A Longitudinal and Reproducible Anti-Coactivation Pattern Between the Cerebellum and the Ventral Tegmental Area Is...

Negative symptoms of schizophrenia (SZ) 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 SZ may underlie striatal hyperdopaminergia. However, the role of cerebellum-VTA connectivity in negative symptoms remains unclear.

From 427 individuals screened, 146 were recruited, including 90 with SZ and 56 healthy control participants (HCs). At 3 months (T2), 65 individuals (36 SZ, 29 HCs) completed follow-up assessments. Participants with SZ 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 HCs). The Brief Negative Symptom Scale was used to quantify negative symptoms. Dynamic functional connectivity of the cerebellum and VTA were analyzed using coactivation pattern analysis.

A reproducible cerebellum-VTA anti-coactivation pattern was found across T1 and T2 (r = 0.98) in the bilateral paravermal crus I/II. Anti-coactivation emergence at T1 negatively correlated with apathy, particularly asociality and avolition. At T2, anti-coactivation persistence negatively related 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 SZ, highlighting its potential as a therapeutic target.