Mapping Cerebellar Connectivity to Cognition in Psychosis: Convergent Evidence From Functional Magnetic Resonance Imaging and Transcranial Magnetic Stimulation

Abstract

Background: Cerebellar dysfunction is strongly implicated in both cognitive impairments and psychosis, and the cognitive dysmetria hypothesis posits cognition as the intermediary in the pathway from cerebellar dysfunction to psychopathology. However, the nuanced cerebellum-behavior relationships in psychosis remain unclear. Establishing such a link is crucial to understand cerebellar mechanisms and to identify treatment targets for cognitive deficits in patients.

Methods: We studied 100 patients with early psychosis from the Human Connectome Project for Early Psychosis study. Connectome-based predictive modeling was conducted to probe cognitive functions most strongly predicted by cerebellar connectivity. Mediation analysis was performed to test for a possible mediating role of cognition between cerebellar connectivity and symptoms. To further support the causality of the findings, we also recruited 16 patients with psychosis for a 2-week randomized, sham-controlled cerebellar transcranial magnetic stimulation (TMS) trial.

Results: Cerebellar connectivity significantly predicted 3 cognitive functions, namely verbal ability, working memory, and cognitive flexibility. Verbal ability fully mediated the relationship between cerebellar connectivity and negative symptoms, in particular alogia. While each cognitive function was predicted by a distinct cerebellar connectivity pattern, the left crus I/II appeared to be a common area with connectivity that consistently predicted all 3 functions. Stimulating this region via TMS was associated with significantly improved cognitive composite score and medium-to-large effects on scores for memory, verbal, and executive functions.

Conclusions: These findings suggest a potential causal pathway from cerebellar connectivity to domain-specific cognitive deficits and psychopathology in schizophrenia. They also point to the cerebellum as a potential target for the treatment of cognitive dysfunction in psychotic disorders.

Keywords: Cerebellum; Cognition; Functional connectivity; Neuroimaging; Schizophrenia; Transcranial Magnetic Stimulation.