The Neurobiology and Treatment of OCD: Accelerating Progress (Current Topics in Behavioral Neurosciences Book 49)

The book highlights important new research approaches of clinical relevance, written by prominent researchers in the field of OCD and related disorders. A broad range of topics is covered, beginning with a description of the phenotypic features of the OCD followed by chapters on developmental aspects, animal models, genetic and biological models including neuro-inflammation, functional neuroimaging correlates and information-processing accounts. Finally, existing and novel treatment approaches are covered including clinical and pharmacogenetic treatment models. In this way the volume brings together the key disciplines involved in the neurobiological understanding of OCD to provide an update of the field and outlook to the future. Together, the volume chapters provide focused and critical reviews that span a broad range of topics suitable for both students and established investigators and clinicians interested in the present state of OCD research. Preface Acknowledgments References Contents Genetics of OCD and Related Disorders; Searching for Shared Factors 1 Introduction 2 Search Strategy 3 Prevalence and Heritability of OCD, OC-Related Disorders and PUI 4 Candidate Gene Studies 5 Genome-Wide Association Studies 6 Conclusion References On the Development of OCD 1 Introduction 2 Why Development? 3 How to Study Development of a Disorder? 4 OCD Symptoms During Development 5 Cognitive Markers in Development 6 Neural Features in Juvenile OCD 7 Outlook References Inflammation, Obsessive-Compulsive Disorder, and Related Disorders 1 Introduction 2 Sydenham ́s Chorea, PANDAS, and PANS 3 Neuroanatomy Implicated in OCD 4 Translocator Protein Imaging in Obsessive-Compulsive Disorder 5 Postmortem Investigation 6 Inflammation in Other Related Disorders 7 Biomarkers of Inflammation 8 Investigations of Putative Inflammation Targeting Interventions in OCD 9 Conclusions References Animal Models for OCD Research 1 Distinguishing Features of OCD That Can Be Modeled in Animals 1.1 Clinical Phenomenology of OCD 1.2 Neural Circuit Abnormalities Associated with OCD 1.3 Genetics of OCD 2 Strategies for Studying OCD Using Animal Model Systems 2.1 Transgenic Models for Studying OCD 2.2 Circuit Manipulation to Study OCD 3 Chemogenetic Investigation of OCD- and TS-Relevant Behaviors 3.1 Striatal Histidine Signaling 3.2 Striatal Interneuron Manipulation 3.3 Dissection of Circuits Underlying Constructs Relevant to OCD 3.4 Dissecting Abnormal Neural Constructs in OCD 4 Conclusion: How Do We Get from Animal Models to Targeted Treatments? References Neurocognitive Endophenotypes of OCD 1 The Rationale for Endophenotypes 2 Genetics of OCD 3 The Theoretical Model for Defining Endophenotypes for OCD 4 Motor Inhibition 5 Cognitive Flexibility 6 Goal-Directed Planning 7 Working Memory 8 Error Monitoring 9 Conclusions and Future Directions References Cognitive Inflexibility in OCD and Related Disorders 1 Introduction 2 Methods 2.1 Search Strategy 2.2 Inclusion and Exclusion Criteria 2.3 Data Collection and Analysis 3 Results 4 Discussion 4.1 Neural and Neurochemical Substrates of Cognitive Inflexibility in OCD 4.2 Cognitive Inflexibility as a Candidate Endophenotype for OCD 4.3 Cognitive Inflexibility in Other Related Clinical Settings and Disorders 4.4 One Thing or Many? Towards Rich, Delineated Measures of Compulsivity 4.5 Concluding Remarks References Recent Developments in the Habit Hypothesis of OCD and Compulsive Disorders 1 Introduction 2 Outcome Devaluation and the Balance Between Habits and Goal-Directed Behaviours 3 Evidence for Imbalance in OCD 4 From Categorical to Dimensional Perspectives on Goals and Habits 5 Goal-Directed Control and the Mental Model 6 What Has Habit Got to Do With It? 7 Where Do We Go from Here? References Electroencephalographic Correlates of Obsessive-Compulsive Disorder 1 Background 2 What Can an Electroencephalographic Approach Provide to the Understanding of OCD? 2.1 Event-Related Potentials 3 Obsessive-Compulsive Disorder and Electrophysiology 3.1 Contingent Negative Variation and OCD 3.2 Mismatch Detection and the N2 3.2.1 Uncertainty as a Generator of the N2 and OCD Symptoms 3.3 Error-Related Negativity as an Endophenotype of OCD 3.3.1 Error Detection/Comparator Theory 3.3.2 Conflict Monitoring Theory 3.3.3 Reinforcement Learning Theory Feedback Error-Related Negativity (fERN) and Evaluation of Errors 3.4 The Readiness Potential 4 Summary and Future Perspectives References Structural Imaging in OCD 1 Introduction 2 Early Studies in OCD 3 Meta-Analyses and Pooled Analyses 4 Meta-and Mega-Analyses: ENIGMA 5 OCD Subdimensions 6 The Role of Comorbidity 7 White Matter: VBM and DTI 8 Discussion References Magnetic Resonance Spectroscopy (MRS) and Positron Emission Tomography (PET) Imaging in Obsessive-Compulsive Disorder 1 Introduction 2 Positron Emission Tomography (PET) 3 Magnetic Resonance Spectroscopy (MRS) 3.1 MRS in OCD 3.2 MRS and OCD: Regional Findings 3.2.1 Neurometabolite Concentrations in the Rostral Anterior Cingulate Cortex 3.2.2 Neurometabolite Concentrations in the Dorsal Anterior Cingulate Cortex 3.2.3 Neurometabolite Concentrations in the Basal Ganglia 3.2.4 Neurometabolite Concentrations in the Thalamus 3.2.5 Neurometabolite Concentrations in Other Brain Regions 4 Associations Between Neurometabolite Concentrations and Clinical Symptoms 4.1 OCD Symptom Severity 4.2 Anxiety and Depression Scales (in OCD) 5 Treatment Effects on Neurometabolite Concentrations in OCD 5.1 Cognitive Behavioural Therapy 5.2 SSRI Medication 6 Discussion 7 Conclusions References Functional Brain Imaging and OCD 1 Introduction 2 Task-Based fMRI 2.1 Executive Functioning 2.2 Emotional Processing 2.3 Symptom Provocation 3 Brain Connectivity 3.1 Resting-State Connectivity in CSTC Circuits 3.2 Resting-State Networks 3.3 Graph Theory Approaches 3.4 Effective Connectivity 4 Prediction of Treatment Response 5 Conclusion References Innovations in the Delivery of Exposure and Response Prevention for Obsessive-Compulsive Disorder 1 Introduction 2 Exposure and Response Prevention 2.1 Treatment 2.2 Theory 3 Effects of EX/RP 3.1 Adult OCD 3.2 Pediatric OCD 4 Factors Associated with EX/RP Outcome 5 Access to EX/RP 6 Technology-Based Innovations in Delivering EX/RP 6.1 Video Conferencing for Family-Based CBT 6.2 Internet-Based CBT for OCD 6.3 Smartphone Apps 7 Translational Neuroscience Approaches to Enhancing EX/RP 7.1 Pharmacological Enhancement of EX/RP 7.2 Behavioral Methods for Enhancing EX/RP Outcomes 7.3 Neuromodulatory Techniques for Enhancing EX/RP Outcomes 8 Conclusions References Pharmacotherapeutic Strategies and New Targets in OCD 1 Introduction 2 Serotonin Reuptake Inhibitors 2.1 Efficacy of Serotonin Reuptake Inhibitors (SRIs) 2.2 SSRI Dosage 2.3 Duration of SSRI Treatment 2.4 Optimization of SSRI Treatment 3 Other Serotonergic Agents 3.1 Serotonin-Norepinephrine Dual Reuptake Inhibitors 3.2 Serotonin Agonists and Antagonists 4 Serotonin Dysregulation in OCD 4.1 The Serotonin Reuptake Transporter 4.2 Serotonin 2A Receptor 4.3 Serotonin 1A Receptor 4.4 Serotonin 1B/1D Receptor 4.5 Serotonin-3 Receptors 4.6 Serotonin Levels in OCD? 5 Dopaminergic Agents in the Treatment of OCD 5.1 D2 Antagonist Monotherapy 5.2 D2 Antagonist Augmentation 5.3 Other Dopaminergic Agents 6 Dopamine Dysregulation in OCD 6.1 Animal Studies 6.2 Genetics 6.3 Receptor Imaging Studies 6.4 Dopamine Levels 7 Glutamate Modulators in the Treatment of Refractory OCD 7.1 Memantine 7.2 Riluzole 7.3 Ketamine 7.4 Other Glutamatergic Agents 8 Glutamate Dysregulation in the Pathophysiology of OCD 8.1 Glutamate-Related Genes in OCD 8.2 Glutamate Receptors and Related Proteins in OCD 8.3 CSF and Brain Glutamate Levels 8.4 Animal Studies 9 Towards Personalized Medicine in the Treatment of OCD 9.1 Phenomenological, Symptomatic, and Cognitive Predictors of Treatment Response 9.2 Genetic Predictors of Treatment Response and Side Effects 9.3 Structural and Functional Neuroimaging Predictors of Treatment Response 9.4 Neurochemical Predictors of Treatment Response 10 Conclusion References Pharmacogenetics of Obsessive-Compulsive Disorder: An Evidence-Update 1 Introduction 2 Methods 3 Results 3.1 Pharmacokinetic Factors 3.2 Pharmacodynamic Factors 3.3 Serotonergic System Genes 3.4 Glutamatergic System Genes 3.5 Dopaminergic System Genes 4 Conclusion and Future Perspective References Invasive and Non-invasive Neurostimulation for OCD 1 Introduction 2 Deep Brain Stimulation 2.1 Techniques and Targets 2.1.1 Targets 2.2 Clinical Results 2.2.1 Results of Randomized, Controlled Trials 2.2.2 Addition of Cognitive-Behavioral Therapy 2.2.3 Effects on Other Symptoms and Quality of Life 2.2.4 Outcome Predictors 2.2.5 Conclusion 2.3 Mechanisms of Action: Neuroimaging and Circuitry 2.3.1 Cortico-Striatal-Thalamic-Cortical Loops in OCD as a Target for DBS 2.3.2 Difficulties in Studying the Neurobiological Effects of DBS 2.3.3 Effects of DBS on Brain Activity 2.3.4 Brain Networks Targeted by DBS 2.3.5 Using Brain Networks to Optimize DBS Targeting 2.3.6 Conclusion 2.3.7 Future Perspectives 2.4 Animal Research and DBS 2.4.1 DBS in Animal Models Exhibiting Compulsive Behavior 2.4.2 Unraveling a DBS Mechanism of Action and a Brain Signature of Compulsive Behavior 2.4.3 Identification of an Electrophysiological Compulsivity Signature for (Closed-Loop) DBS 3 Transcranial Magnetic Stimulation 3.1 Effects of TMS on Brain Networks 3.2 Clinical Effects of TMS 3.3 tDCS and OCD 3.4 Conclusion 4 Conclusion and Discussion References New Directions for Surgical Ablation Treatment of Obsessive Compulsive Disorder 1 Introduction 2 What Is Ablative Neurosurgery? 3 Why Is Ablative Neurosurgery Considered for Some Patients with OCD? 4 Therapeutic Approaches to Treatment Refractory OCD 4.1 Intensive Treatment Programmes 4.2 Neurosurgical Procedure Evolution 4.3 Lesion Surgery for OCD 5 Anterior Cingulotomy 6 Anterior Capsulotomy 7 Observational Evidence 8 Comparisons of Ablative Surgery with DBS for OCD 9 Radiosurgical Capsulotomy 10 Randomised Evidence 11 Magnetic Resonance-Guided Focused Ultrasound (MRgFUS) 12 `Horizon Scanning ́ 13 Procedure-Specific `New Directions ́ 14 Clinical Guidance References The Future of Obsessive-Compulsive Spectrum Disorders: A Research Perspective 1 Introduction 1.1 Patient-Centered Outcomes Research 1.2 Assessing the Developmental Trajectory of Brain Development During Adolescence 1.3 Robot Models for OCRD 1.4 Goal-Directed Versus Habit Behaviors 1.5 Genetic and Pharmacogenomic Factors 1.6 Problematic Usage of the Internet (PUI) 1.7 Novel Digital Interventions 2 Conclusion References