Hidden in the cortical folds: Sex-specific sulcal pits patterns in schizophrenia

BACKGROUND: Prenatal brain development represents a vulnerability window for schizophrenia (SZ). To explore early alterations related to the disorder, we examined sulcal pits -lifespan stable landmarks of fetal cortical folding- as markers of neurodevelopmental differences between SZ patients and healthy controls (HC). METHODS: T1-weighted MRIs (1.5 T) were obtained from 426 individuals (237 SZ patients: 173 males, 64 females; 189 HC: 93 males, 96 females). Sulcal pits were identified from white matter cortical surfaces reconstructed using FreeSurfer. Graphs were constructed for each lobe and hemisphere and compared based on sulcal pits (SP) features: SP-Position, SP-Depth, SP-SurfaceAreaBasin, SP-Topology, and all combined features (SP-Combined). We tested: i) group differences in the sulcal pits heterogeneity between patients and HC; ii) sulcal pits divergence in patients relative to HC; iii) the association between sulcal pits divergence and Positive and Negative Syndrome Scale (PANSS) scores; iv) regional covariation between the sulcal pits heterogeneity differences and transcriptional profiles across lobes using Partial Least Squared regressions (PLS-R). Analyses were performed in the sex-pooled sample and stratified by sex. RESULTS: Patients showed increased heterogeneity compared to HC across hemispheres, frontal, temporal, and parietal lobes. Divergence analyses revealed reduced similarity relative to HC, in the left frontal SP-Combined in males (with a trend-level negative correlation with PANSS scores) and right parietal SP-Topology in females. PLS-R showed sex-specific molecular underpinnings related to the identified differences in the heterogeneity of sulcal pits. CONCLUSION: This study provides novel evidence supporting sulcal pits as early neurodevelopmental markers of sex-specific structural brain variability in SZ.