Altered Brain-Behavior Association During Resting State is a Potential Psychosis Risk Marker

: Alterations in cognitive and neuroimaging measures in psychosis may reflect altered brain-behavior interactions patterns accompanying the symptomatic manifestation of the disease. Using graph connectivity-based approaches, we tested the brain-behavior association between cognitive functioning and functional connectivity at different stages of psychosis. We collected resting-state fMRI of 204 neurotypical controls (NC) in two independent cohorts, 43 patients with chronic psychosis (PSY), and 22 subjects with subthreshold psychotic symptoms (STPS). In NC, we calculated graph connectivity metrics and tested their associations with neuropsychological scores. Replicable associations were tested in PSY and STPS and externally validated in three cohorts of 331, 371, and 232 individuals, respectively. NC showed a positive correlation between the degree centrality of a right prefrontal-cingulum-striatal circuit and total errors on Wisconsin Card Sorting Test. Conversely, PSY and STPS showed negative correlations. External replications confirmed both associations while highlighting the heterogeneity of STPS. Group differences in either centrality or cognition alone were not equally replicable. In four independent cohorts totaling 1,203 participants, we identified a replicable alteration of the brain-behavior association in different stages of psychosis. These results highlight the high replicability of multimodal markers and suggest the opportunity for longitudinal investigations that may test this marker for early risk identification.