Multiscale localization of abnormal functional differentiation within subcortical nuclei in first-episode, antipsychotic-naïve and medicated stable schizophrenia

Background Altered cortico-subcortical connectivity in schizophrenia suggests disrupted functional differentiation within subcortical nuclei, but direct evidence localizing these abnormalities remains limited. We aimed to localize abnormalities in intra-nuclear functional differentiation by quantifying the synchrony of blood oxygenation level dependent (BOLD) signals, with higher values indicating lower functional differentiation. Methods Resting-state functional magnetic resonance imaging (fMRI) data were acquired from 71 first-episode, antipsychotic-naïve schizophrenia (FES) patients and 64 healthy controls at baseline, with patient follow-up at 6 weeks and 12 months after antipsychotic treatment. An independent cohort of 48 medicated stable patients was further examined. Using a multiscale hierarchical subcortical atlas, principal component analysis of voxel-wise fMRI signals quantified intra-nuclear BOLD synchrony as a metric of functional differentiation across spatial scales. Results At baseline, FES patients showed reduced intra-nuclear functional differentiation compared with controls, with abnormalities broadly involving posterior thalamic and dorsal striatal regions at coarser atlas scales. More prominent abnormalities were found in the anterior thalamus and left nucleus accumbens shell at higher spatial resolutions. Longitudinally, striatal abnormalities showed progressive normalization after 6 weeks and 12 months of treatment, suggesting recovery of functional differentiation. Medicated stable cohort further supported normalization in striatal regions, whereas persistent abnormalities remained evident in thalamic regions. Conclusions Schizophrenia is characterized by reduced intra-nuclear functional differentiation, primarily involving thalamic and striatal territories, and finer subcortical parcellation improved anatomical localization of these abnormalities. Striatal alterations appeared treatment-sensitive, whereas thalamic abnormalities may represent more persistent functional dysfunction.