Methylphenidate remediates aberrant brain network dynamics in children with attention-deficit/hyperactivity disorder: A randomized controlled trial

Yoshifumi Mizuno; Weidong Cai; Kaustubh Supekar; Kai Makita; Shinichiro Takiguchi; Akemi Tomoda; Vinod Menon

doi:10.1016/j.neuroimage.2022.119332

Methylphenidate remediates aberrant brain network dynamics in children with attention-deficit/hyperactivity disorder: A randomized controlled trial

Neuroimage. 2022 Aug 15:257:119332. doi: 10.1016/j.neuroimage.2022.119332. Epub 2022 May 28.

Authors

Yoshifumi Mizuno¹, Weidong Cai², Kaustubh Supekar², Kai Makita³, Shinichiro Takiguchi⁴, Akemi Tomoda⁵, Vinod Menon⁶

Affiliations

¹ Department of Psychiatry & Behavioral Sciences, Stanford University School of Medicine, Stanford, CA 94304, USA; Research Center for Child Mental Development, University of Fukui, Fukui, 910-1193, Japan; Division of Developmental Higher Brain Functions, United Graduate School of Child Development, University of Fukui, Fukui, 910-1193, Japan; Department of Child and Adolescent Psychological Medicine, University of Fukui Hospital, Fukui, 910-1193, Japan. Electronic address: mizunoy@u-fukui.ac.jp.
² Department of Psychiatry & Behavioral Sciences, Stanford University School of Medicine, Stanford, CA 94304, USA; Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA 94304, USA; Maternal & Child Health Research Institute, Stanford University, Stanford, CA 94304, USA.
³ Research Center for Child Mental Development, University of Fukui, Fukui, 910-1193, Japan; Division of Developmental Higher Brain Functions, United Graduate School of Child Development, University of Fukui, Fukui, 910-1193, Japan.
⁴ Division of Developmental Higher Brain Functions, United Graduate School of Child Development, University of Fukui, Fukui, 910-1193, Japan; Department of Child and Adolescent Psychological Medicine, University of Fukui Hospital, Fukui, 910-1193, Japan.
⁵ Research Center for Child Mental Development, University of Fukui, Fukui, 910-1193, Japan; Division of Developmental Higher Brain Functions, United Graduate School of Child Development, University of Fukui, Fukui, 910-1193, Japan; Department of Child and Adolescent Psychological Medicine, University of Fukui Hospital, Fukui, 910-1193, Japan. Electronic address: atomoda@u-fukui.ac.jp.
⁶ Department of Psychiatry & Behavioral Sciences, Stanford University School of Medicine, Stanford, CA 94304, USA; Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA 94304, USA; Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA 94304, USA; Maternal & Child Health Research Institute, Stanford University, Stanford, CA 94304, USA.

Abstract

Methylphenidate is a widely used first-line treatment for attention deficit/hyperactivity disorder (ADHD), but the underlying circuit mechanisms are poorly understood. Here we investigate whether a single dose of osmotic release oral system methylphenidate can remediate attention deficits and aberrancies in functional circuit dynamics in cognitive control networks, which have been implicated in ADHD. In a randomized placebo-controlled double-blind crossover design, 27 children with ADHD were scanned twice with resting-state functional MRI and sustained attention was examined using a continuous performance task under methylphenidate and placebo conditions; 49 matched typically-developing (TD) children were scanned once for comparison. Dynamic time-varying cross-network interactions between the salience (SN), frontoparietal (FPN), and default mode (DMN) networks were examined in children with ADHD under both administration conditions and compared with TD children. Methylphenidate improved sustained attention on a continuous performance task in children with ADHD, when compared to the placebo condition. Children with ADHD under placebo showed aberrancies in dynamic time-varying cross-network interactions between the SN, FPN and DMN, which were remediated by methylphenidate. Multivariate classification analysis confirmed that methylphenidate remediates aberrant dynamic brain network interactions. Furthermore, dynamic time-varying network interactions under placebo conditions predicted individual differences in methylphenidate-induced improvements in sustained attention in children with ADHD. These findings suggest that a single dose of methylphenidate can remediate deficits in sustained attention and aberrant brain circuit dynamics in cognitive control circuits in children with ADHD. Findings identify a novel brain circuit mechanism underlying a first-line pharmacological treatment for ADHD, and may inform clinically useful biomarkers for evaluating treatment outcomes.

Keywords: Attention-deficit/hyperactivity disorder; Cognitive control network; Dynamic time-varying cross-network interaction; Methylphenidate; Salience network.

Publication types

Randomized Controlled Trial
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Attention Deficit Disorder with Hyperactivity* / diagnostic imaging
Attention Deficit Disorder with Hyperactivity* / drug therapy
Brain
Central Nervous System Stimulants* / pharmacology
Child
Double-Blind Method
Humans
Magnetic Resonance Imaging
Methylphenidate*

Substances

Central Nervous System Stimulants
Methylphenidate

Abstract

Publication types

MeSH terms

Substances

Grants and funding