Sex-specific temporal-lobe functional connectivity alterations in early-onset bipolar disorder

Sex differences and temporal-lobe abnormalities are well documented in bipolar disorder, yet whether these alterations show sex-specific patterns in early-onset bipolar disorder remains unclear. This study investigated diagnosis- and sex-related alterations in temporal-lobe functional connectivity and their associations with clinical characteristics. Eighty-nine individuals with early-onset bipolar disorder (63 females, 26 males) and 61 healthy controls (36 females, 25 males) underwent resting-state functional magnetic resonance imaging (fMRI). Functional connectivity was calculated using 10 temporal subregions as seeds, and a factorial model tested diagnosis and sex effects, followed by simple-effect and correlation analyses. Compared with controls, early-onset bipolar disorder showed lower functional connectivity between the anterior middle temporal gyrus and the precuneus, alongside higher functional connectivity between the anterior middle temporal gyrus and the frontal pole and between the posterior inferior temporal gyrus and the inferior lateral occipital cortex. Sex-stratified analyses showed distinct patterns: females had abnormalities in temporal-default mode network and frontal-pole pathways, with body mass index- and illness-duration-related temporo-occipital changes, whereas males showed broad temporo-occipital hyperconnectivity plus reduced middle temporal occipital gyrus-orbitofrontal functional connectivity. In males, abnormal temporo-visual functional connectivity was associated with hallucinations and symptom severity. These findings suggest sex-differentiated temporal-lobe connectivity patterns in early-onset bipolar disorder, involving both ipsilateral and contralateral connections, and support sex-specific stratification for understanding heterogeneity and informing individualized interventions.