Methylphenidate effects on target-enriched functional connectivity and response inhibition in stimulant treatment-naive individuals with ADHD

Methylphenidate modulates dopaminergic and noradrenergic neurotransmission by inhibiting dopamine and noradrenaline transporters (DAT, NAT). This leads to improvement in attention-deficit/hyperactivity disorder (ADHD) symptoms and cognitive functions like response inhibition. However, the neural mechanisms linking dopaminergic and noradrenergic modulation to behavioural outcomes remain poorly understood. Novel analyses integrating the spatial distribution of methylphenidate’s pharmacological targets into functional connectivity (FC) analyses provide further mechanistic insights, but have not yet been applied in individuals with ADHD. In this study, we investigated the acute effects of methylphenidate on dopamine- and noradrenaline-related functional circuits, and the relations with response inhibition in males with ADHD. Thirty-five boys (10-12 years) and 48 men (23-40 years) with ADHD (all subtypes) underwent resting-state functional MRI and performed a response inhibition task before and after a single-dose methylphenidate challenge (0.5 mg/kg). Receptor-Enriched Analysis of functional Connectivity by Targets (REACT) was used to estimate FC enriched for methylphenidate’s direct (DAT, NAT) and downstream (D ₁ -receptor, D _2/3 -receptor) targets. Methylphenidate increased DAT- and D _2/3 -enriched FC towards less negative values and decreased NAT-enriched FC towards less positive values. In addition, we identified significant associations between target-enriched FC and response inhibition, but these did not remain significant when accounting for motion. Taken together, our findings show that methylphenidate has both overlapping and distinct effects on dopamine- and noradrenaline-related functional circuits in ADHD, suggesting that these systems are engaged in partially divergent ways.