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

  1. Noemí Hostalet
  2. Daniel Herrera-Escartín
  3. Lluís Cobos-Aumatell
  4. Mateo Berrío-Soto
  5. Banu Ahtam
  6. Amalia Guerrero-Pedraza
  7. Pedro Canut
  8. Jesús J Gomar
  9. Pilar Salgado-Pineda
  10. Josep Salavert
  11. Nuria Ramiro
  12. Emilio J Inarejos Clemente
  13. Salvador Sarró
  14. Raymond Salvador
  15. Edith Pomarol-Clotet
  16. Neus Martínez-Abadias
  17. Kiho Im
  18. Mar Fatjó-Vilas
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Abstract

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 cortical landmarks of fetal cortical folding— as markers of neurodevelopmental differences between SZ patients and healthy controls (HC).

Methods

T1-weighted MRI (1.5T) scans 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 different 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) the sulcal pits divergence in patients relative to HC; iii) the association between sulcal pots divergence and Positive and Negative Symptoms Scale (PANSS) scores; iv) the regional covariation between the sulcal pits heterogeneity differences and transcriptional profiles across lobes using Partial Least Squared regressions (PLS-R). All 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 with respect to HC, in the left frontal SP-Combined in males (negatively correlated 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 structural sex-specific brain variability in SZ.

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  1. Version published to 10.1101/2025.09.29.25336863 on medRxiv