Methylphenidate Enhances Spontaneous Fluctuations in Reward and Cognitive Control Networks in Children With Attention-Deficit/Hyperactivity Disorder

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

doi:10.1016/j.bpsc.2022.10.001

Methylphenidate Enhances Spontaneous Fluctuations in Reward and Cognitive Control Networks in Children With Attention-Deficit/Hyperactivity Disorder

Biol Psychiatry Cogn Neurosci Neuroimaging. 2023 Mar;8(3):271-280. doi: 10.1016/j.bpsc.2022.10.001. Epub 2022 Oct 23.

Authors

Yoshifumi Mizuno¹, Weidong Cai², Kaustubh Supekar², Kai Makita³, Shinichiro Takiguchi⁴, Timothy J Silk⁵, Akemi Tomoda⁶, Vinod Menon⁷

Affiliations

¹ Department of Psychiatry & Behavioral Sciences, Stanford University School of Medicine, Stanford, California; Research Center for Child Mental Development, University of Fukui, Fukui, Japan; Division of Developmental Higher Brain Functions, United Graduate School of Child Development, University of Fukui, Fukui, Japan; Department of Child and Adolescent Psychological Medicine, University of Fukui Hospital, Fukui, Japan. Electronic address: mizunoy@u-fukui.ac.jp.
² Department of Psychiatry & Behavioral Sciences, Stanford University School of Medicine, Stanford, California; Wu Tsai Neurosciences Institute, Stanford University, Stanford, California; Maternal & Child Health Research Institute, Stanford University, Stanford, California.
³ Research Center for Child Mental Development, University of Fukui, Fukui, Japan; Division of Developmental Higher Brain Functions, United Graduate School of Child Development, University of Fukui, Fukui, Japan.
⁴ Division of Developmental Higher Brain Functions, United Graduate School of Child Development, University of Fukui, Fukui, Japan; Department of Child and Adolescent Psychological Medicine, University of Fukui Hospital, Fukui, Japan.
⁵ Centre for Social and Early Emotional Development and School of Psychology, Deakin University, Geelong, Victoria, Australia; Murdoch Children's Research Institute, Parkville, Victoria, Australia.
⁶ Research Center for Child Mental Development, University of Fukui, Fukui, Japan; Division of Developmental Higher Brain Functions, United Graduate School of Child Development, University of Fukui, Fukui, Japan; Department of Child and Adolescent Psychological Medicine, University of Fukui Hospital, Fukui, Japan.
⁷ Department of Psychiatry & Behavioral Sciences, Stanford University School of Medicine, Stanford, California; Department of Neurology and Neurological Sciences, Stanford University, Stanford, California; Wu Tsai Neurosciences Institute, Stanford University, Stanford, California; Maternal & Child Health Research Institute, Stanford University, Stanford, California. Electronic address: menon@stanford.edu.

PMID: 36717325
DOI: 10.1016/j.bpsc.2022.10.001

Abstract

Background: Methylphenidate, a first-line treatment for attention-deficit/hyperactivity disorder (ADHD), is thought to influence dopaminergic neurotransmission in the nucleus accumbens (NAc) and its associated brain circuitry, but this hypothesis has yet to be systematically tested.

Methods: We conducted a randomized, placebo-controlled, double-blind crossover trial including 27 children with ADHD. Children with ADHD were scanned twice with resting-state functional magnetic resonance imaging under methylphenidate and placebo conditions, along with assessment of sustained attention. We examined spontaneous neural activity in the NAc and the salience, frontoparietal, and default mode networks and their links to behavioral changes. Replicability of methylphenidate effects on spontaneous neural activity was examined in a second independent cohort.

Results: Methylphenidate increased spontaneous neural activity in the NAc and the salience and default mode networks. Methylphenidate-induced changes in spontaneous activity patterns in the default mode network were associated with improvements in intraindividual response variability during a sustained attention task. Critically, despite differences in clinical trial protocols and data acquisition parameters, the NAc and the salience and default mode networks showed replicable patterns of methylphenidate-induced changes in spontaneous activity across two independent cohorts.

Conclusions: We provide reproducible evidence demonstrating that methylphenidate enhances spontaneous neural activity in NAc and cognitive control networks in children with ADHD, resulting in more stable sustained attention. Our findings identified a novel neural mechanism underlying methylphenidate treatment in ADHD to inform the development of clinically useful biomarkers for evaluating treatment outcomes.

Keywords: Attention-deficit/hyperactivity disorder; Default mode network; Methylphenidate; Nucleus accumbens; Salience network; Spontaneous neural activity.

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*
Brain
Child
Cognition
Humans
Methylphenidate* / pharmacology
Methylphenidate* / therapeutic use
Reward

Substances

Methylphenidate