Sex-specific cortical brain differences in children at familial high risk for schizophrenia or bipolar disorder
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Background
Schizophrenia (SZ) and bipolar disorder (BP) are severe psychiatric disorders with neurodevelopmental underpinnings. Familial high risk (FHR) is the strongest predictor of developing SZ and BP. Children at FHR offer a unique opportunity to identify early brain markers of vulnerability. However, 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 for SZ (FHR-SZ) or BP (FHR-BP).
Methods
This study included 278 children from the Danish High Risk and Resilience Study (VIA11): 101 FHR-SZ, 64 FHR-BP, and 113 population-based controls (PBCs). Groups matched on age and sex. 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 volume, cortical volume, and surface area (eta 2 =0.030-0.038; p=0.006-0.016). Males at FHR-SZ exhibited smaller brain volume, cortical volume, and surface area than PBC males (Cohen’s d =-0.624--0.489; p=0.002-0.015), while 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. Our findings highlight the importance of incorporating 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.
