Greater amygdala activity and dorsomedial prefrontal–amygdala coupling are associated with enhanced inflammatory responses to stress

Abstract

Psychological stress is implicated in the etiology of many common chronic diseases and mental health disorders. Recent research suggests that inflammation may be a key biological mediator linking stress and health. Nevertheless, the neurocognitive pathways underlying stress-related increases in inflammatory activity are largely unknown. The present study thus examined associations between neural and inflammatory responses to an acute laboratory-based social stressor. Healthy female participants (n = 31) were exposed to a brief episode of stress while they underwent an fMRI scan. Blood samples were taken before and after the stressor, and plasma was assayed for markers of inflammatory activity. Exposure to the stressor was associated with significant increases in feelings of social evaluation and rejection, and with increases in levels of inflammation. Analyses linking the neural and inflammatory data revealed that heightened neural activity in the amygdala in response to the stressor was associated with greater increases in inflammation. Functional connectivity analyses indicated that individuals who showed stronger coupling between the amygdala and the dorsomedial prefrontal cortex (DMPFC) also showed a heightened inflammatory response to the stressor. Interestingly, activity in a different set of neural regions was related to increases in feelings of social rejection. These data show that greater amygdala activity in response to a stressor, as well as tighter coupling between the amygdala and the DMPFC, are associated with greater increases in inflammatory activity. Results from this study begin to identify neural mechanisms that might link stress with increased risk for inflammation-related disorders such as cardiovascular disease and depression.

Therapeutic Implications of Brain–Immune Interactions: Treatment in Translation

“…Activation of the dACC during a social rejection task has also been correlated with the degree of stress-induced activation of oral sTNFR2 during a public speaking stressor (Slavich et al, 2010). In addition, increased stress-induced peripheral blood IL-6 was associated with activation of the amygdala, with subjects who exhibited the highest IL-6 responses to the public speaking stressor demonstrating the greatest connectivity within threat circuitry including the amygdala (Muscatell et al, 2015). Of note, in laboratory animals exposed to social defeat stress, the amygdala is a primary site of monocyte trafficking to the brain, indicating a potential mechanism for the impact of the immune system on fear circuits (Wohleb et al, 2013).…”

“…For example, stress-induced activation of inflammation and administration of inflammatory cytokines have been found to activate neural circuits relative to the processing of threatening stimuli including the dACC, amygdala, and insula (Capuron et al, 2005;Slavich et al, 2010;Muscatell et al, 2015). Moreover, in patient populations such as women with breast cancer, increased peripheral blood inflammatory markers (eg, CRP) have been correlated with increased activation of the amygdala during a threat sensitivity task (Muscatell et al, 2016).…”

Neural mechanisms linking social status and inflammatory responses to social stress

“…Complete details of the experimental procedure have been previously reported (Muscatell et al, 2015). In brief, prospective participants were excluded during phone screening if they endorsed a number of criteria known to influence levels of inflammation (e.g.…”

“…All cytokine data were positively skewed, so raw values were log transformed to normalize the distribution prior to statistical testing. A prior paper from this dataset established that there were significant increases in levels of IL-6, but not TNF-a, following the stressor (Muscatell et al, 2015); as such, in this article, inflammatory responses are calculated as the change in plasma cytokine concentration from BL (average of two BL measures) to the 90-min post-stress time point, given that levels of inflammation were at their highest at this final time point.…”

“…Circulating levels of pro-inflammatory cytokines were assessed at two BL time points prior to the stressor and three time points after the stressor as previously described (Muscatell, et al, 2015). Briefly, EDTA plasma samples were assayed for IL-6 and TNFÀa (Quantikine High Sensitivity ELISAs, R&D Systems, Minneapolis, MN) according to the manufacturer's protocols; all samples from a single participant were assayed on the same plate.…”