Front Cover 1
Alcohol and the Nervous System 4
Copyright 5
Handbook of Clinical Neurology 3rd Series 6
Foreword 8
Preface 10
Contributors 12
Contents 16
Section 1: Introduction 20
Chapter 1: Alcoholism: Diagnosis, Prognosis, Epidemiology, and Burden Of the Disease 22
Natural History and Clinical Assessment 22
Alcoholism Frequency 22
Practical Typology 23
Diagnosis 23
Alcohol Use History 23
Making a Diagnosis 24
Physiologic Dependence: Tolerance And withdrawal 24
Tolerance 24
Withdrawal 25
Loss of Control Phenomenon 25
Social Or Physical Decline 26
Gauging Prognosis 26
Positive Versus Negative 26
Diagnosis is Prognosis 27
Abuse Rather than Dependence 27
Behavioral Versus Hepatic Diagnosis 27
Assessing Ambivalence and Continuing Loss Of Control risk 27
Social Stability 28
Vaillant's Four Prognostic Factors 28
Structured time 28
A Rehabilitation Relationship 28
Sources of Hope Or self-esteem 28
A Negative Behavioral Reinforcer 28
Summing Up Prognosis 29
Other Psychiatric Assessment 29
Dsm-5 and Alcoholism Diagnosis: Progress Or Old Wine in a New Bottle? 29
Economic Costs of Problematic Alcohol use 30
Cost of Illness: Clarifying the Concept 30
Cost: Contribution By Category 30
Interpretation: Cost Consequences 30
Economics and Alcohol 31
Alcohol-related Spending and Other Disease Categories 31
Conclusion 31
References 31
Chapter 2: Perspectives on the Neuroscience of Alcohol From the National Institute on Alcohol Abuse and Alcoholism 34
Introduction 34
The Division of Neuroscience and Behavior (Dnb) and Its Mission 34
Genetics 35
Neuroadaptation 36
Behavior 38
Neurobehavioral, Structural, and Functional Consequences of Human Alcoholism 40
Preclinical Medications Development 41
Future Directions 43
References 44
Section 2: Animal Models: Neurochemistry and Metabolism of Alcohol 50
Chapter 3: Neurocircuitry of Alcohol Addiction: Synthesis From animal models 52
Definitions and Conceptual Framework for Neurocircuitry of Alcoholism 52
Animal Models for Compulsive Alcohol Seeking 53
Animal Models of Motivation, Withdrawal, and Opponent Process 55
Neurocircuits for the Binge/intoxication Stage Associated With Alcoholism 57
Neural Substrates for the Withdrawal/negative Affect Stage Associated With Alcoholism 59
Within-system Neuroadaptations That Contribute to the Compulsivity Associated With the Dark Side of Alcoholism 59
Between-system Neuroadaptations That Contribute to Compulsivity Associated With the Dark Side of Alcoholism 60
Neural Substrates for Executive Function Deficits Associated With alcoholism 63
Compulsivity in Alcoholism: An allostatic view 65
Acknowledgments 66
References 67
Chapter 4: Metabolism 74
Overview 74
Ethanol Metabolism 74
Hepatic Ethanol Metabolism 74
Genetic Factors: Genetic Variants And gender 76
Genetic Variation in Adh, Aldh2, Cyp2E1 and Ethanol Metabolism 76
Genetic Predisposition to Alcoholism 76
Effects of Gender on Alcohol Metabolism 77
Fasting 77
Protein Malnutrition 77
Effect of Fat Content Or Composition Of diet 77
Effect of Dietary Ethanol 78
Miscellaneous Dietary Effects 78
Endocrine Effects 78
Gastrointestinal and Other Tissue Metabolism of Ethanol 78
Alcohol-metabolizing Enzymes In the nervous system 79
Systemic Pharmacokinetics and Pharmacokinetic Modeling 79
Overview - Absorption, first-pass Metabolism, Distribution, and Elimination 79
Compartmental/phenomenologic Modeling 80
Physiologically Based Modeling 81
Summary 82
Acknowledgments 84
References 84
Chapter 5: Use of Animal Models of alcohol-related Behavior 90
Introduction 90
Pharmacologic Considerations 90
Aud is Behaviorally and Genetically Complex 91
What Can Be Modeled? 91
Choice of non-human Animal species 91
Alcohol-related Phenotypes 91
Assessing Alcohol Sensitivity 92
Assessing Alcohol Tolerance Or sensitization 92
Assessing Alcohol Dependence 93
Assessing Alcohol Reinforcement 93
Modeling Genetic Risk in non-human Animals 94
Rodent Lines Selectively Bred for Alcohol responses 95
Alcohol Preference Selections 95
Congruent Findings in Rat Preference Selections 95
Findings From High (Hap) and Low (Lap) alcohol-preferring mice 97
Selection for Drinking in The dark 98
Selection for Locomotor Response to Ethanol 98
Lines Selected to Be Ethanol Withdrawal Seizure-Prone (Wsp) Or -Resistant (Wsr) 98
Long Sleep (Ls) and Short Sleep (Ss) mice 99
Alcohol-tolerant (At) and non-tolerant (Ant) rats 99
Studies With Inbred Strains 99
Can Behavior Genetics Reveal the Structure of ethanol-related Behavior? 100
Acknowledgments 101
References 101
Section 3: Molecular Basis of Alcoholism 106
Chapter 6: Molecular Basis of Alcoholism 108
Molecular Mechanisms Underlying Acute and Chronic Alcoholism 108
Introduction 108
Primary Targets 108
DNA 109
Neurotransmitter Systems 112
Glutamate 112
Dopamine 114
GABA(A) 114
GABA(B) 115
Serotonin (5-Ht) 116
Big Potassium (Bk) Channels 117
Transcription Factors 117
microRnas 118
Synaptic MRna Translation and MicroRnas 118
Neuroimmune 119
Summary and Future Directions 120
References 124
Section 4: Neurologic Signs and Consequences 132
Chapter 7: Alcohol: Intoxication and Poisoning - Diagnosis and Treatment 134
Introduction 134
The Effects of Ethanol on Organ Systems 134
Nervous System 134
Gastrointestinal System 135
Cardiovascular System 135
Other Effects 135
Diagnosis 136
Clinical Features 136
Blood Alcohol Concentration 136
Alcohol Flush Reaction 136
Idiosyncratic Alcohol Intoxication 137
Differential Diagnosis 137
Hepatic Encephalopathy 137
Wernicke-Korsakoff Syndrome 138
Treatment 138
References 139
Chapter 8: Acute withdrawal: diagnosis and treatment 142
Introduction 142
Symptoms And signs 142
Hangover 142
Tremor 142
Hallucinosis 142
Abnormal Movements 143
Seizures 143
Delirium Tremens 144
Comorbid Disorders 144
Treatment 145
Non-pharmacologic Therapy 145
Pharmacotherapy 145
Benzodiazepines 145
Phenobarbital 146
Anticonvulsants 146
Baclofen 146
Gamma-hydroxybutyric acid 146
Neuroleptics 146
Beta-blockers and alpha-2-agonists 147
Ethanol 147
N-methyl-d-aspartate Receptor Blockers 147
Other Pharmacotherapies 147
Treatment of Severe Symptoms 147
Seizures 147
Delirium Tremens 147
Other Management Considerations 148
Summary 148
References 148
Chapter 9: Neurochemical Mechanisms of Alcohol Withdrawal 152
Introduction 152
Signs and Symptoms of the Alcohol Withdrawal Syndrome 153
Cns Hyperexcitability 153
Autonomic Nervous System Hyperactivity 153
Sleep Disturbances 154
Measures of Psychologic Discomfort And negative Affect 154
Anxiety 154
Heightened Stress Responsiveness 155
Anhedonia/dysphoria 155
Neurochemical Adaptations Produced By Chronic Alcohol And withdrawal 156
Adaptations in Amino Acid Neurotransmitter Systems 156
Glutamate 157
Gaba 158
Adaptations in Monoamine Systems 158
Dopamine 158
Norepinephrine 159
Serotonin 159
Adaptations in Neuropeptide Systems 160
Corticotropin-releasing factor 160
Neuropeptide Y 161
Opioid Polypeptides 161
Nociceptin 162
Other Neuropeptides 162
Adaptations in Ion Channels 162
Voltage-gated Ca2+ Channels 162
Small-conductance Ca2+-activated K+ Channels 163
Large-conductance voltage- and Ca2+-activated K+ Channels 163
A-type K+ Channels 164
Conclusions 164
Acknowledgments 165
References 165
Chapter 10: Molecular and Neurologic Responses to Chronic Alcohol use 176
Introduction 176
Molecular Mechanisms of Chronic Alcohol Action on The brain 176
Genetic Contributions to Alcoholism 177
Modulation of Gene Expression With chronic alcohol 177
Persistence of Gene Expression Changes - Role for Epigenetic Regulation? 178
Neurology of Chronic Alcohol Action in the Central Nervous System 179
Overview of Clinical Syndromes 179
Alcohol Blackouts 179
Craving 180
Tolerance and Dependence 181
Alcohol Withdrawal Syndrome Overview 181
Withdrawal Seizures 182
Delirium Tremens 182
Wernicke-Korsakoff Syndrome 183
Cerebellar Degeneration 184
Primary Alcoholic Dementia 184
Central Pontine Myelinolysis 185
Marchiafava-Bignami Disease 186
Conclusions 186
Acknowledgment 186
References 186
Section 5: Neuropsychology 192
Chapter 11: Methods of Association and Dissociation for Establishing Selective Brain-behavior Relations 194
Historic Background 194
Single Dissociation Model: Lesion studies 195
Double Dissociation Model: Lesion studies 195
Double Dissociation Model in Conditions Affecting Multiple Neural Systems 196
Between-groups model 196
Within-group model 196
Multiple Dissociations and Relevance to Establishing Network Selectivity 199
Acknowledgment 199
References 199
Chapter 12: Profiles of Impaired, Spared, and Recovered Neuropsychologic Processes in Alcoholism 202
Introduction 202
The Participants and The tests 202
Characteristics of the Participants 202
Assessing Neuropsychologic Functions And the brain 203
The Impaired, the Spared, And the recovered 203
Impairments 203
Spared Functions and Compensation 203
Recovery 204
Profiles of Damage And repair 204
General Neuropsychologic Abilities 204
Widespread Brain Damage in Alcoholism 205
Frontocerebellar and Mesocorticolimbic Structures 206
The Five Functional Domains 206
Memory 207
Impairments 207
Compensation and Recovery 216
Executive Functions 216
Impairments 217
Compensation and Recovery 218
Emotion and Psychosocial Skills 218
Impairments 219
Compensation and Recovery 220
Visuospatial Cognition 220
Impairments 220
Compensation and Recovery 221
Psychomotor Abilities 221
Impairments 221
Compensation and Recovery 222
Summary and Conclusions 222
Acknowledgments 223
References 223
Chapter 13: Component Processes of Memory in Alcoholism: Pattern of Compromise and Neural Substrates 230
Working Memory and Executive functions 230
Definition 230
Slave Systems of Working Memory 230
Central Executive of Working Memory 230
Neural Substrates of Working Memory In alcoholism 231
Working Memory in Korsakoff's Syndrome 232
Episodic Memory 233
Definition 233
Encoding and Retrieval Processes 233
Contextual Memory, Source Memory, And prospective Memory 233
Metamemory 234
Episodic Memory and Executive Functions 234
Neural Substrates of Episodic Memory Deficits in Alcoholism 234
Autobiographical Memory 234
Episodic Memory in Korsakoff's Syndrome 235
Semantic Memory 235
Definition 235
New Semantic Learning 236
Semantic Memory in Korsakoff's Syndrome 236
Perceptual Memory 236
Definition 236
Implicit Perceptual Learning 236
Perceptual Memory in Korsakoff's Syndrome 237
Procedural Memory 237
Definition 237
Cognitive Procedural Learning 237
Visuomotor Procedural Learning 237
Procedural Memory in Korsakoff's Syndrome 237
Factors Contributing to the Heterogeneity of Memory Disorders in Alcoholism 238
Age 238
Gender 238
Alcohol Use Pattern 238
Smoking Status 238
Nutritional Status 238
Psychiatric Comorbidity 238
Treatment-naïve Versus treatment-seeking Patients 239
Reversibility of alcohol-related Memory Disorders 239
Uncomplicated Alcoholism 239
Korsakoff's Syndrome 240
Clinical Implications of Memory Disorders in the Treatment of Alcohol Dependence 240
Conclusion 240
References 240
Chapter 14: Decision Making, Risky Behavior, and Alcoholism 246
Decision Making, Risky Behavior, and Alcoholism 246
Poor Executive Control Leads to Poor Decision Making 246
Strong Appetitive Drive Leads to Poor Decision Making 247
Other Aspects of Behavior Related to Poor Decision Making in Alcoholics 248
Neural Correlates of Decision Making and Risky Behavior in Alcoholism 249
Brain Function Associated With Decision Making in Binge Drinking 249
Brain Function Associated With Decision Making in Active Drinkers With Alcohol Dependence 249
Brain Function Associated With Decision Making in short-term Abstinent Alcoholics 250
Brain Function Associated With Decision Making in Individuals At Risk for Alcoholism 251
Brain Function Associated With Decision Making in long-term Abstinent Alcoholics 252
References 253
Chapter 15: Motor Systems and Postural Instability 256
Introduction 256
Postural Control in Healthy Individuals 256
Prenatal Exposure to Alcohol 257
Acute Alcohol Intoxication: Neurologic and Behavioral Changes in Postural Control 258
Chemical Effects of Ethanol On postural control 258
Instability During Acute Intoxication 259
The Cerebellum in Acute Alcohol Intoxication 260
Chronic Alcoholism: long-term Motor and Neurologic Effects 260
Motor Symptoms 260
Excessive Sway and Postural tremor 260
Visual and Tactile cues 261
Neurologic Changes in Chronic Alcoholism 262
Cortical Changes 263
Corpus Callosum 263
Cerebellum 264
Pons and Thalamus 264
Peripheral Nervous System 265
Influence of Length of Alcohol Dependence and Sobriety 265
Influence Of age 265
Sexual Dimorphism 266
Recovery 266
Conclusion 268
References 268
Chapter 16: Sex Differences in alcohol-related Neurobehavioral Consequences 272
Introduction 272
Neurobehavioral Consequences of Acute Alcohol Administration 274
Neuropsychological/behavioral Consequences 274
Neurophysiologic Consequences 277
Neuroimaging Correlates of Acute Alcohol Administration 278
Section summary 279
Neurobehavioral Consequences Associated With Alcoholism 279
General notes 279
Neuropsychologic Concomitants 279
Neurophysiologic Concomitants: Eeg 281
Neurophysiologic Concomitants: Erp 282
Neuroimaging Concomitants: Structural 283
Neuroimaging Concomitants: Functional And metabolic Contrasts 285
Other Considerations Pertinent to Exploring Sex Differences And alcohol Effects 286
References 286
Section 6: Neuroimaging of Brain Macrostructure and Microstructure 292
Chapter 17: Structural and Microstructral Imaging of the Brain in Alcohol Use Disorders 294
Introduction 294
Structural Magnetic Resonance Imaging 294
Structural MRI Findings In syndromes Associated With alcoholism 296
Structural MRI Findings in Uncomplicated Alcoholism 297
Structural MRI Findings in Recovery From Alcoholism 299
Diffusion Tensor Imaging 300
Whole-brain Analysis 301
Region of Interest Analysis 301
Quantitative Fiber Tracking and Tractography 301
DTI Findings in Syndromes Associated With Alcoholism 302
DTI Findings in Uncomplicated Alcoholism 302
DTI Findings in Recovery From Alcoholism 303
Conclusion 303
References 303
Section 7: Neuroimaging of Neurochemical Markers 310
Chapter 18: Molecular Imaging in Alcohol Dependence 312
Introduction 312
Review of Imaging Methods 313
Dopamine and Alcohol Dependence 313
The Dopamine Receptor in Alcohol Dependence 313
Neurochemical Imaging of Dopamine Receptors in Alcohol Dependence 313
Alcohol Dependence and Presynaptic Dopamine 315
Dopamine Synthesis in Alcohol Dependence 316
The Dopamine Transporter in Alcohol Dependence 316
Acute Alcohol Intoxication and Dopamine Imaging 316
Gaba and Alcohol Dependence 317
Opioid Receptors and Alcohol Dependence 318
Serotonin and Alcohol Dependence 320
Cannabinoid Receptors And alcohol Dependence 322
Conclusions 322
References 326
Chapter 19: Brain Proton Magnetic Resonance Spectroscopy of Alcohol Use disorders 332
Introduction 332
Neurochemicals Measured By 1H Mrs and Basic Mrs Methods 333
1H Mrs of Alcohol Use Disorders 336
Cross-sectional 1H Mrs 336
Longitudinal 1H Mrs During Alcohol Abstinence 340
Gaba and Glu Concentrations in Alcohol Use disorders 341
Treatment-seeking Vs treatment-naïve alcohol-dependent Individuals 342
Effects of Common Substance Use Comorbidities on 1H Mrs Measures in Alcohol Use Disorders 344
Smoking Comorbidity 344
Other Substance Use Comorbidity 346
Current and Future 1H Mrs Research in Alcohol Use Disorders 347
1H Mrs Correlates of Relapse In Aud 347
Neuroimaging Genetics 348
Knowledge Gaps and Outlook 349
Acknowledgments 350
References 350
Section 8: Neuroimaging of Brain Function 358
Chapter 20: Cognition, Emotion, and Attention 360
Cognition, Attention, And emotion in Alcohol Abuse And dependence 360
Concepts of Attention and Their Neural Correlates 360
Attentional Control Systems Interact With Emotion and Reward Systems 363
Attention and Memory 364
Alcoholism - A neural Disconnection Syndrome? 366
Functional Networks Of attention and Cognition 366
Conclusion 367
References 367
Chapter 21: The Neurobiology of Alcohol Craving and Relapse 374
Introduction 374
Alcohol-related Neuroadaptations 374
Striatal Dopamine Transmission 375
Neuronal Hyperexcitability 375
Clinical Neurobiology of Craving and Relapse in Chronic Alcoholism 376
Alcohol Craving 376
Incentive Salience and Craving 376
Positively Reinforced Craving 376
Negatively Reinforced Craving 377
Alcohol Relapse 377
Functional Alterations Associated With Relapse 378
Structural Alterations Associated With Relapse 378
Factors Increasing Alcohol Craving and Relapse risk 379
Alcohol Or Alcohol cue 380
Stress 381
Stress and the Development of Alcoholism 381
Stress Sensitivity, Alcohol Craving, and Relapse 381
Conclusions 383
References 384
Chapter 22: Compensatory Recruitment of Neural Resources In chronic alcoholism 388
What are Compensatory Mechanisms? 388
Alcoholism-related Increases and Differences in Activity and Functional Connectivity 390
Default Mode Network in Alcoholism 392
Intrinsic Functional Networks 392
Frontocerebellar Structural and Functional Connectivity 394
Are alcoholism-related Increases in Functional Activity and Connectivity Compensatory? 394
Factors Contributing to Compensatory Mechanisms 395
Is there a Continuum in Compensatory Mechanisms? 395
Neuroplastic Changes Possibly Underlying Compensatory Mechanisms 395
Conclusion 397
Acknowledgment 397
References 397
Section 9: Neuroelectrophysiology 400
Chapter 23: Understanding Alcohol Use Disorders With Neuroelectrophysiology 402
Introduction 402
Continuous Electroencephalogram 402
Event-related Potentials 403
Event-related Oscillations 403
Acute Effects of Alcohol on the Brain in Social Drinkers 405
Acute Effects of Alcohol On Eeg 405
Acute Effects of Alcohol On Erps 408
Acute Effects of Alcohol On Eros 412
Effects of Binge Drinking On electrophysiology 413
Binge Drinking And Eeg 413
Binge Drinking And Erps 414
Chronic Alcoholism and Neuroelectrophysiology 415
Chronic Alcoholism and Resting Eeg 415
Theta band 415
Alpha band 415
Beta band 416
Interhemispheric Coherence 416
Chronic Alcoholism and event-related Potentials 416
Attention - N100 and Mismatch Negativity 416
Target Detection (oddball tasks) 417
Recovery With Abstinence 417
Response Inhibition (Go/NoGo tasks) 418
Error Monitoring and Response Evaluation 418
Semantic Processing 419
Chronic Alcoholism and event-related Oscillations 421
Electrophysiologic Measures As endophenotypes 422
EEG Phenotypes 422
Eros as Endophenotypes 423
Conclusion 424
Acknowledgment 424
References 424
Chapter 24: Alcohol and the Sleeping brain 434
Introduction 434
Acute Effects of Alcohol On sleep 435
Acute Effects of Alcohol on Sleep: Repeated Administration 435
Acute Alcohol: Sleep Eeg data 436
Sleep in Alcoholism 437
Alcoholism: Sleep Eeg data 437
Sex Effects in the Impact of Alcohol And alcoholism On sleep 438
Alcohol Dependence and Sleep In adolescence 439
Sleep Homeostasis and Circadian Problems With Alcohol abuse 440
Evoked Potentials During sleep 440
Sleep-evoked Responses in Alcoholism 441
Links Between Sleep Eeg Effects and Altered Brain Structure in Alcoholism 441
Possible Neurochemical Mechanisms of the Acute And chronic Alcohol Effects On sleep Eeg 442
Neurochemistry of Acute Alcohol Effects 443
Neurochemistry of Alcoholism Effects 443
Familial Predisposition for Alcoholism Effects On sleep? 443
A Role for Sleep in Treatment, Recovery, and Relapse 444
Conclusion 445
Acknowledgments 446
References 446
Section 10: Fetal alcohol spectrum disorder 452
Chapter 25: Neurobehavioral, neurologic, and neuroimaging characteristics of fetal alcohol spectrum disorders 454
Introduction 454
Neuropsychologic characteristics 454
Cognitive abilities 454
General intellectual function 454
Academic achievement 457
Executive function 457
Language 457
Learning and memory 458
Cognitive processing speed and attention 458
Behavioral characteristics 459
Problem behaviors 459
Psychopathology 459
Social skills and social communication 459
Neurologic characteristics 460
Sensory integration and processing 460
Motor skills 460
Seizure activity 462
Sleep pathology 462
Using neurobehavioral data to identify individuals affected by prenatal alcohol exposure 462
Neuroimaging characteristics 463
Global structural abnormalities 463
Cerebral volume and shape 464
Cerebrospinal fluid 464
White matter 468
Gray matter 468
Regional brain abnormalities 468
Corpus callosum 468
Cerebellum 470
Hippocampus 470
Basal ganglia 470
Additional subcortical structures 471
Functional brain abnormalities 471
Electrophysiologic studies 471
Functional magnetic resonance imaging 471
Attention 471
Verbal learning 471
Spatial working memory 471
Response inhibition 472
Number processing 473
Default mode network 473
Functional connectivity 473
Metabolic neuroimaging studies 473
Conclusion 473
Acknowledgments 474
References 474
Chapter 26: Fetal Alcohol Spectrum Disorder: Pathogenesis and Mechanisms 482
Introduction 482
Cell death 483
Cell Cycle and Proliferation 485
Cell Migration 485
Cell Morphogenesis 485
Gene Expression Changes 487
Genetic 487
Epigenetic 487
Reactive Oxygen species-mediated Damage 488
Retinoid and Sonic Hedgehog Signaling 488
Conclusion 489
References 491
Chapter 27: Current Hypotheses on the Mechanisms of Alcoholism 496
Alcoholism is a Disease Characterized By Continued Use Despite Negative Consequences 496
Diminished Executive Function in the Alcoholic is Consistent With a Compromise of Prefrontal Cortex Function 497
Human Prefrontal Cortex Case Studies 497
Alcohol-induced Neurodegeneration 498
Alcohol Alters the Neurotrophin/neuroimmune Balance 499
Alcohol and Innate Immune System Activation 500
Alcohol Activates the Neuroimmune Signaling system 502
Induction of Neuroimmune Cascades Contributes to addiction-like Behaviors 505
Risk Factors That Contribute To the Progression of Alcohol Dependence 506
Genetic Contribution to Alcohol Dependence 506
Adolescent Onset of Alcohol Consumption 508
Disorders of Pfc Function 509
Conclusions 510
References 511
Section 11: Adolescent Drinking 518
Chapter 28: The Effect of Alcohol Use on Human Adolescent Brain Structures and Systems 520
Introduction 520
Adolescent Brain Development 520
Prevalence of Adolescent Alcohol Use And drinking Patterns 520
Brain Structural Changes In adolescent Alcohol use 520
Gray-matter Volume 520
Cortical Thickness 521
White-matter Integrity 521
Brain Function Differences In adolescent Alcohol users 522
Genetics, Vulnerability, and Brain Function 524
Cue Reactivity, Level of Response, and Brain Function 525
Neurocognitive Performance In adolescent Alcohol users 526
Summary and Conclusions 527
Acknowledgments 527
References 527
Section 12: Other Topics 530
Chapter 29: Peripheral Systems: Neuropathy 532
History and Prevalence 532
Clinical Features 532
Electrodiagnostic Studies 533
Other Laboratory Studies 533
Neuropathology 534
Differential Diagnosis 535
Pathogenesis 535
Thiamine Deficiency in Humans 535
Deficiency of B vitamins Other than Thiamine 536
Lead In wine 536
Animal Studies of Alcoholic Neuropathy And nutritional Deficiency 537
Molecular Mechanisms 537
Acetaldehyde and Oxidative Stress 537
Glial Dysfunction 537
The Role of Insulin and insulin-like Growth Factor (Igf) in Alcoholic Neuropathy 538
Nociceptor Signaling Via Protein Kinase C (Pkc) 538
Axonal Transport and the Cytoskeleton 539
Prognosis and Treatment 539
Summary and Future Directions 541
References 541
Chapter 30: Pharmacologic Treatment of Alcoholism 546
Introduction 546
Neurochemical Targets For medication Treatment 546
Opioid Antagonists 547
Gaba/glutamatergic Medications 548
Serotonergic Medications 549
Dopaminergic Medications 549
Cholinergic/nicotine Acting drugs 550
Combination Pharmacotherapy 550
Treatment of Aud With co-occurring Mood Or Anxiety Disorders 550
Depression 550
Bipolar Disorder 550
Anxiety Disorders 551
Summary 551
Pharmacogenetics And endophenotype Predictors 551
Use of Neuroimaging to Identify New Drugs and Targets 552
Newer Targets for Medication Development 554
The Future 556
References 557
Chapter 31: Alcohol-medical Drug Interactions 562
Introduction 562
Pharmacokinetic Interactions 562
Absorption and Distribution 563
Elimination 563
Oxidative Pathways of Alcohol Metabolism 565
Adh Family of Enzymes 565
CYP 450 System 565
ALDH System 569
Non-oxidative Pathways of Alcohol Metabolism 569
EtG/EtS 569
FAEE 569
PEth 569
Alcohol Metabolism in The Cns 569
Regulators of Alcohol Metabolism 570
Influence of Genetic Variability in Genes Encoding alcohol-metabolizing Enzymes 570
Adh genes 570
Aldh-coding genes 570
Cyp2E1-coding genes 571
Catalase-coding genes 571
Pharmacodynamic Interactions 571
Interaction of Alcohol With Currently Tested Medications for the Treatment of Alcoholism 572
Concluding Remarks 572
References 573
Chapter 32: Genetics of Alcoholism 580
Genetic Variations Contribute To risk of Alcoholism 580
Defining the Phenotype 580
Genetic Approaches for Identifying Variants That Affect Risk for Alcoholism 581
Candidate Gene Studies 581
Genes Involved in Alcohol Metabolism 581
Nicotinic Acetylcholine Receptors 583
Linkage Studies Followed By positional Candidate Gene analyses 584
Gaba-A Receptor genes 584
Genes on Chromosome 4 584
Genomewide Association Studies to Identify Common Variants 585
Rare Variants 586
Conclusions 586
Acknowledgments 587
References 587
Chapter 33: Co-occurring Psychiatric Disorders and Alcoholism 592
Introduction 592
The Relationship Between Alcohol Use Disorders and Other Psychopathology 592
Identifying Psychopathology In Aud Patients 593
Mood Disorders 593
Differentiating Primary Vs Secondary Mood Symptoms in co-occurring Conditions 596
Anxiety Disorders 597
Differentiating Anxiety From Mood Disorders 598
Personality Disorders (Axis Ii In Dsm) 598
Differentiating Mood From Personality Disorders 599
Organic Brain Disease 600
Drug Use Disorders 600
Neurobiologic Mechanisms Involved in Comorbidities 601
Treatment and Outcomes In comorbidity 602
Conclusion 603
References 604
Chapter 34: Hepatic Encephalopathy in Alcoholic Cirrhosis 608
Introduction 608
Neuropathology Of He 610
Pathophysiology of He In alcoholic Cirrhosis 610
Ammonia 610
Manganese 611
Inflammation 612
Brain Glucose and Energy Metabolism 613
The Gaba System and Neurosteroids 613
Serotonin 614
Histamine 615
Dopamine 615
Therapeutic Advances 615
Ammonia-lowering Strategies 615
Neuropharmacology 616
Liver Support Systems 617
Liver Transplantation 617
Summary 617
Acknowledgments 618
References 618
Chapter 35: Neuropathology of Alcoholism 622
Introduction 622
Alcohol Neurotoxicity 622
Complicating Pathologies 622
Structural Changes In Arbd 624
Neuronal Loss In Arbd 625
Molecular Differences 627
Neurotransmitters and Their Receptors 627
Genetics and Genomics 627
Gene Expression 628
Proteomics 629
Summary 630
Acknowledgments 630
References 630
Chapter 36: Genetic Differences in Response to Alcohol 636
Response to Alcohol as an Endophenotype of Alcohol Use Disorder 636
Heritability of Level of Response to Alcohol 636
Genetic Influences on Level Of response to Alcohol 637
Gamma-aminobutyric Acid A (Gaba) Receptor genes 637
Serotonin Transporter gene 637
Opioid Receptor gene 638
Nicotinic Acetylcholine Receptors gene 638
Interaction of Gene-environment And other factors 638
Alcohol Metabolism and Genetic Variations of alcohol-metabolizing Enzymes 639
Alcohol Dehydrogenase 639
Acetaldehyde Dehydrogenase 641
Conclusions 643
References 643
Chapter 37: Epidemiology of Drinking, Alcohol Use Disorders, and Related Problems in Us Ethnic Minority Groups 648
Introduction 648
Brief Historic Overview 648
What the Chapter will Cover 649
Drinking Among Whites, Blacks, and Hispanics 649
Alcohol Use Disorders and Other Problems Among Whites, Blacks, and Hispanics 652
Drinking, Alcohol Use Disorders, and Other Problems Among Hispanic National Groups 654
Drinking, Alcohol Use Disorders, and Other Problems Among Asian americans 657
Drinking, Alcohol Use Disorders, and Other Problems Among american Indians And alaska Natives 658
A Theory About Health Disparities: cumulative Adversities 660
Conclusions 661
References 662
Chapter 38: Alcohol and The law 668
Interventions to Reduce alcohol-related Consequences 668
Alcohol Taxes and Price Controls 669
Policies Targeting alcohol-impaired Driving 670
Restrictions on Alcohol Availability 671
Minimum Legal Drinking Age laws 671
Information and Education On alcohol use 671
Recovery-oriented Policy 672
Alcohol and Violence 672
Alcohol and Criminal Responsibility 672
Alcohol and Decision Making 673
Conclusion 674
Acknowledgment 674
References 674
Chapter 39: Clinical Management of Alcohol Use Disorders In the neurology clinic 678
Introduction 678
What Is sbirt? 679
What is the Evidence That Sbirt works? 679
Screening 679
Screening Results 681
Brief Intervention 681
Precontemplation stage 683
Goal: to Move the Patient Toward Thinking About Change 683
Contemplation stage 683
Goal: to Encourage the Patient to Examine the Benefits and Risks of Change 683
Referral to Treatment 683
Neurologic Medical Comorbidity 684
Physical Examination 684
Acute Presentations 685
Blood Alcohol Concentration 685
Alcohol Withdrawal 685
Wernicke-Korsakoff Syndrome 685
Pellagra 686
Blackouts (retrograde Amnesia) 686
Central Pontine and Extrapontine Myelinolysis 686
Neuropathy 686
Cognitive Impairment 686
A Note About Alcohol Use as a Risk Factor For traumatic Brain Injury Or Recovery From Tbi 687
Conclusion 687
References 687
Index 690