Widespread white matter microstructural abnormalities in treatment‑naïve patients with first‑episode schizophrenia revealed by fixel-based analysis

Fixel-based analysis (FBA) is an advanced diffusion imaging method that enables the direct estimation of white matter microstructural properties beyond the limitations of traditional diffusion tensor imaging (DTI). Despite its potential, FBA has been rarely applied in schizophrenia research, and its value in providing complementary information to conventional tensor-based approaches remains to be fully established. In this study, we investigated white matter abnormalities of treatment-naïve, first-episode schizophrenia (FES) patients using both FBA and tensor-based method, and examined the concordance between the two approaches to better characterize the nature of white matter pathology in early SZ. MRI data were acquired from 94 treatment-naïve FES patients and 114 healthy controls (HCs). Fractional anisotropy (FA) and mean diffusivity (MD) were calculated using a conventional tensor-based method. In parallel, fibre density (FD), fibre-bundle cross-section (FC), and their combined metric (FDC) were estimate with FBA. White matter was segmented into 72 anatomically defined tracts based on fibre tracking. Between-group comparisons were conducted using a multivariate general linear model (GLM) to assess differences across diffusion metrics. Using the tensor-based method, six white matter tracts exhibited significantly altered FA, while 34 tracts showed significantly increased MD in FES patients compared to HCs (all t -values > 2.34 or t -values < −2.36, all FDR- p < 0.05). In contrast, FBA revealed more widespread abnormalities: 46 tracts showed significantly reduced FD, 29 tracts showed significantly reduced FC, and 52 tracts showed significantly reduced FDC (all t -values < −2.29, all FDR- p < 0.05). Notably, all tracts with significantly reduced FC metrics also demonstrated corresponding FDC reductions. No significant correlation was observed between any diffusion metrics and clinical characteristics (all FDR- p ˃ 0.05). This study highlights the remarkable advantages of the FBA in detecting WM microstructural abnormalities in individuals with FES.