An fMRI study of cytokine-induced depressed mood and social pain: The role of sex differences

Abstract

Although research has demonstrated a relationship between proinflammatory cytokine activity and depressive symptoms, the neurocognitive processes underlying this relationship have remained largely unexplored. Here, we examined the effect of proinflammatory cytokine activation on the neural correlates of socially painful experience and associated depressed mood. Participants received either low-dose endotoxin or placebo through intravenous injection. Levels of the proinflammatory cytokine, IL-6, were repeatedly assessed through hourly blood draws; self-reported depressed mood was assessed hourly as well. Two hours post-injection, participants completed a neuroimaging session in which they were socially excluded during an online ball-tossing game. Replicating previous research, individuals exposed to endotoxin, compared to placebo, showed increases in IL-6 levels and depressed mood. Although there were no meaningful differences between the endotoxin and control groups in neural responses to social exclusion, there were sex differences in the relationships between IL-6 increases and neural responses to exclusion among subjects exposed to endotoxin. Among females, but not males, exposed to endotoxin, increases in IL-6 were associated with increases in social pain-related neural activity (dorsal anterior cingulate cortex, anterior insula) that mediated the relationship between IL-6 increases and depressed mood increases. Implications of these sex differences in the neural correlates of cytokine-associated depressed mood and social pain are discussed.

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

“…The first study that focused specifically on the effect of inflammation on social experience exposed subjects to an experimental inflammatory challenge (ie, endotoxin) and then asked subjects to report on their feelings at hourly intervals (Eisenberger et al, 2009(Eisenberger et al, , 2010b. In addition to being asked to report on changes in depressed mood, subjects were also asked to report on their feelings of social disconnection (eg, 'I feel disconnected,' 'I feel like being alone,' and 'I feel overly sensitive around others').…”

“…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.…”

“…In one study, subjects were randomly assigned to either receive an experimental inflammatory challenge (endotoxin) or not, and then completed a social exclusion task in which they were socially excluded during a virtual ball-tossing game (Cyberball; Eisenberger et al, 2003). Results demonstrated that subjects who showed a greater increase in proinflammatory cytokines in response to the inflammatory challenge also showed greater activity in neural regions associated with the distressing experience of physical pain (Rainville et al, 1997), namely the dorsal anterior cingulate cortex (dACC) and anterior insula (Eisenberger et al, 2009). Hence, greater inflammatory activity to an inflammatory challenge was associated with greater neural sensitivity to social exclusion.…”

“…However, more recently, research has begun to reveal that inflammation is also a particularly powerful organizer of social behavior (Eisenberger et al, 2009(Eisenberger et al, , 2010bHennessy et al, 2014;Moieni et al, 2015b;Moieni et al, 2015c). Although this is somewhat surprising, given the seeming disconnect between sickness on the one hand and social behavior on the other, the relationship between inflammation and social behavior may provide a survival advantage.…”

“…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.…”