A better understanding of how the most commonly used ADHD medications work

Abstract: Study reveals how methylphenidate interacts with cognitive control networks and attentional behavior. Methylphenidate alters spontaneous neural activity in reward and cognitive control systems in children with ADHD. The changes result in more stable sustained attention.

Source: Elsevier

For decades, doctors have treated children with attention deficit/hyperactivity disorder (ADHD) with methylphenidate, a stimulant marketed as Ritalin and Concerta, making it one of the most commonly prescribed drugs targeting the central nervous system. One might expect that researchers would know by now how methylphenidate works in the brain, but little is known about the drug’s mechanism of action.

Now, a new study seeks to close this gap and understand how methylphenidate affects cognitive control networks and attentional behavior.

A new study appears in Biological psychiatry: cognitive neuroscience and neuroimaging.

What researchers do know is that people with ADHD have lower dopamine signaling activity than neurotypicals in interconnected brain networks that control attention and goal-directed behavior.

Specifically, methylphenidate is hypothesized to alleviate ADHD symptoms by increasing dopamine levels in the nucleus accumbens (NAc), the center of dopamine signaling.

In the new study, researchers led by Yoshifumi Mizuno, MD, Ph.D., Weidong Cai, Ph.D., and Vinod Menon, Ph.D., used brain imaging to investigate the effects of methylphenidate on the NAc and the so-called triple network system that plays a key role in behaviors that require adaptive control of attention.

The three networks include the salient, frontoparietal, and default networks. Aberrant activity was detected in the NAc and in multiple brain networks in children with ADHD, suggesting that dysregulation in the system may underlie ADHD symptoms, and that correcting the dysfunction may alleviate these symptoms.

“Our findings show in two independent cohorts that methylphenidate alters spontaneous neural activity in reward and cognitive control systems in children with ADHD. Drug-induced changes in cognitive control networks result in more stable sustained attention.

“Our findings reveal a novel brain mechanism underlying the treatment of ADHD with methylphenidate and inform the development of biomarkers to assess treatment outcomes,” said Dr. Menon, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine.

Researchers used functional magnetic resonance imaging (fMRI) to measure the effects of methylphenidate on spontaneous brain activity in 27 children with ADHD and 49 typically developing control children. The children with ADHD were scanned at two different visits, one to six weeks apart – once while receiving methylphenidate and once while receiving a placebo. (Developing children typically did not receive drugs or placebos.)

Outside the scanner, children with ADHD also completed a standardized task to assess sustained attention. In addition, the researchers tested the replication of the effects of methylphenidate on spontaneous brain activity in another independent cohort.

Not surprisingly, the children performed better on attention tasks when medicated. And as the researchers hypothesized, they also saw greater spontaneous neural activity in the NAc and the salience and default networks when methylphenidate was administered.

Children with ADHD who showed enhanced changes in brain activity patterns in the drug default mode network performed better on medicated attention tasks.

The findings were replicated in two independent cohorts, providing further evidence that methylphenidate can alleviate ADHD symptoms through its effects on the NAc and the triple network cognitive system.

Cameron Carter, MD, Editor Biological psychiatry: cognitive neuroscience and neuroimagingsaid of the study: “The findings, which used a widely available resting-state functional MRI technique, confirm the positive effects of methylphenidate on attention in children with ADHD and reveal a likely mechanism of action, through enhanced coordinated brain network activity and a likely key role for the enhanced effects of dopamine in the NAc region of the brain.”

The work advances researchers’ understanding of how ADHD affects cognitive control networks in the brain and how methylphenidate interacts with these networks to change behavior. The findings could guide future work using brain imaging as a clinically useful biomarker of response to treatments.

About this ADHD and neuropsychopharmacology research news

Author: Press office
Source: Elsevier
Contact: Press office – Elsevier
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Original research: Open access.
“Methylphenidate enhances spontaneous fluctuations in reward and cognitive control networks in children with attention-deficit/hyperactivity disorder” Yoshifumi Mizuno et al. Biological psychiatry: cognitive neuroscience and neuroimaging

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Abstract

Methylphenidate enhances spontaneous fluctuations in reward and cognitive control networks in children with attention-deficit/hyperactivity disorder

Background

Methylphenidate, the first-line treatment for attention deficit/hyperactivity disorder (ADHD), is thought to affect dopaminergic neurotransmission in the nucleus accumbens (NAc) and related brain circuits, but this hypothesis has yet to be systematically tested.

Methods

We conducted a randomized, placebo-controlled, double-blind crossover trial with 27 children with ADHD. Children with ADHD were scanned twice with resting-state functional MRI under methylphenidate and placebo conditions, with sustained attention assessed. We examined spontaneous neural activity in the NAc and saliency networks, frontoparietal and default modes, and their associations with behavioral changes. The replicability of the effects of methylphenidate on spontaneous neural activity was examined in another independent cohort.

the results

Methylphenidate increased spontaneous neural activity in the NAc, and salience and default networks. Methylphenidate-induced changes in spontaneous activity patterns in the default mode network are associated with improvements in within-individual response variability during a sustained attention task. Critically, despite differences in clinical trial protocols and data collection parameters, the NAc and salience and default mode networks showed replicated patterns of methylphenidate-induced changes in spontaneous activity in two independent groups.

Findings

We provide replicable evidence showing that methylphenidate enhances spontaneous neuronal activity in the NAc and cognitive control networks in children with ADHD, resulting in more stable sustained attention. The findings identify a novel neural mechanism underlying the treatment of ADHD with methylphenidate and inform the development of clinically useful biomarkers to assess treatment outcomes.