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
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.