Characterizing Depression Neurobiology through Treatment Outcomes Open Access
McGrath, Callie Lynn (2014)
Published
Abstract
Neurobiological variability is a critical issue in studies of depression pathophysiology with profound implications for treatment selection and outcome. We hypothesize that pretreatment brain metabolism can distinguish patients remitting to psychotherapy and antidepressant medication, categorizing them into metabolism based subtypes. We approach neurobiological variability through this lens of treatment response with three different imaging approaches: (1) resting-state FDG-PET to determine treatment subtypes, (2) multivariate analysis of FDG-PET to relate subtypes to behavior and (3) resting-state fMRI to determine network connectivity differences between subtypes. We identify two clinically relevant subgroups: insula activity greater than whole brain mean (remission to escitalopram/nonresponse to CBT) and insula activity less than whole brain mean (remission to CBT/nonresponse to escitalopram) and show that these insula metabolism based subgroups differently impact network dynamics. Anterior insula variance is not the only neurobiological variance that should be incorporated into models of depression neurobiology. We examine metabolic predictors of non-response to multiple treatments and explore the network dynamics of metabolic outcome predictors. Taken together, these studies define distinct depression subgroups at a network level with direct implications for antidepressant treatment selection in individual patients. Finally, we refine models of depression neurobiology by incorporating variability related to treatment outcomes, contributing to a model with potential for direct clinical linkages.
Table of Contents
CHAPTER 1: INTRODUCTION........................................................... 1
Preamble....................................................................................... 1
Depression's Broad Impact........................................................... 2
Heterogeneity in Depression........................................................ 2
Diagnosis and Clinical Heterogeneity.............................................. 3
Vulnerability, Resilience and Neurobiological Variability................. 5
Variance in Neuroimaging Studies................................................. 8
Development of Neural Models of Depression............................ 10
Evolution from Individual Regions to Systems................................ 10
Systems Neurocircuitry Models.................................................... 11
Neuroimaging Variability Related to Treatment Outcomes..... 17
Strategies for Subgrouping MDD Patients...................................... 18
Why Refocus on Treatment-based Subgroups?................................ 21
Standard Treatments and their Mechanisms of Action.................... 23
Single Treatment Outcomes Relate to Variability in Brain Activity. 24
Overview of Dissertation Goals:................................................. 25
CHAPTER 2: DEFINING CBT AND ESCITALOPRAM RESPONSE SUBTYPES 27
Overview of Treatment Prediction Research............................. 27
Neuroimaging Markers to Guide Treatment.................................. 28
Experiment 1.1: Defining a Treatment-Specific Biomarker (TSB) 30
Methods...................................................................................... 31
Results....................................................................................... 36
Discussion................................................................................... 45
Experiment 1.2: Confirmation of the Anterior Insula TSB- Phase 2 Treatment within Study Replication 49
Methods...................................................................................... 50
Results....................................................................................... 52
Discussion................................................................................... 54
Experiment 1.3: External Replication of Anterior Insula TSB in CBT Treated Patients 55
Methods...................................................................................... 56
Results....................................................................................... 58
Discussion................................................................................... 58
Chapter Summary..................................................................... 60
CHAPTER 3: DYNAMICS OF THE ANTERIOR INSULA................... 61
Overview of Anterior Insula Function........................................ 61
Insula Dysfunction and Variance.................................................. 64
Frameworks for Insula Dysfunction in Depression.......................... 64
Experiment 2.1: Anterior Insula Subgroups Differentially Modulate Affective State 67
Methods:.................................................................................... 68
Results:...................................................................................... 72
Discussion.................................................................................. 83
Experiment 2.2: Anterior Insula Metabolism Modulates Anterior Insula Functional Connectivity 87
Methods..................................................................................... 88
Results....................................................................................... 90
Discussion.................................................................................. 94
Chapter Summary...................................................................... 97
CHAPTER 4: BRAIN VARIANCE RELATED TO TWO-TREATMENT NON-RESPONSE 98
Overview of Treatment Non-Response....................................... 98
Experiment 3.1: Metabolic Predictors of Two-Treatment Non-response 99
Methods.................................................................................... 100
Results:.................................................................................... 104
Discussion:................................................................................ 112
Experiment 3.2: Variance in Network Dynamics Related to Treatment Non-Response 121
Methods.................................................................................... 121
Results..................................................................................... 122
Discussion................................................................................. 128
Chapter Summary.................................................................... 130
CHAPTER 5: INCORPORATING VARIABILITY INTO DEPRESSION MODELS 131
Summary and Significance of Findings.................................... 131
Incorporating Variance into Neurobiological Models.............. 133
Limbic-cortical Dysregulation Model........................................... 134
Negative Bias Model of Depression............................................... 138
Adapted Neurobiology of Emotion Perception model...................... 140
Future Directions...................................................................... 143
Potential Relationships of the Anterior Insula to Biological Measures 145
Final Words............................................................................... 148
REFERENCES............................................................................... 149
APPENDICES................................................................................ 167
APPENDIX A: POST-HOC TESTING OF THE ROSTRAL ANTERIOR CINGULATE AS A PREDICTOR OF TREATMENT OUTCOME.................................................................................. 167
Methods.................................................................................... 167
Results..................................................................................... 170
APPENDIX B: INFLAMMATORY INFLUENCES ON BRAIN VARIABILITY 172
Methods.................................................................................... 173
Results..................................................................................... 174
Discussion................................................................................. 178
APPENDIX C: NEUROIMAGING METHODS AND ANALYSIS STRATEGIES 181
Resting State............................................................................. 181
Positron Emission Tomography................................................... 181
Functional Magnetic Resonance Imaging..................................... 183
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