Resting-state brain age is associated with cognitive and sensorimotor abnormalities in schizophrenia spectrum disorders: a validation & longitudinal study

Brain-age models use neuroimaging features to predict chronological age. The resulting brain-age gap (BAG), defined as predicted brain age minus chronological age, quantifies deviations from age-expected brain characteristics. Structural brain-age acceleration is well established in schizophrenia spectrum disorders (SSD), but the utility of resting-state functional connectivity (rs-FC)-based brain age remains unclear. Here, we trained rs-FC brain-age models on aggregated lifespan data from healthy controls (n ≈ 2200) and evaluated them in four independent SSD case-control cohorts. Across independent cohorts and two brain atlases, SSD showed higher FC-based BAG than healthy controls (β ≈ 0.4-0.6), indicating modest functional brain-age elevation at the group level. However, within SSD, more negative (younger appearing) BAG was associated with poorer cognitive performance, longer duration of illness, and higher neurological soft signs (NSS). Over 12-24 weeks, increases in BAG were associated with reductions in NSS motor coordination and hard signs. Together, these findings suggest that rs-FC brain age captures both a small case-control shift and a clinically relevant dimension within SSD that is not well described by uniform "acceleration". FC-based BAG may therefore reflect heterogeneity in network-level development and reorganization, with younger-appearing functional profiles potentially indexing greater neurodevelopmental burden.