Effects of 4-Month Methylphenidate Treatment on Functional Connectivity in Attention-Deficit Hyperactivity Disorder

Objective Methylphenidate is effective in reducing ADHD symptoms in the short term, but long-term benefits are inconsistent, possibly due to the development of tolerance. Moreover, little is known about its sustained effects on brain functional connectivity. We examined whether a 4-month methylphenidate treatment leads to sustained alterations in resting-state functional connectivity, and whether acute brain responses to methylphenidate decrease after treatment, as a potential marker of neurobiological tolerance. Method This is a secondary analysis of the ePOD-MPH RCT in which 50 boys and 49 men with ADHD were randomized to methylphenidate or placebo. Resting-state fMRI data were collected before, and one week after, a 4-month treatment period. At both visits, participants were scanned before and after an acute oral methylphenidate challenge. We computed whole-brain and default mode network (DMN) global efficiency, and DMN–whole-brain connectivity strength. Results In adults, methylphenidate (but not placebo) led to sustained increases in whole-brain efficiency (p=0.01) and DMN–whole-brain connectivity strength (p=0.03). No significant effects were observed in children (all p>0.17). Exploratory analyses indicated that whole-brain efficiency increases related to decreasing cognitive performance in methylphenidate-treated children, but improving performance in placebo-treated children, suggesting treatment-dependent moderation (p0.15), but increased in children, regardless of treatment (all p