Topographic diversity of structural connectivity in schizophrenia

The neurobiological heterogeneity of schizophrenia is widely accepted, but it is unclear how mechanistic differences converge to produce the observed phenotype. Establishing a pathophysiological model that accounts for both neurobiological heterogeneity and phenotypic similarity is essential to inform stratified treatment approaches. In this cross-sectional diffusion tensor imaging study, we recruited 77 healthy controls, and 70 patients with DSM-IV diagnosis of schizophrenia. We first confirmed the heterogeneity in structural connectivity by showing a reduced between-individual similarity of the structural connectivity in patients compared to healthy controls. Second, at a system level, we found the diversity of the topographic distribution of the strength of structural connectivity was significantly reduced in patients (P = 7.21 × 10⁻⁷, T₁₄₂ = 5.19 [95% CI: 3.37–7.52], Cohen's d = 0.91), and this affected 65 of the 90 brain regions examined (False Discovery Rate <5%). Third, when topographic diversity was used as a discriminant feature to train a model for classifying patients from controls, it significantly improved the accuracy on an independent sample (T₉₉ = 5.54; P < 0.001). These findings suggest a highly individualized pattern of structural dysconnectivity underlies the heterogeneity of schizophrenia, but these disruptions likely converge on an emergent common pathway to generate the clinical phenotype of the disorder.