AFFECTIVE PROCESSING IN MAJOR DEPRESSIVE DISORDER: NEUROANATOMICAL CORRELATES OF STATE AND TRAIT ABNORMALITIES by Jakub Zbigniew Konarski A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy Graduate Department of Institute of Medical Science University of Toronto © Copyright by Jakub Zbigniew Konarski (2010) ABSTRACT Affective Processing in Major Depressive Disorder: Neuroanatomical Correlates of State and Trait Abnormalities Doctor of Philosophy, 2010, Jakub Konarski, Institute of Medical Science, University of Toronto Patients with MDD demonstrate impairments in various components of affective processing, which are believed to persist in the remitted phase of the illness and are believed to underlie the vulnerability for future relapse. Despite advances in neuropsychiatry, the neuroanatomical site of action of various treatment modalities remains unclear, leaving clinicians without an algorithm to guide optimal treatment selection for individual patients. This thesis sought to characterize differences in brain activation during affective processing between MDD treatment responders (RS) and non-responders (NR) by combining clinical and neuroimaging variables in a repeat-measure functional magnetic resonance imaging (fMRI) investigation. We induced increases in positive and negative affect using visual stimuli under fMRI conditions in 21 MDD subjects and 18 healthy controls (HC). Based on previous neuroimaging investigations and preclinical animal data, we hypothesized that increased activation of the amygdala and the pregenual cingulate during negative affect induction (NAI), and decreased activity of the ventral striatum during positive affect induction (PAI), would differentiate ultimate NR from RS. Following the first scan, treatment with fluoxetine and olanzapine was initiated in the MDD group, with follow-up scans at one- and six-weeks thereafter. We hypothesized that decreases in depressive symptoms would be associated with decreased activation of the ventromedial prefrontal cortex (PFC) and amygdala during NAI and increased activation of the hippocampus during PAI. Eleven MDD subjects met criteria for clinical remission at study endpoint. Based on trait differences between MDD and HC, we hypothesized that differences observed during NAI would be limited to brain regions involved in regulation of the affective state, including the dorsolateral PFC and the anterior midcingulate cortex. ii The results of the analyses confirmed the a-prior hypotheses and additionally demonstrated differential activation of the insular, medial temporal, and premotor cortex during repeat PAI and NAI between HC, RS, and NR. These findings provide: i) a neuroanatomical target of successful antidepressant therapy during PAI/NAI; ii) a differential effect of depressive symptoms and dispositional affect on brain activation during PAI/NAI; and iii) an a-prior method to differentiate RS from NR, and iv) demonstrate the need for additional treatment to prevent relapse in the remitted state. iii ACKNOWLEDGMENTS The collection of data that ultimately culminated in the production of this thesis would not be possible without the considerable aid from a number of colleagues, friends, and family. On a professional level, I would like to thank Drs. Sidney H. Kennedy and Roger S. McIntyre not only for their valuable academic contributions, but on a more personal note, their interest and contributions to the realization of my own career and personal ambitions. I am equally indebted to my extended supervisory team that includes my committee members; Drs. Karen Davis, Larry Grupp, and Jean St.-Cyr, and defense examiners; Drs George Awad, Jeff Daskalakis, Paul Sandor, Gwenn Smith, and Claudio Soares who have served as an extended supervisory family. I would also like to acknowledge the assistance of numerous other research staff in the acquisition and processing of MRI data, including Dr. Adrian Crawley, Mr. Shahryar Rafi-Tari, the Toronto Western Hospital Magnetic Resonance medical imaging staff, and the administrative and research staff of the Mood Disorders Psychopharmacology Unit. The analysis of MRI data has also been greatly facilitated by advice from Dr. Helen S. Mayberg, Emory University, Dr. Terence A. Ketter, Stanford University, Dr. Ralf Veit, University of Tübingen, and Dr. Wouter Depuydt, Katholieke Universiteit Leuven. iv TABLE OF CONTENTS ABSTRACT II ACKNOWLEDGMENTS IV TABLE OF CONTENTS V LIST OF TABLES VIII LIST OF FIGURES X LIST OF ABBREVIATIONS XII INTRODUCTION, OBJECTIVES AND AIMS 1 LITERATURE REVIEW 3 MAJOR DEPRESSIVE DISORDER 4 MAJOR DEPRESSIVE EPISODE 4 GLOBAL IMPACT 5 TREATMENT 7 MEASURING SEVERITY OF DEPRESSIVE ILLNESS 10 AFFECTIVE PROCESSING 14 THEORIES OF EMOTION 14 AFFECTIVE PROCESSING IN MDD 16 MEASURING AFFECT 18 INTERACTION BETWEEN DEPRESSIVE SYMPTOMS AND DISPOSITIONAL AFFECT 19 NEUROIMAGING 21 RADIONUCLIDE BASED FUNCTIONAL NEUROIMAGING 22 MAGNETIC RESONANCE IMAGING 23 COUPLING OF METABOLISM AND CIRCULATION 27 ORIGIN OF THE BOLD SIGNAL 28 ANALYSIS OF NEUROIMAGING DATA 30 NEUROANATOMY OF AFFECTIVE PROCESSING 32 NEUROANATOMY OVERVIEW 33 IDENTIFICATION OF EMOTIONAL SIGNIFICANCE 42 PRODUCTION OF AFFECTIVE STATE 44 REGULATION OF AFFECTIVE STATE 50 PHARMACOLOGY OF AFFECTIVE PROCESSING 55 NEUROTRANSMITTERS INVOLVED IN DISPOSITIONAL AFFECT 55 EFFECT OF PSYCHOTROPIC AGENTS OF AFFECTIVE PROCESSING 57 ABNORMALITIES IN BRAIN STRUCTURES MEDIATING AFFECTIVE PROCESSING IN MDD 63 STRUCTURAL FINDINGS 63 METABOLIC AND CEREBRAL PERFUSION 69 AFFECTIVE PROCESSING IN MDD 72 PHARMACOLOGICAL INDUCTION 73 RECALL INDUCTION 75 INDUCTION OF AFFECT WITH VISUAL STIMULI 81 v AIMS AND HYPOTHESIS 96 METHODS 100 SUBJECTS 100 SAMPLE SIZE ANALYSIS 100 SUBJECT RECRUITMENT AND COMPENSATION 100 INCLUSION CRITERIA AND EXCLUSION CRITERIA 100 STUDY OUTLINE 101 RECRUITMENT 101 SCREENING VISIT 102 STUDY VISITS 102 TREATMENT 105 AFFECTIVE PROCESSING PARADIGM 105 NEUROIMAGING PARAMETERS 109 DATA ANALYSIS 110 CLINICAL DATA 110 NEUROIMAGING DATA 110 RESULTS 117 CLINICAL RESULTS 117 PRIMARY AIM A: 124 POSITIVE AFFECT NEUROIMAGING RESULTS AT BASELINE VISIT 124 NEGATIVE AFFECT NEUROIMAGING RESULTS AT BASELINE VISIT 133 PRIMARY AIM B: 142 REPEAT INDUCTION OF POSITIVE AFFECT – INTER SCAN CHANGES IN BOLD SIGNAL 142 REPEAT INDUCTION OF NEGATIVE AFFECT – INTER SCAN CHANGES IN BOLD SIGNAL 150 SECONDARY AIM A: 160 INFLUENCE OF DEPRESSIVE SYMPTOMS SEVERITY ON POSITIVE AFFECTIVE PROCESSING 160 INFLUENCE OF DEPRESSIVE SYMPTOMS SEVERITY ON NEGATIVE AFFECTIVE PROCESSING 166 SECONDARY AIM B: 170 INFLUENCE OF DISPOSITIONAL AFFECT ON POSITIVE AFFECTIVE PROCESSING 170 INFLUENCE OF DISPOSITIONAL AFFECT ON NEGATIVE AFFECTIVE PROCESSING 171 CORRELATION BETWEEN INDUCED AFFECT AND POSITIVE AFFECTIVE PROCESSING 175 CORRELATION BETWEEN INDUCED AFFECT AND NEGATIVE AFFECTIVE PROCESSING 177 vi DISCUSSION 181 SUMMARY OF FINDINGS 181 CONVERGENCE WITH PREVIOUS INVESTIGATIONS 187 DIFFERENCES IN POSITIVE AFFECTIVE PROCESSING: DEPRESSED VS. CONTROL SUBJECTS 187 DIFFERENCES IN NEGATIVE AFFECTIVE PROCESSING: DEPRESSED VS. CONTROL SUBJECTS 189 EFFECT OF EXPOSURE TO ANTIDEPRESSANT 193 EFFECT OF RESPONSE TO ANTIDEPRESSANT 194 AFFECTIVE PROCESSING IN EUTHYMIA 197 RESPONSE PREDICTION 199 EFFECT OF LATERALITY 200 PHARMACODYNAMICS OF OLANZAPINE FLUOXETINE COMBINATION 201 AFFECTIVE PROCESSING MODELS 204 OCCIPITOTEMPORAL CORTEX 205 PREMOTOR CORTEX 208 PRECUNEUS 210 CEREBELLUM 211 LIMITATIONS 216 SAMPLE SIZE 216 STATISTICAL PARAMETRIC MAPPING 217 UNIVARIATE STATISTICS 218 MULTIVARIATE ANALYSIS 219 PARAMETRIC DESIGN 221 BOLD SIGNAL INTERPRETATION 222 CLINICAL LIMITATIONS 223 CONCLUSIONS 224 FUTURE DIRECTIONS 228 REFERENCES 232 APPENDICES 307 APPENDIX 1 - AFFECTIVE PICTURE RATING SCALE 307 APPENDIX 2 - IAPS PHOTOGRAPH DESCRIPTIONS AND RATINGS – MALE – RUN1 308 APPENDIX 3 - IAPS PHOTOGRAPH DESCRIPTIONS AND RATINGS – MALE – RUN2 309 APPENDIX 4 - IAPS PHOTOGRAPH DESCRIPTIONS AND RATINGS – FEMALE – RUN1 310 APPENDIX 5 - IAPS PHOTOGRAPH DESCRIPTIONS AND RATINGS – FEMALE – RUN2 311 vii LIST OF TABLES Table 1 – Study Participants Clinical and Demographic Characteristics: Comparison of HC and MDD Groups .............................................................................................................................. 118 Table 2 – Study Participants Clinical and Demographic Characteristics: Comparison of RS and NR Groups .................................................................................................................................. 118 Table 3 – Between Group Comparison of Study Participants’ Measures of Depression Severity, Dispositional Affect, and Induced Affect at the Baseline, Second, and Final Visit ................... 120 Table 4 – Between- and Within-Group Comparison of Study Participants’ Button Press Accuracy and Response Times at the Baseline, Second, and Final Visit for Positive-Neutral Affect and Negative-Neutral Affect Runs .................................................................................. 123 Table 5 – Activation and Deactivation in BOLD Signal Evoked by Positive Affective Visual Stimuli in All Subjects ................................................................................................................ 125 Table 6 – Changes in BOLD Signal between the Early and Late Components of the Positive Affective Block in All Subjects .................................................................................................. 127 Table 7 – Between Group Differences in BOLD Signal Evoked by Positive Affective Stimuli during