Microstructural Alterations of the Cerebellum-Ventral Tegmental Area Pathways in First-Episode Psychosis

BACKGROUND: The cerebellum plays a critical role in higher-order cognition and motivation, in part through its direct projections to dopaminergic midbrain structures such as the ventral tegmental area (VTA). Although cerebellar dysconnectivity is a robust feature of schizophrenia, the microstructural tissue properties of cerebellar-VTA white-matter pathways have not been examined in first-episode psychosis (FEP). METHODS: We used diffusion-weighted MRI (dMRI) and probabilistic tractography to reconstruct cerebellar-VTA pathways in 46 participants with FEP and 30 healthy controls. Cerebellar-VTA tracts (ipsi- and contra-lateral) were defined using anatomically-informed inclusion and exclusion regions of interest. Mean diffusivity (MD) and fractional anisotropy (FA) were quantified using the diffusional kurtosis model along each tract. Group differences were assessed using generalized additive mixed models, controlling for age, sex, head motion and medication. Associations between tract properties and cognitive performance from the MATRICS Consensus Cognitive Battery were evaluated. RESULTS: FEP patients showed significantly lower MD along both ipsilateral and contralateral cerebellar-VTA pathways in both hemispheres, with effects distributed across large portions of each tract. Lower MD in the contralateral cerebellar-VTA pathways was significantly associated with poorer working memory performance in patients, while a similar association for the ipsilateral pathway was observed in the left hemisphere. CONCLUSIONS: This study provides the first evidence that cerebellar-VTA white-matter pathways are microstructurally altered at the early stage of psychosis, and that these alterations are linked to memory deficits. The results refine models of cerebellar dysconnectivity in schizophrenia by implicating a specific cerebellar-midbrain dopaminergic pathway as a potential substrate of cognitive dysfunction.