Sex-specific cortical brain differences in children at familial high risk for schizophrenia or bipolar disorder.

Abstract

Background: Familial high risk (FHR) is the strongest predictor of developing schizophrenia (SZ) and bipolar disorder (BP). Children at FHR uniquely allow for identifying early brain markers of vulnerability. Previous studies often span wide age ranges and neglect sex differences, despite evidence of distinct sex-specific brain developmental trajectories. We investigated sex-specific group differences in brain morphometry among 11-12-year-old children at FHR-SZ or FHR-BP.

Methods: This study included 278 children from the Danish High Risk and Resilience Study (VIA11): 101 FHR-SZ (51 males), 64 FHR-BP (32 males), and 113 population-based controls (PBCs, 57 males). Structural MRI scans were acquired on 3T scanners at two sites. Brain volume, cortical volume, surface area, and cortical thickness were extracted using FreeSurfer.

Results: Significant group-by-sex interactions were observed for brain, cortical, and intracranial volume, and surface area (eta²=0.030-0.038; p=0.006-0.016). Males at FHR-SZ exhibited smaller brain, cortical, and intracranial volume, and surface area than PBC males (Cohen's d=-0.677--0.489; p=0.001-0.015). FHR-BP females had larger brain and cortical volumes than PBC females (Cohen's d=0.525-0.537; p=0.017-0.020). No significant differences were observed for cortical thickness (p>0.210).

Conclusions: Children at FHR-SZ and FHR-BP exhibited sex-specific morphometric differences, potentially reflecting sex-specific endophenotypic markers of risk. Given the smaller size of the FHR-BP group, these findings should be interpreted cautiously. Nevertheless, our findings underscore the importance of considering sex as a factor in neurodevelopmental psychiatric research. Longitudinal studies are needed to track how these neuroanatomical differences evolve over time and to evaluate their predictive value for transition to SZ or BP.