This preprint investigated whether individual differences in alignment with sex-typical functional connectivity (FC) patterns relate to mood pathology and to molecular signatures implicated in neurodegeneration. The authors tested the hypothesis that, across sexes, greater alignment with female-typical rather than male-typical FC profiles would be associated with internalizing disorders—conditions more often diagnosed in females. They also sought to assess the specificity of any identified sex-aligned FC profile by comparing patterns linked to internalizing disorders with those linked to attention-deficit hyperactivity disorder (ADHD). Finally, the study examined spatial overlap between the FC profile associated with adolescent internalizing diagnoses and transcriptomic maps of genes showing sex-dependent dysregulation in neurodegenerative conditions.
Analyses were performed across three distinct samples described in the preprint: an adolescent sample enriched for anxiety and depression diagnoses, a child sample enriched for ADHD diagnoses, and a cohort of adult patients with treatment-resistant major depressive disorder (MDD). All analyses included statistical controls for chronological age within each sample and for participants' sex. The preprint provides these cohort-level descriptions but does not report detailed sample sizes or additional demographic specifics in the abstract.
The authors combined multivariate neuroimaging approaches with imaging transcriptomics techniques. They derived sex-typical FC patterns and quantified each participant's alignment with those patterns. Multivariate analyses tested whether alignment with female-typical versus male-typical connectivity profiles predicted diagnostic status in adolescents and symptom severity trajectories in adults with MDD. To examine functional specificity, parallel analyses compared sex-aligned FC profiles that differentiated neurotypical from affected participants in adolescence (internalizing disorders) with those that differentiated neurotypical and ADHD-affected children. Finally, spatial correlation analyses assessed overlap between the internalizing-associated FC profile and transcriptomic maps of genes showing sex-dependent dysregulation in neurodegenerative conditions.
Across sexes, increasing alignment with female-typical functional connectivity—notably across regions from sensory-perceptual systems to the default mode network—distinguished typically developing adolescents from those diagnosed with anxiety or depression. The same sex-aligned gradient predicted longitudinal fluctuations in depressive symptoms among adult patients with treatment-resistant MDD, indicating that the identified pattern tracked symptom severity over time.
When comparing disorder groups, the internalizing-related sex-aligned FC gradient showed a negative correlation with risk for ADHD in the child sample. In other words, the FC profile that marked internalizing disorders in adolescents was inversely related to the connectivity pattern that associated with ADHD risk in children, suggesting some diagnostic specificity in the direction of sex-typical alignment.
Regions most strongly aligned with female-typical FC in depression and anxiety overlapped the spatial expression profiles of genes linked to gonadal hormone synthesis. Those areas also overlapped transcriptomic signatures of genes dysregulated in female autism spectrum disorder (ASD) and in male-predominant neurodegenerative conditions, specifically Alzheimer's disease (AD), Huntington's disease (HD), and Multiple Sclerosis (MS).
Conversely, brain regions more strongly aligned with male-typical FC overlapped transcriptomic maps enriched for genes coding androgen and estrogen receptors, and for genes dysregulated in male ASD and in neurodegenerative conditions that were noted as relatively more female-associated for dysregulation (AD, HD, MS in the authors' comparisons).
The authors interpret these convergent findings as raising the possibility that links between mood pathology and later neurodegeneration might reflect, at least in part, a regional reversal or reconfiguration of sex-normative functional brain architecture. The overlap with genes involved in gonadal hormone synthesis and with receptor-related transcriptomic maps suggests a plausible role for sex hormones or hormone-related signaling pathways in shaping these sex-typical connectivity patterns and their relationship to psychopathology and neurodegenerative vulnerability.
These results are presented as a preliminary step toward understanding sex biases in psychiatric and neurodegenerative risk, with potential implications for personalized medicine approaches that consider sex-typical brain organization.
The preprint abstract specifies the overall analytic approach and main outcomes but does not report certain methodological and sample details in the summary. Specifics such as exact sample sizes, demographic breakdowns beyond age and sex controls, full analytic parameters, replication tests, and effect size estimates were not reported in the abstract. The authors declared no competing interests. For complete evaluation and clinical translation, readers should consult the full preprint and supplementary materials for detailed methods, statistical results, and robustness checks.