Children with ADHD often exhibit fluctuations in attention and heightened reward sensitivity. Psychostimulants, such as methylphenidate (MPH), improve these behaviors in many, but not all, children with ADHD. Given the extent to which psychostimulants are prescribed for children, coupled with variable efficacy on an individual level, a better understanding of the mechanisms through which MPH changes brain function and behavior is necessary. MPH's primary action is on catecholamines, including dopamine and norepinephrine. Catecholaminergic signaling can influence the tradeoff between flexibility and stability of brain function, which is one candidate mechanism through which MPH may alter brain function and behavior. Time-varying functional connectivity, which models how functional brain networks reconfigure on short timescales, can be used to examine brain flexibility versus stability, and is thus well-suited to test how MPH impacts brain function. Here, we scanned stimulant-naïve children with ADHD (8-12 years) on and off a single dose of MPH. In the MRI machine, participants completed two attention-demanding tasks: 1) a standard go/no-go task and 2) a rewarded go/no-go task. For both tasks, using a within-subjects design, we compared the degree to which brain organization changed throughout the course of the MRI scan, termed whole brain flexibility, on and off MPH. We found that whole brain flexibility decreased on MPH. Further, individuals with greater decreases in whole brain flexibility on MPH exhibited greater improvements in task performance. Together, these results provide novel insights into the neurobiological mechanisms underlying the effectiveness of MPH administration for children with ADHD.

The authors have declared no competing interest.

NCT04349917

The work presented in this paper was supported in part by National Institute of Mental Health grants R00MH102349 awarded to JRC and F32MH127877 awarded to TN, and National Institute of Child Health and Human Development T32HD40127 awarded to TN. Assistance for this project was provided by the UNC Intellectual and Developmental Disabilities Research Center (NICHD; P50 HD103573; PI: Joseph Piven).

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The Institutional Review Board of The University of North Carolina at Chapel Hill gave ethical approval of this work.

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Data and code used in this manuscript is available upon request to the senior author (JRC).