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

BackgroundNegative symptoms of schizophrenia lack effective treatments. Anomalies in the reward system and cerebellum have been linked to negative symptom 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, cerebellum-VTA connectivity and its impact on negative symptoms in schizophrenia remains unclear. MethodsFrom 427 individuals screened, 146 participants 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. The validation cohort consisted of 53 individuals (28 SZ, 25 HC). The Brief Negative Symptom Scale was used to quantify negative symptoms. Dynamic functional connectivity of the cerebellum and VTA was analyzed using state-of-the-art coactivation patterns analysis. ResultsA reproducible cerebellum-VTA anti-coactivation pattern was found across T1 and T2 (r = 0.98) in bilateral paravermal Crus I/II. Lower anti-coactivation emergence at T1 correlated with worse apathy, particularly asociality and avolition. At T2, lower anti-coactivation persistence related to worse apathy, especially anhedonia, and correlated with worse anhedonia at T3. Similarly, reduced anti-coactivation emergence at T2 linked to worse asociality at T3. In the validation cohort, we replicated the anti-coactivation pattern (r = 0.93) and the correlation of its emergence with apathy, in particular, asociality. ConclusionReduced cerebellum-VTA anti-coactivation is a reproducible neural marker of apathy in schizophrenia, highlighting its potential as a target for therapeutic intervention.