This proposal is designed to provide a mentored clinical research experience for the PI that will facilitate the development of an independent research career at the interface of neuroscience, psychiatry, and immunology. The proposed work will examine causal relationships between inflammation, cortico-amygdala circuit dysfunction, and symptoms of anxiety in patients with major depressive disorder (MDD). Approximately 85% of MDD patients also suffer from significant anxiety symptoms, yet the pathophysiologic mechanisms of anxiety in patients with depression are not fully understood. One biological pathway that may contribute to symptoms of anxiety in depression is the effect of inflammation on anxiety-relevant cortico-limbic circuitry. Neuroimaging studies have demonstrated that acute inflammatory stimuli given to healthy subjects reduce functional connectivity between the amygdala and prefrontal cortex (PFC) to lead to temporary symptoms of anxiety. Disrupted cortico-amygdala circuitry has been consistently reported in patients with anxiety disorders and post- traumatic stress disorder; a number of these patients also reliably exhibit increased cytokines and acute phase reactants like C-reactive protein (CRP). We recently reported that high inflammation (as determined by plasma CRP and cytokines) was associated with decreased functional connectivity between the amygdala and ventromedial PFC (vmPFC) in patients with MDD. Amygdala-vmPFC connectivity was in turn negatively correlated with severity of anxiety symptoms, and this relationship was strongest in patients with a comorbid anxiety disorder and/or PTSD. Relevant to treating anxiety symptoms in MDD, we also previously found that infliximab, a monoclonal antibody against tumor necrosis factor (TNF), reduced anxiety symptom severity in depressed patients with high CRP. Together, these findings suggest that inflammation affects cortico- amygdala connectivity to drive symptoms of anxiety in patients with depression; however, a causal relationship between inflammation and cortico-amygdala circuit dysfunction in psychiatric patient populations has yet to be established. The proposed work will utilize resources from an ongoing NIMH-sponsored study to test the hypothesis that acute inhibition of inflammation with infliximab will improve cortico-amygdala connectivity in association with reduced symptoms of anxiety in MDD patients with high inflammation. To examine this central hypothesis, we will assess the impact of acute challenge with infliximab compared to placebo on 1) amygdala- vmPFC functional connectivity, 2) relationships between amygdala-vmPFC connectivity, anxiety symptoms and the role of comorbidities, and 3) associations between inflammatory biomarkers, cortico-amygdala connectivity and anxiety symptoms. This project represents a first step toward developing novel anti-inflammatory and personalized treatment strategies for symptoms of anxiety in MDD patients with high inflammation. This project also provides an opportunity for the PI to obtain clinical research training under a team with expertise in immunology, psychiatry, and neuroimaging in order to prepare for a career as an independent investigator.
Up to 85% of patients with depression experience significant anxiety, and having an anxiety-related disorder comorbid with depression is associated with poor disease outcomes and treatment resistance. The pathophysiologic mechanisms of anxiety in patients with depression are not fully understood, but may involve the effects of inflammation on anxiety-relevant cortico-amygdala circuitry. The proposed research will assess the causal impact of inhibiting inflammation on cortico-amygdala functional connectivity in relation to symptoms of anxiety in patients with depression.
