Characterizing Depression Neurobiology through Treatment Outcomes 公开

McGrath, Callie Lynn (2014)

Permanent URL: https://etd.library.emory.edu/concern/etds/pn89d6702?locale=zh
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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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