Proinflammatory cytokines are thought to contribute to depression through signaling the central nervous system to promote “sickness behaviors,” such as social withdrawal and increased pain sensitivity, to promote recovery from illness or disease. However, few studies have explicitly tested whether experimental activation of the proinflammatory cytokine network induces depressive symptoms in humans. Moreover, no studies have investigated the specific neurocognitive, affective, or social alterations, induced by inflammation, that make depression more likely.
Our previous work has examined the neural correlates of "social pain," the painful feelings following social rejection or loss, and has shown that the dorsal anterior cingulate cortex (dACC), a neural region associated with the distress of physical pain, also played a role in the distress of social pain. Based on the overlapping neural structures underlying physical and social pain, it is possible that the inflammatory response, aimed, in part, at heightening sensitivity to physical pain, inadvertently recruited systems involved in social pain, heightening sensitivity to social pain as well. We hypothesize that inflammatory mechanisms may induce heightened neural sensitivity to social pain, an experiential state that may contribute to depressive symptoms.
The main goal of the present project is to investigate the effect of experimentally induced systemic inflammation on neural reactivity related to social pain processes and depressive symptoms. More specifically, the present project will investigate:
1. Whether experimentally induced systemic inflammation leads to higher levels of "social pain" in response to an experimental episode of social rejection, as well as greater depressive symptoms later on.
2. Whether experimentally induced systemic inflammation leads to greater dACC activity and greater limbic system activity more generally (e.g., amygdala, insula) in response to social rejection.
3. Whether. for individuals exposed to endotoxin, greater dACC and limbic system activity during social rejection mediates or explains the relationship between increased proinflammatory cytokine activity and greater depressive symptoms.
To investigate the causal role that cytokines may play in the heightened social pain sensitivity that can contribute to depression, participants will be randomly assigned to receive either endotoxin (which increases proinflammatory cytokine activity in a safe manner) or placebo. Participants will then complete a neuroimaging study in which they will be rejected during an online ball-tossing game. We will examine whether individuals exposed to endotoxin report more social distress, endorse more depressive symptoms, and show more dACC activity and more limbic system activity more generally (e.g., amygdala, insula) in response to social rejection. We will also investigate whether, for individuals exposed to endotoxin, greater dACC and general limbic system activity during social rejection mediates or explains the relationship between increased proinflammatory cytokine activity and greater depressive symptoms at the end of the study.