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Disner-Dissertation THE DISSERTATION COMMITTEE FOR SETH GORDON DISNER CERTIFIES THAT THIS IS THE APPROVED VERSION OF THE FOLLOWING DISSERTATION: A TRANSLATIONAL APPROACH FOR MODELING THE COGNITIVE SUBSTRATES OF DEPRESSION: IDENTIFYING BIOLOGICAL PREDICTORS AND NEUROCOGNITIVE INTERVENTIONS FOR BIASED COGNITION Committee: ________________________________ Christopher Beevers, Supervisor ________________________________ Francisco Gonzalez-Lima ________________________________ Stephanie S. Rude ________________________________ David Schnyer ________________________________ Michael Telch A TRANSLATIONAL APPROACH FOR MODELING THE COGNITIVE SUBSTRATES OF DEPRESSION: IDENTIFYING BIOLOGICAL PREDICTORS AND NEUROCOGNITIVE INTERVENTIONS FOR BIASED COGNITION by Seth Gordon Disner, BA DISSERTATION Presented to the Faculty of the Graduate School of The University of Texas at Austin in Partial Fulfillment of the Requirements for the Degree of DOCTOR OF PHILOSOPHY THE UNIVERSITY OF TEXAS AT AUSTIN August, 2015 Dedication For MLG, SFD, & EGD A TRANSLATIONAL APPROACH FOR MODELING THE COGNITIVE SUBSTRATES OF DEPRESSION: IDENTIFYING BIOLOGICAL PREDICTORS AND NEUROCOGNITIVE INTERVENTIONS FOR BIASED COGNITION Publication No. _______________ Seth Gordon Disner, Ph.D. The University of Texas at Austin, 2015 Supervisor: Christopher G. Beevers Abstract: Major Depressive Disorder (MDD) is a pervasive, debilitating condition that affects roughly 16% of Americans in their lifetime. However, treatments for MDD are considered adequate in only 21% of cases. Although biological and cognitive models have significantly added to our understanding of MDD, relatively little work has been undertaken to bridge the two. In particular, the biological factors that contribute to cognitive risk factors for MDD remain largely unknown. This dissertation used a translational approach to identify the specific neurobiological underpinnings of cognitive vulnerability for MDD, with the goal of identifying neurocognitive interventions to help improve treatment outcomes. These results were built on an empirical foundation beginning with the neural substrates of Aaron Beck’s cognitive model of depression, and expanded on that literature by identifying genetic factors that predict the onset of maladaptive cognitive biases. Prospective research linking specific cognitive biases to naturalistic change in dysphoric symptoms was incorporated to establish the link between biased information processing and MDD maintenance. Finally, neuroenhancement techniques, such as low-level light therapy (LLLT), were used to augment the neural substrates of attention bias modification (ABM), a form of neurocognitive intervention, in order to optimize the treatment’s clinical efficacy. This line of research helps to establish cognitive biases as a causal endophenotype for MDD, explores novel augmentative treatment strategies, and advances our understanding about biomarkers that predict improved clinical outcome. iv Table of Contents LIST OF TABLES ...................................................................................................................... vii LIST OF FIGURES .................................................................................................................... viii INTRODUCTION.......................................................................................................................... 1 Depression: Description, Epidemiology, and Impact......................................................... 3 Prominent Models of Depression....................................................................................... 7 Biological and Cognitive Interventions ............................................................................. 9 Overview of Dissertation Studies .................................................................................... 13 STUDY1: Self-referential schemas and attentional bias predict severity and naturalistic course of depression symptoms Introduction ...................................................................................................................... 16 Methods ............................................................................................................................ 18 Results .............................................................................................................................. 26 Discussion ........................................................................................................................ 35 STUDY 2: Neural Mechanisms of the Cognitive Model of Depression Preface .............................................................................................................................. 39 Introduction ...................................................................................................................... 39 The Cognitive Model of Depression ….............................................................................40 Correlates of the Cognitive Model ................................................................................... 43 An Integrated Cognitive-Biological Model .................................................................… 64 STUDY 3: War zone stress interacts with the 5-HTTLPR polymorphism to predict the development of sustained attention for negative emotion stimuli in soldiers returning from Iraq Introduction ...................................................................................................................... 70 Methods and Materials .................................................................................................... 75 Results .............................................................................................................................. 81 Discussion ........................................................................................................................ 88 STUDY 4: Serotonin cumulative genetic score interacts with mood reactivity to predict mood- congruent gaze bias Introduction ...................................................................................................................... 93 Methods ............................................................................................................................ 98 Results .............................................................................................................................105 Discussion ...................................................................................................................... 111 STUDY 5 - Transcranial laser stimulation enhances the clinical impact of attention bias modification in adults with elevated depression symptoms Introduction .................................................................................................................... 115 Methods ...........................................................................................................................119 Results .............................................................................................................................125 Discussion ...................................................................................................................... 129 v GENERAL DISCUSSION ........................................................................................................ 134 REFERENCES .......................................................................................................................... 141 vi List of Tables Study 1, Table 1: Correlations between predictor variables …………………………….………28 Study 1, Table 2: Outcomes from models showing relationship between cognitive assessments and mood persistence ……………………………………………………………...…….………31 Study 3, Table 1: Distribution of 5-HTTLPR genotype as a function of race …………..……... 76 Study 3, Table 2: Gaze fixation across genotype, time point, and stimuli valence .………….... 82 Study 4, Table 1: The three-way interaction between mood reactivity, emotion category, and each of the individual SNPs …………………………………………………….…..………….107 Study 4, Table 2: CGS composition ………………………………………………...………...108 vii List of Figures Introduction, Figure 1: Worldwide causes of years lived with disability …………...………… 5-6 Study 1, Figure 1: Illustration of diffusion model ………………………………………………23 Study 1, Figure 2: Time series plot (solid line) and linear trend (dashed line) of CESD scores over weeks………...………………………………..……………………………………………25 Study 1, Figure 3: Cross-validation error as a function of increasing number of predictors……30 Study 1, Figure 4: Baseline CESD scores as a function of net valence of self-descriptive adjectives from the SRET ……………………………………………………………………… 32 Study 1, Figure 5: Mood-trajectory scores as a function of negative gaze bias in the dot probe task ………………………...…………………………………………………………………… 34 Study 2, Figure 1: Information processing in the cognitive model of depression ………….….. 41 Study 2, Figure 2: Putative cognitive neurobiological model of biased attention for negative stimuli in depressed individuals …………………………………………………………….….. 46 Study 2, Figure 3: Putative cognitive neurobiological model of biased processing of negative stimuli in depressed individuals …………………………………………………………….….. 50 Study 2, Figure 4: Putative cognitive neurobiological model of ruminative thought in depressed individuals ………………………………………………………………………….……………56 Study 2, Figure 5: Putative cognitive neurobiological model of biased memory for negative stimuli in depressed individuals …………………………………………………….………….. 59 Study 2, Figure
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