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

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).

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.

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.

This study provides novel evidence supporting sulcal pits as early neurodevelopmental markers of sex-specific structural brain variability in SZ.