Sex differences in deep brain shape and asymmetry persist across schizophrenia and healthy individuals: A meta-analysis from the ENIGMA-Schizophrenia Working Group

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Abstract Background Schizophrenia (SCZ) is characterized by a disconnect from reality that manifests as various clinical and cognitive symptoms, and persistent neurobiological abnormalities. Sex-related differences in clinical presentation imply separate brain substrates. The present study characterized deep brain morphology using shape features to understand the independent effects of diagnosis and sex on the brain, and to determine whether the neurobiology of schizophrenia varies as a function of sex. Methods This study analyzed multi-site archival data from 1,871 male (M) and 955 female (F) participants with SCZ, and 2,158 male and 1,877 female healthy controls (CON) from twenty-three cross-sectional samples from the ENIGMA Schizophrenia Workgroup. Harmonized shape analysis protocols were applied to each site’s data for seven deep brain regions obtained from T1-weighted structural MRI scans. Effect sizes were calculated for the following main contrasts: 1) Sex effects;2) Diagnosis-by-Sex interaction; 3) within sex tests of diagnosis; 4) within diagnosis tests of sex differences. Meta-regression models between brain structure and clinical variables were also computed separately in men and women with schizophrenia. Results Mass univariate meta-analyses revealed more concave-than-convex shape differences in all regions for women relative to men, across diagnostic groups ( d = -0.35 to 0.20, SE = 0.02 to 0.07); there were no significant diagnosis-by-sex interaction effects. Within men and women separately, we identified more-concave-than-convex shape differences for the hippocampus, amygdala, accumbens, and thalamus, with more-convex-than-concave differences in the putamen and pallidum in SCZ ( d = -0.30 to 0.30, SE = 0.03 to 0.10). Within CON and SZ separately, we found more-concave-than-convex shape differences in the thalamus, pallidum, putamen, and amygdala among females compared to males, with mixed findings in the hippocampus and caudate ( d = -0.30 to 0.20, SE = 0.03 to 0.09). Meta-regression models revealed similarly small, but significant relationships, with medication and positive symptoms in both SCZ-M and SCZ-F. Conclusions Sex-specific variation is an overriding feature of deep brain shape regardless of disease status, underscoring persistent patterns of sex differences observed both within and across diagnostic categories, and highlighting the importance of including it as a critical variable in studies of neurobiology. Future work should continue to explore these dimensions independently to determine whether these patterns of brain morphology extend to other aspects of neurobiology in schizophrenia, potentially uncovering broader implications for diagnosis and treatment. Key Points Statistical analyses revealed significant main effects for diagnosis and sex in deep brain shape morphology. Among patients with schizophrenia, there was a pattern of thinning and surface contraction in the bilateral hippocampus, amygdala, accumbens, and thalamus, and a pattern of significant thickening and surface expansion in the bilateral putamen and pallidum compared to healthy control participants. Between males and females, there was a pattern of significant thinning and surface contraction in the bilateral thalamus, pallidum, putamen, and amygdala in females compared to males. There was no significant interaction between diagnosis and biological sex, suggesting that sex differences in deep brain shape and asymmetry among patients with schizophrenia reflect those observed in healthy individuals. Small but statistically significant relationships exist between brain structure and clinical correlates of schizophrenia were similar for both men and women with the disease, such that higher CPZ was associated with shape-derived thinning and surface contraction in the caudate, accumbens, hippocampus, amygdala, and thalamus, and elevated positive symptoms were associated with shape-derived thinning and surface contraction in the bilateral caudate, right hippocampus, and right amygdala.

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