Severity of alcohol use disorder influences sex differences in sleep, mood, and brain functional connectivity impairments

Abstract

Growing evidence suggests greater vulnerability of women than men to the adverse effects of alcohol on mood and sleep. However, the underlying neurobiological mechanisms are still poorly understood. Here, we examined sex difference in resting state functional connectivity in alcohol use disorder using a whole-brain data driven approach and tested for relationships with mood and self-reported sleep. To examine whether sex effects vary by severity of alcohol use disorder, we studied two cohorts: non-treatment seeking n = 141 participants with alcohol use disorder (low severity; 58 females) from the Human Connectome project and recently detoxified n = 102 treatment seeking participants with alcohol use disorder (high severity; 34 females) at the National Institute on Alcohol Abuse and Alcoholism. For both cohorts, participants with alcohol use disorder had greater sleep and mood problems than healthy control, whereas sex by alcohol use effect varied by severity. Non-treatment seeking females with alcohol use disorder showed significant greater impairments in sleep but not mood compared to non-treatment seeking males with alcohol use disorder, whereas treatment-seeking females with alcohol use disorder reported greater negative mood but not sleep than treatment-seeking males with alcohol use disorder. Greater sleep problems in non-treatment seeking females with alcohol use disorder were associated with lower cerebello-parahippocampal functional connectivity, while greater mood problems in treatment-seeking females with alcohol use disorder were associated with lower fronto-occipital functional connectivity during rest. The current study suggests that changes in resting state functional connectivity may account for sleep and mood impairments in females with alcohol use disorder. The effect of severity on sex differences might reflect neuroadaptive processes with progression of alcohol use disorder and needs to be tested with longitudinal data in the future.

Keywords: alcohol use disorder; negative mood; resting state functional connectivity; sex differences; sleep.

Graphical abstract

Sex differences in sleep, mood and brain functional connectivity in non-treatment seeking and treatment seeking participants with alcohol use disorder.

Figure 1 Sleep and negative mood.

AUD by sex effects on (A and E) sleep, (B and F) depression, and (C and G) anxiety and (D and F) their correlations in HCP (upper, n = 282) and NIAAA cohorts (bottom, n = 220) using LMEs. Marginal means were plotted. *Indicates post-hoc pairwise comparisons (Bonferroni corrected p_FWE < 0.05) for significant AUD by sex interactions. Of note, for sleep measurement PSQI were used in both cohorts, while for mood assessments, different questionnaires were used (HCP cohort: Achenbach adult self-report; NIAAA cohort: CPRS).

Figure 2 Sex differences in RSFC.

Sex differences in HCP AUD (A) and in NIAAA AUD (B); AUD versus HC females in the NIAAA cohort (C); sex differences in HCP HC (D); colour bar represents t values. Cereb, cerebellum; Ver, vermis; aPaHC, anterior parahippocampal; SMA, supplementary motor cortex; PostCG, postcentral gyrus; IFG tri, inferior frontal gyrus pars triangularis; IFG oper, inferior frontal gyrus pars opercularis; SCC, supracalcarine cortex; ICC, intracalcarine cortex; LG, lingual gyrus; CO, central opercular cortex; PO, parietal operculum cortex; toMTG, temporooccipital middle temporal gyrus; ToFusC, temporal occipital fusiform cortex; aTFusC, anterior temporal fusiform cortex; l, left; r, right.

Figure 3 Overlapping patterns of sex differences in AUD from the two cohorts.

Top 10% edges that showed strongest sex differences and unique to AUD are selected in each cohort. Overlaps between two cohorts are illustrated. Cereb, cerebellum; Ver, vermis; pPaHC, posterior parahippocampal gyrus; MedFC, frontal medial cortex, pSTG, posterior superior temporal gyrus; CO, central opercular cortex; PostCG, postcentral gyrus; PreCG, precentral gyrus; SPL, superior parietal lobule; AC, anterior cingulate cortex; IFG tri, inferior frontal gyrus pars triangularis; AG, angular gyrus; MidFG, middle frontal gyrus; pSMG, posterior supramarginal gyrus; pITG, inferior temporal gyrus; IFG oper, inferior frontal gyrus pars opercularis; PO, parietal operculum cortex; OFusG, occipital fusiform gyrus; iLOC, inferior lateral occipital cortex; sLOC, superior lateral occipital cortex; ToFusC, temporal occipital fusiform cortex.