Inflammation-induced anhedonia: endotoxin reduces ventral striatum responses to reward

Abstract

Background: Although inflammatory activity is known to play a role in depression, no work has examined whether experimentally induced systemic inflammation alters neural activity that is associated with anhedonia, a key diagnostic symptom of depression. To investigate this, we examined the effect of an experimental inflammatory challenge on the neural correlates of anhedonia-namely, reduced ventral striatum (VS) activity to reward cues. We also examined whether this altered neural activity related to inflammatory-induced increases in depressed mood.

Methods: Participants (n = 39) were randomly assigned to receive either placebo or low-dose endotoxin, which increases proinflammatory cytokine levels in a safe manner. Cytokine levels were repeatedly assessed through hourly blood draws; self-reported and observer-rated depressed mood were assessed regularly as well. Two hours after drug administration, neural activity was recorded as participants completed a task in which they anticipated monetary rewards.

Results: Results demonstrated that subjects exposed to endotoxin, compared with placebo, showed greater increases in self-reported and observer-rated depressed mood over time, as well as significant reductions in VS activity to monetary 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 anticipated reward.

Conclusions: The data reported here show, for the first time, that inflammation alters reward-related neural responding in humans and that these reward-related neural responses mediate the effects of inflammation on depressed mood. As such, these findings have implications for understanding risk of depression in persons with underlying inflammation.

Trial registration: ClinicalTrials.gov NCT00949845.

Figure 1

Sample trial from the monetary incentive delay task.

Figure 2

Neural activity (mean parameter estimates) for the left (blue) and right (red) ventral striatum regions of interest during reward anticipation versus neutral anticipation for participants in the endotoxin and placebo conditions. Shaded regions denote ventral striatum region of interest location (inset). VS, ventral striatum.

Figure 3

(A) Ventral striatum (VS) activity from the whole-brain analysis that was significantly more active for placebo, compared with endotoxin, subjects (displayed at p < .005, 10 voxels to show extent of activation; left = left). (B) Bar graph of ventral striatum activity from the whole-brain analysis showing significantly more activity in placebo, compared with endotoxin, subjects.