Cerebellar-Prefrontal Connectivity Predicts Negative Symptom Severity Across the Psychosis Spectrum

Negative symptom severity predicts functional outcomes and quality of life in people with psychosis. However, negative symptoms respond poorly to medication, and existing literature has not converged on their neurobiological basis. Previous work in small schizophrenia samples has observed that lower cerebellar-dorsolateral prefrontal cortex (DLPFC) connectivity is associated with higher negative symptom severity and that increasing cerebellar-DLPFC connectivity with neuromodulation reduces negative symptoms. We extended this finding by testing associations between cerebellar-DLPFC connectivity, negative symptoms, and cognitive performance in a large sample of individuals with psychosis.

Individuals with psychosis spectrum disorders (N = 260) underwent resting-state functional magnetic resonance imaging and clinical characterization using the Positive and Negative Syndrome Scale and the Screen for Cognitive Impairment in Psychiatry. Using a previously identified cerebellar region as a seed, we measured connectivity to the DLPFC and regressed connectivity against negative symptom severity, covarying for age, sex, and scanner. Then, we tested whether cognitive performance indirectly affected the relationship between connectivity and negative symptom severity.

Across the psychosis spectrum, higher cerebellar-DLPFC connectivity was associated with lower negative symptom severity (r = -0.17, p = .007). This connectivity-negative symptom relationship was not affected by psychosis subtype or duration of illness. Better delayed verbal learning was associated with higher cerebellar-DLPFC connectivity (r = 0.13, p = .034) and had a significant indirect effect on the relationship between connectivity and negative symptoms.

Our results extend relationships between cerebellar-DLPFC connectivity, negative symptom severity, and cognitive performance across the psychosis spectrum. Larger neuromodulation studies should test whether increasing cerebellar-DLPFC connectivity reduces negative symptoms in psychotic disorders.