Microstructural Alterations of the Corpus Callosum in Patients with First-Episode Schizophrenia Revealed by NODDI: Dissociation Between Neurite Density and Orientation Dispersion in the Splenium

Background: Microstructural abnormalities of the corpus callosum (CC) are a consistent finding in schizophrenia, yet conventional diffusion tensor imaging (DTI) metrics provide limited biological specificity. Neurite orientation dispersion and density imaging (NODDI) can disentangle the neurite density index (NDI) and the orientation dispersion index (ODI), providing indirect, model-based markers of white matter microstructure in vivo. Methods: We applied NODDI to diffusion-weighted MRI data in patients with first-episode schizophrenia (FES) and matched healthy controls (HCs). The CC was used as a mask and subdivided into the genu (GCC), body (BCC), and splenium (SCC). Group differences in z-scores of the NDI and ODI were assessed using voxel-wise statistics within the CC and region of interest (ROI) analyses in the GCC, BCC, and SCC, controlling for age and sex. Associations between NODDI metrics and clinical symptoms were examined using the Positive and Negative Syndrome Scale (PANSS). Results: FES patients showed a significantly increased ODI in portions of the GCC, BCC, and SCC, as well as region-specific NDI alterations, with decreased NDI in parts of the SCC and increased NDI in sub-regions of the GCC/BCC (voxel-wise p < 0.05, FWE-corrected). ROI analyses confirmed a significant reduction in NDI z-scores in the SCC in FES patients compared with HCs (p = 0.009), whereas the ODI z-scores in the SCC did not differ significantly between groups (p = 0.124). Despite the absence of group-level ODI differences in the SCC, the SCC ODI was positively correlated with PANSS negative symptom scores in FES patients (r = 0.554, p = 0.002) and was also positively correlated with PANSS total scores in FES (r = 0.457, p = 0.014). This association remained significant in the region of the SCC after regressing out NDI from ODI (residual z_ODI), which was correlated with PANSS negative scores (r = 0.503, p = 0.006) and PANSS total scores (r = 0.474, p = 0.011), and the ODI/NDI ratio in the SCC was also correlated with negative symptom severity (r = 0.457, p = 0.014). Conclusions: Our findings suggest that, in the SCC, negative symptoms in schizophrenia are linked to altered neurite orientation dispersion under conditions of reduced neurite density. The dissociation between group-level NDI and ODI effects and their distinct relationship with psychopathology highlights the value of composite microstructural indices (e.g., residual z_ODI, ODI/NDI) for capturing clinically relevant white matter abnormalities.