Cortical Hub Vulnerability and Molecular Signatures of Sulcal Widening in Schizophrenia

Schizophrenia (SZ) is increasingly conceptualized as a disorder of large-scale brain network organization arising from atypical neurodevelopment. However, the relationship between early-emerging cortical folding patterns and the maturation of the structural connectome remains poorly understood.

We introduced a sulcal morphology-centered framework that integrated normative modeling of sulcal width with diffusion-derived structural connectivity and cortical transcriptomics in a large multisite cohort (N = 5392; 377 SZ). Deviations from normative folding patterns were mapped to the structural connectome and the Allen Human Brain Atlas.

Individuals with SZ exhibited widespread sulcal widening (30/40 sulci), primarily in frontal, temporal, and occipital regions. Nodal vulnerability followed a clear topological principle: Sulci with higher degree centrality (sulcal network hubs) showed disproportionately greater widening (p_spin = .02). Transcriptomic integration identified a gene expression profile explaining 56.5% of the spatial variance in sulcal abnormalities (p = .049). This profile was significantly enriched for synaptic signaling and energy metabolism genes, showed adult-onset expression bias, and was associated with common cross-disorder genetic risk. Conversely, genes with the opposite spatial weight showed significant prenatal expression bias and enrichment for rare disruptive variants associated with autism spectrum disorder.

These findings demonstrate that aberrant cortical folding in SZ is constrained by network topology and molecular architecture. By linking macroscopic folding to metabolic and synaptic pathways, this work establishes sulcal morphology as a mechanistically grounded biomarker that may help differentiate the neurodevelopmental trajectories of psychiatric disorders.