Sleep effects on brain, cognition, and mental health during adolescence are mediated by the glymphatic system

Abstract: Background: Adolescence is a critical period of brain maturation and heightened vulnerability to cognitive and mental health disorders. Sleep plays a vital role in neurodevelopment, yet the mechanisms linking insufficient sleep to adverse brain and behavioral outcomes remain unclear. The glymphatic system (GS), a brain-wide clearance pathway, may provide a key mechanistic link. Methods: Participants from the Adolescent Brain Cognitive Development (ABCD) Study (n =6,800; age ~ 11 years) were categorized into sleep-sufficient (>=9 h/night) and sleep-insufficient (<9 h/night) groups. Linear models tested associations among sleep, PVS burden, brain volumes, and behavioral outcomes. Mediation analyses evaluated whether PVS burden explained sleep-related effects. Results: Adolescents with insufficient sleep exhibited significantly greater PVS burden, reduced cortical, subcortical, and white matter volumes, poorer cognitive performance across multiple domains (largest effect in crystallized intelligence), and elevated psychopathology (largest effect in general problems). Sleep duration and quality were strongly associated with PVS burden. Mediation analyses revealed that PVS burden partially mediated sleep effects on cognition and mental health, with indirect proportions up to 10.9%. Sequential models suggested a pathway from sleep -> PVS -> brain volume -> behavior as the most plausible route. Conclusions: Insufficient sleep during adolescence is linked to glymphatic dysfunction, reflected by increased PVS burden, which partially accounts for adverse effects on brain structure, cognition, and mental health. These findings highlight the GS as a potential mechanistic pathway and imaging biomarker, underscoring the importance of promoting adequate sleep to support neurodevelopment and mental health.