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Oxford Textbook of

Cognitive Neurology and Dementia

Oxford Textbooks in Clinical Neurology


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Oxford Textbook of

Cognitive Neurology and Dementia

Edited by

Masud Husain

Professor of Neurology & Cognitive Neuroscience, Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, UK

Jonathan M. Schott

Reader in Clinical Neurology, Dementia Research Centre, Department of Neurodegenerative Diseases, UCL Institute of Neurology, UK

Series Editor

Christopher Kennard


Great Clarendon Street, Oxford, OX2 6DP, United Kingdom

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Cognitive neurology, or behavioural neurology as it is known in the United States, has a reputation of being a complex sub- specialty. To the outsider it presents a formidable challenge, seemingly requiring knowledge of several different areas of expertise ranging from basic aspects of neuroscience—molecular, cognitive, and neuroimaging—through to neuropsychology, neuropsychiatry, and bedside neurological assessment. Even for experts, the dramatic growth of basic neuroscience research in these areas has meant that it can be extremely difficult to keep up with new developments or key conceptual advances. Perhaps more challenging still is to know how such advances can best be applied in practice when confronted with a patient with a cogni- tive complaint. Our aim in producing this textbook is to bring some order to the apparent chaos for both the novice and those established in the field. While there are several excellent texts that selectively cover either dementia or the neuroscience underlying cognitive disor- ders, we wanted to produce a modern, pragmatic resource that covers both these areas in an accessible manner for clinicians. Our second objective was to produce a textbook that spans diverse areas of expertise in an integrated fashion. Wherever possible, therefore,

we have tried to link information in chapters on basic sciences to those on clinical syndromes. The text is firmly based on the clinical approach to the patient with cognitive impairment and dementia, but it also provides essential background knowledge that is fundamental to clinical practice. It is written for those who want to learn more about cog- nition and dementia, including neurologists, geriatricians, and psy- chiatrists who are involved in assessing and treating such patients, but also for others curious to find out about cognitive disorders and their underlying neurobiology. We hope that, whatever your background, you will find this the one essential textbook that you want to revisit. Bringing together such a diverse range of information has been a challenge for us. We are extremely grateful to our contributors for being so considerate in taking up our suggestions for changes to their manuscripts and for their patience. Finally, we acknowl- edge with thanks the forbearance of our families who observed our involvement in this project with much more than tolerance and grace.

Masud Husain Jonathan M. Schott

Abbreviations ix

Contributors xv



Normal cognitive function

1 Historical aspects of neurology 3

Charles Gross

2 Functional specialization and network connectivity in brain function 17

Giovanna Zamboni

3 The frontal lobes 27

Teresa Torralva, Ezequiel Gleichgerrcht, Agustin Ibañez, and Facundo Manes

4 The temporal lobes 39

Morgan D. Barense, Jason D. Warren, Timothy J. Bussey, and Lisa M. Saksida

5 The parietal lobes 51

Masud Husain

6 The occipital lobes 59

Geraint Rees

7 The basal ganglia in cognitive disorders 69

James Rowe and Timothy Rittman

8 Principles of white matter organization 81

Marco Catani

9 Neurochemistry of cognition 91

Trevor W. Robbins


Cognitive dysfunction

10 Bedside assessment of cognition 105

Seyed Ahmad Sajjadi and Peter J. Nestor

11 Neuropsychological assessment 113

Diana Caine and Sebastian J. Crutch

12 Acquired disorders of language and speech 123

Dalia Abou Zeki and Argye E. Hillis

13 Memory disorders 135

Lara Harris, Kate Humphreys, Ellen M. Migo, and Michael D. Kopelman

14 Vision and visual processing deficits 147

Anna Katharina Schaadt and Georg Kerkhoff

15 Disorders of attentional processes 161

Paolo Bartolomeo and Raffaella Migliaccio

16 Apraxia 173

Georg Goldenberg

17 Acquired calculation disorders 183

Marinella Cappelletti

18 Disorders of reading and writing 189

Alexander P. Leff

19 Neuropsychiatric aspects of cognitive impairment 197

Dylan Wint and Jeffrey L. Cummings




Cognitive impairment and dementia

20 Epidemiology of dementia 211

Thais Minett and Carol Brayne

21 Assessment and investigation of the cognitively impaired adult 221

Jonathan M. Schott, Nick C. Fox, and Martin N. Rossor

22 Delirium, drugs, toxins 231

Barbara C. van Munster, Sophia E. de Rooij, and Sharon K. Inouye

23 CNS infections 239

Sam Nightingale, Benedict Daniel Michael, and Tom Solomon

24 Metabolic dementia 253

Nicholas J.C. Smith and Timothy M. Cox

25 Vascular cognitive impairment 275

Geert Jan Biessels and Philip Scheltens

26 Cerebral amyloid angiopathy and CNS vasculitis 285

Sergi Martinez-Ramirez, Steven M. Greenberg, and Anand Viswanathan

27 Cognition in multiple sclerosis 295

Maria A. Ron

28 Autoimmune encephalitis 299

Sarosh R. Irani, Thomas D. Miller, and Angela Vincent

29 Pathology of degenerative dementias 315

Tamas Revesz, Tammaryn Lashley, and Janice L. Holton

30 Genetics of degenerative dementias 329

Rita Guerreiro and Jose Bras

31 Other genetic causes of cognitive impairment 339

Davina J. Hensman Moss, Nicholas W. Wood, and Sarah J. Tabrizi

32 Changing concepts and new definitions for Alzheimer’s disease 353

Bruno Dubois and Olga Uspenskaya-Cadoz

33 Presentation and management of Alzheimer’s disease 361

Susan Rountree and Rachelle S. Doody

34 Primary progressive aphasia 381

Jonathan D. Rohrer and Jason D. Warren

35 Frontotemporal dementia 391

Bruce Miller and Soo Jin Yoon

36 Dementia with Lewy bodies and Parkinson’s disease dementia 399

Haşmet A. Hanağası, Başar Bilgiç, and Murat Emre

37 Corticobasal degeneration, progressive supranuclear palsy, multiple system atrophy, argyrophilic grain disease, and rarer neurodegenerative diseases 413

Elizabeth A. Coon and Keith A. Josephs

38 Prion diseases 425

Simon Mead, Peter Rudge, and John Collinge

39 Traumatic brain injury 435

David J. Sharp, Simon Fleminger, and Jane Powell

40 Neurosurgery for cognitive disorders 453

Tom Foltynie and Ludvic Zrinzo

41 Cognition in severe mental illness: Schizophrenia, bipolar disorder, and depression 463

Philip D. Harvey and Christopher R. Bowie

Index 471



Three-City Study


Adenosine 5 -triphosphate


5-choice serial reaction time task




5-hydroxyindoleacetic acid


Alcohol-withdrawal delirium




Beta secretase

amyloid β


Basophilic inclusion body disease


ATP-binding cassette


Binding of item and context


Anterior cerebral artery


Bridging integrator


Anterior cingulate circuit


Brain Injury Rehabilitation Trust


Addenbrooke’s Cognitive Examination


BIRT Memory and Information Processing


Revised Acetylcholine


Battery Blood oxygenation level dependent


Acetylcholinesterase inhibitors


Birmingham Object Recognition Battery


Alzheimer’s disease


Behavioural and psychological symptoms


Apparent diffusion coefficient

of dementia


Alzheimer’s Disease Education &


Bovine spongiform encephalopathy

Referral Center


Behavioural variant frontotemporal


Attention deficit/hyperactivity disorder



Activities of daily living


Cerebral amyloid angiopathy


Autoimmune encephalitis


CAA-related inflammation


Antiepileptic drugs


Cerebral autosomal dominant


Arcuate fasciculus

arteriopathy with subcortical infarcts and


Argyrophilic grains



Argyrophilic grain disease




Anterior insula


Confusion Assessment Method


Anterior intraparietal sulcus


Cambridge Cognition–Revised


amyotrophic lateral sclerosis


Cambridge mental disorders of the older



population examination


amnesic mild cognitive impairment


Cambridge Automatic Neuropsychological



Test Battery

isoxazolepropionic acid


Cerebral autosomal recessive


Abbreviated Mental Test Score

arterioapthy with subcortical infarcts and


Angular gyrus



Asymptomatic neurocognitive impairment


Contactin-associated protein 2


Apraxia of speech


Cas scaffolding


American Psychiatric Association


Computed axial tomography


Adult polyglucosan body disease


Corticobasal degeneration




Cobalamin C disease


Amyloid precursor protein


Corticobasal syndrome


Autosomal recessive spastic ataxia of


Cognitive behaviour therapy



Cambridge City over-75s


Antiretroviral therapy

Cohort Study


Asymptomatic AD


Cerebellar cognitive affective syndrome




Consortium to Establish a Registry of


Executive functions

Alzheimer’s Disease


Encephalitis lethargica




English Longitudinal Study of Ageing



European Medicines Agency


Cholinesterase inhibitors




Confidence interval


Established Populations for Epidemiologic


Clinically isolated syndrome

Studies of the Elderly


Creutzfeld–Jakob disease


Epilepsy, progressive myoclonus


Complementary learning system


Endosomal-sorting complex required



for transport


Cerebral microbleed


Endoscopic third ventriculostomy


Central nervous system


Ewing’s sarcoma protein


Coenzyme A


Fractional anisotropy


Continuous positive airway pressure


Frontal assessment battery


CNS penetration effectiveness


Flavin adenine dinucleotide


Complement component receptor


Familial British dementia


Convergence, Recollection, and


Faciobrachial dystonic seizures

Familiarity Theory


Free and Cued Selective Reminding Test


Corticotrophic releasing factor


Food and Drug Administration


Cognitive remediation therapy


Familial Danish dementia


Contention scheduler




Contrast sensitivity




Subarachnoid blood in the convexity


Frontal eye fields


Canadian Study of Health and Aging


First episode psychosis


Cerebrospinal fluid




Computed tomography


Fusiform face area


Chronic traumatic encephalopathy


Fatal familial insomnia


Cathepsin D


Full-scale IQ


California verbal learning test


Fluid-attenuated inversion recovery




Functional magnetic resonance imaging


Diffuse axonal injury


Functional MRI of the Brain


Disability-adjusted life years


Friedreich’s ataxia


Dorsal attentional network


FMRIB Software Library


Dopamine transporter


Fluorescent treponemal antibody-absorption


Direct detection assay


Frontotemporal dementia


Docosahexanoic acid


Frontotemporal lobar degeneration


Dominantly Inherited Alzheimer Network


Frontotemporal degeneration-tau


Double inversion recovery


Frontotemporal degeneration-ubiquitin


Dystrophic neurites




Dementia with Lewy bodies


Gamma aminobutyric acid


Dorsolateral prefrontal circuit


Glutamic acid decarboxylase


Decision making




Default mode network


Global Burden of Disease


Disease modifying therapies


Glycogen brancher enzyme




Glial cytoplasmic inclusions


Dilated perivascular spaces


Granule cell layer


Dentatorubral-pallidoluysian atrophy


Glasgow Coma Scale


Dementia rating scale


Glial-derived neurotrophic factor


Diagnostic and Statistic Manual


Glial fibrillary acidic protein


Diffusion tensor imaging


Growth hormone deficiency




General linear model


Diffusion-weighted imaging


Global pallidus external


Entorhinal cortex


Globus pallidus internal


Extracytoplasmic function


Geriatric Mental State Examination/


Epidemiological Clinicopathological Studies in Europe

Automated Geriatric Examination Computer Assisted Taxonomy


Electroconvulsive therapy


Gradient-recalled echo


Excessive daytime sleepiness


Gerstmann–Sträussler syndrome




Genome-wide association studies




Proton magnetic resonance spectroscopy


Mild cognitive impairment


HIV-associated dementia


Minimially conscious state


Hospital Anxiety and Depression Scale


Multiple demand


HIV-associated neurocognitive disorders


Myocyte enhancer factor


Hepatitis C virus




Huntington’s disease


Mitochondrial encephalopathy lactic


Huntington’s disease-like syndrome

acidosis and stroke-like episodes


High-income countries


Myoclonic epilepsy with ragged red fibres


Human immunodeficiency virus




HIV encephalopathy


Multi-infarct dementia


Hydroxy-3-methylglutaryl-coenzyme A


Medial intraparietal sulcus


Hazard ration


Methylmalonic acid


Hormone replacement therapy


Mini-Mental State Examination


Herpes simplex virus


Mild neurocognitive impairment


Human T-lymphotropic virus


Motor neurone disease


Inclusion body myopathy with Paget disease


Montreal Neurological Institute

of the bone and frontotemporal dementia


Montreal Cognitive Assessment


123 I-iodobenzovesamicol


Medial occipitoparietal junction


Independent component analysis


Morvan’s syndrome


International Classification of Diseases




Impulse control disorders


Medical Research Council


Intracerebral haemorrhages


Medical Research Council’s cognitive


Iatrogenic CJD

function and ageing study


Intrinsic connectivity networks


Magnetic resonance imaging


Intensive care unit


Magnetic resonance spectroscopy


Intra- and extra-dimensional


Multiple sclerosis


Inferior fronto-occipital fasciculus


Multiple system atrophy


Insulin-like growth factor II


Mental state examination




Maple-syrup urine disease


Iowa Gambling Task


Middle temporal gyrus


Inferior longitudinal fasciculus


Methylenetetrahydrofolate reductase


Italian Longitudinal Study of Ageing


Medial temporal lobes


Inherited prion disease


N-acetyl aspartate/Creatinine


Inferior parietal lobule




Intraparietal sulcus


National Adult Reading Test


Immune reconstitution inflammatory


Normal-appearing white matter


syndrome Inferotemporal


Neurodegeneration with brain iron accumulation


International Working Group


Nucleus basalis of Meynert


John Cunningham


Neuronal cytoplasmic inclusions


Low and medium-income countries




Lisdexanphetamine dimesylate


Non-fluent variant primary progressive


Limbic encephalopathy



leucine-rich glioma inactivated 1


Nerve growth factor


Lateral occipital cortex


National Institute for Health and Care


Lumbar puncture



Logopenic progressive aphasia


Neuronal intermediate filament inclusion


Long-term depression



Long-term memory


Neuronal intranuclear inclusions


long-term observational controlled studies


National Institute of Neurological and


Long-term potentiation

Communicative Disorders and Stroke


Methyl-4-piperidyl acetate

and the Alzheimer’s Disease and Related


Microtubule-associated tau

Disorders Association


Measurement and Treatment Research for Improving cognition in schizophrenia


National Institute of Neurologic Disease and Stroke






Marchiafava–Bignami disease


NMDA receptor


Middle cerebral artery




MATRICS consensus cognitive battery


Neuropsychiatric Inventory




Normal pressure hydrocephalus


Persistent vegetative state


Neuronal surface-directed antibody


Prominent perivascular spaces


Orbitofrontal circuit


Retrograde amnesia


Orbitomedial prefrontal cortex


Rey auditory verbal learning test


Opsoclonus-myoclonus syndrome


REM sleep behaviour disorder


Octapeptide repeat insertion mutation


Regional cerebral blood flow


Odds ration


Randomized controlled trial


Ornithine transcarbamylase


Rapid eye movement


Primary angiitis of the central


Recognition memory test

nervous system


Regions of interest


Parkinson neuropsychometric dementia


Reactive oxygen species



Rapidly progressive dementia


Personnes âgées QUID


Rapid plasma reagin


Periodic acid–Schiff


Relapsing and remitting MS


Paced auditory serial addition test


Resting state network


Posterior cerebral artery


Real-time Quaking-Induced


Posterior cortical atrophy

Conversion Assay


Principal component analysis


Supervisory attentional gateway


Polymerase chain reaction


Supervisory attentional system


PD Cognitive Rating Scale


Spinocerebellar ataxia


Parkinson’s disease with dementia


sporadic CJD


Parietal eye fields


Small cell lung cancer


Progressive encephalomyelitis with rigidity and myoclonus


SCales for Outcomes of PArkinson’s disease-cognition


Positron emission tomography


Semantic dementia


Prefrontal cortex


Senile dementia of Alzheimer type


Progressive nonfluent aphasia


status epilepticus


Pittsburgh Compound-B


Structured event complex


Phosphatidylinositol binding clathrin



assembly protein


Solute carrier


Pick’s disease


Superior longitudinal fasciculus


Postural-instability gait difficulty


Supplementary motor area


Performance IQ


Supramarignal gyrus


Periodic lateralizing epileptiform discharges


Salience network


Progressive multifocal leukoencephalopathy


Single nucleotide polymorphism


Progressive non-fluent aphasia


Substantia nigra pars compacta


Peripheral nerve hyperexcitability


Substantia nigra pars reticulata


Parahippocampal place area


Substantia nigra


Primary progressive aphasia


Serotonin-norepinephrine reuptake


Posterior parietal cortex



Primary progressive MS




Pedunculopontine nucleus


Space-occupying lesion


Palmitoyl-protein thioesterase 1


Sortilin-related receptor


Peabody picture vocabulary test


Single photon emission computed


Prion protein



Potential support ratio


Superior parietal lobule




Statistical parametric mapping


Phase-sensitive inversion recovery


Secondary progressive MS


Progressive supranuclear palsy


Stiff-person syndrome


PSP–corticobasal syndrome


Short portable mental status questionnaire


PSP–corticospinal tract dysfunction


Sylvian parietotemporal




Superficial siderosis


PSP–pure akinaesia with gait freezing


Small subcortical infarct


PSP–primary progressive apraxia of speech


Subacute sclerosing panencephalitis


PSP–Richardson’s syndrome


Selective serotonin reuptake inhibitors


Pancreatic secretory trypsin inhibitor


Stop-signal reaction time


Post-traumatic amnesia


Superior temporal gyrus


Protein tyrosine kinase


Short-term memory


Post-traumatic stress disorder


Subthalmic nucleus




STandards for ReportIng Vascular changes


MCI of vascular origin

on nEuroimaging


Ventral attentional network


Superior temporal sulcus


Voxel-based morphometry


Small vessel disease


Vascular cognitive disorder


Semantic variant primary progressive


Vascular cognitive impairment



variant CJD


Susceptibility-weighted images


Venereal disease research laboratory


Transcranial alternating current stimulation


Von Economo neurons


TATA-binding protein-associated factor


Visual field disorders


Tricarboxylic acid


Voltage-gated potassium channel


Transcortical motor aphasia


Vasoactive intestinal polypeptide


Transcranial direct current stimulation


Ventral intraparietal sulcus


TAR DNA-binding protein


Verbal IQ


Transient focal neurological deficits




Transcranial magnetic stimulation


Voxel-based lesion symptom


Theory of Mind



treponema pallidum haemaglutination assay


Visual object and space perception


treponema pallidum particle agglutination


Ventral tegmental area


treponema pallidum immobilization


Ventral visual stream


Temporoparietal junction


Visual word form area


Treatement-resistant depression


Wechsler Adult Intelligence Scale


Triggering receptor expressed on


Wisconsin Card Sorting Test

myeloid cells


World Health Organization


Uncinate fasciculus


WHO Statistical Information Systems


Unified Huntington’s Disease Rating Scale


White matter MRI hyperintensities


Primary visual cortex


Wide Range Achievement Test


Ventral anterior


Years lost due to disability


Vascular dementia


Years of healthy life lost


Dalia Abou Zeki, Johns Hopkins University School of Medicine, Baltimore, USA

Morgan D. Barense,


of Toronto, Canada; Rotman

Research Institute, Baycrest Hospital, Toronto, Canada

Paolo Bartolomeo, INSERM U 1127, CNRS UMR 7225, Sorbonne Universités, and Université Pierre et Marie Curie-Paris 6, UMR S 1127, Institut du Cerveau et de la Moelle épinière (ICM), Pitié- Salpêtrière Hospital, Paris, France

Geert Jan Biessels, Department of Neurology, Brain Centre Rudolf Magnus, University Medical Centre, Utrecht, The Netherlands

Başar Bilgiç, Associate Professor of Neurology, Istanbul University, Istanbul Faculty of Medicine, Department of Neurology, Behavioral Neurology and Movement Disorders Unit, Istanbul, Turkey

Christopher R. Bowie, Departments of Psychology and Psychiatry, Queens University Kingston, Ontario, Canada

Jose Bras, Department of Molecular Neuroscience, Institute of Neurology, University College London, UK

Carol Brayne, Department of Public Health & Primary Care, University of Cambridge, UK

Timothy J. Bussey,

Department of

Psychology, University of

Cambridge, UK; MRC and Wellcome Trust Behavioural and Clinical Neuroscience Institute, University of Cambridge, UK

Diana Caine, Department of Neuropsychology, National Hospital for Neurology and Neurosurgery, London, UK

Marinella Cappelletti, Department of Psychology, Goldsmiths College, University of London, UK; UCL Institute of Cognitive Neuroscience, UK

Marco Catani, NatBrainLab, Institute of Psychiatry, Psychology and Neuroscience, King's College London, UK

John Collinge, MRC Prion Unit, Department of Neurodegenerative


Neurology and NHS National Prion Clinic, National Hospital for







Neurology and Neurosurgery, UCL Hospitals NHS Foundation Trust, UK

Elizabeth A. Coon, Assistant Professor and Consultant of Neurology, Division of Autonomic Neurology, Mayo Clinic, Rochester, USA




Cambridge, UK






Sebastian J. Crutch, Dementia Research Centre, UCL Institute of Neurology, UK

Jeffrey L. Cummings, Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, USA









Department of Neurology, Houston, USA

Bruno Dubois, Dementia Research Center (IM2A) and Behavioral Unit, Salpêtrière University Hospital, Université Pierre et Marie Curie, Paris, France

Murat Emre, Professor of Neurology, Istanbul University, Istanbul Faculty of Medicine, Department of Neurology, Behavioral Neurology and Movement Disorders Unit, Istanbul, Turkey

Simon Fleminger, Department of Neuropsychiatry, Institute of Psychiatry, King's College London, UK

Tom Foltynie, Senior Lecturer & Honorary Consultant Neurologist, Sobell Department of Motor Neuroscience, UCL Institute of Neurology, UK



Neurodegenerative Diseases, UCL Institute of Neurology, UK









Neurosurgery, Medical University of South Carolina, USA





Georg Goldenberg, Department of Neurology, Technical University Munich, Germany

Steven M. Greenberg, Hemorrhagic Stroke Research Program, Massachusetts General Hospital, USA










Neuroscience Institute, Princeton University, USA

Rita Guerreiro, Department of Molecular Neuroscience, Institute of Neurology, University College London, UK

Haşmet A. Hanağası, Professor of Neurology, Istanbul University, Istanbul Faculty of Medicine, Department of Neurology, Behavioral Neurology and Movement Disorders Unit, Istanbul, Turkey






Psychology and Neuroscience, UK




Philip D. Harvey, Leonard M. Miller Professor of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, USA

Davina J. Hensman Moss, Clinical Fellow, Department of Neurodegenerative Disease, UCL Institute of Neurology and National Hospital for Neurology and Neurosurgery, UK

Argye E. Hillis, Professor of Neurology, Executive Vice Chair, Dept. of Neurology, Director, Cerebrovascular Division, Johns Hopkins University School of Medicine, Baltimore, USA

Janice L. Holton, Queen Square Brain Bank for Neurological Disorders, UCL Institute of Neurology, UK

Kate Humphreys, South London and Maudsley NHS Foundation Trust, UK

Masud Husain, Professor of Neurology & Cognitive Neuroscience, Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, UK

Agustin Ibañez, Institute of Translational and Cognitive Neuroscience (ITCN), Ineco Foundation, Favaloro University, Buenos Aires, Argentina; University Adolfo ibañez, Chile; Centre of Excellence in Cognition and its Disorders, Australian Research Council (ACR), Sydney, Australia

Sharon K. Inouye, Aging Brain Center, Institute for Aging Research, Hebrew SeniorLife, Boston, USA; Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA

Sarosh R. Irani, Honorary Consultant Neurologist and Senior Clinical Fellow, Nuffield Department of Clinical Neurosciences, University of Oxford, UK

Keith A. Josephs, Professor and Consultant of Neurology, Divisions of Behavioural Neurology & Movement Disorders, Mayo Clinic, Rochester, USA

Georg Kerkhoff, Saarland University Department of Psychology, Clinical Neuropsychology Unit and Neuropsychological Outpatient Service, Campus Saarbrücken, Germany









Psychiatry, Psychology and Neuroscience, UK

Tammaryn Lashley, Queen Square Brain Bank for Neurological Disorders, UCL Institute of Neurology, UK

Alexander P. Leff , Reader in Cognitive Neurology and Honorary Consultant Neurologist, Institute of Neurology & National Hospital for Neurology and Neurosurgery, University College London, UK

Facundo Manes, Institute of Translational and Cognitive Neuroscience (ITCN), Ineco Foundation, Favaloro University, Buenos Aires, Argentina; UDP-INECO Foundation Core on Neuroscience (UIFCoN), Diego Portales University, Santiago, Chile; Australian Research Council (ACR) Centre of Excellence in Cognition and its Disorders, Sydney, Australia, National Scientific and Technical Research Council (CONICET), Buenos Aires, Argentina

Sergi Martinez-Ramirez, Hemorrhagic Stroke Research Program, Massachusetts General Hospital, USA

Simon Mead, MRC Prion Unit, Department of Neurodegenerative Disease, University College London (UCL) Institute of Neurology and NHS National Prion Clinic, National Hospital For Neurology and Neurosurgery, UCL Hospitals NHS Foundation Trust, UK

Benedict Daniel Michael, Post-Doctoral Research Fellow, Massachusetts General Hospital, Harvard Medical School; Institute of Infection and Global Health, University of Liverpool, UK; Walton Centre for Neurology and Neurosurgery, Liverpool, UK

Raffaella Migliaccio, INSERM U 1127, CNRS UMR 7225, Sorbonne Universités, and Université Pierre et Marie Curie-Paris 6, UMR S 1127, Institut du Cerveau et de la Moelle épinière (ICM), and Department of Neurology, Institute of memory and Alzheimer's disease, Pitié-Salpêtrière Hospital, Paris, France

Ellen M. Migo, King’s College London, Institute of Psychiatry, Psychology and Neuroscience, UK

Bruce Miller, Department of Neurology, UCSF School of Medicine, San Francisco, USA

Thomas D. Miller, Patrick Berthoud/Encephalitis Society Clinical Research Fellow, Nuffield Department of Clinical Neurosciences, University of Oxford, UK; Specialist Registrar in Neurology, National Hospital For Neurology and Neurosurgery, University College London, London, UK

Thais Minett, Specialty Registrar in Radiology, Academic Clinical Fellow, Department of Radiology, University of Cambridge, UK

Barbara C. van Munster, Department of Internal Medicine, Academic Medical Centre, Amsterdam, The Netherlands; Department of Geriatrics, Gelre Hospitals, Apeldoorn, The Netherlands

Peter J. Nestor, German Centre for Neurodegenerative Diseases (DZNE), Magdeburg, Germany






University of Liverpool, UK




Jane Powell, Goldsmiths, University of London, UK

Geraint Rees, UCL Institute of Cognitive Neuroscience, UK











Disorders, UCL Institute of Neurology, UK



Cambridge, UK






Trevor W. Robbins, Professor of Cognitive Neuroscience and Experimental Psychology Director, Behavioural and Clinical Neuroscience Institute Head of Dept. Psychology, University of Cambridge, UK

Jonathan D. Rohrer, Dementia Research Centre, UCL Institute of Neurology, UK

Maria A. Ron, Emeritus Professor of Neuropsychiatry, UCL Institute of Neurology, UK

Sophia E. de Rooij, Department of Internal Medicine, Academic Medical Centre, Amsterdam, The Netherlands; Department of Internal Medicine, University Medical Centre Groningen, The Netherlands

Martin N. Rossor, Dementia Research Centre, Department of Neurodegenerative Diseases, UCL Institute of Neurology, UK

Susan Rountree, Associate Professor, Baylor College of Medicine, Department of Neurology, Houston, USA

James Rowe, Professor of Cognitive Neurology, University of Cambridge, UK

Peter Rudge, MRC Prion Unit, Department of Neurodegenerative Disease, University College London (UCL) Institute of Neurology and NHS National Prion Clinic, National Hospital For Neurology and Neurosurgery, UCL Hospitals NHS Foundation Trust, UK









Cambridge, UK; MRC and Wellcome Trust Behavioural and Clinical Neuroscience Institute, University of Cambridge, UK

Seyed Ahmad Sajjadi, Neurology Department, Addenbrooke’s Hospital, Cambridge, UK

Anna Katharina Schaadt, Saarland University Department of Psychology, Clinical Neuropsychology Unit and Neuropsychological Outpatient Service, Campus Saarbrücken, Germany

Philip Scheltens, Alzheimer Centre and Department of Neurology, VU University Medical Centre, Neuroscience Campus Amsterdam, the Netherlands

Jonathan M. Schott, Reader in Clinical Neurology, Dementia Research Centre, Department of Neurodegenerative Diseases, UCL Institute of Neurology, UK

David J. Sharp, National Institute of Health (NIHR) Professor and Consultant Neurologist, The Computational, Cognitive and Clinical Neuroimaging Laboratory, Division of Brain Sciences, Imperial College London, UK

Tom Solomon, Institute of Infection and Global Health, University of Liverpool, UK; Walton Centre for Neurology and Neurosurgery, Liverpool, UK

Nicholas J.C. Smith, Department of Neurology, Women’s and Children’s Health Network and Discipline of Paediatrics, School of Medicine, University of Adelaide, Australia

Sarah J. Tabrizi, Professor of Clinical Neurology, Honorary Consultant Neurologist, Department of Neurodegenerative Disease, UCL Institute of Neurology and National Hospital for Neurology and Neurosurgery, UK

Teresa Torralva, Institute of Translational and Cognitive Neuroscience (ITCN), Ineco Foundation, Favaloro University, Buenos Aires, Argentina; UDP-INECO Foundation Core on Neuroscience (UIFCoN), Diego Portales University, Santiago, Chile; Australian Research Council (ACR) Centre of Excellence in Cognition and its Disorders, Sydney, Australia

Olga Uspenskaya-Cadoz, Quintiles; CNS Medical Strategy and Science; Levallois-Perret, France

Angela Vincent, Professor of Neuroimmunology and Honorary Clinical Immunologist, Nuffield Department of Clinical Neurosciences, University of Oxford, UK

Anand Viswanathan, Hemorrhagic Stroke Research Program, Massachusetts General Hospital, USA

Jason D. Warren, Dementia Research Centre, UCL Institute of Neurology, UK

Dylan Wint, Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, USA

Nicholas W. Wood, Galton Chair of Genetics, Vice Dean Research Faculty of Brain Sciences, NIHR UCLH BRC Neuroscience Programme Director, UCL Institute of Neurology, UK

Soo Jin Yoon, Associate Professor, Department of Neurology, Eulji University Hospital, Eulji University School of Medicine, Daejeon, Korea

Giovanna Zamboni, Nuffield Department of Clinical Neurosciences (NDCN), University of Oxford, UK

Ludvic Zrinzo, Senior Lecturer & Consultant in Neurosurgery, Sobell Department of Motor Neuroscience, UCL Institute of Neurology, UK


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Historical aspects of neurology

Charles Gross

Before science

The oldest known neurological procedure is trepanning or trephin- ing, the removal of a piece of bone from the skull. It was practised from the late Palaeolithic period onwards and throughout the world. The motivation for trephining in non-literate cultures is obscure but may have been related to the treatment of epilepsy or headaches caused by skull injury, or relief of symptoms thought to have been caused by demonic forces. From classical Greece to the Renaissance, trephining was used to treat such maladies as head injury, epilepsy, and mental disease. 1,2 The first written reference to the brain is in the Edwin Smith Surgical Papyrus written in about 1700 BCE but a copy of an older treatise dated to about 3000 BCE. It appears to be a handbook for a battlefield surgeon and consists of a coolly empirical description of 48 cases from the head down to the shoulders, when the text breaks off. For each case the author describes the examination, diagnosis, and feasibility of treatment. 3,4 The Smith papyrus stands out as a rock of empiricism in the ocean of magic and superstition in which Egyptian medical writings swim for about the next twenty-four centuries. It reflects craft and some empirical knowledge but it is not what we today call medical science.

Classical neuroscience

The Presocratics and the beginning of science

What we mean by ‘science’ today is the contribution of the Presocratic philosophers. They were responsible for the idea that the physical and biological universe is governed by consistent and universal laws that are amenable to understanding by human rea- son. This was a revolutionary change from the previous prevailing view of the universe as a plaything of gods and ghosts who acted in an arbitrary and capricious fashion. The Presocratics lived from the sixth to the fourth centuries BCE in various Greek city-states. They conceived their inquiries on the universe as demanding rational criticism and public debate and involving observation and meas- urement. (Systematic experimentation, especially in biology, was almost unknown for several centuries). 511 Among the major Presocratics were Thales, Anaximander, Anaximenes, Heraclitus, Pythagoras, Empedocles, Zeno, and Democritus. Many of them were interested in sensory processes as sources of knowledge and several were physicians. One such physi- cian was Alcmaeon (~570–500 BCE), head of a medical school in southern Italy. He was the first writer to advocate the brain as the site of sensation and cognition. He is said to have written:

The seat of sensations is in the brain. This contains the governing faculty. All the senses are connected in some way with the brain;

consequently they are incapable of action if the brain is disturbed or shifts its position, for this stops up the passages through which senses act. This power of the brain to synthesize sensations makes it also the seat of thought: the storing up of perceptions gives memory and belief, and when these are stabilized you get knowledge. 12

Alcmaeon is reported to have been the first to use dissection as a tool for intellectual inquiry. He dissected the eye and described the optic nerves and chiasm and suggested they brought light to the brain. 712

The Hippocratic school

The other centre of Greek medicine was the island of Cos in the Aegean Sea and its most famous inhabitant Hippocrates (~425 BCE). The Hippocratic corpus of writing is the first large body of Western scientific writings that has survived. It consists of over 60 treatises of unknown authorship and date, perhaps a remnant of the library which once existed on Cos. 8 The Hippocratic treatise of greatest relevance to neurology is the famed essay ‘On the Sacred Disease’ (i.e. epilepsy). The author of this treatise has no doubt that the brain is the seat of epilepsy; on the general functions of the brain he is equally clear:

It ought to be generally known that the source of our pleasure, merri-

ment, laughter and amusement, as of our grief, pain, anxiety and tears is none other than the brain. It is specially the organ which enables us to think, see, and hear and to distinguish the ugly and the beautiful,

the bad and the good, pleasant and unpleasant which is the seat of madness and delirium. 13

it is the brain too

Neurological and other disorders were explained and treated in terms of the theory of the four humours: phlegm (from the brain), blood (from the heart), yellow bile (from the liver), and black bile (from the spleen). These ideas, as elaborated later by Galen (129– 210), pervaded medicine and were central to medical education well into the nineteenth century. 710,13,14 Curiously, Aristotle (384–322 BCE) argued against the brain and in favour of the heart as the dominant organ for sensation, cogni- tion, and movement. He systematically attacked the encephalocen- tric views of Alcmaeon and the Hippocratic doctors on a number of anatomical and embryological grounds, but the critical evidence available at this time was from the clinic, the study of brain-injured humans, and clinical medicine held no interest for Aristotle. 15


Galen of Pergamon (129–213) was by far the most important physician, anatomist, and physiologist in classical antiquity. 14 Furthermore, he was the first to carry out systematic experiments on the nervous system, thereby initiating experimental neurol- ogy. 16 Galen’s descriptions of the gross anatomy of the brain were



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4 SECTION 1 normal cognitive function Fig. 1.1 Title page of Galen’s Omnia Opera published in

Fig. 1.1 Title page of Galen’s Omnia Opera published in 1541 in Venice by Junta. The eight scenes, clockwise from the top, are: Galen bowing to a wealthy patient; Galen predicting the crisis in a patient’s sickness; Galen diagnosing lovesickness; Galen bleeding a patient; Galen demonstrating the effect of cutting the recurrent laryngeal nerve in a pig; Galen palpating the liver; Galen and his teachers; Aesculpaius in a dream urging Galen’s father to send him to medical school.

Reproduced from Gross CG, Brain, Vision, Memory: Tales in the History of Neuroscience, Copyright (1999), with permission from MIT Press.

very accurate, particularly with respect to the ventricles and cer- ebral circulation, both important in his physiological system. He usually presented his dissections as if they were of the human, but in fact, because of the taboo on dissecting the human body, they were invariably of animals, usually the ox in the case of brain anatomy. 17

Galen’s truly revolutionary work was to carry out the first system- atic experiments on the functions of the nervous system. He used piglets in his experiments on brain lesions. He found that anterior brain damage had less deleterious effects than posterior. He viewed sensation as a central process since he knew from his clinical obser- vations and animal experiments that sensation could be impaired

CHAPTER 1 historical aspects of neurology


by brain injury even when the sense organs were intact. Since ani- mals could survive lesions that penetrated to the ventricles, Galen thought the soul was not located there but rather in the cerebral sub- stance. He taught that all mental diseases were brain diseases. 16,18,19 Galen’s most famous experiment was the public demonstration of the effects of cutting the recurrent laryngeal nerve on squealing in a pig. Although the encephalocentric view that the brain con- trolled sensation, movement, and cognition remained strong in the Greco–Roman medical community, the opposing cardiocen- tric view, that the heart was the centre of sensation and cognition, was also active in Rome at this time, being advocated by the Stoic school and its leader Chrysippus (280–207 BCE). In order to refute the Stoics’ view that the heart and not the brain controlled cogni- tion, Galen arranged this public demonstration. 16,19 He showed that cutting the recurrent laryngeal nerve would eliminate vocalization. Since vocalization was seen as reflecting the cognitive activity language, Galen’s demonstration that cutting a nerve originating in the brain would eliminate squealing in a pig was the first, and most famous, demonstration that the brain con- trols cognition. The Renaissance edition of Galen’s works included an engraving of him carrying out the experiment on a huge pig in front of a very distinguished audience (Fig. 1.1).

Medieval and Renaissance neuroscience

The medieval doctrine of brain function

At about the time of Galen’s death, classical science and medicine seem to disappear. People prefer to believe rather than to discuss, critical faculty gives way to dogma, interest in this world declines in favour of the world to come, and worldly remedies are replaced by prayer and exorcism. The world view of medieval Christendom found Galen’s teleology congenial to its own and by a smothering of critical facility froze Galen’s research and all biology into a sterile system for over 1500 years. Galen was not to blame. Rather than develop his discoveries and methods, the European medieval world chose to accept his views as fixed and unchangeable facts in every branch of medicine. The central feature of the medieval view of brain function was the localization of the mental faculties in the ventricles (Fig. 1.2). The faculties of the mind (derived from Aristotle) were distributed among the spaces within the brain (derived from the ventricles described by Galen). The anterior ventricle received input from the sense organs and was the site of the common sense, which integrated across modalities. The sensations yielded images and thus fantasy and imagination were also located in the anterior ventricle. The middle ventricle was the site of cognition: reasoning, judgement, and thought. The posterior ventricle was the site of memory. These specific localizations seem to have come from the fourth-century Byzantine physician Poseidon on the basis of his observations of human brain injury. 20,21

The Islamic transmission

Greek medical learning was largely preserved in Islamic centres in the early Middle Ages. Hippocratic, Galenic, and other medical writings were largely lost to Europe both because of lack of familiar- ity with Greek and loss of the manuscripts themselves. This began to change in the tenth and eleventh centuries when translations from the Greek medical works into Syriac, Arabic, and Hebrew, and then into Latin finally reached Europe. 21 With the birth of universities, first in Bologna, anatomical dissections began, initially for forensic

anatomical dissections began, initially for forensic Fig. 1.2 Ventricular doctrine. Messages from the nose,

Fig. 1.2 Ventricular doctrine. Messages from the nose, tongue, eye, and ear go to the first ventricle in which common sense, fantasy, and imagination are found. The second ventricle contains thought and judgment; memory is in the third ventricle.

Reproduced from Reish G, Margarita Philosophica (Pearls of Philosophy), Copyright (1503), Johannes Schott.

purposes and following translations of Galen. However, it was not until Vesalius (1514–1564) that anatomy became largely free from the dominance of Galen. His On the Fabric of the Human Body (Fig. 1.3) along with Copernicus’s (1473–1543) On the Revolutions of the Celestial Spheres mark the beginning of the scientific revolution, the revival in Europe of science.

Thomas Willis and ‘neurology’

Thomas Willis (1621–74) wrote the first comprehensive text on the brain, Cerebri Anatomie, which dealt not only with brain anatomy but also with neurophysiology, neurochemistry, and clinical neu- rology, and introduced, in its English translation, the term ‘neu- rology’. 22 Cerebri Anatomie actually involved the collaboration of a group of savants known as the Virtuosi, such as Robert Boyle and Christopher Wren, who later became founding members of the new Royal Society (see Fig. 1.4). Willis rejected the still pervasive belief in the ventricles as the seats of higher psychological functions and instead implicated ‘the critical and grey part of the cerebrum’ in memory and will. Sensory signals came along sensory pathways into the corpus striatum where common sense was located. They were then elaborated into percep- tion and imagination in the overlying white matter (then called the corpus callosum), and finally passed onto the cortex where they were stored as memories. Willis ascribed voluntary movements to the cortex but involuntary ones to the cerebellum. His ideas on brain function came from his own experiments on brain lesions in animals, from the correlation of the effects of human brain dam- age with post-mortem pathology, and from the comparison of the brains of various animals with those of humans. 2224 Although Willis was a major figure in his time, his ideas on the cerebral cortex soon fell out of favour and theories of the cortex



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6 SECTION 1 normal cognitive function Fig. 1.3 Title page of Andreas Vesalius’s De Humani Corpori

Fig. 1.3 Title page of Andreas Vesalius’s De Humani Corpori Fabrica (On the Structure of the Human Body), 2nd edn.1543 Basel: Oporinus. It shows a public dissection by Vesalius (centre). His assistant is relegated to sharpening knives (front). The bodies were from executions and usually males, unlike here. The dissection is being held outdoors with a wooden structure for spectators. For further details of the symbols and details in this famous woodcut from Titian’s workshop, see CG Gross, Brain, Vision, Memory: Tales in the History of Neuroscience 1998. Cambridge, MA: MIT Press.

Reproduced from Gross CG, Brain, Vision, Memory: Tales in the History of Neuroscience, Copyright (1999), with permission from MIT Press.

as glandular or vascular became dominant. Marcello Malpighi (1628–94), the discoverer of capillaries, was the first to examine the cortex under the microscope. 2425 He saw it as made up of little glands or ‘globules’, and Antoni van Leewenhoek (1632–1723) and others followed suit. This was a common view in the seventeenth

and eighteenth centuries, perhaps because it fit with the much earlier view of Aristotle that the brain was a cooling organ and the Hippocratic theory that it was the source of phlegm. 5,15 The other common view was that the cortex was largely made up of blood vessels; as Frederik Rusch (1628–1731) put it: ‘[t]he cortical

CHAPTER 1 historical aspects of neurology


CHAPTER 1 historical aspects of neurology 7 Fig. 1.4 Ventral view of the brain. Reproduced from

Fig. 1.4 Ventral view of the brain.

Reproduced from Willis T, Cerebri Anatomie, Copyright (1664), Martyn and Allestry, drawn by Christopher Wren.

substance of the cerebrum is not glandular, as many anatomists have described it … but highly vascular’. 26 Albrecht von Haller (1708–77), who dominated physiology in the eighteenth century, also held a vascular view of the cortex. He found mechanical and chemical stimulation to be without effect throughout the cortex and declared it completely insensitive. 27

The beginning of modern neuroscience

Gall and phrenology: Localization of function in the cortex

The revolutionary idea that different regions of the cerebral cortex have different function began with Franz Joseph Gall (1748–1828) and his collaborator, JC Spurzheim (1776–1832) and their system of phrenology. 2830 The central aim of phrenology was to correlate brain structure and function. Phrenology had five basic assumptions:

1. The brain is an elaborately wired machine for producing behav- iour, thought, and emotions

2. The cerebral cortex is a set of organs each corresponding to an affective or intellectual function

3. Differences in traits among people and within individuals depend on differential development of different cortical areas

4. Development of a cortical area is reflected in its size

5. Size of a cortical area is correlated with the overlying skull (‘bumps’)

These otherwise reasonable hypotheses had one fatal flaw: the nature of the evidence. Gall and Spurzheim relied almost entirely on obtaining supportive or confirmatory evidence. They collected large numbers of skulls of people whose traits and abilities were known, examined the heads of distinguished savants and inhabit- ants of mental hospitals and prisons, and studied portraits of the high and low born on various intellectual and affective dimensions (Fig. 1.5). Throughout, they were seeking confirmation of their ini- tial hypothesis usually deriving from a few cases. For example, the idea for a language organ in the frontal lobes comes from Gall’s experience of a classmate who had a prodigious verbal memory and protruding eyes (being pushed out by a well-developed frontal lobe, Gall thought). The idea for an organ of destructiveness came from the skulls of a parricide and of a murderer, from noticing its prominence in a fellow student ‘who was so fond of torturing ani- mals that he became a surgeon’, and from examining the head of a meat-loving dog he owned. 28 They sought confirmations; contradictions were dismissed. Gall and Spurzheim’s cortical localizations were of ‘higher’ intellectual and personality traits. They accepted the prevailing view that the highest sensory functions were in the thalamus and the highest motor functions in the corpus striatum. 29,30 Phrenology met with considerable opposition from political and religious authorities, particularly on the Continent, largely because it was viewed as implying materialism and determinism and denied the unity of the mind (and soul) and the existence of free will. On the other hand, phrenology spread widely particularly in the United States and Great Britain both as a medical doctrine and as a form of



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8 SECTION 1 normal cognitive function Fig. 1.5 The phrenological organs. Reproduced from Human Nature Library,

Fig. 1.5 The phrenological organs.

Reproduced from Human Nature Library, New York, Copyright (1887).

‘pop’ psychology. It generated widespread interest both among the general populace and among such writers and savants as Honore de Balzac, Charles Baudelaire, George Eliot, August Comte, Horace Mann, Alfred Russell Wallace, and George Henry Lewis. It rapidly became a fad and drawing-room amusement, particularly in Great Britain and the US. Phrenological societies and journals continued to flourish in both countries well into the twentieth century. 31 Gall’s mistaken assumption of a correlation between the skull and brain morphology was soon recognized, at least in the scien- tific community. In spite of its absurdities and excesses, phrenology became a major spur for the development of modern neurosci- ence in a variety of ways. It generated an interest in the brain and behaviour. It directed attention to the cerebral cortex. It stimulated study of both human brain damage and of experimental lesions in animals. It inspired tracing pathways from sense organs and to the muscles in order to identify ‘organs’ of the cerebral cortex. It spurred the anatomical subdivision of the cerebral cortex (cyto- architectonics, myeloarchitectonics) to find organs of the brain. 29,30 The cytoarchitectonic, positron emission tomography (PET), func- tional magnetic resonance imaging (fMRI), and other maps of the cerebral cortex that are now ubiquitous in neuroanatomy, neurophysi- ology, and neuropsychology textbooks bear more than a coincidental resemblance to phrenological charts. They are the direct descend- ants of the iconoclastic, ambitious, and heavily flawed programme of phrenology seeking to relate brain structure and behaviour.

Language and the brain

In the middle of the nineteenth century, Gall’s theory of punc- tate localization of function in the cerebral cortex continued to be debated. Reports of correlations between the site of brain injury

and specific psychological deficits in patients as well as experimen- tal animals were published and actively discussed in both phreno- logical and mainstream medical publications. The debate about localization reached a climax at a series of meet- ings of the Paris Societé d’Anthropologie in 1861. At the April meet- ing, Paul Broca (1824–80), professor at the Sorbonne and founder of the society, announced that he had a critical case on this issue. A patient with long-standing language difficulties—nicknamed ‘Tam’, because that was all he could say—had just died. The next day, Broca displayed Tam’s brain at the meeting and it had widespread damage in the left frontal lobe. Over the next few months Broca presented several similar cases of difficulty in speaking, all with left frontal lesions. This discovery was the first clear evidence for a spe- cific psychological defect after a specific brain lesion. Not only did these cases finally establish the principle of discrete localization of function in the cortex, but in addition, the discovery was hailed as a vindication of Gall: both of his idea of punctate localization and his localization of language in the frontal lobes. 29,30,32 By 1865, Broca had accumulated enough cases to notice that all his brains from aphasic patients had their frontal damage on the left side and he described the left hemisphere as dominant for lan- guage. 32,34 (An obscure country doctor, Max Dax, apparently made the same observations in 1836, and his son Gustave Dax fought Broca over the priority for this claim.) 33 In 1874, Carl Wernicke reported another type of language dis- turbance after left hemisphere lesions in which speech is fluent but nonsensical, often known as sensory or Wernicke’s aphasia, as opposed to motor or Broca’s aphasia. Whereas Broca’s aphasia usu- ally followed lesions of the third frontal convolution or Broca’s area, Wernicke’s aphasia usually followed damage to the posterior temporal

CHAPTER 1 historical aspects of neurology


lobe. Today a variety of aphasias have been described with more sophisticated descriptive analysis than ‘motor’ versus ‘sensory’. 34 It was generally assumed that language localization in left-handed individuals was the opposite of that in right-handers; that is, that language was in the right hemisphere in left-handed individuals. However, as pointed out by Alexander Luria on the basis of his large sample of head injuries in the Second World War, language is pri- marily in the right hemisphere in roughly half of all left-handers. This was confirmed by the Wada test (unilateral hemispheric anaes- thesia), and fMRI and PET brain imaging. Today we know that lan- guage localization in left-handers is some kind of complex function of genetics and prenatal trauma, and that bilateral representation of language is much more common in left-handers (and females). Furthermore, even in right-handers, a variety of language functions exist in the right hemisphere. Finally, left hemisphere damage before puberty can be compensated by right hemisphere function. 3537

The discovery of motor cortex

Modern neurophysiology began with Gustav Fritsch (1838–1927) and Edmund Hitzig’s (1838–1907) discovery in 1870 that stimu- lation of the motor cortex produces movement. Their discovery was the first experimental evidence that the cortex was involved in movement, the first demonstration that the cortex was electri- cally excitable, the first strong experimental evidence for functional localization in the cortex, and the first experimental evidence for somatotopic representation in the brain. In their now classic experiment, Fritsch and Hitzig strapped their dogs down on Frau Hitzig’s dressing table. They stimulated the cortex with ‘galvanic stimulation’: brief pulses of monophasic dir- ect current from a battery. The usual response to this stimulation was a muscle twitch or spasm. Their central findings were that: a) the stimulation evoked contralateral movements, b) only stimu- lation of the anterior cortex elicited movements, c) stimulation of specific parts of the cortex consistently produced the activation of specific muscles, and d) the excitable sites formed a repeatable, if rather sparse, map of movements of the body laid out on the cortical surface (Fig. 1.6). They went on to show that lesion of a particular site impaired the movements produced by stimulation of that site. The loss of function was not complete, suggesting to them that there were other motor centres that had not been impaired by the lesion. 39 Fritsch and Hitzig had no hesitation in announcing the general significance of their discovery:

By the results of our own investigations, the premises for many con- clusions about the basic properties of the brain are changed not a little

some psychological functions, and perhaps all of them circumscribed centers of the cerebral cortex. 39


Soon after their paper appeared, the young Scottish physician David Ferrier set out to follow up their work. 40 Ferrier had been heavily influenced by John Hughlings Jackson, and he realized that Fritsch and Hitzig had confirmed Jackson’s ideas. In a variety of species, including macaques, Ferrier replicated their basic findings that stimulation of the cortex can produce specific movements and that there is a topographic ‘motor map’ in the cerebral cortex. 4144 Both Fritsch and Hitzig’s and Ferrier’s papers on the motor cortex were initially greeted with considerable and equal scepticism. Their results went against the generally accepted views that the striatum was the highest motor centre and that the cortex was inexcitable. The critics usually interpreted the results of Fritsch and Hitzig and of Ferrier as artefactual due to ‘spread of current’ to the striatum, then considered the highest motor centre. To overcome these criticisms,

the highest motor centre. To overcome these criticisms, Fig. 1.6 Movements produced by electrical stimulation of

Fig. 1.6 Movements produced by electrical stimulation of the cerebral cortex of the dog.

Notes: Δ, twitching of neck muscles; +, abduction of foreleg; †, flexion of foreleg; #, movement of foreleg; , facial twitching. Reproduced from Fritsch GT, and Hitzig E, On the electrical excitability of the cerebrum [1870]. In: von Bonin G, trans., Some Papers on the Cerebral Cortex, Copyright (1960), with permission from Charles C Thomas.

Victor Horsley, Charles S Sherrington, and others began meticu- lous ‘punctate’ mapping of the cortex using the minimum current to elicit the smallest discernable movement. e.g. 4547 Sherrington’s map of the motor cortex in the chimpanzee, followed by Wilbur Penfield’s human motor homunculus and Clinton Woolsey’s maps of monkeys and other animals, became the standard picture of the motor cortex. 4850 Ferrier’s maps of the motor cortex in the macaque were applied surprisingly quickly to human brain sur- gery. Starting in 1876, the Scottish surgeon William McEwen and the London surgeon RJ Godlee used Ferrier’s maps to successfully locate and remove tumours. 51 Recently, Michael Graziano has revisited Ferrier’s idea that the motor cortex may control complex, highly integrated behaviour. 52

The neuron doctrine

The neuron doctrine—the idea that the nervous system is made up of discrete nerve cells that are the anatomical, physiological, genetic, and metabolic bases of its functions—may be viewed as the single-most important development in the entire history of neuro- science. The work of two men was crucial to the final acceptance of the doctrine: Camillo Golgi (1843–1926) and Santiago Ramón y Cajal (1852–1934). 53 Although Theodor Schwann suggested, in 1838, that all animal tissues are made up of cells, the nervous system resisted interpret- ation in terms of cell theory for about another 50 years. This was because with the stains and microscopes available, the nervous sys- tem often looked like an anastomosing network or ‘reticulum’. The resolution of this enigma came, eventually, from the discovery by



normal cognitive function

10 SECTION 1 normal cognitive function Fig. 1.7 Golgi’s drawing of the reticulum formed by axon

Fig. 1.7 Golgi’s drawing of the reticulum formed by axon collaterals in the dentate gyrus of the hippocampus.

Reproduced from Golgi C, The neuron doctrine–theory and facts. Nobel Lecture, 11 December 1906. In: Nobel Lectures Physiology or Medicine 1901–1921. Copyright (1999), with permission from the Nobel Foundation.

Golgi in 1873 of a new silver stain that stained only a small propor- tion of cells but did so in their entirety. 53 Using this stain, Golgi a) confirmed Otto Deiters’s earlier obser- vation of a single axon (‘axis cylinder’) coming from each nerve cell, b) found that dendrites (‘protoplasmic prolongations’) ended freely, c) discovered axon collaterals and thought they merged with the axon collaterals of other nerve cells to form a diffuse reticu- lum, and d) classified nerve cells by their processes. Golgi believed that the function of dendrites was nutritive and not the conducting of messages. He had a holistic view of brain function and thought that the reticulum, made up of anastomosing axon collaterals, was the basic mechanism of brain function (Fig. 1.7). This, he thought, accounted for such phenomena as recovery from brain damage. His holism led him to disbelieve the localization results of Fritsch and Hitzig and of Ferrier. 53 Fourteen years later, Ramón y Cajal came across the Golgi sil- ver stain and immediately began making the often-capricious Golgi method more reliable, particularly by working with younger ani- mals who have less myelin, since myelin is resistant to silver stain- ing. Unlike Golgi, Cajal concluded that axon collaterals did not anastomose but ended freely: neurons were separate independent units. Although microscopes were not able to visualize the gap between neurons, Cajal inferred (intuited might be a better term) its existence on several grounds. One was by using immature or even foetal animals where he observed axons growing out of cell bodies before approaching other neurons or muscles. Another was that when cutting a nerve fibre it would degenerate, but only up to the border with the next cell. 53 (See Fig. 1.8). Beyond confirming the idea of the neuron as an independent unit, Cajal developed the ‘Law of Dynamic Polarization’, the idea

that information transmission was from the dendrites to the cell body and out along the axon. He then used this ‘law’ to work out several neural circuits that began with sensory receptors in the ret- ina or in the olfactory bulb. 53 In 1906, Golgi and Cajal shared the Nobel Prize. Golgi’s Nobel address was a vigorous defense of the reticular theory with the claim that the neuron theory ‘is generally recognized as going out of favor’. 53,54 Over 100 years later, the neuron doctrine still stands as the bedrock of neuroscience. Its fundamental tenet of the dis- continuity between neurons was finally confirmed by the electron microscope in the 1950s only to be soon modulated by the discov- ery of a very small number of gap junctions in which the cell mem- branes of adjacent neurons are immediately opposed and synaptic transmission is electrical. 55,56 The Law of Dynamic Polarization is still considered to be a fundamental property of neural circuits, although the existence of axon-less neurons, dendro-dendritic and axon–axonal synapses has complicated the picture. 53

Twentieth-century neuroscience

Prefrontal cortex

The association of the prefrontal cortex with the higher intellec- tual faculties has a long history. Classical busts of gods, heroes, and famous writers and artists usually show a high forehead in contrast to both lower-class individuals and women, both of whom were usually depicted to have retreating foreheads. 57 The eighteenth-century Swedish theoretical neuroscientist and philosopher, Emanuel Swedenborg, attributed imagination, memory, thought, and will to the anterior regions of the brain. 58 Gall and Spurzheim placed the ‘intellectual’ faculties in the most anterior brain regions. When the

CHAPTER 1 historical aspects of neurology


CHAPTER 1 historical aspects of neurology 11 Fig. 1.8 Cajal’s drawing of the sensory-motor connections of

Fig. 1.8 Cajal’s drawing of the sensory-motor connections of the spinal cord according to his neuron theory (right) and to Golgi’s reticular theory (left). A: anterior roots; B; posterior roots. According to Golgi, collaterals of the motor axon (a) anastomose forming part of a diffuse interstitial network (c). According to Cajal, the axon collaterals (f) do not.

Reproduced from Cajal S Ramon y. Recollections of My Life, Trans. EH Craigie, Copyright (1937), American Philosophical Society.

systematic study of human brain injury and of experimental lesions in monkeys began in the nineteenth century, intellectual function was usually located in the prefrontal cortex. For example, from their observations of frontal lobe damage, the frontal lobes were thought by Hitzig to contain the highest intellectual centre, by Ferrier to be the centre of attention and therefore of ideation and perception, by Paul Flechsig to be the area for volition and the higher levels of personality, by Giovanni Bianchi to be the centre of centres, and by Wilhelm Wundt to be an ‘apperception’ centre. 59 In 1848, one of the most notable cases of prefrontal injury occurred in a man working with explosives on the railroad, whose skull was accidentally pierced by an iron bar pierce. Remarkably, Phineas Gage survived the accident but his personality and behav- iour changed irrevocably. From being a considerate, responsible foreman, he became ‘fitful, indulging at times in the grossest pro- fanities … manifesting but little deference for his fellows, impatient of restraint or advice when it conflicts with his desires, at times per- tinaciously obstinate, yet capricious and vacillating, devising many plans of future operation, which are no sooner arranged that they are abandoned’. 60 Gage’s case was not widely reported and its true importance was not fully appreciated until much later, but it stands as a landmark case in the history of observations of human prefron- tal function. 61

In the first objective tests of prefrontal function in animals, after prefrontal lesions, monkeys and chimpanzees were found to be severely and permanently impaired on performance of the ‘delayed response test’ in which the animal is required to remember, after a brief delay, at which of two sites a bait is hidden. 62 This was con- sidered to be a test of ‘recent memory’ 62 and later one of ‘working memory’. 63 The dorsolateral prefrontal cortex was subsequently shown to be crucial for performance of this task. 59,64 An incidental observation on a single chimpanzee’s behaviour- during this task led directly to the widespread clinical use of fron- tal lobe surgery to treat a variety of psychiatric disorders. Prior to lesion of its frontal lobe, this animal would have temper-tantrums whenever she made an error on the delayed response test. She no longer did so following the operation. 62 When the Portuguese neu- rologist Egas Moniz heard of this observation at the International Congress of Neurology in London in 1935, he was inspired to initiate a series of frontal ‘leucotomies’ (cutting the white matter under the frontal cortex) to treat mental illness, and versions of the procedure technique were rapidly adopted elsewhere. In 1949, Moniz received the Nobel Prize for the introduction of frontal leu- cotomy. This and other psychosurgical procedures on the frontal lobe were carried out on an estimated 60 000 people in the US alone (Fig. 1.9). The practice radically declined in the 1980s largely



normal cognitive function

12 SECTION 1 normal cognitive function Fig. 1.9 W. Transorbital lobotomy used extensively by Walter Freeman:

Fig. 1.9 W. Transorbital lobotomy used extensively by Walter Freeman: ‘A transorbital leucotome is inserted through the orbital roof into the brain and the handle is swung medially and laterally to sever fibers at the base of the frontal lobe.’

Reproduced from Proc. R. Soc. Med. (Suppl.). 42, Freeman W, Transorbital leucotomy: the deep frontal cut. pp. 8–12, Copyright (1949), with permission from SAGE Publications.

because of the introduction of chlorpromazine and other psycho- active drugs. 6567 Assessment of the effects of frontal lobotomies is difficult because very few patients were studied objectively before and after surgery by independent investigators. Elliot Valenstein, who investigated the efficacy of the older lobotomies, summarized the situation as follows:

In general, there seems to be strong suggestive evidence (if not abso- lutely convincing) that some patients may have been significantly helped by psychosurgery. There is certainly no grounds for either the position that all psychosurgery necessarily reduces people to a ‘veg- etable status’ or that is has a high probability of producing marvelous cures …There is little doubt, however, that many abuses existed. Quite apart from the effectiveness of the surgery there were always some risks. Patients did occasionally die from the operation, epilepsy was not an uncommon aftermath and various symptoms from infections and neurological damage could be attributed directly to the surgery. 68

A small number of limited psychosurgical procedures are still car- ried out on the frontal lobe but they appear to be much more effica- cious than the older procedures. 65 Today, the prefrontal cortex is often divided into several systems with different functions and damage to each system tending to pro- duce a different set of symptoms. To summarize (and simplify) one parcellation, damage to the dorsolateral system produces execu- tive dysfunction, to the orbitofrontal system, disinhibition, and to the medial frontal system, apathetic motivation. 66 Another, more integrative theory has been offered by Earl Miller and Jonathan Cohen 69 (see also chapter 3).

Visual cortex

Bartolemo Panizza (1785–1867) was the first individual to produce detailed experimental and clinicopathological evidence for a visual

area in posterior cerebral cortex. He carried out anatomical and lesion experiments on a variety of species as well as observations on brain-injured humans. His work was largely ignored, perhaps because it was published in Italian in a local journal, and because, following both Gall and Pierre Flourons, visual functions were con- sidered subcortical, the cortex being reserved for ‘higher psychic’ functions. 70 Soon after Fritsch and Hitzig’s publication on the motor cortex, David Ferrier confirmed their results (see section on discovery of motor cortex above). Ferrier then applied their electrical stimula- tion methods to search for sensory cortices in monkeys. He found that stimulation of the angular gyrus produced eye movements and inferred that this area was the seat of visual perception. He sup- ported this by showing that bilateral lesions of this area produced blindness (for the few post-operative days that the infected ani- mals lived). Apparently confirming this view, he found that large occipital lesions had no visual effects unless they encroached on the angular gyrus. 71 By contrast, soon after, Hermann Munk found that large occipi- tal lesions produced blindness in both dogs and monkeys. Sanger Brown and Edward Schafer then confirmed Munk’s report of total blindness after total occipital lesions in monkeys. 72 (We now know that Ferrier’s failure to produce blindness after occipital lesions was because his lesions spared the representation of the fovea, whereas those of Munk and Brown and Schaeffer did not.) By the turn of the century, anatomical, clinico-pathological, and experimental data were converging on the identity of a visual area in the posterior cerebral cortex corresponding to the region of the stripe of Gennari, described by Francisco Gennari in 1782 and named by G Elliot Smith as area striata. 72 In 1941, SA Talbot and Wade Marshall, using visually evoked responses, mapped the visual topography of striate cortex in

CHAPTER 1 historical aspects of neurology


cats and monkeys (i.e. the projection or ‘map’ of the retina onto cortex). David Hubel and Torsten Wiesel, recording from sin- gle neurons, subsequently confirmed this retinotopic organiza- tion. Through the brilliant use of single neuron physiology, they revealed the functional architecture of striate cortex. They showed that single striate cells integrated binocular input and were sen- sitive to oriented lines and edges. Their research promised the possibility of understanding perception in terms of neurons and became the model for subsequent explorations of the visual cor- tex and for all of contemporary neurophysiology. They shared the Nobel Prize with Roger Sperry in 1961. Hubel and Wiesel then showed a second and third retinotopic area (V2 and V3) adjacent to striate cortex (V1) in the regions previously called para- and prestriate cortex. 73 A new phase of cortical visual physiology began in the 1970s when John Allman and Jon Kass described a multiplicity of extra-striate visual areas in the squirrel monkey. 74 Even more visual areas were subsequently discovered in the macaque and human by Semir Zeki, Van Essen, and Charles Gross and their colleagues, a total of over 30 having been found to date. 75 Leslie Ungerleider and Mortimer Mishkin showed that these areas were organized into two main processing streams: a dorsal stream extended into posterior parietal cortex and was specialized for the analysis of space and movement, and a ventral stream extended into the temporal lobe and was specialized for pattern recognition, that is, for form and colour. 76 Proceeding down each stream, the successive visual areas tend to have larger receptive fields, less topographic organization, and neurons with more spe- cialized properties. 7779 The inferior temporal cortex lies at the terminus of the ventral stream. Its neurons are no longer retinotopically organized and they respond selectively to complex shapes. In both monkeys and humans, the inferior temporal cortex contains several areas that selectively respond to images of faces. 76,77 There are also areas that specialize in representing locations and body parts. In both macaques and humans, these specialized areas were delineated with imaging methods. 78 The later stages in both the dorsal and ventral hierarchy of visual areas send projections to the hippocam- pus by way of perirhinal and parahippocampal cortex. 77,79

Brain laterality

Broca and Wernicke’s discoveries that left-hemisphere damage, at least in right-handers, resulted in deficits in producing and under- standing language respectively, led to the idea that the left hemi- sphere was the dominant hemisphere and the right hemisphere was the non-dominant or minor hemisphere. At first, the dominant hemisphere was thought to be the most important hemisphere not only for language but also for other cognitive functions. For exam- ple, Hugo Liepmann (1863–1925) attributed ‘purposeful’ move- ments to the dominant hemisphere, 57 and his classification of limb apraxia remains highly influential to this day. As early as 1865, John Hughlings Jackson, the ‘father’ of English neurology suggested that the so-called minor hemisphere might be more important than the major hemisphere for perceptual func- tions. However, it was not until the 1930s that evidence from the study of human patients showed that a variety of disorders in non-language functions were more common or more severe after right- than after left-hemisphere damage. 79,80 These sequleae of

right-hemisphere lesions included perceptual deficits (such as in object and face recognition and in visuo-constructive tasks), atten- tional deficits, and emotional disorders. Thus it became clear that the left hemisphere was the major one for language and related

functions, whereas the right hemisphere was dominant for a var- iety of perpetual, attentional, and emotional functions. This lateral- ization of cognitive functions could also be shown in intact subjects

by the unilateral anaesthetization of one hemisphere, a procedure

know as the ‘Wada’ test, developed by the neurologist JA Wada

in 1949. 80

A new and powerful method of comparing the functions of the

two hemispheres was developed by Roger Sperry and his colleagues

in the 1950s. The clinical literature on patients with damage or

agenesis of the corpus callosum had been contradictory, with many studies reporting no effect of a damaged or absent callosum. For example, Andrew Akelatis had sectioned the corpus callosum for treatment of epilepsy in a number of patients and reported a total absence of any cognitive effects of this surgery. 57

By contrast, Sperry and his students showed, first in cats and monkeys and then in human patients, that section of the corpus cal- losum resulted in each hemisphere having ‘its own mental sphere— that is, its own independent perceptual, learning, memory and other mental processes’. 81 Suddenly, it became possible to compare the functions of the two hemispheres directly. The key to Sperry’s discovery was, in subjects with the corpus callosum sectioned,

to direct sensory input into each hemisphere independently. For

example, in the visual modality, he sectioned the optic chiasm sagitally so that information from the left eye went only to the left hemisphere and information from the right eye only to the right hemisphere. In humans, he achieved the same result by having the subject with sectioned corpus callosum fixate so that information presented to each visual half-field went to the contralateral hemi- sphere. 82 Sperry received the Nobel Prize in Medicine/Physiology for this work in 1981.

It should be mentioned that this important work became rather

distorted in the popular literature by its neglecting the fact that

although the hemispheres have specialized functions, in fact they work together in the intact individual.

Functions of the hippocampus in memory

A major advance in the neurology of memory came from the

study of Patient HM who received bilateral lesions of the hip- pocampus and adjacent tissues to alleviate epileptic seizures in frankly experimental surgery by William Scoville in 1953. After the surgery, as studied primarily by Brenda Milner and later her student Suzanne Corkin, HM had very severe anterograde amne- sia: he appeared to be unable to store any new information for more than a few minutes, and his short-term memory never became long term. 83 Subsequent research indicated that only his ‘declarative’ mem- ory (memory for facts and events) was impaired, whereas his ‘procedural’ memory (such as memory for motor and perceptual skills, and classical conditioning) was intact. 84,85 Similar dissocia- tions between the two types of memory have been found in other patients after hippocampal damage (but see also chapter 13). The

hippocampus is necessary for the formation of long-term declara- tive memories, which appear to be stored in portions of the cerebral cortex. 85



normal cognitive function


The most important advance in neurology in the last half-century has been the development of brain imaging, both structural (ana- tomical) and functional.

Structural imaging

CAT scanning (computed axial tomography), introduced in 1971, involves first X-raying the brain (or other body part) at different angles from which is produced a three-dimensional image recon- structed by computer. This was a remarkable advance in neurology replacing inferior techniques for estimating brain lesions or tumours such as pneumoencephalography, cerebral angiography, and clinical examination. MRI (magnetic resonance imaging) of the brain was developed at about the same time as CAT scanning but has much higher resolution. It derives from a technique developed in chemis- try in the 1970s, ‘nuclear magnentic resonance’, involving the prop- erties of hydrogen atoms in a magnetic field. MR techniques also permit visualization of white-matter connections in the brain using diffusion-weighted imaging and tractography (see chapter 8).

Functional imaging

Functional imaging of the brain measures changes in local activity in different brain structures as functions of cognitive activity. The first to do this was Angelo Mosso in 1881. He observed brain pul- sations through skull openings in human patients, noted that they increase locally during cognitive tasks, and inferred increased blood flow with increased brain function. 86 A few years later, Charles C Roy and Sherrington, from their animal experiments, suggested ‘automatic mechanisms’ that regulated blood flow depending on variations in neural activity. In the 1920s, John Fulton studied a relationship of increased blood flow with the act of reading in a human patient. 86 After the Second World War, several techniques were developed that enabled blood flow to be locally measured as a function of brain activity. In PET, a radioactive isotope such as 15 O is intro- duced into the bloodstream and its emitted gamma rays can be detected by the PET scanner. A reconstructed image will then show the distribution of blood flow and, presumably, regional difference in brain activity. 87 fMRI is also a method of measuring local blood flow in the brain. It is based on the same technique as MRI except that the imaging is focused on measuring the ratio of oxygenated to deoxygenated haemoglobin known as the ‘blood oxygenation level dependent’ or BOLD effect. The BOLD response is a slightly delayed index of local brain activity. fMRI is today largely replacing PET for studies of brain activation because it is has much better spatial and temporal resolution, individuals can be safely studied repeatedly, activity on single trials can be measured, and it does not require a large medi- cal centre for its use. 87 fMRI studies have provided numerous new insights into cogni- tive neuroscience and promise many more in the future.


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