A Longitudinal and Reproducible Anti-coactivation Pattern Between the Cerebellum and the Ventral Tegmental Area Relates to Apathy in Schizophrenia

Negative symptoms of schizophrenia lack effective treatments. Anomalies in the reward system and cerebellum have been linked to these symptoms. The cerebellum modulates reward circuitry via the ventral tegmental area (VTA). The "cognitive dysmetria theory" posits that reduced cerebellar inhibition in schizophrenia may underlie striatal hyperdopaminergia. However, the role of cerebellum-VTA connectivity in negative symptoms remains unclear. From 427 individuals screened, 146 were recruited: 90 with schizophrenia (SZ) and 56 healthy controls (HC). At 3 months (T2), 65 individuals (36 SZ, 29 HC) completed follow-up. SZ participants were invited for clinical interviews at 9 months (T3; 33 SZ). After quality check, 105 participants were retained at T1, 41 at T2, and 21 at T3. A validation cohort included 53 individuals (28 SZ, 25 HC). The Brief Negative Symptom Scale quantified negative symptoms. Dynamic functional connectivity of the cerebellum and VTA was analyzed using coactivation patterns analysis. A reproducible cerebellum-VTA anti-coactivation pattern was found across T1 and T2 (r = 0.98) in bilateral paravermal Crus I/II. Anti-coactivation emergence at T1 correlated negatively with apathy, particularly asociality and avolition. At T2, anti-coactivation persistence related negatively to apathy, especially anhedonia, and to anhedonia at T3. Similarly, reduced emergence at T2 was linked to worse asociality at T3. In the validation cohort, we replicated the pattern (r = 0.93), and its emergence negatively correlated with apathy, particularly asociality. Reduced cerebellum-VTA anti-coactivation is a reproducible neural marker of apathy in schizophrenia, highlighting its potential as a therapeutic target.