Putamen function and MAOA genotype define genetic and neural subtypes of hyperactivity-impulsivity in ADHD

Hyperactivity-impulsivity (HI) is a core ADHD symptom associated with the monoamine oxidase A (MAOA) gene. The neurobiological mechanisms underlying HI heterogeneity in children carrying the MAOA risk genotype remain unclear and may involve distinct subtypes.

A total of 326 children with ADHD were genotyped for MAOA, including 108 non-risk and 218 risk carriers. Semi-supervised clustering of HI and executive function (EF) scores from the ADHD Rating Scale, Conners' Rating Scale, and BRIEF was used to classify MAOA risk carriers into subtypes, with non-risk patients as the reference. fALFF differences across subtypes, cognitive mediation between brain activity and behavior, and treatment response at follow-up were examined.

Two subtypes were identified among MAOA risk carriers. Compared with the non-risk group, Subtype 1 showed elevated HI and impaired EF, whereas Subtype 2 showed preserved EF and no HI elevation. Subtype 1 had increased fALFF in the inferior temporal gyrus and higher putamen fALFF than Subtype 2, while Subtype 2 showed increased fALFF in the angular gyrus relative to the non-risk group. Putamen fALFF was associated with inhibition, shifting, emotional control, and the Behavioral Regulation Index (BRI), and mediation analysis suggested an indirect effect on HI via the BRI. After 4 weeks of medication, Subtype 2 showed greater improvement in conduct problems and anxiety.

Putamen function may underlie HI heterogeneity among MAOA risk carriers and was associated with better EF, milder symptoms, and greater treatment response.