The Role of Glymphatic Clearance in Affective Decision‐Making in Adolescents with Non‐Suicidal Self‐Injury

ABSTRACT Background Adolescents with non‐suicidal self‐injury (NSSI) frequently exhibit severe sleep disturbances and heterogeneous cognitive impairments, yet the underlying neurophysiological basis remains unclear. The glymphatic system, a sleep‐dependent macroscopic clearance network, is critical for metabolic waste removal and neurocognitive homeostasis. Therefore, this study aimed to investigate the physiological role of glymphatic function in linking sleep burden to distinct cognitive performances in adolescents with NSSI. Methods We assessed 44 NSSI adolescents and 33 healthy controls (HCs). Using resting‐state functional magnetic resonance imaging (rs‐fMRI), glymphatic function was quantified by calculating the coupling strength between global blood‐oxygen‐level‐dependent (gBOLD) signals and cerebrospinal fluid (CSF) flow. To capture the heterogeneity in their cognitive profiles, we evaluated “hot” affective decision‐making via the Iowa Gambling Task (IGT) and “cold” executive function via the Wisconsin Card Sorting Test (WCST). Subjective sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI). Results In the NSSI group, poorer sleep quality was positively correlated with stronger gBOLD‐CSF coupling ( r  = 0.317, p  = 0.036), and stronger gBOLD‐CSF coupling predicted better IGT performance, especially during the high‐load strategy phase (Block 3) ( r  = 0.447, p  = 0.002). Furthermore, glymphatic function fully mediated the relationship between sleep quality and affective decision‐making performance (indirect effect = 0.682, 95% CI [0.062, 1.515]). Interaction analyses confirmed this physiological‐behavioral coupling was disease‐specific (present only in NSSI; interaction p  = 0.011) and domain‐specific (supporting “hot” affective cognition rather than “cold” executive function). Conclusions In NSSI adolescents, sleep‐associated glymphatic upregulation reflects a stress‐induced compensatory response. This mechanism domain‐specifically preserves high‐load affective decision‐making against severe psychopathological stress. These findings highlight brain metabolic clearance as a novel physiological target for bolstering cognitive resilience in high‐risk youth.