Anhedonia: Preclinical, Translational, and Clinical Integration

Description

Anhedonia is a key symptom (and often risk factor) for various neuropsychiatric disorders, including depression, schizophrenia, substance use disorders, post-traumatic stress disorders, and Parkinson's Disease, among others. Across disorders, anhedonia has been associated with worse disease course, including poor response to pharmacological, psychological and neurostimulation treatments as well as completed suicide. Mounting evidence emerging from preclinical and translational sciences has clarified that "anhedonia" can be parsed into partially independent subcomponents, including incentive motivation, consummatory pleasure, reward learning, and effort-based decision making, pointing to distinct neurobiological substrates that could underlie anhedonic phenotypes. Taking an integrative approach that emphasizes cross-species integration and dimensional conceptualization of mental illnesses (e.g., Research Domain Criteria (RDoC)), this book represents the most comprehensive evaluation, synthesis and integration of theories and empirical findings focused on anhedonia. Organized across five parts, the handbook starts with chapters on the history, etiology, and assessments of anhedonia (Part I), followed by a section on the role of anhedonia in psychiatric and neurological disorders (Part II). Using the RDoC Matrix as a guide, Part III presents chapters synthetizing preclinical and clinical findings on different reward processing subdomains (e.g., reward responsiveness, reward valuation, reward learning). Part IV is focused on selected special topics, including historical and current perspectives on the transdiagnostic nature and importance of social anhedonia, the role of inflammation in the pathophysiology of anhedonia, the use of computational modeling to “dissect” anhedonia and improve its understanding, and links between anhedonia and suicide. Finally, Part V includes chapters on pharmacological, psychological and neurostimulation treatments for anhedonia.  Preface Contents Part I: Anhedonia - History, Etiology, and Assessments Clinical and Preclinical Assessments of Anhedonia in Psychiatric Disorders 1 Introduction 2 Clinical Scales of Anhedonia and Reward Deficits: Beyond Pleasure and Interest 2.1 Early Measures (1970-2000) 2.2 Contemporary Measures (2001-2021) 2.3 Other Measures of Anhedonia 2.4 Gaps in Existing Anhedonia Clinical Scales 3 Preclinical and Clinical Reward Tasks 3.1 Anticipation 3.1.1 Preclinical 3.1.2 Clinical 3.2 Motivation and Effort Expenditure 3.2.1 Preclinical 3.2.2 Clinical 3.3 Valuation of Reward 3.3.1 Preclinical 3.3.2 Clinical 3.4 Expectation and Prediction Error 3.4.1 Preclinical 3.4.2 Clinical 3.5 Outcome and Consummatory Pleasure 3.5.1 Preclinical 3.5.2 Clinical 3.6 Reward Learning and Feedback Integration 3.6.1 Preclinical 3.6.2 Clinical 3.7 Translational Difficulties in Behavioral Assessments of Anhedonia 4 Conclusions References Developmental Trajectories of Anhedonia in Preclinical Models 1 The Concept of Anhedonia and Its Operationalization in Preclinical Models 1.1 Novel Tools for the Study of Anhedonia in Preclinical Models 1.2 The Reward Circuit and Its Study in Experimental Models 2 Anhedonia and Early-Life Adversity (ELA) 2.1 Why Study ELA and Anhedonia? The Human Landscape 2.2 What Is ELA and How Do We Model It? 2.3 Anhedonia Following ELA Involves a Developing Reward Circuit 2.4 Anhedonia After ELA: Manifestations and Sex Specificity 3 General Conclusions References Origins of Anhedonia in Childhood and Adolescence 1 Introduction 2 Impact of Positive Caregiving During Infancy 3 Impact of Memory Processes and Social Engagement During Early and Middle Childhood 4 Role of Self-Concept Development During Childhood and Adolescence on Anhedonia 5 Conclusions and Future Directions References Understanding Anhedonia from a Genomic Perspective 1 Introduction 2 Contemporary Psychiatric Genetics Frameworks: Relevance to RDoC 3 Genetic Studies of Anhedonia and Related Constructs 3.1 Twin and Family Studies 3.2 Candidate Gene Studies 3.3 GWAS 3.4 Polygenic Studies 4 Conclusions and Future Directions References Environmental Contributions to Anhedonia 1 Introduction 2 Definitional Issues: Consummatory vs. Motivational Anhedonia 3 Definitional Issues: Stress Exposure and Response 4 Relation of Stress to Reward Processing in the Preclinical Literature 4.1 Chronic Mild Stress 4.2 Acute Stress 4.3 Social Stress 4.4 Maternal Separation 4.5 Stress Response and Reward 4.6 Summary 5 Relation of Stress to Reward Processing in Humans 5.1 Proximal Stressful Life Events 5.2 Early Adversity and Maltreatment 5.3 Acute Laboratory Stress 5.4 Stress Response and Reward 5.5 Summary 6 Disclosures References Part II: Anhedonia in Psychiatric and Neurological Disorders Anhedonia in Depression and Bipolar Disorder 1 Introduction 2 History, Epidemiology, and Phenomenology of Anhedonia in Mood Disorders 2.1 Anhedonia as a Diagnostic Criterion for Depression 2.2 Epidemiology of Anhedonia in Mood Disorders 2.2.1 Prevalence of Anhedonia in Mood Disorders 2.2.2 Severity of Anhedonia Across Distinct Mood Disorder Diagnoses 2.3 Anhedonia Phenomenology 3 Clinical Significance of Anhedonia in Mood Disorders 3.1 Association with Illness Course 3.2 Association with Treatment Response 4 Neurobiology of Anhedonia in Mood Disorders 4.1 Neural Correlates of Reward Processing in MDD 4.1.1 Blunted Anticipation-Related Activation in the Ventral Striatum as a Trait-Like Feature of MDD 4.1.2 Disrupted Corticostriatal Activation to Reward Outcome (Consumption) in MDD 4.1.3 Disrupted Reward Prediction Errors in MDD 4.2 Neurobiology of Reward Processing in BD 4.2.1 Heightened Reward-Related Activation in the Lateral OFC Characterizes BD 4.2.2 Mixed Pattern of Striatal Activation in Response to Reward in BD 4.3 Differences in Reward-Related Brain Activation Between MDD and BD 5 Summary References Anhedonia in Schizophrenia 1 Anhedonia as a Cardinal Symptom of Schizophrenia 2 A Heuristic Model of the Motivation-Action-Outcome Pathway 3 Mechanisms 3.1 Initial Response to Reward 3.2 Reward Anticipation and Reinforcement Learning 3.2.1 Reward Anticipation 3.2.2 Reinforcement Learning and Prediction Error 3.3 Effort Valuation 3.4 Cognitive Control and Goal-Directed Action 4 Using Technology to Assess Anhedonia in Daily Life 4.1 Ecological Momentary Assessment 4.2 Mobile Sensing Applications 4.3 Deploying Experimental Tasks on Mobile Devices 5 Summary References Anhedonia, Hyperkatifeia, and Negative Reinforcement in Substance Use Disorders 1 Addiction, Hyperkatifeia, and Anhedonia: Definitions and Heuristic Framework 1.1 Addiction, Hyperkatifeia, Anhedonia, Negative Reinforcement, and Opponent Process 1.2 Learned Hyperkatifeia/Anhedonia and Conditioned Negative Reinforcement 2 Neurochemical Neurocircuitry Mediating Hyperkatifeia/Anhedonia 3 Crosstalk with Physical and Emotional Pain 4 Neurobiology of Conditioned Hyperkatifeia, Including Anhedonia 5 Hedonic Set Point: An Allostatic View References Anhedonia in Nicotine Dependence 1 Introduction 2 Neurobiological Overlaps of Nicotine Dependence and Anhedonia 3 Anhedonia and Nicotine Dependence Within the Frameworks of the NIMH Research Domain Criteria (RDoC) and the Situation by Tra... 3.1 Reward Responsiveness 3.1.1 Reward Anticipation 3.1.2 Initial Response to Reward 3.1.3 Reward Satiation and Habituation 3.2 Reward Learning 3.2.1 Probabilistic and Reinforcement Learning 3.2.2 Reward Prediction Error (RPE) 3.2.3 Habit 3.3 Reward Valuation 3.3.1 Probability/Reward (Ambiguity/Risk) of Reward 3.3.2 Delayed Reward Value 3.3.3 Effort to Obtain Reward 4 Summary: Toward a Situation x Trait Anhedonic Response (STAR) RDoC Framework for Understanding Nicotine Dependence References Anhedonia in Posttraumatic Stress Disorder: Prevalence, Phenotypes, and Neural Circuitry 1 Anhedonia: A Consequential Transdiagnostic Construct 2 Anhedonia in Posttraumatic Stress Disorder: Prevalence, Outcomes, and Theories 3 Altered Reward Processing and Circuitry in Posttraumatic Stress Disorder 4 Areas of Future Research References Anhedonia in Anxiety Disorders 1 Introduction 2 Anhedonia in Anxiety: Early Observations to Current Empirical Status 2.1 Reward Valuation 2.2 Reward Responsiveness 2.3 Reward Learning 3 Vulnerability and Amplifying Factors 3.1 Etiological Origins 3.2 Cognitive and Regulatory Anhedonia Amplifiers 4 A Functional Account of How Anhedonia Could Impede Recovery from Anxiety 4.1 Sacrificing Rewards Due to Costly Avoidance 4.2 Consequences of Diminished Responsiveness 4.3 Lessons from Positive Emotion Science 4.4 Anhedonia and Threat Reactivity in Analogue and Clinical Samples 5 Treatment Implications 5.1 Anhedonia as a Predictor of Treatment Response 5.2 Anhedonia as a Treatment Target to Improve Outcomes for Anxiety 6 Concluding Remarks References Anhedonia in Eating Disorders 1 Introduction 2 Clinical Presentation of Anhedonia in ED 2.1 Social Anhedonia 3 Anhedonia and Reward Processing in ED 3.1 Altered Sensitivity and Motivation to Pursue Reward in ED: Evidence from Subjective Measures 3.2 Altered Reward Responsiveness (Liking) and Anticipation (Wanting) in ED: Evidence of Altered Neurotransmitter Function 3.3 Altered Reward Responsiveness (Liking) and Anticipation (Wanting) in ED: Evidence from Task-Based Functional Neuroimaging ... 3.4 Altered Reward Learning in ED: Evidence from Neurocognitive and Neuroimaging Studies 4 Anhedonia in Animal Models of Disordered Eating 5 Future Research Directions and Implications for Treatment 6 Conclusion References Anhedonia and Hyperhedonia in Autism and Related Neurodevelopmental Disorders 1 The Social Motivation Theory of Autism 2 Translational Evidence of Impaired Motivational Responses in Autism 3 Neurobiological Mechanisms of Impaired Motivational Responses in Autism 4 Studying Motivational Responses in Syndromic Developmental Disorders Associated with Autism to Understand Idiopathic Autism 5 A New Nosology to Describe Motivational Impairments in Autism and Related Neurodevelopmental Disorders References Anhedonia in Neurodegenerative Diseases 1 Introduction 2 Parkinson´s Disease 2.1 Anhedonia and Its Relationship with Depression in Parkinson´s Disease 2.2 Anhedonia and Its Relationship to Apathy in Parkinson´s Disease 2.3 Treatment of Anhedonia in Parkinson´s Disease 3 Dementia with Lewy Bodies 4 Parkinson´s Plus Syndromes 5 Alzheimer´s Disease 6 Vascular Dementia 7 Frontotemporal Dementia 8 Amyotrophic Lateral Sclerosis 9 Huntington´s Disease 10 Conclusions References Part III: Reward Processing Systems in Anhedonia Pleasure, Reward Value, Prediction Error and Anhedonia 1 Introduction 2 Anhedonia and Reward Processing 3 Pleasure 3.1 Self-Report Questionnaires 3.2 Ecological Momentary Assessments 3.3 Laboratory Assessments 3.4 Physiological Responses 4 Reward Value 4.1 Behavioural Studies 4.2 Neuroimaging Studies 5 Learning and Reward Prediction Error 5.1 Neuroimaging Studies 5.2 Behavioural Studies 6 Directions for Future Research 6.1 Characterising Reward Processing Alterations Using Suitable Paradigms and Computational Approaches 6.2 Understanding Heterogeneity Across Disorders Using Transdiagnostic Assessments 6.3 Improving the Validity and Reliability of Reward Processing Measures 6.4 Addressing Causality with Longitudinal and Intervention Studies 7 Conclusion References Anticipation: An Essential Feature of Anhedonia 1 Dopamine and Anhedonia 2 Dopamine and Preparatory Behaviors as Distinct from Consummatory Behaviors 3 Emergence of Anticipation as a Key Construct in the Anhedonia Story 4 Novel Insights from Preclinical Studies of Contrast Effects on the Role of Incentive-Anticipation in Mood Disorders 5 Anhedonia, Anticipation, and the RDoC Classification System 6 Concluding Remarks References Vigor, Effort-Related Aspects of Motivation and Anhedonia 1 Introduction 2 Neurochemistry and Pharmacology of Behavioral Activation and Effort-Related Processes: Preclinical Foundations 2.1 Brain Circuitry Involved in Effort-Based Choice 3 Translation to Humans 3.1 The Task of the Translator: Considerations for Translating Rodent EBDM Studies to Humans 3.2 Dopaminergic Drive in Human EBDM 3.3 Hierarchical Circuits for Effort Allocation 4 Implications in Psychopathology and Treatment 4.1 Treatment Development: Animal Models 4.2 Effects of Dopaminergic Manipulations in Animal Models: Anhedonia or Avolition/Anergia? 5 Conclusions References Probabilistic Reinforcement Learning and Anhedonia 1 Introduction 1.1 Anhedonia: Definition and Statement of Problem 1.2 Using Probabilistic Contingencies to Examine Anhedonia 2 How Probabilistic Contingencies Inform the Study of Anhedonia and Its Symptoms 2.1 Probabilistic Reward Task 2.2 Probabilistic Stimulus Selection Task 2.3 Probabilistic Pavlovian Conditioning Task 2.4 Drifting Double Bandit Task 3 Reverse Translation of Probabilistic Assays in Laboratory Animals 4 Neurobiological Mechanisms of Probabilistic Reinforcement Learning 4.1 Prefrontal Cortex and Probabilistic Learning 4.2 Striatum and Probabilistic Learning 4.3 Basolateral Amygdala (BLA) and Probabilistic Learning 4.4 Overlapping Neural Circuits Underlying Probabilistic Learning and Anhedonia 5 Conclusions and Future Directions References Part IV: Special Topics The Transdiagnostic Nature of Social Anhedonia: Historical and Current Perspectives 1 Anhedonia, the Broader Construct 2 The Unique Nature of Social Anhedonia 3 The Transdiagnostic Nature of Social Anhedonia 4 An Integrative, Transdiagnostic Conceptualization of Social Anhedonia 5 The Role of Attention in Social Pleasure 6 The Role of Social Cognition in Social Pleasure 7 The Role of Reward Learning and Reward Valuation 8 The Role of Working Memory in Social Pleasure 9 The Cognitive-Affective Interface: Anticipation, Prediction, and Remembering 10 The Role of Social Skills in Social Pleasure 11 The Role of Motivation and Effort in Social Anhedonia 12 Future Research Directions References Inflammation as a Pathophysiologic Pathway to Anhedonia: Mechanisms and Therapeutic Implications 1 Introduction and Overview 2 Inflammation and Anhedonia in Psychiatric Disease 2.1 Inflammation in Depression and Other Psychiatric Disorders: Causes and Consequences 2.2 Relationships Between Inflammation and Symptoms of Anhedonia Across Diagnoses 2.3 Inhibition of Inflammation Reduces Anhedonia Symptoms 3 Impact of Inflammation on Reward Pathways and Anhedonia: Clinical Evidence 3.1 Cytokine-Induced Depression: Mechanisms and Relevance to Anhedonia 3.2 Acute Inflammatory Challenge and Reward Processing 3.3 Endogenous Inflammation in Psychiatric Disorders and Reward Circuitry 4 Neurobiological and Neurotransmitter Mechanisms: Basic and Translational Studies 4.1 Laboratory Animal Models of Inflammation Effects on Motivation 4.2 Neurotransmitter Mechanisms: Dopamine Synthesis, Release, and Reuptake 4.3 Neurotransmitter Mechanisms: Glutamate Release, Reuptake, and Modulation by Kynurenines 5 Therapeutic Targets to Reverse the Impact of Inflammation on the Brain 5.1 Neurotransmitter Targets 5.2 Anti-Inflammatory and Immunomodulatory Strategies 6 Translational Challenges and Future Directions References A Computational View on the Nature of Reward and Value in Anhedonia 1 Introduction 2 The Components of Anhedonia and Patient Experience 3 Existing Computational Research 4 Reward as Distance 4.1 A General Effect of Unsatisfied Drives on Reward 4.2 The Geometry of Drive Space Influences Preference for Multi-dimensional Rewards 5 Rewards on Graphs 5.1 How Cognitive Distortions Can Reduce Hedonic Experience 5.2 How the Meaning of Events May Arise from Associational Graphs 6 Discussion References Anhedonia and Suicide 1 Introduction 2 Anhedonia as a Risk Factor for STBs 2.1 Anhedonia and Suicidal Behaviors 2.2 Youth, Anhedonia, and STBs 2.3 State Versus Trait Anhedonia and STBs 3 RDoC Positive Valence System (PVS) and Suicide 3.1 PVS: Reward Responsiveness 3.2 PVS: Reward Learning 3.3 PVS: Reward Valuation 3.4 PVS: Molecular Pathways 4 Contextualizing Anhedonia in Leading Suicide Theories 4.1 Anhedonia and Diathesis-Stress Model 4.2 Anhedonia and Interpersonal Theories of Suicide 5 Targeting Anhedonia in Treatments for Suicide 6 Conclusion References Part V: Treatments Pharmacological Treatments for Anhedonia 1 Kappa-Opioid Receptor Antagonists 2 KCNQ Channel Modulators 3 Ketamine 4 Psychedelics 5 Conventional Antidepressants 6 Conclusion References Psychological Treatments for Anhedonia 1 What Is Anhedonia? 2 Traditional Treatments Are Ineffective for Anhedonia 2.1 Behavioral Activation 3 Positive Valence Systems 4 Treatments Consistent with the Positive Valence Systems 4.1 Positive Affect Treatment (PAT) 4.2 Virtual Reality-Reward Training (VR-RT) 4.3 Amplification of Positivity (AMP) 4.4 Augmented Depression Therapy (ADepT) 4.5 Behavioral Activation for Anhedonia (BATA) 5 Targeted Cognitive Approaches 5.1 Memory Specificity Training 5.2 Positive Imagery Training 5.3 Episodic Future Thinking (EFT) 6 Neurofeedback 7 Regulation of Positive Affect 7.1 Positive Emotion Regulation Treatments 8 Conclusions and Recommendations for Future Research References Circuit-Targeted Neuromodulation for Anhedonia 1 Introduction: Circuit-Targeted Therapeutics for Mental Illness 1.1 A Brief History of Brain Circuit Therapeutics in Psychiatry 1.2 Clinical Applications of Circuit-Targeted Brain Stimulation in Psychiatry 1.3 Targeting Brain Circuits with TMS and DBS 2 Mapping Brain Circuits to Identify Treatment Targets for Anhedonia 2.1 Approaches to Brain Circuit Mapping 2.2 Models of Anhedonia Derived from Correlative Neuroimaging 3 Treating Anhedonia with Circuit-Targeted Neuromodulation 3.1 TMS for Anhedonia 3.2 DBS for Anhedonia 4 Novel Approaches to Neuromodulation for Anhedonia 4.1 Identifying Neuromodulation Targets Using Causal Sources of Information 4.2 Mapping Inter-Individual Variability to Personalize Neuromodulation 5 Conclusions References