Although previous research has demonstrated that inflammatory activity contributes to depressive symptoms (1
), no work in humans has examined the effect of experimentally induced inflammation on anhedonia—a key diagnostic feature of depression. The goal of the current study was to examine the effect of an experimental inflammatory challenge on the neural correlates of anhedonia—reduced VS activity to reward cues—and to explore whether this altered neural activity related to inflammatory-induced increases in depressed mood.
Results revealed that subjects exposed to endotoxin versus placebo showed greater increases in self-reported and observer-rated depressed mood and showed significant reductions in VS activity to reward cues. Moreover, the relationship between exposure to inflammatory challenge and increases in observer-rated depressed mood was mediated by between-group differences in VS activity to reward cues. Thus, inflammatory-induced decreases in reward-related VS activity were found to significantly contribute to the relationship between inflammatory activity and depressed mood.
Two points are worth noting regarding these results. First, although there were no between-group differences in behavioral responses to the monetary reward task, neuroimaging analyses revealed reliable differences in VS responsivity to reward cues that related to increases in observer-rated depressed mood. Thus, neuroimaging may be a useful tool for examining the mechanistic correlates of inflammatory-induced depressed mood that may not be revealed by behavioral observations alone. Second, while both self-reported and observed-rated depressed mood increased as a function of endotoxin, only observer-rated depressed mood correlated negatively with VS activity. This effect may have been due to sex differences in the tendency to report depressed mood, as male subjects showed a negative correlation between self-reported and observer-rated depressed mood (r =−.61, p =.08), whereas female subjects showed a positive correlation (r =.55, p =.08). Future studies would benefit from including both subjective as well as more objective assessments of depressed mood to further explore how altered reward-related responding contributes to depression. In addition, future studies would benefit from including measures of clinically assessed depressed mood as well, as the current measure of observer-rated depressed mood was not made by a clinician.
The findings reported here are consistent with animal research showing that inflammatory activity can increase anhedonic-like behavior (7
), as well as human research demonstrating a role for altered reward-related neural responding in depressive states. Although it is not yet clear how cytokines alter reward-related neural responding, it is known that cytokines have central effects, either through leaky regions in the blood-brain barrier or through the transmission of cytokine signals through the vagus nerve (11
). Furthermore, it has been shown that the administration of cytokine-producing agents can alter monoamine levels (dopamine, serotonin) in the brain more generally (1
) and in the striatum specifically (32
). To the extent that monoamines, such as dopamine and serotonin, play a role in both reward processing and depressive symptoms (12
), it is possible that proinflammatory cytokines relate to reduced reward processing and increased depressive symptoms through altered activity in these neurotransmitter systems.
Together, the results reported here highlight the importance of examining altered reward-related processing in inflammatory-related depression. Previous work exploring the psychological and neural consequences of inflammatory activity has tended to focus on the negative affective processes that might relate to depression (2
). However, to the extent that depressive symptoms relate to altered activity in neural systems associated with positive affective processes (e.g., reward), it will be important to continue to investigate the effects of inflammation on altered activity in reward-related processing.
In summary, although previous research in humans has demonstrated that proinflammatory cytokine activity can increase depressed mood (1
), the neurocognitive mechanisms that mediate these effects remain unknown. Here, we demonstrate, for the first time, that alterations in reward-related processing are an important neural mediator of the effects of inflammation on depressed mood. Identifying the neural processes that are altered as a function of inflammation may allow for greater precision in treating and preventing inflammatory-associated depression. For example, future work could examine whether pharmacological agents that directly target reward-related neural regions (dopaminergic drugs) could attenuate the effects of inflammatory activity on depressed mood. As such, alterations in reward-related neural circuitry represent an important avenue for understanding inflammatory-associated depression.