A brain-wide risk score for psychiatric disorder evaluated in a large adolescent population reveals increased divergence among higher-risk groups relative to controls

Accurate psychiatric risk assessment requires biomarkers that are both stable and adaptable to development. Functional network connectivity (FNC), which steadily reconfigures over time, potentially contains abundant information to assess psychiatric risks. However, the absence of suitable analytical methodologies has constrained this area of investigation.We investigated brain-wide risk score (BRS), a novel FNC-based metric that contrasts the relative distances of an individual's FNC to that of psychiatric disorders versus healthy control references. To generate group-level disorder and healthy control references, we utilized a large brain imaging dataset containing 5231 total individuals diagnosed with schizophrenia, autism spectrum, major depressive, and bipolar disorders, and their corresponding healthy controls. The BRS metric was employed to assess the psychiatric risk in two new datasets: Adolescent Brain and Cognitive Development (ABCD, N=8191) and Human Connectome Project Early Psychosis (HCP-EP, N=170).The BRS revealed clear, reproducible gradient of FNC patterns from low-to-high-risk for each psychiatric disorder in unaffected adolescents. We found that low-risk ABCD adolescent FNC patterns for each disorder were strongly present in over 25% of the ABCD subjects and homogeneous, whereas high-risk patterns of each psychiatric disorder were strongly present in about 1% of ABCD subjects and heterogeneous. The BRS also showed its effectiveness in predicting psychosis scores and distinguishing individuals with early psychosis from healthy controls.The BRS could be a new image-based tool for assessing psychiatric vulnerability over time and in unaffected individuals, and it could also serve as a potential biomarker, facilitating early screening and monitoring interventions.