Sex differences in connectivity-based prediction of working memory and its neural organization

Working memory (WM) depends on coordinated interactions among distributed brain systems. Although sex differences in WM have been widely studied, most previous work has focused on group-level activation differences. As a result, it remains unclear whether males and females can be characterized by distinct functional connectivity-based models of WM performance. We analyzed 622 participants (311 females and 311 males) from the Human Connectome Project who were retained after data quality and completeness screening, with the male and female groups matched on relevant covariates and showing no significant between-group differences. Using n-back task functional magnetic resonance imaging data and corresponding behavioral measures, we constructed connectome-based predictive models of WM performance separately in females and males. WM performance could be predicted in both sexes. However, cross-sex validation showed that the female-trained model significantly predicted male WM performance, whereas the male-trained model did not significantly predict female WM performance. To examine factors associated with this asymmetry, we analyzed inter-subject consistency within each sex group. Females showed greater within-sex neural dynamic consistency than males across multiple brain regions, and subsampling analyses further linked higher inter-subject consistency to greater predictive feature stability and better cross-sex prediction performance. Importantly, sex differences extended beyond model performance to the predictive connectivity patterns themselves, mainly involving higher-order cognitive control and lower-level visual systems. Functional connectivity gradient analyses provided convergent support for this pattern. Together, these findings deepen our understanding of WM network mechanisms and provide a basis for understanding sex-related differences in WM impairment and for exploring potential interventions.

The online version contains supplementary material available at 10.1007/s11571-026-10525-0.