Hyeonmin Ahn, PhD





Brigham and Women's Hospital


Division of Women's Health


Hyeonmin Ahn*, Julia Hall, Jill M. Goldstein, Daniel G. Dillon, Diego A. Pizzagalli, and Laura M. Holsen

Principal Investigator:

Laura M. Holsen

Sex differences in the association between functional connectivity of reward neurocircuitry during food reward processing following acute psychosocial stress in MDD

Increased prevalence of stress-related disorders, including Major Depressive Disorder (MDD), has been a more significant burden on other health issues, quality of life, and the economy, and women are approximately twice as likely to be diagnosed with Major Depressive Disorder as men. The observed sex-specific difference may be partly attributed to the different brain physiology in reward processing between men and women. Here, we sought to identify whether there are sex differences in neural networks during food reward processing, and the results indicate distinct sex differences in the neural circuitry of reward processing in MDD.

Compared to women, men showed decreased FC between the hedonic systems of reward processing after acute stress, suggesting more sensitive or reactive reward circuitry in women to food reward. Our findings identify sex differences in reward circuitry in response to acute stress highlighting new pathways to target for the treatment of stress-related psychiatric conditions.


Stress-related overeating has been suggested as a mechanism potentiating weight gain and is affected by psychiatric disorders including Major Depression Disorder (MDD), which show significant sex differences in prevalence. However, the mechanisms underlying sex differences in these conditions, in particular the coordinated activity of neural circuits which orchestrate stress-induced feeding behavior, remain clear. We investigated whether there are sex differences in the functional connectivity (FC) of reward circuits during food reward processing under psychosocial stress in MDD.


Seventy-four individuals with current MDD (M35/F39) and 39 healthy controls (HC; M20/F19) completed a study involving exposure to acute psychosocial stress, followed by functional MRI scanning during a food incentive delay task. Data were analyzed to investigate FC between key regions of reward circuits (nucleus accumbens, thalamus, insula, caudate, putamen) during processing of food reward compared to non-incentive cues.


During food reward anticipation, MDD-M exhibited stress-induced decrease in right insula (p-FDR < 0.05) and right thalamus (p-unc < 0.01; p-FDR = 0.063) FC to left caudate, compared to MDD-W, while HC showed no sex differences. During food reward receipt, right insula showed decreased FC to hypothalamus (p-unc < 0.05) in MDD men while left thalamus showed increased FC to right and left putamen (p-unc < 0.01; p-FDR < 0.063) compared to MDD-W.


We found distinct sex differences in neural circuitry of reward processing in MDD with hypoconnectivity in insula and thalamus to striatum during food reward anticipation, and with hyperconnectivity in thalamus to striatum during food reward receipt for men. Insula and thalamus have dense reciprocal connections with the striatum and play an important role in processing external information linked to hedonic system. These findings provide novel evidence of a dissociation between reward circuit network connectivity in men and women in MDD, highlighting new pathways to target for treatments of stress-related psychiatric conditions.