Discussion
memory performance deficits, memory deficits, Stevens, ADHD
RECRUITMENT, LACK OF DRUG EFFECT
This study investigated the effects of single doses of methylphenidate and atomoxetine relative to placebo on working memory-related functional connectivity in boys with ADHD and compared to neurotypical controls. Relative to controls, individuals with ADHD under placebo exhibited increased connectivity between rSPG and left central operculum/insula. This cluster was not observed when individuals with ADHD under methylphenidate or atomoxetine were compared to controls. Under methylphenidate, youth with ADHD compared to neurotypical controls showed increased connectivity between rMFG and bilateral insula, ACC, putamen, right thalamus, and other bilateral parieto-temporal regions, as well as between rSPG and predominantly right-hemispheric ACC and parietal areas. No differences, however, were observed within patients across drug conditions or between ADHD participants under atomoxetine and controls. Participants with ADHD under each drug condition showed comparable performance to controls and no effects of drug condition on performance were observed within patients.The hyperconnectivity in youth with ADHD relative to controls between rSPG and left central operculum/insula was no longer observed when individuals with ADHD were under either methylphenidate or atomoxetine. Combined with the lack of difference when comparing drug to placebo directly, the conjunction analysis supports a conclusion that neither medication was associated with complete functional normalisation. Furthermore, under methylphenidate, additional widespread connectivity increases were observed relative to controls between rMFG and fronto-striato-temporo-parietal regions, and between rSPG and cingulo-parietal areas. Additionally, conjunction analyses revealed that methylphenidate-related upregulation of rMFG-SMG and rSPG-SMG connectivity was observed relative to both placebo and controls. Nevertheless, the lack of differences between methylphenidate and placebo sessions across the whole brain within patients complicates the interpretation of this finding. Although our study did not observe as widespread changes in working memory-related connectivity between placebo and methylphenidate sessions as past research (Wong and Stevens The regions showing hyperconnectivity under methylphenidate relative to controls overlap with fronto-parietal networks comprising ACC, middle frontal, postcentral, supramarginal, and lingual gyri shown to be upregulated with stimulants relative to placebo in previous working memory studies in regularly treated youth with ADHD (Wong and Stevens Similar to methylphenidate, atomoxetine led to a partial reduction of rSPG-operculum/insula hyperconnectivity observed in ADHD under placebo relative to controls, while not showing full normalisation or within-patients effects relative to placebo. In contrast to methylphenidate, which enhanced connectivity in several fronto-parieto-temporal and fronto-striato-thalamic regions, atomoxetine did not induce any changes relative to controls. This may be due to the single-dose design of this study. Although single doses of atomoxetine have been shown to modulate brain activation during working memory in this cohort (Cubillo et al. Our observation of abnormally increased rSPG-operculum/insula connectivity in ADHD under placebo compared to controls is consistent with past reports of hyperconnectivity in fronto-parietal networks including SPG in youth with ADHD (Massat et al. Lack of drug effects, case-control differences, or main effects of working memory load within controls on rDLPFC connectivity were unexpected. However, while this region was chosen due to its strong involvement in verbal n-back tasks, this seed was derived from a meta-analysis in adults (Owen et al. Lack of methylphenidate and atomoxetine effects on task performance may be due to the absence of working memory deficits observed in our ADHD cohort. Although there is meta-analytic evidence for working memory performance deficits in ADHD, they seem larger in visuospatial than verbal domain (Martinussen et al. This study is strengthened by a double-blind, placebo-controlled design and inclusion of medication-naïve individuals with ADHD. Considering previous reports of associations between long-term stimulant treatment and structural (Nakao et al. This study is not without limitations. Our participants were unmedicated at the time of the study randomisation potentially because many of them were newly diagnosed with ADHD and have not yet begun medication treatment. While recruitment of a medication-naïve cohort protected against the confounding impact of chronic pharmacological treatment, it may have biased our sample towards those with less severe symptoms (Hong et al. Overall, this is the first study of comparative effects of methylphenidate and atomoxetine on working memory-related functional connectivity in medication-naïve boys with ADHD. We showed that while both drugs shared incomplete normalising effect of abnormally enhanced connectivity in parieto-insular regions, only methylphenidate, but not atomoxetine, led to widespread increases in connectivity within task-relevant networks in ADHD relative to controls. This evidence extends past research showing upregulating effects of methylphenidate on functional connectivity during working memory in ADHD (Wong and Stevens 