A Stable Anti-Coactivation Pattern Between the Cerebellum and Ventral Tegmental Area Relates To Negative Symptoms in Schizophrenia: Implications for Neuromodulation Targets

Background Negative symptoms in schizophrenia (apathy, diminished expression) are disabling and resistant to treatment. Dysfunctions in reward circuits, along with cerebellar abnormalities, play a role in these symptoms. The cerebellum regulates the reward system via the ventral tegmental area (VTA), but the role of cerebellum-VTA connectivity on these symptoms remains unclear. Methods We conducted interviews and acquired resting-state functional MRI in 146 individuals including patients with schizophrenia (SZ) and healthy controls (HC). Following strict quality check, the final sample comprised 105 individuals (58 SZ) at baseline (T1), 41 individuals (22 SZ) at 3-month follow-up (T2), and 21 patients at 9-month follow-up (T3; interviews only). We analyzed the dynamic functional connectivity of cerebellum and VTA activity using Co-Activation Patterns analysis. Results We identified a stable anti-coactivation pattern cerebellum-VTA pattern across distinct recordings at T1 and T2 (r = 0.98) encompassing bilateral paravermal regions of Crus I and II. This pattern’s duration was significantly reduced in SZ in T1 and in T2, indicating an enduring deficiency in cerebellar inhibition of VTA. Lower emergence of this pattern at T1 and lower persistence at T2 associated with more severe apathy, but not diminished expression. Lower persistence at T2 related to more severe apathy but not diminished expression at T3. Conclusions Stable longitudinal evidence of cerebellum's ‘dysmetric’ regulation of reward circuitry opens a new therapeutic avenue for targeted cerebellar non-invasive brain stimulation to alleviate negative symptoms in schizophrenia. Our ongoing triple-blind RCT testing a cerebellum-VTA anti-coactivation-guided stimulation will provide crucial evidence on its efficacy as intervention for these symptoms.