Inflammation selectively enhances amygdala activity to socially threatening images

Abstract

Although social withdrawal is a prominent symptom of sickness, the mechanisms associated with this behavioral change remain unclear. In animals, the amygdala is a key neural region involved in sickness-induced social withdrawal. Consistent with this, in humans, heightened amygdala activity to negative social cues is associated with social avoidance tendencies. Based on these findings, we investigated whether an experimental inflammatory challenge selectively increased amygdala activity to socially threatening images as well as whether this activity related to feelings of social disconnection. Thirty-nine participants were randomly assigned to receive either placebo or low-dose endotoxin, which increases inflammatory activity. Pro-inflammatory cytokines were assessed at 7 hourly time points via blood draws; self-reported feelings of social disconnection and physical sickness symptoms were assessed hourly as well. Two hours post-injection, participants underwent an fMRI procedure to assess amygdala reactivity during the presentation of socially threatening images (fear faces) as well as non-socially threatening images (guns), socially non-threatening images (happy faces), and non-social, non-threatening images (household objects). Endotoxin led to greater amygdala activity in response to socially threatening vs. all other types of images. No such differences were found for placebo participants. Additionally, increased amygdala activity in endotoxin participants during the viewing of socially vs. non-socially threatening images was associated with increased feelings of social disconnection. These findings highlight the amygdala as a neural region that may be important for sickness-induced social withdrawal. The implications of amygdalar involvement in sickness-induced social withdrawal are discussed.

In Sickness and in Health: The Co-Regulation of Inflammation and Social Behavior

“…To date, two broad categories of social experience have been found to be altered as a function of inflammation. Specifically, inflammation alters neural sensitivity to negative social stimuli or experiences (eg, social rejection, receiving negative social feedback, and viewing threatening faces; Eisenberger et al, 2009;Inagaki et al, 2012;Muscatell et al, 2016) as well as sensitivity to positive social stimuli or experiences (eg, viewing close others and receiving positive social feedback; Inagaki et al, 2015;Muscatell et al, 2016). A heightened sensitivity to both positive and negative social stimuli may help an individual to more quickly determine which individuals might be supportive and provide help in times of need and which individuals will not and should be avoided.…”

“…Finally, other work has examined how an inflammatory challenge affects neural sensitivity specifically to threatening social stimuli (eg, images of fearful faces), compared with threatening non-social stimuli (eg, images of snakes) as well as matched control stimuli (non-threatening social images: happy faces, and non-threatening non-social images: household objects; Inagaki et al, 2012). Based on work showing that both social and non-social threatening stimuli activate the amygdala (Hariri et al, 2002), analyses examined whether endotoxin, as compared with placebo, led to greater activation of the amygdala in response to these socially threatening images.…”

“…Thus, endotoxin led to a specific increase in sensitivity to threatening social (but not threatening, non-social) stimuli, suggesting that inflammation may specifically enhance sensitivity to the danger of the social world, possibly for self-protective purposes. It has also been suggested that inflammation-induced sensitivity to socially threatening stimuli may be one mechanism that helps to promote social withdrawal from unfriendly others during times of sickness (Inagaki et al, 2012), which may not only be self-protective, but may also help to curtail the spread of illness or infection through social networks (Cole, 2006).…”

“…Being in a 'sick state' or a state of heightened inflammation puts a social organism in a particularly vulnerable situation and thus sensitivity to the social world may need to be altered to navigate this more vulnerable situation. Navigating sickness for a social species may be accomplished by: (1) increasing sensitivity to threatening social experiences (Eisenberger et al, 2009;Inagaki et al, 2012;Muscatell et al, 2016) in order to better identify and avoid threats to well-being while in this vulnerable state and (2) increasing approach-related behavior towards close others (Inagaki et al, 2015) or other individuals who might be able to provide support (Muscatell et al, 2016) in order to recruit help and care in order to facilitate recovery from sickness ( Figure 1, left side). Here, we review evidence from both animal and human research showing that states of heightened inflammation lead to several important changes in social behavior.…”

Mouse chronic social stress increases blood and brain kynurenine pathway activity and fear behaviour: Both effects are reversed by inhibition of indoleamine 2,3-dioxygenase

“…Given the importance of amygdala and hippocampus in fear conditioning (Duvarci and Pare, 2014;LeDoux, 2000;Maren et al, 2013;Wolff et al, 2014) and stress-related psychiatric disorders (Harmer, 2013;Phelps and LeDoux, 2005;Price and Drevets, 2010; 31 Sheline et al, 2001), it is noteworthy that amygdala and vHIPP, together with other brain regions, exhibited increased levels of kynurenines. In healthy humans, LPS induced increased amygdala reactivity to fearful faces (Inagaki et al, 2012). Amygdala volume was reduced in MDD patients with reduced KYNA/QUIN plasma ratios (Savitz et al, 2015).…”