Inflammation negatively correlates with amygdala-ventromedial prefrontal functional connectivity in association with anxiety in patients with depression: Preliminary results

Abstract

Biomarkers of inflammation, including inflammatory cytokines and the acute-phase reactant C-reactive protein (CRP), are reliably increased in a subset of patients with depression, anxiety disorders and post-traumatic stress disorder (PTSD). Administration of innate immune stimuli to laboratory subjects and the associated release of inflammatory cytokines has been shown to affect brain regions involved in fear, anxiety and emotional processing such as the amygdala. However, the role of inflammation in altered circuitry involving amygdala and other brain regions and its subsequent contribution to symptom severity in depression, anxiety disorders and PTSD is only beginning to be explored. Herein, medically-stable, currently unmedicated outpatients with a primary diagnosis of major depressive disorder (MDD; n = 48) underwent resting-state functional MRI (rfMRI) to determine whether altered connectivity between the amygdala and whole brain was observed in a subset of patients with high inflammation and symptoms of anxiety. Whole-brain, voxel-wise functional connectivity analysis of the right and left amygdala as a function of inflammation (plasma CRP concentrations) revealed that increased CRP predicted decreased functional connectivity between right amygdala and left ventromedial prefrontal cortex (vmPFC) (corrected p < 0.05). Amygdala-vmPFC connectivity was, in turn, negatively correlated with symptoms of anxiety (r = -0.33, df = 46, p = 0.022). In exploratory analyses, relationships between low amygdala-vmPFC connectivity and high anxiety were only observed in patients with a secondary diagnosis of an anxiety disorder or PTSD (r = -0.54 to -0.87, p < 0.05). More work is needed to understand the role of inflammation and its effects on amygdala-vmPFC circuitry and symptoms of anxiety in MDD patients with comorbid anxiety disorders or PTSD.

Neuroimmune nexus of depression and dementia: Shared mechanisms and therapeutic targets

“…reduced connectivity in this subset of depressed patients was correlated with anxiety-like symptoms (Mehta et al, 2018).…”

“…Moreover, the involvement of the temporal lobe in the progression of degeneration may be a threshold event for AD, as onset of its degeneration has predicted conversion to AD in patients with MCI (Visser, Verhey, Hofman, Scheltens, & Jolles, ). In support of an immune link to the aforementioned conditions with MDD, a subset of depressed patients co‐morbid with high inflammation and anxiety‐like symptoms, exhibited decreased connectivity between the right amygdala and the left ventromedial prefrontal cortex; reduced connectivity in this subset of depressed patients was correlated with anxiety‐like symptoms (Mehta et al, ).…”

Neural Correlates of Positive and Negative Valence System Dysfunction in Adolescents Revealed by Data-Driven Parcellation and Resting-State Network Modeling

“…Others have previously reported amygdala functional connectivity was reduced with the orbitofrontal cortex/vmPFC in adults with social anxiety disorder (58) and with the anterior cingulate and insula in adults with generalized anxiety disorder (59). In adults with depression, reduced amygdala connectivity with the dorsomedial PFC, mid-/posterior cingulate, and lateral temporal areas was predictive of comorbid anxiety (60), and amygdala-vmPFC connectivity negatively correlated with anxiety levels (61). Possibly related to its unique position as an NVS, rather than PVS, construct, anxiety was the only symptom to have predominantly negative associations with graph theoretical metrics in our study.…”

A double-hit of stress and low-grade inflammation on functional brain network mediates posttraumatic stress symptoms

“…Notably, these regions are also known to undergo functional alteration in response to stress exposure 13,14 , and constitute much of the higher-order cognitive network system 15,16 . Recent studies have demonstrated that increased inflammation can alter functional connectivity of the major brain regions related to the development of anxiety in the case of major depression as well as those with comorbid PTSD 17 . Studies have also noted that altered functional connectivity due to increased inflammation correlates with the severity of clinical symptoms 17,18 .…”

“…Recent studies have demonstrated that increased inflammation can alter functional connectivity of the major brain regions related to the development of anxiety in the case of major depression as well as those with comorbid PTSD 17 . Studies have also noted that altered functional connectivity due to increased inflammation correlates with the severity of clinical symptoms 17,18 . However, little is known about the potential role of these brain regions in the reciprocal interactions between lowgrade inflammation and repeated stress exposure.…”