Ventral Striatal-Hippocampus Coupling During Reward Processing as a Stratification Biomarker for Psychotic Disorders.

ABSTRACT Background Altered ventral striatal (vST) activation to reward expectancy is a well-established intermediate phenotype for psychiatric disorders, specifically schizophrenia. Preclinical research suggests that striatal alterations are related to a reduced inhibition by the hippocampal formation but its role in human transdiagnostic reward-network dysfunctions is not well understood. Methods We performed functional magnetic resonance imaging during reward processing in 728 individuals including healthy controls (N=396), patients (schizophrenia: N=46; bipolar disorder: N=45; major depressive disorder: N=60), and unaffected first-degree relatives (schizophrenia: N=46; bipolar disorder: N=50; major depressive disorder: N=85). We assessed disorder-specific differences in functional vST-hippocampus coupling as well as transdiagnostic associations with dimensional measures of positive, negative and cognitive symptoms. We also probed the genetic underpinning using polygenic risk scores for schizophrenia in a subset of healthy participants (N=295). Results Functional vST-hippocampus coupling was 1) reduced in patients with schizophrenia and bipolar disorder (PFWE .05, SVC) symptoms and 3) reduced in first-degree relatives of patients with schizophrenia (PFWE=.017, SVC) and linked to the genetic risk for SZ in healthy participants (P=.035). Conclusion We provide evidence that reduced vST-hippocampus coupling during reward processing is an endophenotype for schizophrenia linked to positive and cognitive symptoms, supporting current preclinical models of the emergence of psychosis. Moreover, our data indicate that vST-hippocampus coupling is familial and linked to polygenic scores for schizophrenia, supporting the use of this measure as an intermediate phenotype for psychotic disorders.