Professor Trimble was for many years Professor of Behavioural Neurology and Consultant Physician to the Department of Psychological Medicine at the National Hospital Queen Square, London. He now holds emeritus status at the above institutions. He studied general medicine, obtaining membership of the Royal College of Physicians before going to the National Hospital Queen Square and then the Maudsley Hospital to advance his training in neurology and psychiatry. Following an internship in psychiatry at the Johns Hopkins Hospital, Baltimore, he returned to the National Hospital to pursue a career in neuropsychiatry. He set up a research group with main interests in the interface disorders between neurology and psychiatry, reflected in the developing recognition of neuropsychiatry and behavioural neurology as independent disciplines. The research group (Raymond-Way Unit) explored the behavioural consequences of neurological disorders and their treatment, with a major interest in epilepsy and movement disorders. His current writing and academic interests involve teaching and lecturing on neuroanatomical concepts relevant to understanding behaviour and its variations, in particular with an interest in neuroaesthetics and neurotheology, namely the cerebral basis of artistic and religious experiences.

Dr. George received his medical degree from the Medical University of South Carolina in Charleston in 1985, where he continued with dual residencies in neurology and psychiatry. He is board certified in both areas. He worked for one year (1990-91) as a Visiting Research Fellow in the Raymond Way Neuropsychiatry Research Group at the Institute of Neurology, London. He and Professor Trimble used pharmacology and imaging to study the overlaps between Obsessive-Compulsive Disorder and Gilles de la Tourette Syndrome. During this year he also worked on new functional imaging techniques (SPECT and PET) at the Institute of Nuclear Medicine, University College of London and Middlesex School of Medicine, London. He wrote one of the first textbooks in the new area of brain activation and imaging. Dr George then moved to Washington, DC, working with Dr. Robert Post in the Biological Psychiatry Branch of the Intramural National Institute of Mental Health. He was one of the first to use functional imaging (particularly oxygen PET) to assess brain changes associated with normal emotions, as well as using imaging to understand brain changes which occur in depression and mania. This imaging work directly led to his pioneering use of transcranial magnetic stimulation (TMS) as a probe of neuronal circuits regulating mood, and to clinical trials using TMS as an antidepressant. In 2008 prefrontal TMS was FDA approved as an antidepressant treatment. In 1995 he moved back to Charleston and built the functional neuroimaging division and brain stimulation laboratories. This imaging group has grown into the MUSC Center for Advanced Imaging Research, which is now part of the SC Brain Imaging Center of Excellence. He continues to use imaging and non-invasive stimulation, either separately or more recently in combination, to understand the brain regions involved in emotion regulation in health and disease. In 1998, he pioneered another new treatment for resistant depression, vagus nerve stimulation, that was recently FDA approved. He and his group have used MRI imaging to understand brain stimulation brain effects. He is on several editorial review boards, and has published over 200 scientific articles, and has written or edited 5 books. He is the editor-in-chief of a new journal, Brain Stimulation.

He has received several international awards, including the World Federation of Societies of Biological Psychiatry Lifetime Achievement Award (2007), the NARSAD Falcone Award (2008) and he was honored as one of 14 'Pioneers of Medical Progress' saluted in the August 2009 edition of US News & World Report.

Acknowledgements xi

Quotations xiii

Preface to the First Edition xv

Preface to the Second Edition xix

Introduction and Preface to the Third Edition xxi

1 Principles of Brain Function and Structure: 1 Genetics, Physiology and Chemistry 1

Introduction 1

Genetics 1

Brain chemistry and metabolism 8

The metabolism of glucose 9

Proteins and fatty acids 9

Cell membranes 10

Synapses 12

Receptors 14

Neurones 21

Neurotransmitters 24

Interrelationships among transmitters 29

Transmitter dispersal 29

CNS inflammation 29

2 Principles of Brain Function and Structure: 2 Anatomy 31

Introduction 31

The neuroanatomy of emotion 32

Individual anatomical structures 41

Ascending and descending limbic-system connections 53

Macrosystems 55

The basal ganglia and the re-entrant circuits 57

The ventral striatum and 'limbic striatum' 58

The ascending cholinergic systems 60

Cortical regions of interest 60

The cerebellum 63

3 Important Brain-Behaviour Relationships 65

Introduction 65

Important anatomical structures for understanding behaviour 68

Some specific behaviours 74

Limbic lobe disorders in a clinical context 77

Re-entrant circuits in a clinical context 78

The frontal lobes in a clinical context 79

Laterality 81

4 Classifications and Clinical Investigations 83

Introduction 83

Signs, symptoms, syndromes and disease 84

Classification in psychiatry 84

Clinical investigation 87

5 Personality Disorders 113

General introduction 113

Introduction to the concept of personality 113

Genetics 118

Somatic variables 121

Metabolic and biochemical findings 121

Neurophysiological and neurological data 123

Some outstanding issues 127

6 Anxiety Disorders 131

Introduction 131

Genetics 134

Somatic variables 135

Metabolic and biochemical findings 135

Neurochemical investigations 137

Neurophysiological and neurological data 140

Imaging 140

Obsessive-compulsive disorder 142

Post-traumatic stress disorder 143

Some outstanding issues 144

7 The Schizophrenias 147

Introduction 147

Genetics 150

Somatic variables 153

Metabolic and biochemical findings 154

Neurochemical investigations 159

Neurophysiological and neurological data 164

Some outstanding issues 176

8 Affective Disorders 183

Introduction 183

Genetics 184

Metabolic and biochemical findings 186

Neurochemical investigations 198

Neurophysiological and neurological data 200

Some outstanding issues 209

9 The Addictions and Disorders of Motivation 215

Introduction 215

Disorders of motivation 216

Conditioning 217

Genetics 219

Metabolic and biochemical findings 221

Neurophysiological and neurological data 223

Some outstanding issues 228

10 Epilepsy 231

Introduction 231

Prevalence and clinical characteristics 231

Classification 231

Genetics 235

Symptomatic epilepsy 235

Biochemical findings 236

Investigation and differential diagnosis 237

Psychiatric disorders in epilepsy 237

Cognitive deterioration and epilepsy 254

Some outstanding issues 255

11 The Dementias 257

Introduction 257

Definition 257

Prevalence 258

Diagnosis and classification 258

Alzheimer's disease 259

Dementia of frontal-lobe type 267

Focal cortical atrophies 268

Dementia with Lewy bodies 268

Vascular dementias 269

Other forms of dementia 271

Further causes of dementia 275

Some outstanding issues 275

12 Biological Treatments 281

Introduction 281

Pharmacology: pharmacokinetics and pharmacodynamics 281

Antidepressants 284

Antipsychotic drugs 296

Anxiolytics and hypnotics 304

Beta-Adrenergic blockers 308

Lithium 308

Anticonvulsants 310

Drugs for the treatment of dementia 316

Medications for the addictions 317

Brain-stimulation therapies 318

Sleep-deprivation therapy 329

13 Epilogue: Progress toward a Neuroanatomically, Biological-psychiatrically Informed Classification Scheme in Psychiatry 331

References 335

Index 395