Sex Differences in the Relationship Between Inflammation and Reward Sensitivity: A Randomized Controlled Trial of Endotoxin

Abstract

Background: There are robust sex differences in the prevalence of depression. Inflammation and anhedonia may play a role in understanding these sex differences. Indeed, sex differences in inflammation-induced neural responses to reward may provide insight into the sex gaps in depression, but no study has examined this question.

Methods: As such, the current study examined whether there were sex differences in reward-related neural activity (i.e., ventral striatum [VS] activity) in response to an experimental inflammatory challenge. Human participants (N = 115; 69 female) were randomly assigned to receive either placebo or low-dose endotoxin, which increases inflammation in a safe, time-limited manner. Two hours after receiving placebo or endotoxin (the height of the inflammatory response to endotoxin), participants completed a task in which they anticipated monetary reward in a functional magnetic resonance imaging scanner.

Results: Results demonstrated that endotoxin (vs. placebo) led to reduced VS activity in anticipation of reward and that there were sex differences in this effect. Specifically, in female participants, endotoxin (vs. placebo) led to decreased VS activity in anticipation of reward, but this effect was not present in male participants. In addition, within the endotoxin condition, decreases in VS activity in anticipation of reward were related to increases in inflammation for female but not male participants.

Conclusions: These findings may have implications for understanding how inflammation may contribute to sex differences in rates of depression.

Trial registration: ClinicalTrials.gov NCT01671150.

Keywords: Anhedonia; Depression; Endotoxin; Inflammation; Reward; Sex differences.

Conflict of interest statement

The authors report no biomedical financial interests or potential conflicts of interest.

Copyright © 2019 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1

A sample trial from the monetary incentive delay (MID) task.

Figure 2

Neural activity (mean parameter estimates) in response to the anticipation of reward for bilateral ventral striatum regions of interest as a function of condition (endotoxin vs. placebo). One asterisk denotes p < .05.

Figure 3

Neural activity (mean parameter estimates for bilateral ventral striatum regions of interest) in response to the anticipation of reward as a function of condition (endotoxin vs. placebo) and sex. Two asterisks denotes p < .01.

Figure 4

Correlations between cytokines and neural activity (mean parameter estimates for bilateral ventral striatum (VS) regions of interest) in response to anticipation of reward. Correlations between VS activity and levels of IL-6 at T2 shown separately for a) males and b) females, as well as VS activity and levels of TNF-α at T2 shown separately for c) males and d) females. All displayed values and statistical analyses controlled for body mass index (BMI) and T0 values of cytokines. One asterisk denotes p < .05, and two asterisks denotes p < .01.