Background Negative symptoms in schizophrenia are debilitating and lack effective treatments. Reward system dysfunction and cerebellum anomalies have been linked to negative symptoms. Evidence suggests the cerebellum modulates the reward system via the ventral tegmental area (VTA). The "cognitive dysmetria theory" posits that reduced cerebellar inhibition in schizophrenia may underlie striatal hyperdopaminergia. However, cerebellum-VTA connectivity and its impact on negative symptoms in schizophrenia remains unclear.

Method In a longitudinal study, we conducted interviews and acquired resting-state functional magnetic resonance imaging (rs-fMRI) in 146 individuals, including patients with schizophrenia (SZ) and healthy controls (HC). The Brief Negative Symptom Scale (BNSS) was used to quantify negative symptoms. After quality check, the final sample included 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 (CAPs) analysis.

Results We identified a longitudinally stable anti-coactivation cerebellum-VTA pattern across baseline and T2 (rho = 0.98) encompassing bilateral paravermal regions of Crus I and II. Across all timepoints, the anti-coactivation spatial pattern’s persistence quantified by its duration, was significantly reduced in schizophrenia, indicating an enduring deficiency in cerebellar inhibition of the VTA. Lower emergence of this pattern at T1 and lower persistence at T2 were associated with more severe apathy but not diminished expression. Further, lower persistence at T2 predicted more severe apathy but not diminished expression 6 months later.

Conclusion These results provide stable longitudinal evidence on the cerebellum’s "dysmetric" regulatory effect on reward circuitry in schizophrenia and open the perspective for targeted cerebellar non-invasive brain stimulation to alleviate negative symptoms.

SK has received advisory board honoraria from Boehringer Ingelheim and Exeltis. The other authors report no conflicts of interests.

Leenaards Foundation grant awarded to IB. Swiss National Science Foundation Grant No 169783 to SK.

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Geneva Ethics Committee in Switzerland gave approval for this work (CCER. BASEC ID: 2017-01765 and 2020-02169).

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