Schizophrenia Bulletin · Mar 7, 2026

Longitudinal Trajectories of Cortical Folding in Schizophrenia Spectrum Disorders: A 13-Year Follow-Up Study

By Martini LA, Wortinger LA, Barth C et al.

BACKGROUND AND HYPOTHESIS: Altered cortical folding is a well-established finding in schizophrenia spectrum disorders (SSD). Patients with SSD have been hypothesized to exhibit an accelerated decline in age-related cortical folding, quantified with the local gyrification index (LGI). Here, we assessed longitudinal and cross-sectional LGI differences in patients with chronic SSD relative to healthy controls across 13 years. STUDY DESIGN: The sample comprised patients with SSD (mean baseline age = 41.28 years) and healthy controls (mean baseline age = 41.56 years), with magnetic resonance imaging acquisitions at baseline (103 SSD patients and 99 controls) and follow-up after 5 (50 SSD patients and 57 controls) and 13 years (42 SSD patients and 60 controls). T1-weighted images were processed with the longitudinal pipeline in FreeSurfer. Spatiotemporal linear mixed-effects models were used to test for longitudinal and cross-sectional case-control differences in LGI, as well as the impact of symptom severity and antipsychotic medication dose among patients. STUDY RESULTS: Although cross-sectional LGI was lower in patients in extensive frontal, parietal, and occipital regions, we observed no significant differences in longitudinal trajectories between patients and controls after FDR correction. Medication dose was linked cross-sectionally to lower LGI of the anterior cingulate, orbitofrontal cortex, and postcentral gyrus. CONCLUSION: In the longest longitudinal study on cortical folding in SSD patients to date, we found no evidence for accelerated progressive decline in cortical folding. Rather, chronic SSD appears to be characterized by a state of stable hypogyria relative to healthy controls, consistent with the interpretation of LGI as a marker of early gyrification disturbances in SSD.

doi.org/10.1093/schbul/sbaf245 Open access PubMed 41863378 Biomarkers