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A Translational Approach to the Neurobiology of Persecutory Ideation in Schizophrenia a DISSERTATION SUBMITTED to the FACULTY OF

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A Translational Approach to the Neurobiology of Persecutory Ideation in Schizophrenia a DISSERTATION SUBMITTED to the FACULTY OF A Translational Approach to the Neurobiology of Persecutory Ideation in Schizophrenia A DISSERTATION SUBMITTED TO THE FACULTY OF THE GRADUATE SCHOOL OF THE UNIVERSITY OF MINNESOTA BY Melissa Kay Johnson IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY Advisor: Angus W. MacDonald III, Ph.D August 2011 © Melissa Kay Johnson, August/2011 Acknowledgements In these acknowledgements I thank my advisor, Angus MacDonald, for his mentorship. He has had a tremendous positive influence in my life. He is the most important teacher I ever had. I thank my husband who has supported me financially and emotionally over the past 10 years on this academic rollercoaster. We have grown so much together. I thank Dori Henderson, Madelyn Steen and Edward Patzelt for all of their help and for being such awesome people. I thank Kristen Haut and Rachel Force for their support and friendship. Finally, I thank the NARSAD foundation and Loiuse Francouer for their generous financial support of this project. i Dedication First, I dedicate this manuscript to my mother who would have been so insanely proud of me. Second, I dedicate this manuscript to my son. I’ve had so many people comment on how hard it must have been to have a child in graduate school. I honestly don’t know what I would have done without him. He gives me purpose and keeps me centered. Having him is the most important thing I have ever done. ii Table of Contents Acknowledgements……………………………………………………..……………....…i. Dedication……………………………………………………………………..………......ii Table of Contents………………………………………………………………...............iii List of Tables.....................................................................................................................vii List of Figures...................................................................................................................viii 1. Introduction....................................................................................................................1 1.1. Diagnosis and Symptoms in Schizophrenia….......................................................3 1.1.1. Diagnosis......................................................................................................3 1.1.2. Dimension....................................................................................................5 1.1.3. Persecutory Ideation.....................................................................................6 1.2. Measures of Persecutory Ideation in the Schizophrenia Literature........................7 1.3. A Translational Model of Persecutory Delusions.................................................10 1.3.1. Translational Models in Schizophrenia.....................................................10 1.3.2. Developing a Cognitive Model of Persecutory Ideation: Findings from the Personality Literature...................................................................................13 1.3.3. Developing a Cognitive Model of Persecutory Ideation: Findings from the Decision-making Literature...........................................................................15 1.4. Application of Current Neurobiological Findings to Persecutory Delusions.......22 1.4.1. The Amygdala and Oxytocin.....................................................................22 1.4.2. Higher-order Cognitive Regions Associated with Trust and Persecution…………………………………………………………………...24 1.4.2.1. Economic Decision-making Studies..............................................24 iii 1.4.2.2. Theory of Mind Studies.................................................................28 1.4.2.3. Self-reference Studies....................................................................31 1.4.2.4. Studies Contrasting Self-referential Judgments and Theory of Mind......................................................................................................34 1.5. Conclusions and Future Directions.......................................................................36 2. Specific Aims and Hypotheses....................................................................................42 2.1. Specific Aims........................................................................................................43 2.2. Decision-making and Symptom Hypotheses........................................................43 2.3. Neuroimaging Hypotheses....................................................................................45 2.3.1. Decision-making Activation......................................................................45 2.3.1.1. Ventromedial Prefrontal Cortex.....................................................45 2.3.1.2. Paracingulate Cortex......................................................................46 2.3.1.3. Orbital Frontal Cortex....................................................................48 2.3.1.4. Anterior Cingulate Cortex..............................................................49 2.3.1.5. Insular Cortex.................................................................................50 2.3.1.6. Amygdala.......................................................................................50 3. Method.........................................................................................................................51 3.1. Participants...........................................................................................................51 3.2. Psychiatric Diagnoses and Symptom Ratings......................................................52 3.3. Experimental Design and Behavioral Analyses...................................................53 3.3.1. Minnesota Trust Game Design..................................................................53 3.3.1.1. First Mover Game..........................................................................54 3.3.1.2. Second Mover Game......................................................................54 iv 3.3.1.3. Stimuli Presentation and Responses..............................................56 3.3.1.4. Protocol Chronology and Training................................................56 3.4. Analysis................................................................................................................57 3.4.1. Decision-making Analyses: First Mover...................................................57 3.4.2. Decision-making and Persecutory Ideation Analyses................................57 3.5. Neuroimaging Data Acquisition and Preprocessing.............................................58 3.5.1. Imaging Acquisition..................................................................................58 3.5.2. Functional Neuroimaging Data Preprocessing..........................................58 3.6. Functional Neuroimaging Data Analysis..............................................................60 4. Results..........................................................................................................................61 4.1. Participant Demographics.....................................................................................62 4.2. Diagnosis and Symptoms Ratings........................................................................62 4.3. Decision-making Results......................................................................................64 4.3.1. Characterization of First Mover Decisions................................................64 4.3.2. MTG Decision-making Results & Brief Psychiatric Rating Scale Persecutory Ideation......................................................................................67 4.4. Functional Neuroimaging Results........................................................................71 4.4.1. Effect of Condition greater than Fixation..................................................71 4.4.2. Decision-agent by Financial Risk Activation............................................73 4.4.3. Effect of Financial Risk in the Suspiciousness, Rational Mistrust and Risk Aversion Conditions......................................................................................76 4.5. Neuroimaging Results and Brief Psychiatric Rating Scale Persecutory Ideation.................................................................................................................78 v 5. Discussion....................................................................................................................80 5.1. Discussion of Decision-making Findings.............................................................80 5.2. Discussion of Neuroimaging Findings.................................................................82 5.2.1. Ventromedial Prefrontal Cortex.................................................................82 5.2.2. Paracingulate Cortex..................................................................................83 5.2.3. Orbital Frontal Cortex................................................................................83 5.2.4. Anterior Cingulate Cortex..........................................................................84 5.2.5. Insular Cortex.............................................................................................85 5.2.6. Amygdala...................................................................................................86 5.3. Potential Concerns and Limitations......................................................................89 5.4. Conclusions and Future Directions.......................................................................88 References..........................................................................................................................92
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