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 {Delta} r=0.21-0.35; all p<10-5). In paravermal cerebellar territories, it tracked apathy severity in two patient cohorts (early psychosis, Crus I/II: n=99; r97=0.36, p=2.65 {middle dot} 10-4; chronic schizophrenia, Lobules VIIB/VIIIA: n=87 scans [65 patients]; t85=4.06, p=1.1 {middle dot} 10-4). 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.