Cerebellum-ventral tegmental connectivity as a mechanism-informed target for apathy in schizophrenia

Apathy is a leading driver of functional disability in schizophrenia, yet effective mechanism-based therapies are lacking. We evaluated whether cerebellum–ventral tegmental area functional connectivity (CB-VTA FC) meets the criteria for clinical translation as a therapeutic neuromodulation target. Using resting-state fMRI in three independent repeated-imaging cohorts (healthy controls, early psychosis or chronic schizophrenia patients, minutes–months inter-scan intervals), CB-VTA FC was always stable and individual-specific (stability r =0.52–0.69; differential identifiability Δ r =0.21–0.35; all p <10⁻ L). In paravermal cerebellar territories, it tracked apathy severity in two patient cohorts (early psychosis, Crus I/II: n =99; r LL=0.36, p =2.65·10⁻L; chronic schizophrenia, Lobules VIIB/VIIIA: n =87 scans [65 patients]; t LL=4.06, p =1.1·10⁻L). In a meta-analysis of 39 randomized controlled transcranial magnetic stimulation trials ( n =1,624; 867 active), connectivity of neighboring areas to stimulation site predicted negative symptoms improvement. CB-VTA FC thus emerges as a stable, individual-specific, and symptom-related therapeutically relevant circuit, constituting a mechanism-informed precision neuromodulation target in schizophrenia, ready for prospective clinical trials.