Relationship of glymphatic dysfunction and frontothalamic structure with cognitive impairment in attention deficit...

Cognitive deficits constitute a core feature of attention deficit hyperactivity disorder (ADHD), yet their underlying neurobiological mechanisms remain incompletely understood. This study investigates the tripartite relationship among glymphatic function, gray matter volume (GMV), and cognitive deficits in pediatric ADHD. We enrolled 159 children with ADHD and 163 typically developing controls. All participants underwent cognitive assessments and multimodal magnetic resonance imaging (MRI). We analyzed group differences in cognitive performance, GMV, and glymphatic function. Exploratory mediation analyses using a regression-based approach (PROCESS) were used to examine the relationships between these variables. Children with ADHD showed significant impairment in sustained attention and emotional regulation (P < 0.001). The ADHD group exhibited reduced glymphatic function, as indicated by a lower along the Perivascular Space (ALPS) index (P < 0.001). GMV abnormalities in ADHD spatially overlapped with ALPS-anchored regions in the parahippocampal-thalamo-frontal circuits. Critically, exploratory mediation analysis provided preliminary, hypothesis-generating evidence that the association between reduced GMV in prefrontal regions (left medial prefrontal cortex and medial superior frontal gyrus) and cognitive deficits may be mediated by glymphatic dysfunction (P < 0.05). Our findings establish glymphatic dysfunction as a feature of pediatric ADHD that co-occurs with fronto-thalamic abnormalities, nominating the glymphatic system as a potential therapeutic target for cognitive comorbidities in ADHD.