Transdiagnostic Neurobehavioral Gradients and Environmental Interactions in Youth with Major Psychiatric Disorders

Abstract Major psychiatric disorders typically emerge in youth and exhibit shared and disorder-specific behavioral phenotypes and neuroanatomical alterations, yet the transdiagnostic neurobehavioral gradients and environmental interactions contributing to this heterogeneity remain poorly understood. Here, we present a transdiagnostic cohort of 1,755 youths aged 10-24 years, including 1,040 patients with bipolar disorder (BD), major depressive disorder (MDD), or schizophrenia spectrum disorder, and 715 healthy controls. Individualized gray matter volume (GMV) were quantified relative to population-based norms and integrated with behavioral phenotypes and environmental exposures. We identified transdiagnostic severity gradients across emotional and non-emotional symptoms, cognition, and personality traits, alongside widespread negative GMV deviations and diagnosis-specific effects in the pars opercularis and posterior cingulate, key hubs of the action-mode network orchestrating goal-directed functions. Two brain-behavior modes were identified: a cognitive mode linking posterior cortical variation with processing speed and an emotional mode associating prefrontal regions and the paracentral lobule with self-injurious behaviors. Further analyses indicated that adverse social environments were indirectly associated with brain structural deviations through behavioral pathways in BD and MDD, whereas air pollution (PM 2.5 ) specifically moderated brain-behavior relationships in MDD. Together, these findings elucidate transdiagnostic neurobehavioral gradients across youth psychiatric disorders, with environmental exposures differentially embedded within neurobehavioral systems.