical amnesia, and defective maze learning. These results support the distinction between STM and LTM processes, but are not compatible with a serial organisation of the system, such as that shown in Fig. 15.1, suggesting instead a parallel architecture. A serial organisation does not predict selective STM deficits, because they would also produce a LTM impairment. By contrast, a parallel architecture, in which, after perceptual analysis, the signal independently gains access to short-term and long-term storage systems, is compatible with the existence of selective deficits of either component (discussion in Shallice, 1970). The early observations of De Renzi and Nichelli (1975) have been confirmed by Hanley et al. (1991). Their right brain-damaged patient ELD had a low visuospatial span and her immediate memory for unknown faces was defective. ELD’s performance was also defective in a task requiring the recall of sentences of increasing length, which described the spatial position of a sequence of digits, in a 4 x 4 matrix. Auditory-verbal span was normal, and the presence of the effects of phonological similarity suggests that the phonological STS-rehearsal system (Fig. 15.2) was preserved. Visuo-verbal span was normal also during articulatory suppression (the continuous uttering of an irrelevant speech sound). Under these conditions, visuo-verbal material does not enter the phonological STS, and may be held in a visual STS, different from the visuospatial system damaged in the patient. Finally, ELD’s performance was also defective in tasks requiring spatial operations on mental images, such as rotation, while access to visual nonspatial representations stored in LTM (the prototypical colour of an object, size judgements) was preserved. Recognition of other nonverbal materials (unfamiliar faces, objects, and voices) was also defective (Hanley, Pearson, & Young, 1990). The deficit of patient LH (Farah, Hammond, Levine et al., 1988) was opposite to that of ELD.

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This patient was able to perform spatial operations on mental images (rotation of shapes and letters, memory for matrices), but generation of visual images was defective. LH’s bilateral lesions involved the temporo-occipital areas and the right inferior frontal region. To summarise, the observations of De Renzi & Nichelli (1975) and Hanley et al. (1990, 1991) on the one hand, and those of Warrington and Rabin (1971) and Farah et al. (1988) on the other, provide evidence for a distinction between visuospatial and visual short-term retention systems. Other short-term components may exist. Davidoff and Ostergaard (1984) suggested a STS for colours, participating in the activation of a specific lexicon in naming tasks. The main deficit of their patient, who had a left temporo-occipital lesion, was colour anomia, while pointing to colours named by the examiner was preserved. The deficit was specific for colours, as immediate memory for meaningless shapes was normal.

Deficits of auditory-verbal STM It has long been known that aphasic patients with lesions in the left hemisphere have a pathologically low auditory-verbal repetition span (Zangwill, 1946). Selective deficits were reported only in the late 1960s, however, Luria et al. (1967) described two patients (B and K) who had suffered a traumatic lesion of the temporal lobe and showed a defective immediate repetition of sequences of phonemes, words, and digits. Luria et al. (1967) suggested a selective deficit of auditory-verbal memory traces. Warrington and Shallice (1969) reported in left brain-damaged patient KF a selective deficit of auditory-verbal span, which they interpreted in terms of the impairment of auditory-verbal STM. In the following years, a number of patients with a similar pattern of impairment have been described. The deficit has three main features: (1) auditory-verbal span for sequences of verbal material (digits, letters, words) is selectively impaired; (2) the patients’ level of performance is higher with visual presentation of the stimuli; (3) the impairment cannot be attributed to deficits of acoustic-phonological analysis or of processes involved in the production of a verbal

response (Shallice & Vallar, 1990; Vallar & Papagno, 1995). The latter characteristics of the deficit indicate that the pathological reduction of span is due to a memory impairment. In many patients repetition of individual stimuli was errorless. In addition, some patients had a normal performance in tasks requiring phonological analysis, but posing a minimal memory load (e.g. same-different judgements on consonant-vowel pairs differing in a single distinctive feature, phonemic categorisation: review in Vallar & Papagno, 1995). In this type of patient the memory deficit is primary, being produced by the pathologically reduced capacity of the auditory-verbal STS, and cannot be attributed to perceptual deficits. Other patients show associated deficits of phonological analysis. In these cases, the memory deficit is secondary, being produced, wholly or in part, by a perceptual disorder (Vallar, Basso, & Bottini, 1990; Vallar & Papagno, 1995). The span performance of some patients did not improve when a nonverbal response, such as recognition by pointing, was used (e.g. patients PV and KF: Basso, Spinnler, Vallar et al., 1982; Vallar, Corno, & Basso, 1992, for a group study; Warrington & Shallice, 1969). This rules out the hypothesis that the repetition deficit is produced by the impairment of output processes, involved in speech production, According to the traditional taxonomy of language disorders, these patients may be classified as conduction aphasics, because they show a disproportionate impairment of repetition. In the early 1970s a number of alternative interpretations have been proposed, in the context of the WemickeLichtheim model of aphasia, Kinsboume (1972) suggested a disconnection between processes involved in the analysis of the stimulus and processes participating in response production, with a reduced capacity of the transmission pathway; and Tzortis and Albert (1974) a specific deficit of memory for sequences; and Strub and Gardner (1974) and Allport (1984a, 1984b) a central phonological deficit. The hypothesis of a reduced capacity of the connection between input and output processes does not explain the patients’ defective

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performance in conditions in which the memory load was minimal (a single letter), such as the Brown-Peterson task (patients PV and KF: Basso et al., 1982; Warrington & Shallice, 1972), or when the patient was required to communicate whether or not a stimulus had been presented in the sequence (patients MC and KF: Caramazza, Basili, Koller et al., 1981; Shallice, 1970). In this probing task no signal had to be transmitted to output processes. The hypothesis of a defective memory for sequences does not explain the patients’ impairment in the recency part of the free recall curve (Vallar & Papagno, 1986; Warrington, Logue, & Pratt, 1971), and in the Brown-Peterson task. In these conditions no serial recall was required. The hypothesis of a central phonological deficit does not account for the selectivity of the span disorder, which may occur in the absence of phonological impairments of both stimulus analysis and response production. To summarise, the selective deficit of auditoryverbal span cannot be readily interpreted in the light of the traditional anatomo-clinical model of aphasia. The clinical syndrome of conduction aphasia, in which repetition is disproportionately impaired, fractionates into discrete disorders: 1. Defective auditory-verbal STS: the patients’ immediate memory of sequences of auditoryverbal stimuli is defective, while repetition of individual words and spontaneous speech are preserved. 2. Defective phonological processes involved in speech production (Dubois, Hecaen, Angelergues et al., 1973; Kohn, 1992): repetition of individual words is defective— and the deficit is more severe with polysyllabic and low frequency items—while span for highfrequency stimuli such as digits may be relatively preserved (Damasio & Damasio, 1980). In one patient the impairment has been explained in terms of defective rehearsal (see section The fractionation o f auditory-verbal STM, and Vallar, Di Betta, & Silveri, 1997). 3. Disconnection between phonological processes involved in language perception and production: repetition is defective, more than spontaneous speech (Green & Howes, 1977;

Kinsbourne, 1972; McCarthy & Warrington, 1984). Auditory-verbal STM: A selective deficit Most patients with a selective deficit of auditoryverbal span have a higher level of performance when the stimuli are presented visually (Shallice & Vallar, 1990; Vallar & Papagno, 1995). Normal subjects, by contrast, show a better serial and free recall of the final positions of the list when presentation is auditory (modality effect: Crowder, 1976; Watkins & Watkins, 1980). This auditory/visual dissociation indicates that the affected STM system is not supramodal (Atkinson & Shiffrin, 1971; Waugh & Norman, 1965), fractionating instead into an auditory-verbal (phonological) STS and a visual-verbal STS (see Fig. 15.2 and Deficits of visual and spatial STM). Coding in the latter store may be in terms of shape. Warrington and Shallice (1972) showed that patient KF made visual errors (confusions among visually similar letters, such as O vs. Q, P vs. R) in a visual span task. Normal subjects, by contrast, also make phonological errors when the stimuli are presented visually; this indicates retention in the phonological STS, after phonological recoding. Fig. 15.10 shows the auditory/visual dissociation in the recency part of the free recall curve of patient PV: the deficit of recency was confined to the auditory modality, suggesting a selective deficit of the auditory-verbal STS (Vallar & Papagno, 1986). The auditory-verbal STS is specific for verbal material. The performance of patients KF and JB (Shallice & Warrington, 1974) in the short-term recall of sequences of three familiar sounds was comparable to that of control patients, who were engaged in a concurrent articulatory suppression task (i.e. the continuous uttering of an irrelevant speech sound, such as blah, blah, blah). This prevents the operation of the rehearsal process, which is not utilised by patients with a defective auditory-verbal span (see later). In the three patients of Tzortis & Albert (1974) recall of nonverbal sequences (meaningful sounds and rhythms) was defective. Their performance, however, was not compared to that of normal subjects during articulatory suppression. The putative impairment of Tzortis and Albert’s (1974) patients could

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FIGURE 15.10

Deficits of auditory-verbal STM. Immediate free recall of 12 word lists by patient PV and 16 normal control subjects. The patient’s performance in the recency part of the list was defective with auditory (a), but not with visual (b), presentation of the stimuli (redrawn from Vallar & Papagno, 1986).

therefore be due to the availability to normal controls of the process of rehearsal, rather than to a deficit of auditory nonverbal memory. The view that retention of auditory nonverbal material makes use of a component different from the auditoryverbal STS is also supported by the finding that patient EA was able to monitor sequences of tones presented at a rate higher than two stimuli per second, which did not allow the utilisation of rehearsal (Friedrich, Glenn, & Marin, 1984). To summarise, the observation that some patients with a defective auditory-verbal span show a preserved immediate retention of auditory nonverbal material (meaningful sounds, tones) suggests the existence of an auditory nonverbal STS, independent of the auditory-verbal component. The locus o f the auditory-verbal STS: Perception or production ? Many multicomponential models of memory proposed in the early 1970s include a STM component. According to some of them the verbal STS is acoustic in nature, with an input locus (e.g. Sperling & Speelman, 1970). In others models the verbal STS is articulatory, with an output locus

(Baddeley, Thomson, & Buchanan, 1975; Ellis, 1979; Morton, 1970) The two types of models also differ in the relationships between verbal STM and linguistic processes. The input STS may participate in the process of language comprehension, while the output STS may be involved in speech production. Neuropsychological evidence concurs to suggest an input locus of the verbal STS. Patient JB had a normal spontaneous speech, as assessed through a quantitative analysis of pauses and speech errors (Shallice & Butterworth, 1977). In patient PV spontaneous speech was normal at a clinical assessment and articulation rate was within the normal range (Vallar & Baddeley, 1984a). The hypothesis of an output locus of the verbal STS predicts, by contrast, an abnormal speech output, with increased pauses and phonemic errors. An additional case for an input locus of the store is provided by the auditory/visual dissociation discussed earlier. A functional architecture including two input STSs (auditory-verbal and visual, see Fig. 15.2) readily accounts for the visual advantage in immediate memory, as the latter store is preserved. An output locus of the store does not

15. NEUROPSYCHOLOGICAL DISORDERS OF MEMORY

explain this modality difference, unless a further distinction is drawn between two output stores, one for auditory and one for visual material. The articulatory nature of the output store, and its role in language production, make this hypothesis unlikely, however. The fractionation of auditory-verbal STM Studies in normal subjects suggest a fractionation of auditory-verbal STM into a phonological STS, the main storage component of the system, and an articulatory rehearsal process. Auditory-verbal material has a direct access to the phonological STS, which has an input locus. The rehearsal process prevents the decay of the phonological trace, and conveys written material to the phonological STS, after phonological receding (Baddeley, 1992; Sperling, 1967; Vallar & Baddeley, 1984a; Vallar & Cappa, 1987). The fractionation of verbal STM is suggested by the effects of two phonological factors on immediate serial span, and by their interactions with articulatory suppression (Baddeley, Lewis, & Vallar, 1984), which prevents the operation of the rehearsal process. Normal subjects have a higher memory span with phonologically dissimilar stimuli, compared to similar (e.g. K, F, Z, vs. B, C, T: phonological similarity effect). Articulatory suppression abolishes the effect of phonological similarity with visual, but not with auditory presentation of the stimuli. This modality difference suggests that auditory material has a direct access to a nonarticulatory phonological STS. Visual stimuli, conversely, require the additional operation of rehearsal, which is disrupted by articulatory suppression (Baddeley et al., 1984; Levy, 1971). The articulation of irrelevant speech abolishes also the effect effect of item length, a phenomenon whereby span is higher for short letter strings (e.g. dog) than for long ones (e.g. hippopotamus), Suppression wipes out the item length effect with both input modalities, suggesting an articulatory nature of the phenomenon. In this respect the rehearsal process may be metaphorically described as a tape with a finite length, which carries more short letter strings than long ones, and where the temporal duration of the stimuli is the relevant variable (Baddeley et al.,

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1975, 1984; Baddeley & Andrade, 1994; Caplan, Rochon, & Waters, 1992, for an alternative view). These effects have been studied in a number of patients with a selective deficit of auditory-verbal span. Most patients showed the effect of phonological similarity with auditory, but not with visual presentation, while the effect of item length was absent in both input modalities. This pattern, which is similar to the behaviour of normal subjects during articulatory suppression, suggests an account of the span deficit in terms of a selective impairment of the rehearsal process. This interpretation is implausible, however. In addition to the arguments discussed in the previous section, which suggest an input locus of the disorder, articulatory suppression produces in normal subjects a minor, albeit significant, reduction of auditory digit span (from 7.96 to 5.79 in Baddeley & Lewis, 1984). By contrast the patients' span is much lower (2.3 digits, according to the metaanalysis of Vallar & Papagno, 1995). Furthermore, in immediate free recall of auditory lists of words these patients show a defective recency effect, to which the rehearsal process provides a minor contribution (discussion in Vallar & Papagno, 1986). Finally, patient PV had a normal performance in phonological tasks (rhyme judgement, stress assignment) that involve the process of rehearsal (Vallar & Baddeley, 1984b). In sum a selective deficit of rehearsal does not account for the complete pattern of impaired and preserved performances of patients with a defective auditory-verbal span. The more plausible interpretation is in terms of a pathologically reduced capacity of the phonological STS. Vallar and Baddeley (1984a), who assumed that the process of rehearsal makes use of components participating in the production of speech, suggested that patient PV did not make use of rehearsal due to a strategic choice. There may be little advantage in conveying visual-verbal material to a defective phonological STS, or rehearsing traces held in this damaged system (see Fig. 15.2). This hypothesis predicts that articulatory suppression, (which impairs the performance of normal subjects) should not affect the patients' defective visual-verbal span; they would hold visual-verbal material in the preserved visual-verbal STS, rather than in the

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damaged phonological STS, and, therefore, would not use the process of rehearsal. The lack of disruptive effects of articulatory suppression on the visual-verbal span of patients PV (Vallar & Baddeley, 1984a) and RR (Bisiacchi, Cipolotti, & Denes, 1989) confirms this interpretation. The phonological output buffer (or phonological assembly system, see Fig. 15.2) component of the rehearsal process is preserved, however. This accounts for the normal speech production of some patients with a defective auditory-verbal span (Shallice & Butterworth, 1977, patient JB; Vallar & Baddeley, 1984a, patient PV). The operation of the process of rehearsal has also been investigated in anarthric patients, who, due to brainstem or cortical damage, were unable to utter any speech sound. Auditory digit span was within the normal range, even though in some patients the response was very slow and effortful, due to the severity of the motor deficit. In some of them, normal effects of phonological similarity and item length have been found (Baddeley & Wilson, 1985; Cubelli & Nichelli, 1992; Vallar & Cappa, 1987; Vallar & Papagno, 1995, for review). Furthermore, children with congenital anarthria had a normal span and showed the standard effects of phonological similarity and item length (Bishop & Robson, 1989). This indicates that the process of rehearsal does not require to be implemented at the level of the peripheral musculature, involving instead a more central stage, such as premotor programming of speech output (the phonological output buffer or assembly system of Fig. 15.2). Vallar et al. (1997) have recently investigated a patient with a major impairment of the process of articulatory rehearsal, with little, if any, damage to the phonological STS. This patient, who had nonfluent spontaneous speech, showed a reduced auditory-verbal span, which improved when a nonverbal response (recognition by pointing among alternatives) was used (related evidence in Kinsboume, 1972; Romani, 1992). The patient was also impaired in phonological tasks (rhyme and initial sound judgements), which involve the operation of rehearsal (see also Caplan & Waters, 1995), but showed a

relatively preserved recency effect, suggesting that some capacity of the phonological STS was available. Finally, the process of phonological recoding may be selectively impaired, with sparing of both articulatory rehearsal and the phonological STS. Two patients have been described: MDC (Vallar & Cappa, 1987) and FC (Cubelli & Nichelli, 1992), who had a normal auditoryverbal span, and bilateral and left-sided damage to the prerolandic frontal regions. The effects of phonological similarity and item length were present with auditory presentation, but absent when input was visual. This dissociation suggests that written material could not enter a preserved rehearsal process, due to a defective phonological recoding. This interpretation is supported by the finding that MDC’s ability to make phonological judgements on written material was defective. STS and long-term learning Phonological STS. Patients with damage to auditory-verbal (phonological) STM may have a preserved performance in a number of tasks that assess long-term acquisition and retention of verbal material: learning of word lists and of a short story, paired-associate learning (review in Vallar & Papagno, 1995). In the immediate free recall of lists of auditory words, the level of performance in the earlier positions, which is mainly based on LTM processes, was preserved, but the patients showed a reduced or absent recency effect, which represents the output of the phonological STS (see Fig. 15.10). The ability of these patients to learn visuospatial sequences may be also preserved (patient PV: Basso et al., 1982). This dissociation between defective verbal STM and preserved verbal LTM is however confined to real words, which have pre-existing lexicalsemantic representations. The acquisition of novel words, by contrast, is also based on STM processes. Patient PV was unable to learn novel words (Russian words transliterated into Italian) in a paired-associate paradigm, while learning of Italian words was normal (Baddeley, Papagno, & Vallar, 1988, see Fig. 15.11). A 22-year-old man, SR, who had a defective auditory-verbal span compared to

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controls matched for age and educational level, exhibited a similar pattern of impairment (Baddeley & Wilson, 1993). Unlike patient PV, subject SR did not suffer a brain disease in adult age, but his deficit was likely to be congenital. These observations suggest that phonological memory participates in the acquisition of vocabulary. Studies in normal subjects and children have provided converging evidence. Phonological similarity, item length, and articulatory suppression, which reduce verbal span, interfering with the operation of the articulatory rehearsal-phonological STS system, disrupted learning of nonwords, but did not affect the acquisition of real words (Papagno, Valentine, & Baddeley, 1991; Papagno & Vallar, 1992). In children, the level of performance in tasks that assess phonological memory, such as nonword repetition, was highly correlated with the successive acquisition of vocabulary, both in the native (Gathercole & Baddeley, 1989) and in a foreign language (Service, 1992; Service & Kohonen, 1995). The correlation of vocabulary acquisition with other abilities

(reasoning, syntactic and semantic skills, copying nonwords) was comparatively minor. In line with these results, polyglot subjects had a higher auditory-verbal span and a superior learning of non words, compared to matched nonpolyglot subjects; the two groups had a similar level of performance in tasks assessing visuospatial memory, reasoning, and word learning (Papagno & Vallar, 1995). Finally, FF, a 23-year-old woman, suffering from Down’s syndrome, with defective intelligence, episodic memory, and visuospatial processes, was able to learn three languages (Italian, English, French). FF’s phonological STM was preserved and she was able to learn novel words (Fig. 15.11), with an acquisition rate similar to that of normal subjects (Vallar & Papagno, 1993). This observation, which complements patient PV’s pattern of impairment, suggests a relevant role of phonological STM in vocabulary acquisition, which may take place also in the presence of severe cognitive deficits. These findings have been replicated in a 20-year-old

FIGURE 15.11

Phonological STM and vocabulary acquisition. Paired-associate learning of (a) Italian word pairs and (b) Italian word-nonword pairs (Russian words transliterated into Italian). Patients: PV, a left brain-damaged patient, suffering from a selective deficit of phonological STM; FF, suffering from Down’s syndrome. PV, but not FF, was able to learn Italian words with a rate similar to that of normal subjects. FF, but not PV, was able to learn nonwords (redrawn from Baddeley, Papagno, & Vallar, 1988; Vallar & Papagno, 1993).

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woman, CS, suffering from Williams’ syndrome (Barisnikov, Van der Linden, & Poncelet, 1996). Visuospatial STS. Patient ELD (Hanley et al., 1990; Hanley et al., 1991), who had a defective visuospatial span (see earlier) was also unable to learn novel material, such as faces and objects. Her memory for familiar material was, by contrast, preserved. Her defective recognition of faces was confined to individuals who became famous after the onset of her disease (1985). These experimental findings confirm the patient’s report: defective orientation in houses where she had never been before, defective recognition of faces of people met after the onset of her illness. This pattern of LTM impairment is similar to PV’s defective learning of nonwords (Baddeley et al., 1988). Taken together, these findings suggest that the acquisition of unfamiliar verbal and nonverbal material (nonwords or new faces) requires temporary retention in specifically committed STS systems. The studies concerned with vocabulary acquisition mentioned earlier indicate that the building up of stable phonological entries may be supported by the temporary availability of such representations, provided by the phonological STSrehearsal system. By contrast, the acquisition of lists of real words does not involve novel phonological representations, being supported instead by preexisting lexical and semantic knowledge. The findings of Baddeley et al. (1988), Vallar and Papagno (1993), and Hanley et al. (1990,1991) support therefore the traditional serial architecture of memory processes (see Fig. 15.1), whereby the stable acquisition and retention of novel material (e.g., novel words or faces) requires temporary storage in the specifically committed STS (phonological, visuospatial). Some results in patients with defective visuospatial STM suggest however a parallel, independent architecture of STM and LTM systems, in which some types of material may be acquired in the presence of defective STM. The two patients of De Renzi and Nichelli (1975) showed a disproportionately low visuospatial span (2.5 positions), without deficits of spatial orientation, and were able to learn the pathway of an unfamiliar visual maze.

Neural correlates Phonological STM The main anatomical correlate of defective auditory-verbal span is a lesion in the left inferior parietal lobule (supramarginal gyrus). These observations are based on a variety of anatomical data (neurosurgery, post-mortem exam, brain scan, CT) (reviews in Shallice & Vallar, 1990; Vallar & Papagno, 1995). In line with these findings, Risse et al. (1984) showed in a series of 20 left braindamaged patients an association between defective auditory-verbal span and posterior lesions (inferior parietal lobule), while damage to the frontal regions or the basal ganglia did not impair the patients’ immediate memory. The PET study of Perani et al. (1993) in 18 patients suffering from dementia of Alzheimer type showed a correlation between auditory-verbal span and metabolic activity in a number of regions in the left hemisphere (associative and basal frontal areas, posterior parietal, and superior temporal regions). Converging evidence has been more recently provided by functional neuroimaging activation studies. In normal subjects Paulesu et al. (1993) measured by PET rCBF during immediate memory for letter sequences, a task that engages both the phonological STS and the rehearsal process, and a rhyme judgement task, specific for the latter component of phonological STM. A comparison between the patterns of activation during these two tasks suggested that the inferior parietal lobule (supramarginal gyrus) is the neural correlate of the phonological STS, a left premotor frontal region (Broca’s area 44) of the process of rehearsal. Successive activation studies in normal and dyslexic subjects have confirmed and extended these results, showing that the neural correlates of rehearsal include a number of regions in the left hemisphere (premotor areas 44 and 6, and the insula, Fiez et al., 1996, for review of recent PET activation studies; Paulesu, Frith, Snowling et al., 1996; Schumacher, Lauber, Awh et al., 1996, for related evidence). This localisation is compatible with the view that the process of rehearsal makes use of systems that participate in the articulatory programming of speech production (see Shallice & Vallar, 1990; Vallar & Baddeley, 1984a).

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This anatomical dissociation of the neural correlates of the phonological STS and the process of rehearsal has recently been confirmed in two patients (LA and TO) with selective deficits of these components of phonological STM (Vallar et al., 1997). In patient LA, who had a disproportionately reduced capacity of the phonological STS, the left inferior parietal lobule and the superior and middle temporal gyri were damaged, in line with previous observations (Vallar & Papagno, 1995). Patient TO, in whom rehearsal was defective, had a subcortical frontal lesion, involving the left premotor and rolandic regions, the frontal paraventricular area, and the anterior part of the insula. Visual and spatial STM In the 1960s Kimura (1963) and Warrington & James (1967) found that right brain-damaged patients were disproportionately impaired in number estimation, a task that is likely to involve both perceptual and STM processes. In addition, in the series of Warrington and James (1967) patients with parietal damage had the more defective performance, in both the contralesional and the ipsilesional half-field. Right brain-damaged patients, however, were also impaired in a dot detection task; this suggests the existence of a perceptual deficit, which might account, at least in part, for the memory disorder. De Renzi and his co-workers used Corsi’s block tapping test (De Renzi, Faglioni, & Previdi, 1977a; De Renzi & Nichelli, 1975). Both left and right brain-damaged patients with visual half-field deficits had a disproportionately low visuospatial span, but damage to the right hemisphere appeared to be more relevant. This hemispheric asymmetry was confirmed by single-case studies of patients with a defective visuospatial span. De Renzi and Nichelli (1975) reported two patients whose only neurological deficit was a left homonymous hemianopia: one had undergone a right occipital lobectomy and coagulation of the right amygdaloid complex and the right fornix, the other had suffered a cerebrovascular attack in the right hemisphere. Patient ELD (Hanley et al., 1990, 1991) had an extensive fronto-temporal infarction, due to the rupture of an aneurysm of the right middle cerebral artery.

Also PET studies suggest a main role of the right hemisphere. Perani et al. (1993) in patients with dementia of the Alzheimer type found a correlation between the patients’ performance in the block tapping test and metabolic activity in the right fronto-parietal association cortex. Jonides (1993) compared rCBF in two conditions in normal subjects: deciding whether or not an outline circle encircled a dot (perceptual task), or the position where a dot had been presented three seconds before (STM task). In the latter condition a number of right hemisphere regions were activated: visual association cortex (area 19), inferior parietal lobule (area 40), prefrontal cortex (area 47). According to Jonides et al. (1993) these regions may be involved in different aspects of short-term retention of visuospatial information: the occipital regions in image generation (related evidence in Kosslyn, Alpert, Thompson et al., 1993), the parietal cortex in the computation of the coordinates of the stimulus, the prefrontal cortex in storage and retention. Kinsboume and Warrington (1962) described four patients who were able to recognise individual visual stimuli (letters, numbers, geometric figures). If two stimuli were simultaneously presented, however, one of them was not identified (defective simultaneous form perception). The deficit was independent of the spatial position of the stimuli (horizontal, vertical), and, therefore, was not a manifestation of spatial hemineglect. Number estimation (see Warrington & James, 1967) was also preserved. This deficit was interpreted in terms of the reduced capacity of a visual STS (see McCarthy & Warrington, 1990, pp.280-285). All four patients had lesions in the left hemisphere. In one patient a post-mortem examination showed left occipital damage, with a minor involvement of the superior temporal region (Kinsbourne & Warrington, 1963). Finally, left parieto-occipital lesions disrupt the patients’ ability to reproduce sequences of visual-verbal and nonverbal stimuli, immediately after presentation (Warrington & Rabin, 1971). Recent PET activation studies by Smith et al. (1995) provide evidence for an anatomical dissociation between spatial (position) and object visual short-term memory. The spatial task, as

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discussed previously, activated primarily right hemisphere regions (occipital, posterior parietal, premotor, and prefrontal), and a comparable object recognition task activated left hemisphere regions (inferior temporal, posterior parietal) (review in Smith & Jonides, 1995). In line with these findings, McCarthy et al. (1994) found by fMRI a right-sided prefrontal activation in a task requiring the shortterm retention of spatial locations. To summarise, a distinction can be drawn between two visual STS systems with discrete anatomical correlates: (1) a visuospatial STS in the right posterior-inferior parietal and frontal cortices; (2) a visual STS in the left occipito-parietal association cortex. The former system is involved in the retention of information concerning the spatial position of a stimulus (a “where” system, see Wilson, O’Scalaidhe, & Goldman-Rakic, 1993). The specific role of the frontal component may concern a representation of spatial position in terms of motor programmes towards relevant targets. The latter system is concerned with the retention of visual stimuli, coded in terms of shape.

NOTES 1. Since the end of the 19th century up to the 1950s, unitary models of memory have been the leading view. The early and seminal studies by Ebbinghaus (1885), Bartlett’s (1932) original approach, and the great deal of experimental studies that investigated the learning processes in the context of the theory of associative interference, very influential between the 1930s and the 1950s (discussion in Baddeley, 1976), were concerned with problems different from the fractionation of memory systems. 2. The pairs of terms STM/LTM and primary/secondary memory (James, 1895; Waugh & Norman, 1965)

may be considered largely equivalent. In this chapter the terms STM and LTM are preferred, as they are widely used in the neuropsychological literature. According to Atkinson and Shiffrin (1968) STM and LTM denote the experimental paradigms. A typical STM task involves the immediate recall of a limited amount of material. A LTM task, by contrast, requires the acquisition of a larger amount of material, which is recalled or recognised after a longer retention interval. The term “Store” (STS, LTS) denotes the components that subserve the retention process (theoretical construct). 3. Immediate memory span is the longest sequence of letters, digits, words, or other stimuli (e.g. spatial positions), that a subject is able to repeat or reproduce in the presentation order (Jacobs, 1887). According to a popular view immediate memory span is 7 ± 2 stimuli (Miller, 1956). 4. According to Atkinson and Shiffrin (1971, p.88) short-term forgetting is due to a displacement mechanism: as the capacity of the STS is limited, new items displace the old ones. According to Waugh and Norman (1965), the decay of the memory trace also contributes to forgetting, as material that is not rehearsed may be lost, in the absence of displacement. 5. In the early 1980s, the term procedural memory denoted systems different from declarative memory (Cohen & Squire, 1980). Procedural memory, however, referred mainly to the progressive acquisition of specific skills (e.g. visuo-perceptual abilities), and did not include the whole variety of nonconscious LTM processes. The more neutral term nondeclarative memory is therefore used. The term propositional memory (Tulving, 1983,1984) refers to declarative memory systems. 6. In memory experiments (e.g. the Brown-Peterson task), the term proactive interference refers to the negative effect of preceding stimuli on the recall of subsequently presented material. The interference effect is revealed by a progressive decrement of performance level.

Part IV

Recognition Disorders

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16 Agnosia Ennio De Renzi

The concept of agnosia is defined in both positive and negative terms. It refers to patients who show recognition deficits in one sensory modality, which are not accounted for by elementary sensory or oculomotor disorders, attentional impairment, disruption of language mechanisms, and severe mental deterioration. These constraints do not imply that these functions must be wholly intact, but that the degree of their impairment is not proportionate to the recognition impairment, as shown by the absence of agnosia in patients with comparable deficits and the fact that the breakdown occurs at definite levels of the perceptual process. Although agnosia is an uncommon symptom (there are around 100 published cases of visual agnosia, Farah, 1991, and those of tactile agnosia are much rarer), its contribution to our understanding the brain organisation of recognition is of paramount importance. Before dealing with recognition disorders, we will briefly outline the anatomo-functional organisation of the visual cortex and the more elementary perceptual symptoms that can result from its damage.

ANATOMO-FUNCTIONAL ORGANISATION OF THE VISUAL CORTEX Traditionally, visual functions were attributed to the calcarine cortex (area 17) and to the surrounding associative areas (area 18 and 19). Actually, a much larger number of visual areas have been identified in the monkey, some localised outside the occipital lobe. Eleven have a prevalent or exclusive visual function, four are polyfunctional, and five have a probable visual characterisation (Van Essen, 1985). In agreement with this multiple cortical representation, vision is currently conceived of as a process that involves successive stages and assigns the analysis of the stimulus perceptual features to discrete centres (DeYoe & Van Essen, 1988; Livingstone and Hubei, 1988). A functional specialisation of visual input is already apparent at the level of the retina, where two types of ganglion cells, with opposite properties, have been identified both in the cat (where they are called Y and X cells) and in the monkey (where they are called A and B cells). The former respond steadily to the presence of the 371

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stimulus, have small receptive fields and slow conducting axons. The latter respond transiently to the presence of the stimulus, have large receptive fields and fast conducting axons. These cells give rise to two discrete efferent systems, which maintain their independent course throughout the brain, well beyond the primary visual areas, and have distinct functions. One is called the magno system and corresponds to the efferents from retinal A cells to the two ventral magnocellular layers of the lateral geniculate nucleus, from where it projects to area V 1, first making connection with the cells of the sublayer 4Calpha and then with those of the sublayer 4B. The magno system terminates in area MT, located on the lateral surface of the posterior temporal lobe at the border of the occipital lobe. The projections from 4B to MT are either direct or indirect, via a preliminary synapse in a region of area V2, where cells stained with cytochrome ossidase appear grouped in thick stripes. This system is devoted to the processing of information related to movement direction and stereoscopic vision. The cells of the thick stripes also project to area V3 and V3A, where there are neurones sensitive to line orientation and possibly engaged in the processing of form information. The other system is called parvo and corresponds to the projections of retinal B cells to the four dorsal layers of the geniculate body. Its output is to the cells of the sublayer 4Cbeta of VI, from which two discrete pathways can be traced. One projects first to spots or “blobs” of cells that are located in layers 2 and 3 of V 1 and are stained by cytochrome oxidase, then to the thin stripes of V2 and finally reaches area V4. This subdivision is thought to be dedicated to colour detection. The other subdivision projects to the “interblob” cells of area V 1 (not stained by cytochrome oxidase) and then to the pale stripes of area V2, whose output is to V4 and to the visual area TEO of the temporal lobe. It would be specialised for the processing of information concerned with line orientation and shape. The main conclusion to be drawn from these findings is that different areas of the brain are dedicated to the processing of different features of the visual stimulus. Movement and stereopsis

pertain to the competence of the magno system and are encoded by MT. Colour is analysed by the subdivision of the parvo system that has its terminal station in V4. Cells sensitive to line direction and shape are found in several areas, but particularly in V2, V3, V4, and TEO. The further processing of visual data is thought to occur in the inferior temporal and the parietal cortex, linked to the lower centres by a ventral and a dorsal pathway, respectively (Mishkin et al., 1983). The ventral pathway consists of multisynaptic connections that follow the route of the inferior longitudinal fasciculus and connect the occipital areas with the inferior temporal areas (areas TEO and TE in the monkey), where the identification of “what” the stimulus represents occurs. The dorsal pathway, which consists of multisynaptic connections that follow the route of the superior longitudinal fasciculus, links the striate and peristriate areas with the inferior parietal lobule, which analyses “where” the stimulus is located. This strict segregation of functions, proposed by Livingstone and Hubei (1988), has been partially attenuated and modified by recent studies. They have shown that blobs and interblobs also receive input from the magno system (Nealey & Maunsell, 1994), that within area V4 there are anatomical subdivisions, which correspond to discrete input and output projections with presumably different functional characteristics (DeYoe et al., 1994) and that an important contribution to the dorsal channel is also made by collicular projections, probably via the medial pulvinar (Gross, 1991).

PERCEPTUAL DEFICITS Cortical blindness A bilateral lesion of the calcarine fissure or of the optic radiations causes blindness, characterised by: 1. Loss of vision, which in some cases may not be total, permitting light and movement perception. 2. Preservation of the light reflex. 3. Substitution of the dominant alpha rhythm with a slow posterior dominant rhythm of reduced voltage, unresponsive to eye opening. Visual

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evoked potentials are of limited value in the evaluation of cortical blindness (Aldrich et al., 1987). 4. Anosognosia for blindness and an amnesicconfabulatory syndrome, which are, however, present in few patients only. By far the most common aetiology is vascular, caused by emboli to the posterior cerebral arteries, which occur either spontaneously or following medical procedures (heart surgery, vertebral angiography, etc.). The onset of blindness is usually sudden, though in some cases it is preceded by unilateral hemianopia, the disease progressing in two successive strokes that involve first one occipital lobe and then the other (Bogousslavsky et al., 1983). In the course of a spontaneous or eclamptic hypertensive crisis, cortical blindness can also result from a rapidly developing brain oedema, which compresses the posterior cerebral arteries against the tentorium and produces bilateral occipital ischaemia. The literature (see Symond & McKenzie, 1957, for a review of old cases) has pointed out great variability in the evolution of the deficit, which ranges from complete blindness — in no more than 10% of cases, according to Aldrich et al. (1987) — to complete recovery (Gloning et al., 1968). Brindley and Janota (1975) reported on a patient who, 11 years after the stroke, was still unable to distinguish darkness from light. Yet in a similar patient (Perenin et al., 1980), it was possible to demonstrate with the forced choice method that he could detect moving stimuli and estimate by pointing the position of flickering lights. These residual capacities, similar to the phenomenon of “blind sight”, observed in hemianopic patients, were attributed to the transmission of visual information by extrastriate (collicular-pulvinar) pathways. If no improvement occurs within the first week, visual function is likely to remain severely impaired (Aldrich et al., 1987) and some of these patients pass on to the stage of apperceptive agnosia. Denial of blindness, or lack of concern for the loss of sight, was the first instance of anosognosia reported in the literature (Anton, 1898). Its manifestation is often astonishing. The patient reported by Dejerine and Vialet (summarised by

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Symonds & McKenzie, 1957) denied being blind, gave confabulated names to the objects presented by the examiner and, if his responses were questioned, apologised for his mistake by saying that a tear in his eye had prevented him from seeing clearly. It has been argued (Goldenberg, 1995; Redlich & Bonvicini, 1907) that the patients’ claim to be able to perceive and describe the visual features of stimuli they do not actually see is contingent on the translation of acoustic or tactile images into visual images and on the confusion between visual images and visual perceptions. Denial of blindness tends to be associated with amnesia, temporal disorientation, and mental confusion, a symptom complex the French authors call Dide and Botcazo’s syndrome and that is consequent to the extension of the lesion to the medial temporal lobes. It must be stressed, however, that the frequency of denial of blindness is rarer than thought by the early literature and that it is a transient phenomenon (Gloning et al., 1968 ).

Disorders of movement perception Loss of movement perception, or akinetopsia (Shipp et al., 1994) is often found in the context of a severe disorder of form perception (Goldstein & Gelb, 1918; Milner et al., 1991; Poetzl & Redlich, 1911). A case has, however, been reported (Zihl et al., 1983), in whom akinetopsia appeared in the absence of deficits of depth and space perception, colour and form discrimination, and object and face recognition. The deficit remained substantially unmodified for 13 years after the stroke (Zihl et al., 1991) and has been the subject of repeated investigations (Baker etal., 1991; Hess etal., 1989; Paulus & Zihl, 1989; Shipp et al., 1994; Zihl et al., 1991) that have clarified its nature. The patient complained of seeing a person or an object first in one place and then in another, but of not being able to see them moving between the two places. She could not cross a road, because of her inability to judge the speed of a car. “When I am looking at the car first, it seems far away. But then, when I want to cross the road, suddenly the car is very near” (Zihl et al., 1983). She was unable to pour tea or coffee into a cup, because the liquid appeared to be frozen, like a glacier and she could not estimate its rise in the cup. A series of experiments showed that

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akinetopsia was not absolute, but varied as a function of the spatial and physical features of the movement. The perception of moving stimuli was completely lost when they occurred in depth, was limited to the discrimination between a steady and a moving stimulus at the periphery of the visual field, and was relatively preserved for slow movements at the centre of the visual field. Movement velocity was also an important variable. Only stimuli moving at a velocity between 0.1° and 10° degrees per second were perceived as moving, but their direction was often not discriminated. The movement of auditory and tactile stimuli was correctly appreciated. The lesion was located by MRI (Zihl et al., 1991) and PET (Shipp et al., 1994) on the lateral surface of the hemispheres, where it involved bilaterally areas 39 and 19 and the underlying white matter, at the border between the temporal and the occipital lobe. In primates this region corresponds to area V5 or MT, which is located in the posterior bank of the superior temporal sulcus and is thought to be specialised in movement perception. PET studies carried out in normals have confirmed the activation of an area at the confluence of the occipital, temporal, and parietal lobe on the hemisphere convexity, (corresponding to V5) ,when subjects looked at a moving random square pattern (Zeki et al., 1991) and of the left inferior parietal lobe, when they attended to changes of stimulus velocity (Corbetta et al., 1990). Interestingly, an area located 2cm in front of V5 was activated when subjects looked at object drawings and had to generate the name of an associated action (Martin et al., 1995). Disorders o f depth perception The reader is referred to Chapter 20 for a discussion of the psychophysiological basis of depth perception. Here we will limit ourselves to a reminder that a severe impairment of depth perception has occasionally been reported in patients with bilateral parieto-occipital damage (Gloning, 1965; Holmes & Horrax, 1919; Michel et al., 1965; Valkenburg, 1908), often associated with Balint’s syndrome. This was confirmed by Rizzo and Damasio (1985), who, on the basis of CT scan and MRI data, localised the lesion at the

parieto-occipital junction of both hemispheres. The deficit is usually reported by the patients themselves. Gloning et al.’s (1965) patient complained of seeing a flattened world, “like in a picture or photograph” and Holmes and Horrax’s (1919) patient was unable to say which of two persons or objects was closer or farther away. As the deficit did not change by closing one eye, it could not be attributed to loss of stereopsis alone. Milder deficits, which escape clinical observation, are brought out in a much larger number of patients, when they are systematically investigated with sensitive tests. Carmon and Bechtold (1969) used Julesz’ stereograms and found a selective impairment in right brain-damaged patients. This hemispheric asymmetry has been confirmed by Benton and Hécaen (1970) and Hamsher (1978), even in the absence of deficits in conventional tests that measure local stereopsis, such as the Titmus or the Keystone test. Danta et al. (1978), who used the “doppling bead” and the “haploscopic” method, also had data pointing to a greater contribution of the right brain to stereopsis, but cautioned that the asymmetry might be contingent on an uncontrolled matching of the locus of lesion across the hemispheric samples, especially with respect to parieto-occipital damage. Also the infero-temporal cortex is likely to contribute to global stereopsis, which was found impaired after its bilateral ablation in monkeys (Cowey, 1985) and after unilateral temporal lobectomy of either side in humans (Ptito et al., 1991). Disorders of colour perception Impairment of colour perception (a- or dyschromatopsia) will be treated later, under the heading of colour recognition disturbances.

VISUAL AGNOSIA Brain damage does not necessarily impair the recognition of all visual stimuli, but can selectively affect certain categories of percepts (objects, faces, written words, or colours), leaving others intact, in agreement with evidence from neurophysiological and neuroimaging studies that discrete cerebral

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areas are dedicated to their perceptual processing and storage. In this view, the autonomy of visual agnosias is the consequence of the anatomical separation of the corresponding neuronal substrates. Farah (1990, 1991) took exception to this assumption and claimed that what plays a crucial role in determining which kind of stimuli are impaired by the lesion is not the category to which they belong, but the way they are perceptually processed. Some stimuli (faces) are coded as a whole, while others (words) are broken up into their constituent elements (letters) and still others (objects) share one or both apperceptive modes, depending on their features.

Object agnosia In 1890 Lissauer, then a 27-year-old German neurologist of Breslau, published a paper that had a lasting influence on the way subsequent authors were to deal with the problem of visual agnosia and which for the first time clearly distinguished a perceptual from an associative form. Just a year before, Freund (1889), who worked in the same institute, had reported a case of visual recognition disorders that he interpreted as consequent to the disconnection of visual areas from language areas and named optic aphasia. These three syndromes—apperceptive agnosia, associative agnosia, and optic aphasia— still represent the building blocks of the current conceptualisation of visual recognition disorders. [The reader who is not familiar with the German language is referred to the English translation of Lissauer’s and Freund’s articles, published in Cognitive Neuropsychology, 5, 153-192, 1988 and 8, 21-38, 1991, respectively.] Apperceptive agnosia corresponds to the breakdown at the stage where the sensory features of the stimulus are processed and its structural description is achieved. Associative agnosia is believed to result from the failure of the structured perception to activate the network of stored knowledge about the functional, contextual, and categorical properties of objects that permit their identification. Optic aphasia, in turn, defines the inability to name a visually presented object that has been correctly recognised.

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Apperceptive agnosia By apperception Lissauer (1890) intended “the conscious awareness of a sensory impression” and by apperceptive agnosia, the deficits of recognition that are due to the disruption of perceptual processing in a patient who has no major deficit of elementary visual functions. The latter qualification is important to establish the autonomy of apperceptive agnosia, all the more so because several of these patients were cortically blind at the beginning of disease, and agnosia was diagnosed when elementary visual functions had partially recovered, thus raising the question of whether their residual impairment contributed to the perceptual impairment. The evidence adduced to rule out this hypothesis is that visual acuity, visual fields, movement perception, and colour discrimination are intact or at least not more impaired than in patients who can perceive objects (Adler, 1944, 1950; Benson & Greenberg, 1969; Goldstein & Gelb, 1918; Landis et al., 1982; Milner et al., 1991; Shelton et al., 1994). Benson and Greenberg’s patient (see also Efron, 1968) was able to discriminate small differences in luminance and hue, to report if an object was moving, and to decide which was the larger of two objects. Yet he failed to recognise any object, face, and letter, to match identical figures, to copy simple drawings, to isolate an object from the background (unless it was moved), to trace the contours of a curved line, or even of an object the examiner was holding. He also made many errors in discriminating a square from a rectangle of the same area (Fig. 16.1). It was concluded that the patient was unable to perceive the form of a stimulus. A few of these patients (Goldstein & Gelb, 1918; Landis etal., 1982) show an amazing ability to compensate for the visual deficit, by tracing the contours of letters and objects with minimal movements of their fingers or head. The concept of apperceptive agnosia has been subjected to attacks from two fronts; one more radical, which claims that the perceptual impairment is entirely accounted for by sensory deficits, the other, more articulated, which contrasts impaired form discrimination with the inability to construct a three-dimensional structural description of the stimulus and reserves the name of agnosia to the latter form. Bay (1953) was the strongest

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proponent of the former theory. He argued that if agnosic patients were examined with appropriate methods, they would invariably show much more severe sensory deficits than those ascertained with routine procedures. More precisely, he underscored the need to test each sector of the visual field with a dynamic procedure, based on local adaptation, i.e. on the time necessary to detect the appearance or disappearance of the stimulus. Using this procedure, it would be possible to show that stimuli presented in apparently normal areas of the field fade away much more rapidly in agnosic than in normal subjects and leave the patients with tubular vision, unsuitable for face perception. Bay’s methodology was rather crude and his claim was not supported by the findings of a much more rigorous study, in which Ettlinger (1956) investigated 30 brain-damaged patients on a wide range of elementary visual tasks (brightness discrimination, flicker fusion, acuity for small objects, tachistoscopic acuity, local adaptation, apparent movement perception). He confirmed that a certain number of patients, especially those with visual field defects, do show an impaired discrimination in perimetrically intact sectors of the field, but did not find a reliable association between sensory impairment and the presence of higher perceptual disorders. In particular, a patient with a face recognition deficit, though performing poorly, was less impaired than three patients who did not show agnosia. The same also held in an object agnosic patient reported in another paper (Ettlinger & Wyke, 1961) and in three patients with agnosia for faces and objects, recently studied with the same procedures (De Haan et al., 1995). It is unfortunate that neither Bay (1953) nor Ettlinger (1956) made a distinction between apperceptive and associative agnosia, as only in the former is the bearing of the sensory deficit upon perception crucial. For instance, the relative sparing of elementary functions manifested by the case reported by Ettlinger and Wyke (1961) may not be decisive, because the patient likely suffered from an associative form. Using a “fine-grained” static perimetry, Campion and Latto (1985) were able to show that the visual fields of their patient with apperceptive agnosia were peppered with scotomata that had gone undetected by Goldman perimetry. The authors argued that they may have

exerted a masking effect on perception. It is clear that the question of probing sensory deficits with more sensitive methods remains, but even if they were found to be invariably present, this would not necessarily imply that they are a sufficient cause of apperceptive agnosia. Let us not forget that Ettlinger (1956) reported patients who had severe sensory deficits and yet could recognise objects. Levine (1978), who found in his patient an impairment of the threshold of tachistoscopic perception and of flicker fusion, thought that sensory deficits may be necessary, but are not sufficient to cause apperceptive agnosia. A different kind of criticism of the traditional conceptualisation of apperceptive agnosia was raised by Warrington and her colleagues (Warrington, 1985; Warrington & Rudge, 1995). She emphasised that a prerequisite for differentiating these patients from those who are impaired at early stages of perception is the evidence that they are able to trace and isolate the form of the stimulus from the background. Practically all of the patients classified under the heading of apperceptive agnosia in the literature did not meet this requirement and thus should be called “pseudo-agnosie”. On the contrary, the term apperceptive agnosia should be reserved for patients who fail on perceptual categorisation, namely, the stage at which a common perceptual category is assigned to an object, whatever its condition of orientation, distance, illumination, etc. The differentiation between the two syndromes hinges on the outcome of two sets of tests. To qualify for the diagnosis of apperceptive agnosia, patients must, on the one hand, pass tests of shape discrimination and detection, such as the Efron test, in which a square must be differentiated from an oblong, matched in terms of total flux (Fig. 16.1) and a test in which a fragmented shape must be distinguished from a fragmented background (Fig. 16.2). On the other hand, they must fail a series of tests that manipulate the perceptual dimensions of the stimulus by degrading it or obscuring its salient features, such as recognising figures taken from an unusual perspective, incomplete figures, overlapping figures, foreshortened silhouettes, and shadow image projections. These tasks would implicate the ability

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FIGURE 16.1

An example of Efron’s test. The subject must say whether the two pairs of figures are the same or different.

to categorise complex visual stimuli, making reference to a stored canonical representation. This ability would be the province of the right parietooccipital cortex. This claim was based on studies in which patients with right posterior damage were found to be impaired by comparison with controls and left posterior patients in matching photographs of the same objects, taken from different views (Warrington & Taylor, 1973, 1978) and it found support in the right parieto-occipital location of lesion in three patients, who were considered typical cases of apperceptive agnosia (Warrington & James, 1988; Warrington & Rudge, 1995).

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Warrington’s position is not wholly convincing. While there is robust evidence that right hemisphere damage impairs tasks requiring subtle perceptual discrimination more than left brain damage (De Renzi & Spinnler, 1966b; De Renzi et al., 1969; Warrington & James, 1967c; Warrington & Taylor, 1973), the attribution of the deficit to a failure of perceptual categorisation rests on more flimsy data, as the hemispheric asymmetry found in matching objects photographed from different views has not been replicated by subsequent studies (Bulla Hellwig et al., 1992; Mulder et al., 1995). Moreover, it must be remarked that none of the three cases reported by Warrington and James (1988) as examples of apperceptive agnosia could be properly defined as agnosic, as they performed in the normal range when requested to recognise canonical views of objects. The same was true for patient BRA (Warrington, 1986), who failed the Efron test and did not show a deficit of object recognition. To use the label agnosia for patients who are not impaired in standard tests of object recognition is questionable and does not help us to clarify the issue. We prefer not to dwell on nominalistic discussions and to focus on the level at which the processing of perceptual information is disrupted in patients who do not have major

FIGURE 16.2

An example of Warrington and Taylor’s figure-ground discrimination test. The subject must say whether the fragmented letter superimposed upon the fragment of background is an 0 o ra n X .

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TABLE 16.1 Measures of basic visual functions and visuo-perceptual skills. Sensory tests

Visual field perimetry Visual acuity Sinusoidal gratings of different frequencies Visual evoked potentials Critical fusion frequency Hue and lightness discrimination Stereoscopic depth Movement perception P e rc e p tu a l tasks

Tracing the contours of a shape Same-different judgements of figures differing for minor details Efron test Figure-ground discrimination test Overlapping and incomplete figure identification Copying figures Perceptual categorisation

sensory deficits. Table 16.1 summarises the tasks suitable to assess sensory and perceptual functions. Shape agnosia is the inability to organise the sensory input into a coherent shape perception by discriminating the boundaries of the stimulus from the background and other contiguous or overlapping shapes. The patient is unable to: trace the contours of the stimulus; match identical shapes and distinguish those that differ for minor details; perform the Efron test and the figure-ground discrimination test; copy a figure (see Table 16.1). Recognition of drawings or photographs taken from a prototypical view is usually poorer than recognition of the corresponding objects. It is worth stressing that some of these patients maintain the ability to process the visual information that guides limb and hand movements during reaching, in spite of being unable to make simple discrimination judgements on shape and orientation. The patient with severe apperceptive agnosia reported by Milner and co-workers (Goodale et al., 1991; Milner et al., 1991; Milner & Goodale, 1995) was unable to report the orientation of a slot cut into a vertical disk or that of solid rectangular blocks, but

she oriented her hand correctly when requested to insert it into the slot or to grasp the blocks. Likewise, she failed to indicate the width of a block using her forefinger and thumb to make a perceptual judgement, but made accurate calibration of the finger-thumb separation when she had to pick up blocks of different sizes. This dissociation suggested to the authors that V 1 cells responsive to line orientation were intact, but disconnected from higher centres of the ventral streams, while maintaining connections with those of the dorsal stream. The disruption of form perception is not an all or nothing phenomenon that can be univocally assessed on the basis of the Efron test and the figure-ground discrimination test, as originally suggested by Warrington (1985), as the two performances can dissociate. Kartsounis and Warrington’s patient (1991) passed the former, but failed to identify overlapping, incomplete or poorly differentiated figures, while Davidoff and Warrington’s patient (1993) presented the opposite pattern, i.e. poor identification of simple forms and preserved discrimination of a shape from the background. Even more striking was the

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dissociation exhibited by De Renzi and Lucchelli’s patient (1993), who was able to: perform the Efron test; match an object with its pair, presented with three distractors; distinguish figures differing for minor details; and copy complex drawings in a nonslavish way. Yet she failed the figure-ground discrimination test, Ghent’s overlapping figure test, and a possible-impossible figure decision test (impossible figures are those containing subtle surface and edge violations that make their existence in space impossible). It is clear that apperceptive agnosia covers a spectrum of disorders that only a detailed analysis can bring out. A distinct form of apperceptive agnosia was identified by Riddoch and Humphreys (1987; see also Humphreys & Riddoch, 1987 and Boucart & Humphreys, 1992) under the name of integrative agnosia. Patients are able to trace the contour of a figure, to match objects for their physical appearance, and to copy a drawing they do not recognise, though the reproduction is slavish and carried out with a piecemeal approach. They fail, however, to segment elements of a complex display and to bind them together. Patients suffering from this deficit (Butter & Trobe, 1994; Graillet et al., 1990; Riddoch & Humphreys, 1987; Thaiss & De Bleser, 1992) can identify single details, which they rely on to interpret the figure, but are unable to integrate the information gleaned from these elements into a general shape and so do not attain an integrated form description. Their performance

improves when silhouettes with reduced internal details instead of drawings are used for discrimination but deteriorates when overlapping figures must be identified (Butter & Trobe, 1994; Riddoch & Humphreys, 1987) or when the exposure time is shortened. Impairment o f internal representations. The recognition process involves comparing the structured description of the object with its representation, stored in presemantic memory. In none of the reported cases was agnosia exclusively due to the inability to access stored representations or to their disruption. However, their impairment has been thought to contribute to featuring the disorders, exhibited by the patients reported by Ratcliff and Newcombe (1982), Sartori and Job (1988), Grailet et al. (1990), De Renzi and Lucchelli (1993), and Rumiati et al. (1994). The integrity of visual representations is assessed with bottom-up visual tasks or top-down verbal tasks (Table 16.2) and from their comparison it is possible to establish whether the representation is degraded or intact, but cannot be activated via a given route. Bottom-up visual assessment is based on object decision tests, requiring the patient to decide whether a stimulus corresponds to a real object or not. They range from nonsense shapes, which show a high approximation to real shapes (Kroll & Potter, 1984) to drawings that combine parts of different figures (Fig. 16.3), e.g. the head of an animal with

TABLE 16.2 Tasks to assess the internal representation. Visual s tim u la tio n

Object-nonobject decision (Kroll and Potter’s drawings; Riddoch and Humphreys’ drawings) Identifying the missing part of a drawing V erb a l stim u la tio n

Drawing from memory Verbal description of an object shape Difference between two similar objects Capital and small print letter configuration Tail and ear test Clock test

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FIGURE 16.3 Examples of the object decision test. The subject must say whether the figures correspond to a real animal or object (figures kindly provided by G. Sartori).

the body of another or the handle of an object with the body of another (Riddoch & Humphreys, 1987). Alternatively, patients can be presented with a figure missing a detail that must be identified and found among distractors. Note that none of these tasks demands the recognition of the stimulus, but simply to decide whether its configuration corresponds to a representation stored in presemantic memory. Top-down verbal tasks call for the generation of visual images, in response to the verbal requests made by the examiner. These images are thought (Farah, 1984; Goldenberg, 1993) to be retrieved from the long-term store of structured representations and to be kept in a short-term memory buffer for the time needed for their analysis. Several tasks have been devised to assess this ability: 1. Drawing from memory. Drawing skills differ from subject to subject, but what suffices here is that the basic features of the object are represented and correctly arranged in space. The possible bearing on the performance of constructional disability can be checked by copying tasks. 2. Verbal description of the shape of the stimulus. 3. Explaining the difference in shape between two perceptually similar objects, e.g. a needle and a pin, the blade of a knife and the blade of a saw, a lizard and a snake, etc. (see a list of these pairs in De Renzi & Lucchelli, 1994). 4. Judging whether a capital letter contains curved lines (D) or straight lines (M) and whether a

small print letter contains segments that extend above (t) or below (p) its main body. 5. Evoking the perceptual features of animal body parts, e.g. whether its tail is long or short and its ears are round or pointed. 6. The clock test (Grossi et al., 1989), in which the patient is asked to judge which of two orally given times (e.g. 7.15 or 7.45) has a larger angle subtended by the two hands of the clock. Occasionally dissociations among these performances are noted (Trojano & Grossi, 1992). Apperceptive agnosia may leave mental representations unimpaired, as was shown by the patient reported by Servos et al. (1995), who recognised only 11% of the line drawings of common objects and only 15% of letters, but was nevertheless able to make size discrimination, when given the name of two similar-sized objects or animals, to scan a mental image in search of particular features, and to draw lower and upper case letters from memory. Also the patient reported by Behrman et al. (1992), showed imaging integrity on verbal tasks, in the face of a severe integrative agnosia (Moscovitch et al., 1994). A likely interpretation of this dissociation is that the long-term store was accessible from higher centres, but not visual information. When the patient fails both bottom-up and top-down tasks, (De Renzi & Lucchelli, 1993), there is evidence that the long-term memory store is degraded Associative agnosia The diagnosis of associative agnosia must be envisaged when the patients fail to recognise a

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meaningful visual stimulus, whose perceptual structure has been adequately encoded. The term adequately does not mean that some minor deficit cannot be detected, as emphasised by Farah (1990), but simply that it is not sufficient to account for the recognition failure, because a comparable degree of perceptual impairment can also be found in patients who are not agnosic. Apart from the possibility that the lesion responsible for associative agnosia can impinge upon neighbouring perceptual areas, it must be pointed out that Lissauer (1890) himself had explicity warned that an associative impairment is bound to be associated with a certain degree of perceptual deficit in the fine-grained discrimination of complex stimuli, because top-down information is helpful in focusing attention on significant details. He consequently anticipated that no case of pure associative agnosia would ever be found but, at most, patients with a predominantly associative agnosia. Nevertheless, he maintained that the gist of the syndrome had to be identified in the defective arousal of associations by the visual percept. Evidence that the patient has not grasped the meaning of the stimulus must be sought in the failure on the following tasks. 1. Visual naming. The inability to name a visual stimulus in patients whose perceptual functions are adequate and whose spontaneous speech is apparently normal must raise the suspicion of agnosia and prompt testing of their naming skills in other modalities (e.g. naming on verbal definition). Some features of patients’ verbal behaviour are suggestive of the semantic nature of their deficit. Unlike aphasic anomies, they do not resort to circumlocutions in the attempt to define what the object is for. Errors are rarely based on the perceptual resemblance between the stimulus and the response, and tend to be semantic (e.g. fork for spoon) or totally unrelated to the stimulus (e.g. hammer for horse) or consist in the mere identification of the superordinate (animal for dog). Unlike apperceptive agnosia, naming drawings is not much more impaired than naming objects. Performance on verbo-visual matching tasks, i.e. pointing to a figure named by the examiner,

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is also impaired, albeit less than naming, especially when the foils are semantically related to the target. Interestingly enough, the performance can improve, if, instead of object naming, the description of a complex scene is required, possibly because recognition is helped by contextual cues (Hecaen et al., 1974). Unless the patient is prosopagnosic, familiar faces are recognised (Benke, 1988; Rubens & Benson, 1971), but named with difficulty. Naming is not the only way to show that an object has been identified and it is important to check whether the patients are also unable to demonstrate their knowledge nonverbally. 2. Miming the use o f objects. An identifying attribute of an object is the way it is used (this method is indeed frequently adopted by aphasics) and thus miming is useful in verifying whether there is a recognition deficit underlying the naming failure. The test can be given in two variants that mimic naming and comprehension, respectively. Either the patient must mime the action corresponding to a visually presented object or the examiner pretends to use an object and the patient has to select it from among foils. These performances are to be compared with miming in response to a verbal command, namely a condition that does not involve the processing of visual information. The assumption that miming represents a reliable alternative to naming as a means of proving recognition has been questioned by Ratcliff & Newcombe (1982), who argued that it lacks sufficient specificity and the use of an object can be suggested by its physical structure. There are in fact case reports of patients who produce correct mimes when shown various objects, but who fail not only to name them, but also to classify them on a semantic basis (Riddoch & Humphreys, 1987b; Schwartz et al. 1979). Particularly impressive was the dissociation shown by the patient of Sirigu et al., (1991), who could verbally describe and mime the manipulation of objects, whose function he could not identify. As he frequently remarked, “I can tell you how to use it, but I have no idea what it is used for”. The authors argued that sensorimotor experience can provide a

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self-cueing kinaesthetic strategy that helps the retrieval of actions, without activating semantic representations. It would be hazardous to make sweeping generalisations from so few case reports, not least because it has been remarked that when the patient misnames an object, he often mimes its use in agreement with the wrong identification. Yet caution must be exercised when inferring recognition from correct gesturing. 3. Semantic categorisation and association tasks. Recognition can be assessed by categorisation or association tasks, which imply knowledge of the semantic properties of the stimulus. Categorisation tasks: a set of pictures is placed on the desk in front of the patient, who must group all those belonging to the same semantic class (e.g. fruits, vegetables, tools, transportation, etc.). Association tasks: the patient is presented with a target and a number of pictures and must select which of them is related to the target, either because they have a common superordinate (e.g. both are mammals), or because they are used within the same context (e.g. tennis-racket and tennis-ball). The task may be made more difficult, if all of the alternatives bear some relation to the target and the patient is asked to identify that with the closest link (e.g. the target is a thimble and the choice is among scissors, threaded needle, buttons, and reels of thread). 4. Knowledge o f the semantic attributes that are not present in the figure, but can be readily activated, if its meaning has been decoded. For instance, a patient can be given a black and white drawing of a frog and asked the following questions. 1. Is it an animal? 2. Is it dangerous? 3. Does it live in your country? 4. Is it heavier than a cat? 5. How does it move? 6. What colour is it? The finding that a patient who has completed perceptual processing up to the activation of mental shape representations fails in the foregoing tasks is evidence that the visual input cannot gain access to semantic memory, where the attributes of an object, which confer its meaning, are stored. This condition must be differentiated from two different patterns

of deficits, optic aphasia and semantic amnesia. In the former a visual stimulus is recognised, but cannot elicit naming, whereas in the latter the knowledge of objects and their verbal labels is inaccessible, regardless of how the input is conveyed. Optic aphasia The clinical profile of optic aphasia was outlined by Freund (1889) just a year before Lissauer published his seminal paper on visual agnosia. The relation between the two syndromes has been a matter of debate for many years and is still not completely clarified. In optic aphasia there is no impairment of visual recognition, but merely an inability to name objects presented in the visual modality. It was Freund’s (1889) contention that such impairment resulted from the concurrent presence of two deficits, a lesion of the left optic pathways, which would hinder the processing of visual information by the left occipital lobe and the interruption of the pathways that connect the intact visual areas of the right occipital lobe with the speech centres, located in the left temporal lobe. The patient he reported in more detail also showed anomia in spontaneous speech, but could name objects placed in his hands, reject wrong names proposed for a visually presented object, and had no difficulty in name comprehension. Thus his language deficit did not conform to any classical aphasic syndrome. More problematic was the assumption that recognition was intact. It rested on his rare successful attempts to convey the meaning of the missing name by circumlocutions and on the claim that he knew the use of objects he could not name, but it is unclear how this was tested, as miming was not reported. Categorisation tasks were not given. In the subsequent literature, the lack of reliable criteria for distinguishing optic aphasia from visual agnosia was criticised and led to the syndrome eventually sinking into oblivion as did the fact that Freund had preceded Dejerine (1907) in introducing a disconnection paradigm to account for visuo-verbal matching deficits. Spreen et al. (1966) must be credited for having rekindled interest in optic aphasia, by reporting a patient with a left parietal tumour, whose visual naming was remarkably impaired relative to tactile

16. AGNOSIA

naming and naming on definition and who was able to define the use of objects he could not name and to point to them, when their name was given. At about the same time, Geschwind (1965) proposed an interpretation of visual agnosia, associated with left occipital damage, which was practically identical to that advanced by Freund (1889) for optic aphasia, although no reference was made to his work. The main reason Geschwind gave in support of the theory that visual agnosia did not represent a recognition disorder, but rather a visuoverbal disconnection was that agnosic patients never mistake objects in real life, as would be expected if they had indeed misidentified them. This statement is too sweeping by far and was disproven by case reports of patients who did make these mistakes (Hecaen & Ajuriaguerra, 1956; Hecaen et al., 1974; McCarthy & Warrington, 1986; Rubens & Benson, 1971). Moreover, a mere reduction of visual agnosia to optic aphasia would not account for patients’ poor performance on tasks that do not involve verbal skills, such as miming and semantic categorisation. It is, however, true that in most agnosic patients there is a disproportion between the few errors they make in everyday life and the much more severe impairment shown on naming tasks, if the latter were entirely due to a recognition deficit. Although this discrepancy may in part be due to the fact that contextual cues and tactile information provided by handling the object make recognition easier, it does suggest that a disconnection component contributes to the poor naming performance even in associative agnosics. In recent decades the number of reported cases of associative agnosia and optic aphasia has increased quite considerably (for a review, see Iorio et al., 1992 and Davidoff & De Bleser, 1993, to which the case reports of Hillis & Caramazza, 1995, Campbell & Manning, 1996, and De Renzi & Saetti, 1997, must be added), thus providing a sufficient body of information for a balanced discussion of the relation between the two syndromes. An important, preliminary remark is that the two forms may be associated with the same locus of lesion, a finding not easily reconcilable with the assumption that they are subserved by discrete mechanisms. Contrary to apperceptive agnosia,

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which is usually caused by bilateral damage, a large number of patients with associative agnosia have a lesion confined to the left medial occipitotemporal areas (most cases have an infarct of the left posterior cerebral artery), as do patients with optic aphasia. This coincidence cautions against too rigid a differentiation between the two syndromes and invites to close inspection of whether the criteria used to contrast them are reliable. As already mentioned, patients with associative agnosia are expected to fail and patients with optic aphasia to pass the following tests: 1. Verbo-visual matching in name comprehension tasks. 2. Ability to circumvent anomia on visual confrontation tasks by providing information on the function and other nonperceptual features of the stimulus. When naming errors occur in optic aphasia, they should be predominantly semantic, indicating that some information on the nature of the stimulus has reached the left hemisphere. 3. Miming the use of objects. 4. Grouping stimuli on the basis of their categories and matching stimuli on the basis of their semantic association. As a matter of fact only a minority of patients labelled optic aphasics have been exhaustively tested and very few of them (Coslett & Saffran, 1992; Gil et al., 1985; Manning & Campbell, 1992) comply with all of the requirements set forth to validate the integrity of recognition. Moreover, their semantic knowledge was not perfect (Gil et al., 1985; Manning & Campbell, 1992, see also Campbell & Manning, 1996) and the tests proposed were not demanding enough. For instance, both Hillis and Caramazza (1995) and De Renzi and Saetti (1997) have shown that patients who perform well on association tests fail when the foils bear a semantic relation to the target as well, albeit not such a close relationship as the correct answer. These findings suggest that it is exceptional for patients labelled optic aphasics to give evidence of intact access to the complete semantic entry of the stimulus. On the other hand, a closer inspection of the cases of associative agnosia consequent to left

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brain damage (for a review, see De Renzi & Saetti, 1997) reveals that patients classified in this way were able to pass some tasks requiring the identification of the meaning of the stimulus. It seems, therefore, that patients with optic aphasia and associative agnosia differ quantitatively more than qualitatively and lie in a continuum of progressively more severe semantic deficits, whose opposite ends may be instantiated by Lhermitte and Beauvois’ (1973) patient, who apparently had only a naming problem, and Lhermitte et al.’s (1973) patient, who failed all tests of nonverbal recognition (despite passing a semantic association test with unrelated foils). In agreement with this account, are reported cases (Bauer & Rubens, 1985; De Renzi et al., 1987) whose clinical pattern has evolved from associative agnosia to optic aphasia, possibly thanks to the improved exploitation of the semantic potential of the right hemisphere. So, the question of interest is what factor accounts for the different semantic impairment of these patients? Coslett and Saffran (1989, 1992) agreed with Freund’s interpretation of optic aphasia as a disconnection between the right hemisphere and the left hemisphere, but added that the former uses structured descriptions to activate its own semantic store, which would be as capable as that of the left hemisphere to mediate nonverbal semantic knowledge, except for the inability to access the phonological output lexicon, as it is located on the left side. This account incurs two difficulties. First, if the semantic potential of the right hemisphere is adequate for object recognition, why does it not work in those agnosic patients who have the same lesional pattern as optic aphasics? Second, there is evidence from group studies (De Renzi et al., 1969; Warrington & Taylor, 1978) that the level of nonverbal semantic competence of the right hemisphere is not as effective as that of the left hemisphere, an asymmetry in agreement with the less than perfect performance shown by almost all optic aphasics on demanding semantic tests. So, Coslett and Saffran’s hypothesis requires two further specifications: first, the right hemisphere is usually less proficient at decoding the meaning of visual stimuli than the left hemisphere and, second, its semantic competence may show remarkable variation from subject to subject. It is this

premorbid individual feature that determines the degree to which the right hemisphere can compensate for the left side’s lack of contribution to visual semantic processing and whether the clinical profile of the patient is more skewed towards optic aphasia or visual agnosia. The issue of individual differences tends to be neglected by the neuropsychological literature, mainly because they cannot be ascertained in the healthy subject and are only inferred post-hoc, on the basis of different patterns of impairment associated with the same pathological findings (De Renzi et al., 1987,1994). Hopefully, functional MRI studies carried out in normal subjects will provide empirical evidence that will help to solve this issue, if, instead of averaging across subjects, they focus on interindividual variations and assess how consistent they are. A marked variability in the size of the primary visual cortex has been documented by anatomical studies (Dobell & Mladejowsky, 1974; Stensaas et al., 1974) and in the functional representation of language by stimulation studies (Ojemann & Whitaker, 1978). This conceptual framework accounts for some of the features of optic aphasia. One of them is the superiority of comprehension over naming in a visuo-verbal matching paradigm. This discrepancy may be contingent on anatomical reasons, as the splenial lesion interrupts the transmission of visual information to the speech centres, while leaving the anteriorly located auditory callosal connections that transmit the output of Wernicke’s area to the right hemisphere undamaged (McCormick & Levine, 1983). Moreover, the investigation of epileptic patients who underwent callosal section (Zaidel, 1990) has shown that the right brain has lexical competence in name comprehension. It follows that, while the entity of the naming impairment is proportional to the severity of splenial disconnection, the ability to match a name with an object is a function of the right hemisphere lexical and semantic knowledge. As for miming, its performance depends on the extent of interhemispheric connections involved by the task. Miming on command is intact, as the semantic store for gestures is located in the same left hemisphere that decodes verbal information (De

16. AGNOSIA

Renzi & Lucchelli, 1988). More problematic for a disconnection interpretation is the putative sparing of gesturing on visual presentation, as it involves the transmission of visual information from the right hemisphere to the gesture store, located on the left side. However, the preservation of miming in optic aphasia is much less consistent than traditionally assumed and a review of the literature (De Renzi & Saetti, 1997) has shown that it represents the exception rather than the rule (in the few patients who are able to mime it might be argued that the gesture store is represented bilaterally). There are still a few outstanding questions: 1. Granted that the right hemisphere has decoded the stimulus, why does it not succeed in transmitting its knowledge to the left hemisphere via the callosal pathways linking the tactile and auditory associative areas of the two sides? Geschwind (1965) addressed this question apropos of the absence of object naming errors in pure alexics, who also have damage in the left medial occipito-temporal region. He ventured that object naming is impaired when the splenial lesion extends forwards and impinges on the callosal fibres transmitting tactile information, but this conjecture has never received empirical support. Moreover, the claim that pure alexics are free of object naming errors is contradicted by the findings of a study in which their naming performance was systematically assessed (De Renzi et al., 1987). 2. One would expect that patients who are unable to retrieve the name of an object they have recognised either admit their inability or use circumlocutions to show their knowledge of the functional or contextual features of the stimulus. This behaviour is frequent in anomic aphasics, but rare in the majority of optic aphasics, who tend to give the same type of response as associative agnosics suffering from left hemisphere lesions, namely, identification of the superordinate, semantic paraphasias, paraphasias unrelated to the stimulus, and perseverations. Errors of the first two types suggest that a certain amount of information has

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reached the left hemisphere (through the more anterior callosal fibres ?), but that it is not able to control whether its verbal production tallies with visual data. In some patients (Gallois et al., 1987; Glenn et al., 1985) miming the use of an object that was wrongly named was appropriate to the semantic paraphasia, but not to the stimulus, as if the left hemisphere had gained control of behaviour, responding to its own cues and ignoring what the right hemisphere had transmitted to it. 3. By definition, naming errors should be limited to the visual modality, while, as underlined by Morin et al. (1984), they also occur in the tactile modality in a considerable number of patients with left brain damage, both among those diagnosed as associative agnosic (Benke, 1988; Caplan & Hedley-White, 1974; Feinberg et al., 1986; Hecaen & Ajuriaguerra, 1956; Rubens & Benson, 1971) and those diagnosed as optic aphasic (Assal & Regli, 1980; Glenn et al., 1985; Poeck, 1984; Rapcsak et al., 1987). In a consecutive series of 16 patients with an infarct of the left posterior cerebral artery De Renzi et al. (1987) found a deficit of visual naming in 11 and of tactile naming in 10. As the occipitalsplenial lesion alone cannot interrupt the connections between the right associative somaesthetic area and the left language area, an anatomical interpretation cannot account for the tactile naming deficit, which was attributed by De Renzi et al. (1987) to the mediation exerted by visual images in tactile recognition. This hypothesis is bolstered by reports of patients who showed apperceptive visual agnosia (Ratcliff & Newcombe, 1982; Shelton et al., 1994) and tactile recognition disorders. Unilateral visual agnosia In the literature there are a few case reports of visual recognition disorders confined to one visual field, i.e. involving stimuli that have been processed by the contralateral hemisphere. Mazzucchi et al. (1985) pointed out that, leaving aside the cases of splenial section, the majority of patients showed a deficit of colour discrimination and belonged, therefore, to the category of unilateral dyschromatopsia (see later). In two patients, however,

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the impairment extended to other classes of stimuli. One (Mazzucehi et al., 1985) had a haemorrhage in the right lateral occipito-temporal region, causing left superior quadrantopia. In the intact inferior quadrant of the same field, which was apparently intact at Goldman perimetry, he could not recognise objects, faces, letters, and colours, while they were correctly identified in the right field. In the patient ofCharnalletetal. (1988), CT scan showed a lesion of the left lingual and fusiform gyri, plus two small lesions, encroaching on the forceps major of both sides, without impairment of the visual fields. Letters, colours, geometrical figures, and objects were not recognised in the right field, while matching identical forms was better, but very slow and hesitant. A subtle deficit in form recognition was hypothesised. The actual frequency of these unilateral deficits is a matter of speculation, because unilateral recognition was seldom tested. Loss o f visual imagery The inability to retrieve mental images characterises a clinical pattern that bears some relation to visual agnosia and is relevant to the understanding of the processes underlying visual perception. Patients affected by this syndrome complain of no longer being able to visualise objects or other representations of the external world and this inability can be verified with tests demanding the presence in the mind’s eye of distinct mental representations, such as those listed earlier. The deficit may be restricted to certain categories of stimuli, e.g. living objects, faces, letters, colours, spatial maps (Goldenberg, 1993). Cessation of dreams and daydreams is often reported. First described by Charcot (Bernard, 1883), this condition was occasionally reported in the subsequent literature, but became the subject of detailed investigation only when a seminal paper by Farah (1984) drew attention to its theoretical potential and worked out a model, first proposed by Kosslyn (1980), aimed at identifying the components of the imagery process and their susceptibility to brain damage. The model assumes that the same mental representations underlie imagery and perceptual recognition and that their activation involves two storage systems (a longterm memory store and a short-term visual buffer)

and three discrete processes (generation, inspection, transformation). The information about the appearance of objects is stored in a subset of longterm memory, dedicated to the knowledge of the perceptual features of objects. Its conscious reproduction in the mind’s eye requires a generation process and the transfer of the image into a visual buffer, where it can be inspected and submitted to further mental operations (verbal description, drawing, spatial transformation, etc.). The same visual buffer also provides a temporary store for encoded structured descriptions, which, to be recognised, must be matched with the corresponding mental representations, stored in long-term memory. Depending on which component of the model is damaged, imagery and recognition can be concurrently or differentially impaired. When the lesion affects the mental representations stored in long-term memory, both abilities will be disrupted, leaving the patient unable to recognise objects and imagine their visual appearance. This association has indeed been found in a number (probably the majority) of properly investigated cases of agnosia (for a review of the relevant literature, see Trojano & Grossi, 1994) and, interestingly, it can be specific for certain classes of objects (e.g. living things, De Renzi & Lucchelli, 1994;Methaetal., 1992;Sartori & Job, 1988). Loss of mental images, with intact or at least much less impaired recognition (Basso et al., 1980; Brain, 1954;Delevaletal., 1983; Farah etal., 1988b; Goldenberg, 1992; Grossi et al., 1986; Riddoch, 1990) results from damage to the generation process. The opposite pattern, visual agnosia and preservation of mental imagery, has also been reported, and it can reflect the impairment of perceptual processing at two distinct levels. Either the structured descriptions have been so poorly encoded that they fail to activate mental representations (apperceptive agnosia, see the case reports of Behrman et al., 1992, Servos et al., 1993, Servos & Goodale, 1995) or they are adequate, but cannot reach the long-term store, which, though intact (and hence able to generate images), is disconnected from the visual buffer (associative agnosia). In these cases the integrity of the image generation mechanism is inferred from the good performance in drawing from memory (Ferro & Santos, 1984; Kawahata & Nagata, 1989; Levine,

16. AGNOSIA

1978; Rubens & Benson, 1971), and/or from verbal operations carried out on mental images (Jankowiak et al., 1992; Morin et al., 1984). While this model provides a reasonable overview of the architecture of the imaging processes, to some extent it remains conjectural and is in need of further refinement, if it is to account for the whole range of clinical findings. For instance, it has been found that in agnosic patients with a loss of mental images, there may be a discrepancy between the severity of imagery and recognition greater than would be expected from the theory that both are consequent to the disruption of the same mental representations. Nor is it clear why the disruption of the generation mechanism may have different consequences on various image categories. Hopefully, these and other questions will be settled by studies encompassing larger numbers of patients with wider batteries of imagery tests. The issue of the relation of mental images to encoded perceptions has also involved their anatomical underpinnings. The debate has mainly revolved around the question of whether the same areas participating in perception, in particular those engaged in the early processing of visual information (areas 17 and 18), are also activated by imagery. According to this view, the top-down information, triggering mental representations, is projected back to early visual areas, recreating a condition similar to that of perception. The issue has been addressed by investigating which areas of the brain showed increased metabolism in comparison to a baseline condition, when the subject was engaged in imagery tasks. SPECT (Goldenberg et al., 1987, 1989), PET (Kosslyn et al., 1993; Roland & Gulyas, 1994), and functional MRI (Le Bihan et al., 1993) studies concurred in showing increased metabolism in temporooccipital and parieto-occipital areas, but the data on the involvement of the primary visual areas were less consistent, with some authors (Goldenberg, 1993; Kosslyn & Ochsner, 1994; Le Bihan et al., 1993) reporting positive findings and others (Roland & Gulyas, 1994) failing to confirm them. Variations in the experimental paradigms used to elicit imagery and individual differences may account for such conflicting results. In a recent experimental study (Kosslyn et al., 1995) the

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evidence upholding the primary visual cortex activation was particularly impressive, because the site of maximal activity was related to the difference in size at which images were formed, being located posteriorly with small images, anteriorly with large images, and in an intermediate position with medium size images, in agreement with the functional anatomy of the calcarine cortex. However, even the demonstration that under certain conditions the activation of the primary visual areas is a constant concomitant of imagery operations does not provide unequivocal evidence that it represents a crucial, necessary stage in image retrieval. As pointed out by Moscovitch et al. (1994), this is an issue that can hardly be settled by normal studies and badly needs the contribution of clinical findings. If medial occipital areas play a crucial role in the retrieval of mental images, then patients with occipital damage causing impairment or loss of perception should be impaired or unable to carry out tasks requiring imagery. Patients with agnosia and preserved mental images are problematic for this theory, but the crucial test is represented by patients affected by cortical blindness, following bilateral occipital damage, who should fail every imaging task. At variance with this prediction, Goldenberg et al.’s (1995) cortical blind patient was able to describe the shape of capital letters and scored within the lower range of the normal performance on a sentence verification test concerning the shape and the colour of objects. The authors were loath to draw firm conclusions from this case, as the destruction of the occipital cortex was incomplete and small islands of the intact visual cortex might have contributed to the imagery performance. This was not the case in at least one of the three cortically blind patients reported by Chatterjee and Southwood (1995), who passed a series of visual imagery tests, in spite of a total destruction of the primary visual areas. Furthermore, the case reports of achromatopsia with preserved colour imaging and ability to name visual imaged colours (Bartolomeo et al., 1997; Shuren et al., 1996) do not tally with the assumption that the activation of early perceptual areas is a prerequisite for triggering imaging processes. Another issue addressed by the investigation of the anatomical substrates of visual imagery is

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whether they are equally or asymmetrically represented in the two hemispheres. Early speculations that imaging is a right brain function were dismissed because of the lack of experimental support (Ehrlichman & Barrett, 1983) and were reversed by Farah (1984), who, after reviewing the clinical literature, claimed that patients with a specific deficit in visual image generation suffer from left brain damage. In Sergent’s (1990) view, this inference rested on flimsy evidence, but subsequent reports of patients with pure image generation were in keeping with Farah’s hypothesis (Trojano & Grossi, 1994). Further support was provided by a number of SPECT and event-related potential studies (summarised in Goldenberg at al., 1993 and Farah, 1995, respectively) and also by a clinical study (Stangalino et al., 1995), which showed a greater incidence of image generation deficit in a left than in a right brain-damaged group. However, PET investigation yielded inconsistent support for a left hemisphere ascendancy in imagery tasks, possibly due to individual variations and the nature of the images required by the task (Kosslyn et al., 1993). A tentative conclusion may be that the greater specialisation of the left hemisphere is a matter of degree and is not absolute, otherwise generation deficits would be encountered far more frequently. Acoustic aphasia The inability to name a meaningful sound, whose source has been recognised, was reported in just one case. Denes and Semenza’s (1975) patient was affected by verbal agnosia, that is, he did not understand oral language because he could not discriminate the phonemic features of words, but had normal speech (in particular visual and tactile naming). Presented with a meaningful sound and four drawings of objects, he was able to correctly match the sound with a picture in 17/20 trials, but in only four could he retrieve the name of the object. Whenever he failed, he claimed not to know what the source of the sound was and, if pressed, would provide bizarre answers, without any semantic or acoustic relation to the real source. No information on the locus of lesion was available, but clinical data suggest that it involved the left hemisphere and the authors speculated that it

disconnected the Wernicke’s area from both primary acoustic areas and prevented it from receiving the acoustic information that the intact right temporal lobe had decoded. What is amazing in this case, as well as in some of those with optic aphasia, is that, instead of simply saying that he could not retrieve the name of the object, the patient claimed not to know what it was. Semantic amnesia The recognition disorders considered so far are characterised by the selective impairment of information transmitted through one sensory channel. Even if the unimodal nature of the deficit is sometimes not as strict as the definition of agnosia would imply, it is still possible to demonstrate that the patient is able to recognise the stimulus, if an appropriate channel is used. On the contrary, in semantic amnesia, patients have lost their knowledge of objects, regardless of the way information related to their features is activated (De Renzi et al., 1987; Marin et al., 1983; Warrington, 1975; Taylor & Warrington, 1971; Schwartz et al., 1979; Warrington & Shallice, 1981). The encyclopedia storing the attributes of things (their names, sensory features, functional and conceptual properties, etc.) is either damaged or inaccessible. Patients are not demented, have no language deficits, apart from lexical impairment, have preserved spatial and praxic skills, and may not suffer from global amnesia. Thus the label semantic dementia, proposed to define this clinical pattern (Hodges et al., 1992; Snowden et al., 1989) appears questionable, even if some of these patients suffer from a slowly progressive disease that leads to dementia. A frequently reported aetiology is encephalitis and in these cases the semantic deficit may be restricted to certain categories, e.g., living things (Basso et al., 1988; De Renzi & Lucchelli, 1994; Pietrini et al., 1988; Sartori & Job, 1988; Silveri & Gainotti, 1988; Warrington & Shallice, 1984). Location of lesion and aetiology Apperceptive agnosia is almost always associated with bilateral damage of the visual areas, although the contribution of the right brain to perceptual processing is likely to prevail (De Renzi et al.,

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1969; Warrington & Taylor, 1973) and two cases of apperceptive agnosia (De Renzi & Lucchelli, 1993; Levine, 1978) were found to have a lesion apparently confined to the posterior areas of the right brain. The most common aetiology is CO poisoning (Adler, 1944, 1950; Benson & Greenberg, 1969; Campion & Latto, 1985; Milner et al., 1991), followed by trauma (De Renzi & Lucchelli, 1993; Goldstein & Gelb, 1918; Kertesz, 1979), bilateral infarcts (Grailet et al., 1990; Riddoch & Humphreys, 1987a; Shelton et al., 1994) and mercury intoxication (Landis et al., 1982). Also in associative visual agnosia cases with bilateral occipito-temporal damage have been reported (for a review, see Iorio et al., 1992). Some of them evolved from an early pattern of apperceptive agnosia. Their deficit was interpreted (Albert et al., 1979; Kawahata & Nagata, 1989) as secondary to the interruption of the inferior longitudinal fasciculus, which links the occipital areas, where the stimulus is perceptually processed, with the medial temporal cortex, where its visual memory is stored. However, in the majority of cases, Lissauer’s patient (Hahn, 1895) included, there is evidence from anatomical (Caplan & Headley-White, 1974; Scheller, 1966), surgical (Hecaen & Ajuriguerra, 1956; Hecaen et al., 1974) and, more recently, CT and MRI findings that the lesion can be confined to the left side. The most common aetiology is an infarct in the territory of the left posterior cerebral artery, encroaching on the lingual and fusiform gyri, the hippocampal gyrus and the inferior longitudinal fasciculus (Feinberg et al., 1994). Visual areas are disconnected from area TE, which in monkeys has been found to play a crucial role in object recognition (Ungerleider & Mishkin, 1982). Exception to this location of damage are represented by the patient reported by McCormick and Levine (1983), who had a parietooccipital tumour and that of Rapcsak et al. (1987), who had a haemorrhage in the infero-lateral posterior region of the temporal lobe. Schnider et al. (1994) ventured that the difference between associative agnosia and optic aphasia is contingent on the extent of splenial damage, which would be spared in the former and invariably destroyed in the latter. It would follow

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that in optic aphasia object recognition is carried out by the right hemisphere, which has the competence to do it, while in associative agnosia its performance is inhibited by the left hemisphere, which receives visual information but, being damaged, is unable to process it. However, the claim that the splenium is intact in associative agnosia was not confirmed by Feinberg et al. (1994), who found that it was extensively damaged in three of seven patients. There is, therefore, no convincing evidence that the two syndromes differ in terms of location of lesion.

Prosopagnosia The term prosopagnosia (from the Greek word prosopon, meaning face) has been proposed by Bodamer (1947) to refer to the inability to recognise familiar faces. The deficit is strictly confined to the the identification of physiognomic traits, as shown by the fact that voices are readily recognised and that the patient takes advantage of nonphysiognomic visual cues (a scar or a mole, a particular item of clothing, etc.). The symptom was first reported by Quaglino (1867), an Italian ophthalmologist, who described a patient suffering from left hemianopia, achromatopsia, and an inability to recognise familiar faces, after a cerebrovascular disease. As he was able to read words printed in small print, the bearing of elementary visual deficits on face recognition was ruled out and Quaglino attributed the patient’s impairment to brain damage. The paper went unnoticed, possibly because it was published in an ophthalmological journal, and, in spite of occasional mention of the disorder in the subsequent literature, prosopagnosia had to wait for Bodamer (1947) before becoming a focus of neurological interest. In the most severe cases patients cannot recognise their own face, when they look at themselves in the mirror, or that of closest relatives. A patient of mine addressed his wife by saying “I do realise that there is no other woman at home, but tell me: are you really my wife?” In milder forms, the deficit may be limited to friends and acquaintances, especially when they are met in an unusual context, and to famous people, or it may only concern faces that have been known after

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disease onset (Hecaen & Angelergues, 1962; Hanley et al., 1990; Shuttleworth et al., 1982; Takahashi et al., 1995). Patients know that a face is a face and are usually able to differentiate its sex, race, and age. Even emotional expressions are correctly identified and the report of the opposite dissociation— prosopo-affective agnosia without prosopagnosia (Kurucz & Felmar, 1979)—attests that independent substrates subserve the two abilities (see later). What the patient cannot do is recognise a face as “that” face. A few of them complain of seeing faces in a dim light or distorted, but the majority do not report visual difficulty. They are well aware of their predicament (for an exception, see Sergent & Villemure, 1989) and often feel ashamed of it, because such a circumscribed visual deficit sometimes leaves them and their relatives puzzled. In two patients of mine the ophthalmologist diagnosed a psychogenic disorder, as he could not understand how a subject, who had normal elementary visual functions, could just fail to recognise faces. Recognition o f known and unknown faces In 1962, a paper of Hecaen and Angelergues (1962) provided impetus for considering faces as a class of stimuli suitable for bringing out hemispheric differences in performance. A review of the literature, made by these authors, pointed out that prosopagnosia was frequently associated with left visual field defects and led them to submit that the right brain plays a prominent role in face recognition. This hypothesis gained support from group studies (Benton & van Allen, 1968; De Renzi et al., 1968; De Renzi & Spinnler, 1966; Milner, 1968; Tzavaras et al., 1970; Warrington & James, 1967a), which consistently showed that right brain-damaged patients performed worse than left brain-damaged patients on unknown face recognition tests. The hemispheric asymmetry was confirmed in normal subjects, when they were requested to make an old/new discrimination of photographs of unfamiliar faces, flashed to either lateral visual field. Both accuracy and speed of response were higher for faces projected to the left visual field than for those projected to the right visual field. While the outcome of these

studies was unequivocal in providing evidence for right hemisphere ascendancy in processing unfamiliar faces, its bearing on prosopagnosia, which consists in the inability to recognise familiar faces, was challenged by the report of prosopagnosics who performed normally on these tasks (Assal, 1969; Benton & Van Allen, 1972; Tzavaras et al., 1970)and by the lack of correlation between unfamiliar and familiar recognition scores found in right brain-damaged patients (Warrington & James, 1967). Benton (1980) inferred from these data that there are two independent deficits, produced by brain damage, one concerning the perceptual processing of face information and brought out by unfamiliar face tasks, the other involving an additional mnestic factor and brought out by familiar face tasks. Apperceptive and associative prosopagnosia The identification of a face is the end stage of a process in which visual information is analysed by discrete, hierarchically organised modules. According to the model, developed by Bruce and Young (1986), perceptual processing results in the structured encoding module with the construction of an object centred, tri-dimensional description of the face. If the face is known, its structured description activates an abstract representation of it, stored in recognition units, giving rise to a feeling of familiarity. Recognition obtains, when the information gains access to the identity nodes, a sector of semantic memory, containing knowledge about familiar persons’ biography, the relationship we have with them, the circumstances in which we met them, etc. A separate module is devoted to their names and can only be accessed from identity nodes. Its independent status is suggested by the frequent inability, experienced by normal subjects, to retrieve the proper name of an otherwise perfectly recognised person, and is confirmed by the specific anomia for proper names, shown by a few left brain-damaged patients. In the most common form, the deficit is apparent whatever the modality (visual, verbal, acoustic) through which the name is elicited, contrasts with the perfectly preserved semantic knowledge about the same persons, and may or may not extend to other categories of proper names (e.g. geographical). A

16. AGNOSIA

case of anomia limited to the visual presentation of a face (Carney & Temple, 1993) has been reported and named prosopanomia. Depending on the level at which the functional lesion occurs, two types of prosopagnosia occur. When perceptual processing is disrupted, the inability to recognise familiar faces is but an aspect of an apperceptive disorder across the board, as found in the patients of Goldstein and Gelb (1918), Adler (1944,1950). Benson and Greenberg (1969), Landis et al. (1982), Bauer (case 2, 1986), Grailet et al. (1990), Milner et al. (1991), and Shelton et al. (1994). More problematic are patients whose nonfacial recognition deficit is limited to discriminating the exemplars of a category, which, like faces, show remarkable similarity, e.g. car makes, banknotes, playing cards, some types of fruit and animals (De Renzi, 1986; Macrae & Trolle, 1956; Shuttleworth et al., 1982). They also tend to score poorly on perceptually demanding tests, such as Ghent’s overlapping figures, Gollin and Street’s interrupted figures, photos of objects taken from noncanonical views, face matching tests (Benton & Van Allen, 1968), and face age discrimination tests (De Renzi et al., 1989), thus suggesting a mild to moderate perceptual impairment. Its bearing on prosopagnosia must, however, be evaluated with caution, as a poor performance on one or more of these tests can also be found in right brain-damaged patients, who do not present prosopagnosia (McNeil & Warrington, 1991). In an attempt to rest the classification of face recognition deficits on more solid grounds, De Renzi et al. (1991) gave two face perception tests (unknown face matching and age discrimination) and two face memory tests (familiarity and verbovisual matching) to 100 normal subjects, and computed the external and internal tolerance limits of the difference between the two sets of scores. These norms made it possible to identify braindamaged patients who were outliers either for an exceedingly poor performance on perceptual tests (apperceptive prosopagnosia) or for an exceedingly poor performance on mnestic tests (associative prosopagnosia). It remains to be seen whether these measures also discriminate prosopagnosics from right brain-damaged patients, who recognise familiar faces.

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An amnestic or associative form of prosopagnosia can be envisaged when the patient passes all perceptual tests (in particular those involving face identification) and fails the recognition of familiar faces, though showing intact semantic knowledge of the persons to whom they refer. The impairment may occur either at the level of recognition units or identity nodes. In principle, the former should cause the inability to perform familiarity tests (to identify among alternatives the one known face), while they are passed in the latter, and the failure occurs on recognition tests (to name a familiar face or to choose it among distractors belonging to the same semantic category, when its name is given). As a matter of fact, almost all reported cases of associative prosopagnosia fail on both types of tests. An exception is represented by the patient of De Haan et al. (1991), who showed preserved familiarity and impaired recognition. De Renzi and di Pellegrino (in press) reported a patient with an apparently paradoxical dissociation, poor scores on the familiarity test and a face naming test, but almost perfect responses (though given with delay and hesitation) on a visuo-verbal matching test. The key to understanding this behaviour was the patient’s good performance on a face imaging test, in which she was given a triplet of proper names corresponding to famous persons and was requested to identify the person, whose face was markedly different from the others. Thus she could compare the face images generated on name presentation with the output of structured encoding and come, after painstaking analysis, to a correct response in the visuo-verbal matching test. This top-down strategy could not be used in the familiarity and naming tests, where the only available information was perceptual Loss o f semantic knowledge fo r individual entities Prosopagnosia must be distinguished from the inability to retrieve from semantic memory any type of information related to an individual, his or her face, name, and voice. In Ellis et al.’s (1989) patient the deficit was not limited to persons, but also involved famous animals (e.g. Lassie, Moby Dick), buildings (e.g. the Kremlin), and old product names, while other aspects of semantic and

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autobiographic memory were fairly well preserved. In Hanley et al.’s (1989) patient, the knowledge of living things was also impaired. Also Kartsounis and Shallice’s patient (1996) showed a deficit in recognising famous contemporary people in both the verbal and the visual modality, while famous historical people and buildings were misidentified in the visual modality only. When assessed with photographs of relatives and friends, he did not manifest prosopagnosia. A progressive transition from a pure impairment of familiar face recognition to a loss of knowledge of every piece of information concerning the same persons was reported in a patient (Evans et al., 1995) with light temporal lobe atrophy. In this case unique exemplars from other categories (e.g. buildings) were well recognised. Unconscious recognition An interesting phenomenon, brought out in prosopagnosia, as well as in other cognitive domains, is unconscious recognition. It consists in the fact that, when confronted with famous faces that they deny recognising, prosopagnosic patients react differently from when they are presented with faces never seen before, thus showing that they have retained an implicit knowledge of them. This behaviour was first investigated by Bauer (1984), by adapting to the experimental situation the Guilty Knowledge Test, a criminological procedure in which suspects are presented with a stimulus relevant to the crime with the aim of assessing whether it elicits changes in their galvanic skin reaction. Bauer presented a prosopagnosic patient with the photograph of familiar, but not recognised persons that he had to match with one of five names. While correct matching only occurred in 22% of trials, i.e. at chance level, a positive electrodermal response was recorded in 61% (in two control subjects it was present in 100% and 80% of trials). This finding was confirmed in subsequent studies (Bauer, 1986; Tranel & Damasio, 1985), providing evidence for an implicit identification of familiar faces that the patient was unable to overtly recognise. Other neurophysiological techniques yielded the same results. Renault et al. (1989) reported an increase in the amplitude of the P300 component of the event-related brain

potential, associated with the presentation of familiar faces provided they occurred less frequently than unfamiliar faces and Rizzo et al. (1987) showed that the scanpaths made in inspecting a known face were different from those elicited by an unknown face. Psychological procedures are also effective in revealing covert recognition. Prosopagnosic patients showed improved learning and increased priming if the stimuli were photographs of familiar rather than unfamiliar people. For instance, they were better at learning to associate a familiar face with a proper name or a profession if the pair was true rather than untrue (Bruyer et al., 1983; De Haan et al., 1987a; Diamond et al., 1994; Sergent & Poncet, 1990). However, the effect disappeared, if the task became more demanding (Young & De Haan, 1988), for instance, if only the first name, instead of the full name was given, or if more specific information was required (not simply whether the face was of a politician, but to which political party the person belonged). Another suitable paradigm to demonstrate covert recognition is priming, that is, the improvement in performance that occurs in a proper name decision task following the previous presentation of a semantically related photograph. For instance, one patient was able to decide more quickly whether the name Paul Newman was famous, when it was preceded by the presentation of the face of Robert Redford as opposed to that of Margaret Thatcher, though neither of them were recognised (Young et al., 1988). Sergent and Poncet’s (1990) patients were able to match two photographs of the same famous person across a 30-year period much better than control subjects from a different country, who were unfamiliar with him, despite claiming not to know the faces. Even more amazing was the finding, reported by Sergent and Poncet (1990) and partially replicated by De Haan et al. (1991) and Diamond et al. (1994), of a patient who, when informed that the faces he had not recognised belonged to the same semantic category, succeeded first in identifying the category and then in retrieving the names of the faces. However, none of them was recognised, when, after a while, they were presented again, intermingled with unfamiliar faces.

16. AGNOSIA

It must be added that a residual knowledge about faces that the patient claims not to recognise has also been shown with tests that explicitly require overt recognition, provided a forced choice paradigm was used. When asked to choose the name matching a non-recognised face among distractors, some prosopagnosic patients responded above chance, though commenting that they were merely guessing (De Haan et al., 1991; Diamond et al., 1994; McNeil & Warrington, 1991; Sergent & Poncet, 1990) and, when requested to match different views of the same face, they gave quicker responses to familiar faces (De Haan et al., 1987b). Surprisingly, no advantage accrued from the use of the forced-choice paradigm, when a familiarity judgement was requested. The phenomenon of unconscious recognition is not, however, present in every prosopagnosic patient. Negative cases have been reported by Bauer (1986), Newcombe et al. (1989), Sergent and Villemure (1989), Young and Ellis (1989), De Haan and Campbell (1991), and De Haan et al. (1992) and interpreted as consequent to damage at the level of perceptual encoding or recognition units, which would hinder the transmission of information about the physical appearance of faces to higher levels (Newcombe et al., 1989). There are, however, both patients who do not show covert recognition in the absence of perceptual deficits (Etcoff et al., 1991; McNeil & Warrington, 1991; Schweinberger, 1991) and patients who present the reverse pattern (McNeil and Warrington, 1991). The dissociation between covert and overt recognition has been accounted for in terms of there being two routes transmitting the perceptual output to the semantic system, one directly projecting to identity nodes and the other bypassing them and making a connection either with the name system (De Haan et al., 1991; McNeil & Warrington, 1991) or with other structures. Bauer (1984) couched this interpretation in anatomical terms, making reference to the two pathways transmitting visual information to higher centres, one directed to the inferior temporal cortex, where the meaning of the stimulus is decoded, and the other projecting to the parietal cortex, where its spatial features are processed (Ungerleider & Mishkin, 1982). The former would be damaged,

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preventing conscious recognition, the latter would be spared and would mediate unconscious recognition, by virtue of its connections with the cingulate cortex. Neither of these hypotheses is able to account for all of the manifestations of covert recognition. Names played no role in the aforementioned experiment, in which the identification of the same face across a 30-year period was required (Sergent & Poncet, 1990) or in the superior ability to match different views of the same face, when it was familiar rather than unfamiliar (De Haan et al., 1987a). Neither is it clear why, in a forced choice paradigm, the alternative occipito-parietal cingulate route was able to mediate a face-name matching, but not a familiarity judgement. Perhaps the most straightforward interpretation is that the threshold for triggering conscious recognition is higher than that for unconscious recognition. According to this view, a complete lesion of recognition units would impair both mechanisms, whereas partial damage would render their output insufficient to activate conscious recognition, but not unconscious recognition. In normal subjects, it is possible to show a dissociation between covert and overt recognition, when the latter is made more difficult by delaying it over a six-month period (Wallace & Farah, 1992). It is also worth noting that the magnitude of the neurophysiological and neuropsychological responses that assess unconscious recognition tends to be smaller in prosopagnosic patients than in normal controls (Schweinberger et al., 1995), in agreement with the hypothesis that reduced information is transmitted both to the overt and the covert system, but that the latter is more reactive to it, having a lower threshold. Specificity o f the face deficit A recurrent issue throughout the history of prosopagnosia is whether the impairment is specific to faces, as suggested by Bodamer (1947), who conceived prosopagnosia as the disruption of a primary ability, already present in the early months of life and destined to play a crucial role in the development of social skills. This speculation finds some support in experimental studies showing that at just 4 days of age neonates manifest a preference

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for face-like stimuli and look longer at their mother’s face than at a stranger’s face (Bushnell et al., 1989; Pascalis et al., 1995), although only at 2-4 months do they recognise their mother’s face, even after the hairline is masked by a scarf (de Schonen & Mathivet, 1990). Moreover, a right hemisphere advantage in a mother’s face recognition test, given with the divided field presentation procedure, was apparent in 4-10 month-old infants (de Schonen & Mathivet, 1990). Other considerations that must be kept in mind are that the individuality of a face must be identified among alternatives that are perceptually very similar, and that the number of face exemplars that subjects store in their life is incomparably higher than that of any other category, probably around one thousand, including relatives, acquaintances, and famous persons. Yet the contention that prosopagnosia is an autonomous disorder, contingent on the disruption of a discrete cerebral mechanism, has been disputed by several authors, who remarked that these patients also run into difficulty in discriminating the members of other categories, e.g. a chair from an armchair (Faust, 1955), car makes (Lhermitte et al., 1972), mammals of similar shape (Lhermitte et al., 1972; Lhermitte & Pillon, 1975), and so forth. There have been reports of farmers, who had become unable to identify their own cows (Assal et al., 1984; Bornstein et al., 1969) and an ornithologist who could no longer discriminate birds of different species (Bornstein, 1963). These findings were taken as evidence (Humphreys & Riddoch, 1987) that prosopagnosia represents a mild form of visual agnosia, apparent in everyday life for faces, but actually detectable whenever the patient must discriminate similar shapes. Damasio et al. (1982) breathed new life into the hypothesis, first put forward by Lhermitte and Pillon (1975), that underlying prosopagnosia is a more general disorder, namely, the inability to identify an exemplar within a category. They rightly remarked that object and face recognition are tested in different ways, because for objects patients are requested to identify the category to which the stimulus belongs (is it a hammer, a horse, etc?), while for faces they must identify its individuality. Prosopagnosics are not asked whether a face is a face, but whether it is that particular face, the one

they have previously met in a definite spatiotemporal context. Damasio et al. (1982) claimed that if object recognition is assessed through the same kind of questions (e.g. asking not whether a book is a book, but whose book it is), patients with face recognition impairment will also be found to perform poorly with other classes of stimuli. The evidence they adduced in support of this contention was, however, not very pertinent, as it did not concern the recognition of the stimulus individuality, but the errors made among subclasses belonging to the same general superordinate, e.g. a cat was mistaken for a tiger or a panther, and the British pound sign for a musical notation. It would, therefore, appear that their patients’ impairment boiled down to a deficit in discriminating figures that were similar in shape. This is not, however, a constant feature of prosopagnosics and there is evidence that some of them can show an amazing ability to differentiate exemplars of the same category, when they are not faces. Sergent and Signoret’ s (1992) patient had made a hobby of collecting miniature cars and was, therefore, an expert on car makes and models. When he was presented with 210 photographs of cars, of 14 models from 15 makes, he identified 172 of them correctly and for the remainder he was able to report the company for 31 and the model for 22. McNeil and Warrington’s (1991) patient was a shepherd, who had become proficient at recognising sheep faces. Contrary to normal controls, he showed a greater ability to learn arbitrary associations between sheep faces and proper names than between human faces and proper names. A direct test of the hypothesis that prosopagnosics fail whenever they have to identify a familiar object among exemplars of the same class, was carried out by De Renzi (1986). His patient was requested to select a personal belonging (his own wallet, electric razor, necktie, glasses, etc.) from an array of objects of the same class, and to recognise his handwriting in a sentence written by him and by nine other persons. He showed no hesitation in making the correct choice. The finding was replicated in a second patient (De Renzi et al., 1991) and confirmed by Sergent and Signoret (1992). These authors, however, argued that this successful performance was contingent on the use

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of a forced-choice paradigm, because it also permitted their patients to recognise their own face or that of a close relative among distractors, once their names were provided. Only a limited number of items were given (two in one patient and five in another) and, moreover, the same procedure failed when the patients had to identify a famous person, in agreement with the results reported by De Renzi (1986) in a familiarity test and a visuo-verbal matching test. Thus the findings of this experiment remain open to question and it is possible that correct face identification was due to unconscious recognition and was not related to the use of a forced-choice paradigm. In the literature there are examples of patients who do not recognise a face, despite knowing that it must belong to a given person. For instance, Lhermitte et al.’s (1972) patient, who suddenly became prosopagnosic, said to his physiotherapist, “Miss, what’s happening to me, I am no longer able to recognise you?” The idea that the inability to recognise familiar faces is specific has found experimental support in the different patterns of impairment shown by a prosopagnosic patient (Farah et al., 1995), when he was requested to make an old/new recognition judgement in front of faces and of different exemplars of the same object (e.g. similar-looking eyeglass frames). In comparison with normal controls, he found faces disproportionally more difficult to recognise. Why such specificity? Farah (1990) championed the view that it does not result from an intrinsic quality of the face class, but from the nature of the perceptual processing they undergo, which would be different from that used for words and objects. Specifically, faces are coded as a whole, while words are broken up into their constituent elements (letters), and objects share both apperceptive modes in various proportions, depending on their formal features. It follows that, depending on whether the global mode or the analytical mode or both are impaired, different patterns of deficit involving faces, words, and objects are to be expected, while some associations are highly unlikely. If it is mild, a deficit of global perception will result in face agnosia, whereas if it is severe it will extend to objects that are perceptually similar. Conversely, a mild deficit of analytical perception will cause alexia, while a more

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marked impairment will also involve object recognition. Finally, a disruption of both modes of perceptual processing will be associated with global agnosia, impairing all categories. There are, however, two patterns of deficit that are explicitly excluded by the theory: agnosia for faces and words with integrity of objects, and agnosia for objects without impairment of either faces or words. Farah (1991) sought support for her theory in a review of all of the published cases of agnosia and found that none of them invalidated its predictions. However, they did not stand the test of time. In the subsequent years both of them were disproven by the report of a patient with object agnosia without alexia and agnosia for faces (Rumiati et al., 1995) and two patients with alexia and agnosia for faces, but not object agnosia (Buxbaum et al., 1996; De Renzi & di Pellegrino, in press). It is likely that the patterns of association and dissociations emphasised by Farah (1991) were due to the hemispheric specialisation in processing different types of perceptual stimuli, with the left side specialised in word identification and the right side playing a more important role in face identification. The association of alexia and agnosia for faces can only appear when the lesion is bilateral, a pathological event that will frequently, but not necessarily, encroach on the areas involved in object recognition. Further evidence in support of the theory that faces are special comes from monkey studies, which have shown the existence in the inferior temporal cortex (area TE) and in the superior temporal sulcus (area STP) of cells that fire selectively, when the animal is presented with faces (for a review, see Perret et al., 1987 and Desimone, 1991). Some of them are sensitive to certain parts of the face (the eyes, mouth, or hair region), others to face orientations (front-view, profile, etc) and about 10% to personal identity, being triggered by familiar faces. The last cells are mainly represented in the inferior temporal cortex, i.e. in the region whose damage is associated with prosopagnosia, while neurones in the superior temporal sulcus are sensitive to emotional expressions and gaze direction (Perret et al., 1992). Both abilities are impaired in patients with lesions of the amygdala (Adolphs et al., 1994; Young et al., 1995), a structure that has strong connections with the

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superior temporal sulcus. In monkeys social communication relies heavily on gaze direction and it has been speculated that in these animals the role played by the amygdala-superior temporal sulcus circuit is to some extent analogous to that played in humans by the language network, located in the left temporal lobe (Desimone, 1991). In the monkey the different functional specialisation displayed by the inferior and the superior temporal lobe has a correspondence with the dissociation between face and emotion recognition, found in brain-damaged patients. Although prosopagnosic patients do not usually show any deficit in identifying the emotional expression of the faces they do not recognise, two patients without prosopagnosia (Rapcsak et al., 1989, 1993) have been reported, who manifested a selective impairment in naming face expressions and in pointing to them when the name was provided, though they understood their meaning. Both had a lesion located in the right middle temporal lobe, an area where in epileptic patients cells have been found (Ojemann et al., 1992) to discharge when the patient had to label facial expressions. Location o f lesion As already mentioned, the prevalence of a left field defect in patients with prosopagnosia led Hecaen and Angelergues (1962) to surmise that the disorder may be associated with right brain damage. Twelve years later, Meadows (1974b) made a new review of the literature and confirmed the disproportionate frequency with which the left visual field was affected, but cautioned against drawing inferences about the prominent role of right hemisphere damage, because in six of the eight cases with pathological documentation, the damage to the temporal-occipital area was bilateral and in the other two there was, in addition to the right temporal-occipital lesion, a gliosis of the left angular gyrus and a neoplastic involvement of the splenium up to the left ventricular wall, respectively. Bilateral occipital lesions were also present in subsequent autoptic cases (two reported by Cohn et al., 1977 and four reported by Nardelli et al., 1982). Particularly telling was a patient (Ettlin et al., 1992), who did not show a face recognition deficit following two right-sided

infarcts, one of which completely destroyed the temporo-occipital region, but became prosopagnosic when he incurred a haemorrhage in the left occipital lobe. Based on pathological evidence, Damasio et al. (1982) posited that bilateral damage is a constant and necessary correlate of prosopagnosia. This claim, which gained wide consensus, is too drastic. First of all, it must be observed that cases coming to autopsy may yield a biased sample, in which patients with bilateral infarcts, and hence more severely ill, tend to be over-represented. In this respect, the evidence provided by CT scan and MRI is more trustworthy, because it is available in practically every patient and is collected at the time they are tested. A scrutiny of cases with this documentation, plus those with surgical documentation, reveals a substantial number of exceptions to the rule of the bilaterality of damage. In 1994 De Renzi et al. managed to marshal as many as 31 patients with evidence of a lesion confined to the right hemisphere (in 7 there were also PET data), to which 4 new cases (Evans et al., 1995; Takahashi et al., 1995; Tohgi et al., 1994) can now be added. Moreover, two cases of prosopagnosia showing at autopsy lesion of the right hemisphere alone, have been recently published (Kawamura & Takahashi, 1995; Landis et al., 1988). It is, therefore, apparent that bilateral damage does not represent a sine qua non condition for the occurrence of prosopagnosia, which can result from a lesion confined to the right side alone, in agreement with its superiority in face processing indicated by normal and brain-damaged group studies. However, it would be hazardous to draw a parallel between right hemisphere dominance for face recognition and left hemisphere ascendancy for speech. Prosopagnosia is a rare symptom, which does not usually accompany the infarct of the occipito-temporal area produced by right posterior cerebral artery occlusion. I did not find it in 10 consecutive cases, explicitly investigated, while, for instance, alexia was present in 13 of 16 consecutive cases with left posterior cerebral artery infarct (De Renzi et al., 1987). A balanced conclusion on the hemispheric contribution to the treatment of face information is that in the majority of human subjects both occipitotemporal areas participate in its processing, though

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with a prevalence of the right side. Interestingly, the recognition of familiar voices is also more impaired following right brain-damage, particularly when the parietal lobe is involved, whereas a deficit in samedifferent discrimination between pairs of unfamiliar voices is found in association with damage to either hemisphere (Van Lancker et al., 1989). We can summarise the issue of the hemispheric contribution to prosopagnosia by saying that usually damage to the right brain areas can be compensated by the healthy hemisphere. However, the degree of hemispheric asymmetry may differ remarkably from subject to subject and in a sizeable minority can be so marked that the right brain failure is no longer repairable. Gender may be an important factor in determining the extent to which face processing skills are unevenly represented in the hemispheres, as there is a substantial prevalence of prosopagnosia in males (Mazzucchi & Biber, 1983). The lesion responsible for prosopagnosia is located in the medial occipito-temporal region. In apperceptive forms, damage involves bilaterally the subcalcarine occipital cortex, in keeping with PET (Haxby et al., 1994; Sergent et al., 1992) and fMRI (Clark et al., 1996) studies, which have found an increased blood flow in the posterior part of the fusiform gyrus and adjacent occipito-temporal cortex, while the subject performed face discrimination tasks. From the same areas in epileptic patients Allison et al. (1994) recorded surface-negative potentials in response to the presentation of human faces. In associative forms, the lesion likely interrupts the inferior longitudinal fasciculus, which links the perceptual area with the infero-medial temporal lobe. Autopsy and neuroimaging data do not allow for the differentiation between the anatomical substrate of apperceptive and associative disorders but PET studies (Kapur et al., 1995; Sergent et al., 1992) suggest that tasks involving face memory specifically activate more anteriorly located inferior temporal cortices. The retrieval of familiar face names is associated with the bilateral activation of the temporal pole (Damasio et al., 1996). A hemispheric asymmetry was pointed out by Sergent et al. (1992), who found a more marked increase in cerebral blood flow in the right than in the left parahippocampal gyrus, and by two

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neurophysiological investigations. Uhl et al. (1990) reported a more prominent enhancement of the late negative event-related potential component from the right than the left occipital lead when familiar faces were presented, while, using depth electrodes, Seek et al. (1993, 1995) recorded a distinct pattern of neural responses to familiar faces from various sites of the temporal lobe, especially the amygdala, where they were confined to the right side. The amygdala plays an important role in the interpretation of emotional face expression. It is strongly linked with unimodal and polymodal sensory association areas and projects to motor, endocrine, and autonomic effector systems, located in the striatum, hypothalamus, and brain stem, thus providing a route for associating sensory information with emotional reaction (Tovee, 1995). Clinical evidence consistent with this assumption has been collected only recently. Adolphs et al.’s (1994) patient suffered from Urbach and Wiethe congenital disease, in which there is deposition of hyaline material in the amygdala. She showed preserved recognition of facial personal identity, but impaired recognition of fear and the blends of multiple emotions that a face can transmit. Although this finding was not replicated in two encephalitic patients with bilateral destruction of the amygdala and temporal lobe structures (Hamann et al., 1996), it is in keeping with PET measures of increased neuronal activity in the left amygdala, found in normal subjects, when they view fearful as opposed to happy facial expressions (Morris et al., 1996). In a patient submitted to partial bilateral amygdalotomy for the relief of intractable epilepsy, Young et al. (1995, 1996) documented difficulties in matching and identifying emotional facial expressions and in imagining facial expression of emotions. In addition, he was impaired in the recognition of faces learned postoperatively and in discriminating gaze direction, a function to which neurones in the superior temporal sulcus, strongly connected with those of the amygdala, are dedicated. Congenital and slowly progressive prosopagnosia In a few patients, prosopagnosia dates back to the early years of life, either without any detectable

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aetiology or as a consequence of brain disease. McConackie (1976) reported a congenital case in a 12-year-old girl, who was re-assessed by De Haan and Campbell (1991) 15 years later. She was an intelligent young woman, with a VIQ of 144 and a normal school curriculum. Her visual recognition deficit also extended to the recognition of emotional expressions and objects, and no unconscious face recognition could be demonstrated. The deficit was deemed to be apperceptive. The same was true for the patient reported by Ariel and Sadeh (1996), an 8-year-old girl with high verbal intelligence, who had severe problems in recognising not only face identity, but also their gender, age, and emotional expressions. She was poor on object drawings, particularly if they were presented from an unusual view or were partially masked. On the contrary the recognition deficit was restricted to faces in Temple’s (1991) patient and in that reported by Kracke (1994), a 19year-old man, who presented autistic features of the Asperger type. Interestingly, all of these patients (except Ariel & Sadeh’s) had a relative who experienced mild difficulty in face recognition. Yisuoperceptual disorders involving faces as well objects were also found in a boy who had encephalitis in infancy (Young & Ellis, 1989). In adults, the most common aetiology of prosopagnosia is stroke in the territory of the posterior cerebral artery. Among other aetiologies it is worth noting that the inability to recognise familiar faces can antedate other cognitive deficits in a few patients with progressive degenerative disease, mainly affecting the right temporal lobe (Evans et al., 1995; Tyrell et al., 1990b). In Alzheimer disease misidentification of familiar persons is detectable at clinical level in about 20% of patients (Della Sala et al., 1995; Mendez et al., 1992), while an impairment at psychometric level is present in about 50% of patients (Della Sala et al., 1995).

Colour agnosia Colours play an important role not only in enriching our emotional and aesthetic appreciation of the world, but also in discriminating an object from its background. They are processed by specific systems both at retina and brain level. In the retina

there are three types of receptors (cones), whose pigment has peak sensitivity to short-, middle-, and long-wavelength regions of the spectrum. They mediate the perception of blue, green, and red, respectively, while that of other colours of the spectrum results from the different grade of stimulation of these basic receptors by light. This information is transmitted by the parvocellular system (see earlier) and ends in area V4, which in humans seems to be located more medially than in the monkey, in a region encompassing the lingual and fusiform gyrus. Physiological studies have shown that in this area cells are clustered according to their peak sensitivity to light wavelength (especially for blue, green, purple, and red) and not to their relation to the topography of the visual field (Zeki, 1980, 1988). The following parameters define the perceptual features of a colour: 1. Hue, corresponding to the wavelength or the wavelength combination of the light reflected by the stimulus. It is equivalent to what we usually mean by colour. 2. Saturation, or purity, which reflects how much a hue has been diluted by greyness, depending on the the degree to which the cone mechanism is stimulated by both the object and the background. 3. Brightness, corresponding to light intensity. Hue and brightness information is transmitted by the same neurones up to the level of the visual cortex, where different subsets of neurones are dedicated to their analysis. Cortical lesions can selectively impair colour cognition either at a perceptual level or associative level, giving rise to a welter of disorders (Davidoff, 1991). Disorders o f colour perception (achromatopsia) Disorders of colour vision following a cerebral injury (acquired achromatopsia or dyschromatopsia) can occur in isolation; that is, without impairment of acuity, visual fields, form perception, or other cognitive deficits (Zeki, 1991). The first detailed description of complete achromatopsia was made by Samelsohn in 1881

16. AGNOSIA

and of hemiachromatopsia by Verrey in 1888, who must also be credited with having pointed out that the anatomical basis of the deficit was a subcortical lesion of the lingual gyrus. In the most severe forms, the patient spontaneously complains of being unable to see colours and of the world appearing like a black and white film or in different shades of grey (Damasio et al., 1980; Green & Lessel, 1977; Meadows, 1974a; Pearlman et al., 1979). In milder cases, hues appear washed out or as if they were seen through a filter and sometimes a suffix is added to the end of a colour name (as in reddish, bluey) or two colours are combined (reddish-orange). Patients often rely on brightness to distinguish colours and can name the colours of brightly coloured objects (Green & Lessel, 1977). Rizzo et al. (1992) used psychophysiological techniques to study a patient suffering from dyschromatopsia and showed that a severe deficit in hue discrimination was associated with a preserved threshold for luminance detection, spatial contrast sensitivity, stereopsis, and movement vision. Visual field defects, which are frequent, but not necessary accompaniments, generally involve both or just one of the superior quadrants, suggesting a subcalcarine lesion. This localisation is upheld by a few autopsies (reviewed by Meadows, 1974) and, in a larger number of cases, by neuroimaging findings, which point to a lesion encompassing the lingual and the fusiform gyrus, mainly at their junction (Damasio et al., 1980; Green & Lessel, 1977; Heywood et al., 1991). Consistent with these findings, PET studies in normal subjects (Corbetta et al., 1990; Lueck et al., 1989), have demonstrated a cerebral flow increase in the same region, when the subject looks at coloured patterns, e.g. a Mondrian picture. Unilateral occipital damage, not causing hemianopia, can be associated with contralateral hemiachromatopsia with features analogous to those of total achromatopsia: hues are not discriminated and appear grey (Albert et al., 1975a) and are named with an “ish” suffix (Henderson, 1982). A few patients show quadrantopsia in the contralateral upper field and achromatopsia in the lower field (Damasio et al., 1980; Koelmel, 1988). In conclusion, there

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is converging evidence from animal, PET, and pathology studies that each hemisphere contains a centre devoted to processing chromatic information from the contralateral visual field. Bilateral damage produces bilateral achromatopsia, unilateral damage contralateral hemiachromatopsia. As already mentioned on page 387, achromatopsia is not necessarily associated with deficit of colour imagery. Dyschromatopsia associated with a non-occipital lesion Damage to extraoccipital areas not directly concerned with vision were found to cause impaired colour discrimination in unselected patients with right brain injury. They did not complain of any deficit, but their mean scores on colour perception tests (Ishihara, Farnsworth, etc.), presented in central vision, were lower than those of control and left brain-damaged patients (De Renzi & Spinnler, 1967; Scotti & Spinnler, 1970), pointing to a greater contribution of the right hemisphere to chromatic discrimination, in analogy with what is seen for other visuoperceptual tasks and in keeping with the better accuracy shown by normal subjects in recognising colours tachistoscopically projected to the left rather than the right field (Davidoff, 1976; Hannay, 1979; Pennal, 1977). Other authors (Lhermitte et al., 1969; Vola et al., 1973) focused on patients with left posterior damage and visual field defects and found a defective performance on the Farnsworth test, presented in central vision, in 50% of them. The deficit mainly concerned blue-green discrimination (Dubois-Poulsen, 1982), in agreement with what Scotti and Spinnler (1970) most often found in brain-damaged patients. Capitani et al. (1978) investigated patients submitted to the ablation of well defined cortico-subcortical areas for the relief of epilepsy and found that the performance was poorer following a right frontal removal (occipital patients were very rare in this study). Associative disorders Since the turn of the nineteenth century, there have been reports of patients who show a deficit in colour naming and/or colour-object associations

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that cannot be accounted for by aphasia or dyschromatopsia. They perceive colours on Ishihara and Farnsworth tests well, but are unable to name them; to retrieve their name when given the name of an object of a definite colour; to match a colour with an object; or to sort colours according to their hue. Some of them fail only when they must make a verbo-visual match, others whenever a colour must be retrieved from semantic memory. The disorder of the latter type has often been labelled colour agnosia (Kinsboume & Warrington, 1964; Poetzl, 1928; Sittig, 1921), but it is doubtful whether this term is appropriate, when applied to stimuli such as colours, which are processed in one modality (Bauer & Rubens, 1985) and do not have meaning on their own. I prefer to call the syndrome colour amnesia. Test methods A thorough examination of the patient’s knowledge of colours requires, in addition to perceptual tasks,

a broad set of tests (Davidoff, 1991; De Vreese, 1991). These are summarised in Table 16.3. It is preferable to use common colours only (from 8 to 10) in naming and pointing tasks, because people differ in their competence in colour name knowledge, mostly as a function of their educational level. Generating the names of colours is a verbal fluency task, whose performance should be compared with that for other categories. Generating the names of objects of a definite colour assesses visual imagery. In preparing lists of object-colour associations, care must be taken to distinguish those in which the chromatic attribute of the object represents an overlearned verbal association from those that require visual imaging. For instance, knowledge that blood is red comes into many verbal expressions (red blood cells, red-blooded people, to turn red, blood-red to designate a certain variety of red, etc.) and can be retrieved from verbal

TABLE 16.3 Colour cognition tests. V erb o -vis u al tests

Colour naming: What colour is this? Pointing to colours: Show me the green. C o lo u r-n a m e g e n e ra tio n

Generate the names of colours. Generate the names of objects of a particular colour (e.g. red). O b je c t-c o lo u r association

Name the colour of an object that has a typical colour: What colour is a frog? Name the colour of a personal belonging. Decide whether two objects are the same colour (e.g. banana and sunflower). Colouring in drawings of objects of a typical colour or deciding whether a drawing has been correctly coloured. Provide a metaphoric colour on verbal definition (e.g. white lie, blue-blooded, red herring). C o lo u r le a rn in g

Short-term memory for colours. Learning arbitrary colour-object associations. C o lo u r ca teg o ris atio n

Holmgren’s skein categorization test.

16. AGNOSIA

memory without implying the formation of a mental image, which is likely, on the contrary, to be necessary when we evoke a conventional association, such as the colour of a mail box. Generally speaking, verbal knowledge is the only determinant of metaphoric associations (to be green with envy). It also contributes greatly to the retrieval of the colour of certain natural objects, but has minimal or no role for objects of a conventional colour and for the colour of personal belongings (De Vreese, 1991). As stressed by Beauvois (1982), what is interesting about this distinction is that the performance of some patients may change, depending on whether the visual or the verbal strategy is favoured. Colouring tasks can be given to patients with language disorders, while rejection of wrongly coloured drawings is an easier task (Stengel, 1948) that has shown little discriminative power in a group study (Basso et al., 1976). Short-term memory tests and learning arbitrary colour-object associations can be presented both in the visual and verbal modality and may be useful to assess whether the impairment in dealing with colours extends to anterograde memory. In the Holmgren skein sorting task, patients are presented with woollen skeins of different hues and shades and requested to pick out all the skeins belonging to the same colour category (e.g. all the reds, greens, etc.). In former times it was viewed as a colour perception test, but Sittig (1921) and Gelb and Goldstein (1924) stressed its potential for assessing the patient’s ability to categorise colours and assigned it a paramount role in the evaluation of so-called colour agnosia (for a more recent reappraisal of the test, see De Renzi et al., 1972b). Unfortunately, for the most part, the patients reported by the literature have not been exhaustively investigated and cannot be readily classified. There is, however, sufficient evidence to distinguish two main categories of disorders, namely, those characterised by a visuo-verbal disconnection and those by a colour amnesia. Visuo-verbal disconnection (colour anomia or aphasia) These patients, who do not complain of disorders of colour perception, fail colour tasks in which verbal information must be matched with visual

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information—that is, naming a visually presented colour and pointing to a colour named by the examiner—whereas they pass tasks that are carried out in one modality, either verbal (what colour is a frog?) or visual (colouring in a drawing of a frog). The classical interpretation is couched in anatomical terms. The patients have a left occipital lesion that causes right hemianopia and, consequently, confines the perceptual processing of visual data to the right visual areas. While this information is readily utilisable in visual tasks (e.g. colouring drawings), which can be carried out by the same hemisphere, it is not available in naming tasks, because the lesion interrupts, at the level of either the splenium or the forceps major, the fibres connecting the right occipital lobe with the left language areas, where names of colours are stored. An exemplar of this condition is the patient exhaustively studied by Geschwind and Fusillo (1966), though quantitative data were not reported, and that of Gainotti et al. (1974), although pathological documentation was lacking. Other less thoroughly investigated cases were reported by Boucher et al. (1976), who did not test pointing, and by Oxbury et al. (1969, case 1), M ohret al. (1971), and Levin and Rose (1979), who did not provide information on colouring drawings. Naming is often more impaired than pointing, which was normal in a few patients of this group as well as of the successive one (Davidoff & Ostergaard, 1984; De Vreese, 1991; Sasanuma, 1974; Varney & Digre, 1983). Possibly, the performance was carried out entirely by the right hemisphere, which may also be endowed with verbal comprehension skills in right handers. In the patient reported by De Vreese (1991) the visuo-verbal disconnection hypothesis was apparently challenged by the finding that he too failed on a colour imaging task, carried out in the verbal modality (what colour is a frog?). However, the impairment only involved colour-object associations that are not aided by verbal mediation, such as objects that have an arbitrary, conventional colour, and personal objects. As the patient correctly performed the task of colouring in drawings, the deficit could not be attributed to a mental imagery impairment and was viewed as consequent to the inability to link the output of

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visual imagery with the lexicon, thus confirming the visuo-verbal disconnection hypothesis. Geschwind and Fusillo (1966) had not drawn a distinction between verbally and nonverbally coded colours, and De Vreese’s case stresses the need to keep their assessment separate. Colour anomia is usually associated with pure alexia, which stems from the same visuo-verbal disconnection mechanism (Dejerine, 1892). Only a few exceptions are on record (Davidoff & De Bleser, 1994; Mohr et al., 1971; Vincent et al., 1977). Colour anomia restricted to the left visual field was observed (Zihl & von Cramon (1980) in a patient with damage to the right occipito-temporal white matter and the splenium, and it was attributed to the disconnection of the right visual areas from the left language centres. Colour amnesia The disconnection hypothesis is inadequate to account for the performance of patients whose failure involves tasks that are carried out in one modality, either verbal (what colour is a frog?) or visual (colouring in a drawing of a frog). Lewandowsky (1908, see the partial English translation of his paper in Cognitive Neuropsychology, 1