Unique Functional Neuroimaging Signatures of Genetic Versus Clinical High Risk for Psychosis

Abstract

Background22q11.2 deletion syndrome (22qDel) is a copy number variant that is associated with psychosis and other neurodevelopmental disorders. Adolescents who are at clinical high risk for psychosis (CHR) are identified based on the presence of subthreshold psychosis symptoms. Whether common neural substrates underlie these distinct high-risk populations is unknown. We compared functional brain measures in 22qDel and CHR cohorts and mapped the results to biological pathways. MethodsWe analyzed 2 large multisite cohorts with resting-state functional magnetic resonance imaging data: 1) a 22qDel cohort (n = 164, 47% female) and typically developing (TD) control participants (n = 134, 56% female); and 2) a cohort of CHR individuals (n = 240, 41% female) and TD control participants (n = 149, 46% female) from the NAPLS-2 (North American Prodrome Longitudinal Study-2). We computed global brain connectivity (GBC), local connectivity (LC), and brain signal variability (BSV) across cortical regions and tested case-control differences for 22qDel and CHR separately. Group difference maps were related to published brain maps using autocorrelation-preserving permutation. ResultsBSV, LC, and GBC were significantly disrupted in individuals with 22qDel compared with TD control participants (false discovery rate–corrected q < .05). Spatial maps of BSV and LC differences were highly correlated with each other, unlike GBC. In the CHR group, only LC was significantly altered versus the control group, with a different spatial pattern than the 22qDel group. Group differences mapped onto biological gradients, with 22qDel effects being strongest in regions with high predicted blood flow and metabolism. Conclusions22qDel carriers and CHR individuals exhibited different effects on functional magnetic resonance imaging temporal variability and multiscale functional connectivity. In 22qDel carriers, strong and convergent disruptions in BSV and LC that were not seen in CHR individuals suggest distinct functional brain alterations.