Single-dose effects of methylphenidate and atomoxetine on functional connectivity during an n-back task in boys with ADHD

RATIONALE: Working memory deficits and associated neurofunctional abnormalities are frequently reported in attention-deficit/hyperactivity disorder (ADHD). Methylphenidate and atomoxetine improve working memory performance and increase activation of regions under-functioning in ADHD. Additionally, methylphenidate has been observed to modulate functional networks involved in working memory. No research, however, has examined the effects of atomoxetine or compared the two drugs. OBJECTIVES: This study aimed to test methylphenidate and atomoxetine effects on functional connectivity during working memory in boys with ADHD. METHODS: We tested comparative effects of methylphenidate and atomoxetine on functional connectivity during the n-back task in 19 medication-naïve boys with ADHD (10–15 years old) relative to placebo and assessed potential normalisation effects of brain dysfunctions under placebo relative to 20 age-matched neurotypical boys. Patients were scanned in a randomised, double-blind, cross-over design under single doses of methylphenidate, atomoxetine, and placebo. Controls were scanned once, unmedicated. RESULTS: Patients under placebo showed abnormally increased connectivity between right superior parietal gyrus (rSPG) and left central operculum/insula. This hyperconnectivity was not observed when patients were under methylphenidate or atomoxetine. Furthermore, under methylphenidate, patients showed increased connectivity relative to controls between right middle frontal gyrus (rMFG) and cingulo-temporo-parietal and striato-thalamic regions, and between rSPG and cingulo-parietal areas. Interrogating these networks within patients revealed increased connectivity between both rMFG and rSPG and right supramarginal gyrus under methylphenidate relative to placebo. Nonetheless, no differences across drug conditions were observed within patients at whole brain level. No drug effects on performance were observed. CONCLUSIONS: This study shows shared modulating effects of methylphenidate and atomoxetine on parieto-insular connectivity but exclusive effects of methylphenidate on connectivity increases in fronto-temporo-parietal and fronto-striato-thalamic networks in ADHD. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00213-023-06422-7.