Aus dem Institut für Psychiatrische und Psychosomatische Psychotherapie des Zentralinstituts für Seelische Gesundheit der Medizinischen Fakultät Mannheim der Universität Heidelberg (Direktor: Prof. Dr. med. Martin Bohus) Emotional Reactivity in Posttraumatic Stress Disorder: Behavioral and Neurobiological Correlates of Underlying Mechanisms and the Role of Emotional Memory Modification Inauguraldissertation zur Erlangung des Doctor scientiarum humanarum (Dr.sc.hum.) an der Medizinischen Fakultät Mannheim der Ruprecht-Karls-Universität zu Heidelberg vorgelegt von Janine Thome aus Wadern 2017 Dekan: Prof. Dr. med. Sergij Goerdt Referent: Prof. Dr. med. Martin Bohus Co-Referent: Priv. Doz. Dr. Stefanie Lis Memory ... is the diary that we all carry about with us - Oscar Wilde - TABLE OF CONTENT ABBREVATIONS .................................................................................................................. 6 A. THEORETICAL BACKGROUND ..................................................................................... 8 A1. EMOTIONAL REACTIVITY AND MEMORY IN PTSD .............................................. 10 A1.1 Implicit and explicit memory ..................................................................................10 A1.2 Implicit and explicit memory in PTSD ....................................................................12 A1.3 Emotional reactivity and memory generalization in PTSD .....................................14 A2. EMOTIONAL REACTIVITY AND EMOTION REGULATION IN PTSD...................... 18 A2.1 Emotion regulation and its neurobiological correlates ............................................18 A2.2 Emotion regulation and its neurobiological correlates in PTSD..............................20 A2.3 Emotional reactivity and emotion regulation in PTSD ............................................21 A3. EMOTIONAL REACTIVITY AND TRANSLATING EXPTERIMENTAL FINDINGS INTO THERAPY .............................................................................................................. 23 A3.1 Reconsolidation ....................................................................................................23 A3.2 Behavioral and pharmacological interventions during reconsolidation ...................24 A3.3 Emotional reactivity and therapeutical techniques during reconsolidation .............25 B. SCIENTIFIC AIMS AND HYPOTHESES ........................................................................ 27 B1. AIMS OF STUDY I .................................................................................................... 28 B2. AIMS OF STUDY II ................................................................................................... 29 B3. AIMS OF STUDY III .................................................................................................. 30 C. EMPIRICAL STUDIES .................................................................................................... 31 C1. STUDY I: GENERALIZATION OF FEAR IN PTSD RELATED TO PROLONGED CHILDHOOD MALTREATMENT: AN EXPERIMENTAL STUDY .................................... 32 C1.1 Abstract ................................................................................................................33 C1.2 Introduction ...........................................................................................................34 C1.3 Methods ................................................................................................................36 C1.4 Results ..................................................................................................................40 C1.5 Discussion ............................................................................................................46 C1.6 Conclusion ............................................................................................................48 C1.7 Supplemental Material ..........................................................................................49 C2. STUDY II: DESYNCHRONIZATION OF AUTONOMIC RESPONSE AND CENTRAL AUTONOMIC NETWORK CONNECTIVITY IN POSTTRAUMATIC STRESS DISORDER ........................................................................................................................................ 54 C2.1 Abstract ................................................................................................................55 C2.2 Introduction ...........................................................................................................56 C2.3 Methods ................................................................................................................58 4 C2.4 Results ..................................................................................................................62 C2.5 Discussion ............................................................................................................69 C2.6 Conclusion ............................................................................................................72 C2.7 Supplemental Material ..........................................................................................72 C3. STUDY III MODIFICATION OF FEAR MEMORY BY PHARMACOOGICAL AND BEHAVIORAL INTERVENTIONS DURING RECONSOLIDATION ................................. 85 C3.1 Abstract ................................................................................................................86 C3.2 Introduction ...........................................................................................................87 C3.3 Methods ................................................................................................................89 C3.4 Results ..................................................................................................................95 C3.5 Discussion .......................................................................................................... 102 C3.6 Conclusion .......................................................................................................... 106 C3.7 Supplemental Material ........................................................................................ 107 D. GENERAL DISCUSSION ..............................................................................................118 D1. SUMMARY OF STUDY RESULTS ..........................................................................119 D1.1 Summary of study I ............................................................................................. 119 D1.2 Summary of study II ............................................................................................ 121 D1.3 Summary of study III ........................................................................................... 121 D2. INTEGRATION INTO PREVIOUS RESEARCH .......................................................123 D2.1 Emotional reactivity and impaired memory functioning in PTSD .......................... 124 D2.2 Emotional reactivity and disturbances in emotion regulation in PTSD ................. 127 D2.3 Targeting emotional reactivity: Reconsolidation and its relation to PTSD ............ 129 D3. METHODOLOGICAL LIMITATIONS .......................................................................132 D4. CONCLUSIONS AND FUTURE DIRECTIONS ........................................................133 E. SUMMARY ....................................................................................................................135 F. LIST OF FIGURES .........................................................................................................137 G. LIST OF TABLES..........................................................................................................139 REFERENCES ...................................................................................................................140 CURRICULUM VITAE ........................................................................................................171 PUBLICATIONS ................................................................................................................172 DANKSAGUNG .................................................................................................................173 5 ABBREVATIONS ABBREVATIONS ANOVA Analysis of Variance ACC Anterior Cingulate Cortex ANS Autonomic Nervous System BA Brodmann Area BP Blood Pressure CAN Central Autonomic System CNS Central Nervous System CS Conditioned Stimulus CR Conditioned Reaction DBT-PTSD Dialectical Behaviour Therapy for Posttraumatic Stress Disorder DSM Diagnostic and Statistical Manual of Mental Disorders e.g. example gratia, for example fMRI Functional Magnetic Resonance Imaging FDR False Discovery Rate FPS Fear Potentiated Startle FWE Family Wise Error HC Healthy Control HF High Frequency GS Generalization Stimulus HR Heart Rate HRV Heart Rate Variability i.e. id est, that is LF Low Frequency MMSS Mutlimodal Sensory Stimulation MNI Montreal Neurological Institute NS Neutral Stimulus ORR Online Risk Rating OE-R Online Expectancy Rating SCR Skin Conductance Response TC Trauma Control PAG Periaqueductal Gray PNS Parasympathetic Nervous System PTSD Posttraumatic Stress Disorder RA Reappraisal RMSSD Root Mean Squared Successive Differences 6 ABBREVATIONS SNS Sympathetic Nervous System SPM Statistical Parametric Mapping US Unconditioned Stimulus vmPFC Ventromedial Prefrontal Cortex 7 A.THEORERTICAL BACKGROUND A. THEORETICAL BACKGROUND The risk of experiencing traumatic events has always been a part of human life. However,