Heterogeneous Neurophenotypes of Adolescent Sleep Insufficiency Stratify Natural Short Sleepers from Comorbidity or Environment Driven Insufficiency

Insufficient sleep has become an increasing public health issue in adolescents, which is associated with complex social-ecological factors and a wide range of neurodevelopmental outcomes. The highly heterogeneous determinants and outcomes of insufficient sleep impose challenges in effective interventions. To understand such heterogeneity in terms of its impact on the brain, we employed a data-driven ​Subtype and Stage Inference (SuStaIn)​ model to classify the spatiotemporal trajectories of MRI-based neurobiology in 3,266 adolescents from the ABCD study (853 of them had sleep duration less than 8 hours according to Fitbit measurements). We identified three distinct subtypes with reduced cortical thickness, starting from the postcentral cortex, pericalcarine cortex, and entorhinal cortex, respectively. These subtypes diverged significantly in sleep-related social-ecological factors. The postcentral-originated subtype mirrored healthy controls in sleep behavior and sleep environment and showed no psychiatric comorbidities, which aligned phenotypically with natural short sleepers. Notably, this subtype displayed significantly advanced brain age, suggesting advanced neurodevelopment that explained the reduced sleep demand, and polygenetic score analysis revealed a genetic predisposition for short sleep in these adolescents. The pericalcarine-originated subtype displayed environmentally driven sleep insufficiency (e.g., light/noise pollution) where sleep duration mediated environmental effects on pericalcarine cortical thinning. The entorhinal subtype showed elevated psychiatric risk, younger brain age, and spatial correlations with psychosis-related neurotransmitter systems. This work deciphered heterogeneous impacts of insufficient sleep on the brain and the relation with biological, mental, and environmental determinants, offering a framework to guide stratified prevention and intervention strategies.