Inflammation-Associated Alterations in Corticolimbic Circuits and Transdiagnostic Symptoms of Anxiety and PTSD in Clinical Populations Restricted; Files Only
Mehta, Namrataa (Summer 2022)
Published
Abstract
Patients with major depressive disorder (MDD), anxiety disorders, and post-traumatic stress disorder (PTSD) reliably exhibit evidence of increased inflammatory activity, which is thought to contribute to the pathophysiology of these highly comorbid disorders and associated with treatment resistance. Administration of inflammatory stimuli has been shown to affect neural activity of the amygdala and functional connectivity (FC) of amygdala with regions involved in fear, anxiety and emotional regulation such as the prefrontal cortex (PFC). Despite strong evidence of a role for inflammation in symptoms in these disorders, research investigating how endogenous inflammation may affect the brain to contribute to symptoms of anxiety or PTSD in MDD patients is limited. Thus, I hypothesized that inflammation is associated with alterations in amygdala-PFC FC and amygdala reactivity, which in turn drives symptoms of anxiety and PTSD in patients with MDD. I found that systemic inflammation (as measured by plasma C-reactive protein and inflammatory cytokines) was negatively correlated with resting-state FC between the right amygdala and ventromedial (vm)PFC in MDD patients (~50% with comorbid anxiety disorders and/or PTSD). Amygdala-vmPFC FC was negatively correlated with symptoms of anxiety, which was only observed in patients with a comorbid anxiety disorder and/or PTSD. I also demonstrated that inflammation was negatively correlated with ventral striatum to vmPFC FC in women with PTSD, which predicted symptoms of anhedonia, while inflammation negatively correlated with right amygdala-vmPFC in association with symptoms of anxiety and PTSD in trauma-exposed women with or without PTSD. Finally, I replicated the negative relationship between CRP and right amygdala-vmPFC FC in association with anxiety in patients with MDD, and I also found a positive association between inflammation and amygdala reactivity to threat, which was correlated with symptoms of hyperarousal. Herein, I established that inflammation-associated reductions in corticolimbic FC in association with symptoms of anxiety was reproducible across psychiatric samples of patients with depression and trauma-exposed women with and without PTSD, and that inflammation is associated with heightened amygdala reactivity to fear, which in turn predicted PTSD symptoms of hyperarousal. Elucidating the role of inflammation in these disorders may lead to more targeted therapeutics to personalize treatment for these patients.
Table of Contents
CHAPTER 1: INTRODUCTION - INFLAMMATION EFFECTS ON THE BRAIN AND BEHAVIOR: IMPLICATIONS FOR TRANSDIAGNOSTIC SYMPTOMS RELATED TO DEPRESSION, ANXIETY, AND PTSD 1
1.1 Brief Overview 2
1.2 Inflammation in the context of depression, anxiety, and PTSD 3
1.3 Sources of innate immune activation in clinical populations: role of stress and trauma 11
1.4 Mechanisms of inflammation effects on the brain and behavior: focus on translational models of fear and anxiety 16
1.5 Impact of exogenous inflammatory stimuli on corticolimbic circuits: evidence from neuroimaging challenge studies 23
1.6 Inflammation and corticolimbic circuit deficits in clinical populations: translational implications and thesis goals 30
CHAPTER 2: INFLAMMATION, LOW AMYGDALA-VMPFC FUNCTIONAL CONNECTIVITY AND SYMPTOMS OF ANXIETY IN DEPRESSION - Inflammation is negatively correlated with amygdala-ventromedial prefrontal functional connectivity in association with anxiety in patients with depression: preliminary results 34
2.1 Abstract 35
2.2 Introduction 36
2.3 Methods 37
2.4 Results 43
2.5 Discussion 49
CHAPTER 3: INFLAMMATION, LOW FUNCTIONAL CONNECTIVITY IN
REWARD CIRCUITRY, AND RELEVANT SYMPTOMS OF DEPRESSION AND PTSD IN TRAUMA-EXPOSED WOMEN - Inflammation is negatively correlated ventral striatum-ventromedial prefrontal functional connectivity and anhedonia-related symptoms of depression and PTSD in trauma-exposed African American women recruited from an inner-city hospital 54
3.1 Abstract 55
3.2 Introduction 56
3.3 Methods 58
3.4 Results 65
3.5 Discussion 72
CHAPTER 4: INFLAMMATION, AMYGDALA-VENTROMEDIAL PREFRONTAL FUNCTIONAL CONNECTIVITY AND SYMPTOMS OF ANXIETY AND PTSD IN TRAUMA-EXPOSED WOMEN - Inflammation is negatively correlated with amygdala-ventromedial prefrontal functional connectivity and symptoms of anxiety and PTSD in trauma-exposed African American women recruited from an inner-city hospital 79
4.1 Abstract 80
4.2 Introduction 82
4.3 Methods 85
4.4 Results 91
4.5 Discussion 96
CHAPTER 5: INFLAMMATION, LOW AMYGDALA-VMPFC FUNCTIONAL CONNECTIVITY AND SYMPTOMS OF ANXIETY IN DEPRESSION: REPLICATION AND RELATION TO AMYGDALA REACTIVITY – Inflammation is associated with lower right amygdala-ventromedial prefrontal functional connectivity and higher right amygdala reactivity to fearful faces in association with symptoms of anxiety and PTSD in patients with depression 103
5.1 Abstract 104
5.2 Introduction 106
5.3 Methods 107
5.4 Results 116
5.5 Discussion 123
CHAPTER 6: CONCLUSIONS 128
6.1 Summary of findings 129
6.2 Contributions to the field 130
6.3 Clinical implications and future directions 136
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