Brain structural abnormalities of the associative striatum in adolescents and young adults at genetic high-risk of schizophrenia: Implications for illness endophenotypes

Objective: Dysfunction in cortico-striatal circuitry represents a core component of the pathophysiology in schizophrenia (SZ) but its potential as a candidate endophenotype of the illness is often confounded by neuroleptic medication. Methods: Accordingly, 26 adolescent and young adult participants at genetic high-risk for schizophrenia, but who were asymptomatic and neuroleptic naïve, and 28 age-matched controls underwent 3T structural magnetic resonance imaging of the striatum, manually parcellated into limbic (LST), associative (AST), and sensorimotor (SMST) functional subregions. Results: In relation to their age peers, participants at genetic high-risk for schizophrenia showed overall lower striatal gray matter volume with their most pronounced loss, bilaterally in the AST, but not the LST or SMST. Neuropsychological testing revealed reduced executive functioning for genetically at-risk participants, although the groups did not differ significantly in overall intelligence or oral reading. For controls but not for at-genetic high-risk participants, stronger executive functioning correlated with increased bilateral AST volume. Conclusions: Reduced bilateral AST volume in genetic high-risk adolescents and young adults, accompanied by heritable loss of higher cognitive brain-behavior relationships, might serve as a useful endophenotype of SZ.