Sex differences in the associations between symptom severity, social cognition, and connectivity between default mode...

The default mode network (DMN) fractionates into well-established sub-networks that play pivotal roles in social cognition. Prefrontal nodes of DMN sub-networks are vulnerable to alcohol neurotoxicity, which may impair social function in individuals with alcohol use disorder (AUD). The current study examines interacting effects of AUD and sex on the relationship between social cognition and connectivity between DMN sub-networks.

Matched groups of males and females without (matched control: MC) and with (AUD) a lifetime diagnosis of AUD (N = 156; n = 39/group) were selected from the Human Connectome Project. Resting-state functional magnetic resonance imaging data (~58min/participant) were used to compute functional connectivity between four DMN sub-networks: anterior dorsomedial (aDMN), ventromedial (vmDMN), medial temporal lobe (mtlDMN), and posterior (pDMN). Interacting effects of sex, AUD diagnosis/symptoms, and composite social cognition scores on between-network connectivity were assessed via non-parametric permutation testing.

Connectivity between aDMN-mtlDMN (AUDcor=.016) and vmDMN-pDMN (AUD>MC, p_cor=.030) differed between AUD and MC. Social cognition was associated with aDMN-vmDMN connectivity (p_cor=.003), with the relationship being moderated by sex, AUD-status and severity; males and females with mild AUD showed associations between aDMN-vmDMN connectivity and social cognition that were opposite to their matched counterparts. In individuals with greater symptom severity, associations between connectivity and social cognition were absent.

This study provides evidence for possible network connectivity-based mechanisms underpinning social cognition alterations in males and females with AUD. Findings show significant sex differences in these potential vulnerabilities, emerging at mild-to-moderate symptom severity, suggesting sex-specific treatment considerations are warranted.