Sex-related differences in the cortico-thalamo-cerebellar circuit in patients with schizophrenia

Schizophrenia is characterized by substantial clinical heterogeneity, with average differences between males and females in symptom presentation, cognitive function, and treatment response. The cortico-thalamo-cerebellar circuit (CTCC) has been implicated in schizophrenia; however, whether schizophrenia-related alterations in CTCC functional connectivity vary by sex remains unclear. This study examined diagnosis-by-sex interaction effects on CTCC-related functional connectivity using resting-state functional magnetic resonance imaging.

Resting-state fMRI data were obtained from 108 patients with schizophrenia (53 females) and 93 healthy controls (54 females). Seed-based functional connectivity (FC) analysis and independent component analysis (ICA) were used to examine group-by-sex interaction effects on CTCC-related functional organization.

Significant diagnosis-by-sex interaction effects were identified in several connections involving CTCC-related basal ganglia, thalamic, cerebellar, and cortical regions. Post hoc analyses indicated that male patients exhibited increased FC between basal ganglia, thalamic, or cerebellar seed regions and temporal or calcarine cortical areas. Female patients showed a different pattern, including reduced FC between primary sensory cortical regions and basal ganglia or thalamic seed regions. These findings indicate that schizophrenia-related CTCC connectivity alterations differed between male and female participants. Chlorpromazine-equivalent dose was not significantly associated with the interaction-related functional connectivity values in either female or male patients.

Sex moderated selected patterns of CTCC-related functional connectivity in schizophrenia. The findings represent group-level differences with substantial potential overlap between males and females and should not be interpreted as evidence of categorical brain sexual dimorphism or directional circuit mechanisms. Larger, prospectively sex-balanced studies incorporating longitudinal, dynamic, and effective-connectivity analyses are needed to confirm these findings and clarify their functional significance.