Cited by 171Attention Deficit Hyperactivity DisorderNeural and Behavioral Psychology StudiesNeurotransmitter Receptor Influence on Behavior

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Methylphenidate Normalizes Frontocingulate Underactivation During Error Processing in Attention-Deficit/Hyperactivity Disorder

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Abstract

BACKGROUND: Children with attention-deficit/hyperactivity disorder (ADHD) have deficits in performance monitoring often improved with the indirect catecholamine agonist methylphenidate (MPH). We used functional magnetic resonance imaging to investigate the effects of single-dose MPH on activation of error processing brain areas in medication-naive boys with ADHD during a stop task that elicits 50% error rates. METHODS: Twelve medication-naive boys with ADHD were scanned twice, under either a single clinical dose of MPH or placebo, in a randomized, double-blind design while they performed an individually adjusted tracking stop task, designed to elicit 50% failures. Brain activation was compared within patients under either drug condition. To test for potential normalization effects of MPH, brain activation in ADHD patients under either drug condition was compared with that of 13 healthy age-matched boys. RESULTS: During failed inhibition, boys with ADHD under placebo relative to control subjects showed reduced brain activation in performance monitoring areas of dorsomedial and left ventrolateral prefrontal cortices, thalamus, cingulate, and parietal regions. MPH, relative to placebo, upregulated activation in these brain regions within patients and normalized all activation differences between patients and control subjects. During successful inhibition, MPH normalized reduced activation observed in patients under placebo compared with control subjects in parietotemporal and cerebellar regions. CONCLUSIONS: MPH normalized brain dysfunction in medication-naive ADHD boys relative to control subjects in typical brain areas of performance monitoring, comprising left ventrolateral and dorsomedial frontal and parietal cortices. This could underlie the amelioration of MPH of attention and academic performance in ADHD.

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Crossref · 10.1016/j.biopsych.2011.04.018

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Figure 1 Increased brain activation with the single dose of methylphenidate compared with placebo in patients with attention-deficit/hyperactivity disorder during inhibition failures. Within-group analysis of variance in boys with attention-deficit/hyperactivity disorder comparing methylphenidate and placebo for the inhibition failure condition at family-wise error-corrected cluster-level contrast of p < .05. Methylphenidate compared with placebo enhanced activation in left inferior prefrontal cortex reaching into putamen, in right inferior frontal cortex/insula, reaching into caudate and putamen, in left dorsolateral prefrontal cortex, and in right inferior parietal lobe and precuneus. No brain regions were enhanced under placebo compared with methylphenidate. No within-group activation differences between drug conditions were observed for the successful inhibition contrast. The right side of the figure corresponds to the right side of the brain.
Figure 1 Increased brain activation with the single dose of methylphenidate compared with placebo in patients with attention-deficit/hyperactivity disorder during inhibition failures. Within-group analysis of variance in boys with attention-deficit/hyperactivity disorder comparing methylphenidate and placebo for the inhibition failure condition at family-wise error-corrected cluster-level contrast of p < .05. Methylphenidate compared with placebo enhanced activation in left inferior prefrontal cortex reaching into putamen, in right inferior frontal cortex/insula, reaching into caudate and putamen, in left dorsolateral prefrontal cortex, and in right inferior parietal lobe and precuneus. No brain regions were enhanced under placebo compared with methylphenidate. No within-group activation differences between drug conditions were observed for the successful inhibition contrast. The right side of the figure corresponds to the right side of the brain.CC BY · PubMed Central
Figure 2 Between-group analysis of variance comparison between healthy control boys and boys with attention-deficit/hyperactivity disorder (ADHD) under the placebo condition. Significantly reduced activation in boys with ADHD under placebo compared with healthy comparison boys at family-wise error-corrected cluster-level contrast of p < .05 for (A) failed stop trials and (B) successful stop trials. No increased activation was observed in ADHD boys compared with healthy control boys. Under the methylphenidate condition, brain activation differences between groups were no longer observed in any of the two task conditions. The right side of the image corresponds to the right side of the brain.
Figure 2 Between-group analysis of variance comparison between healthy control boys and boys with attention-deficit/hyperactivity disorder (ADHD) under the placebo condition. Significantly reduced activation in boys with ADHD under placebo compared with healthy comparison boys at family-wise error-corrected cluster-level contrast of p < .05 for (A) failed stop trials and (B) successful stop trials. No increased activation was observed in ADHD boys compared with healthy control boys. Under the methylphenidate condition, brain activation differences between groups were no longer observed in any of the two task conditions. The right side of the image corresponds to the right side of the brain.CC BY · PubMed Central
Figure 3 Conjunction analysis for the stop failure condition: common brain activation clusters that were significantly upregulated with methylphenidate within the attention-deficit/hyperactivity disorder group and which in addition were underactivated in attention-deficit/hyperactivity disorder patients relative to control subjects and then normalized with methylphenidate. The right side of the image corresponds to the right side of the brain.
Figure 3 Conjunction analysis for the stop failure condition: common brain activation clusters that were significantly upregulated with methylphenidate within the attention-deficit/hyperactivity disorder group and which in addition were underactivated in attention-deficit/hyperactivity disorder patients relative to control subjects and then normalized with methylphenidate. The right side of the image corresponds to the right side of the brain.CC BY · PubMed Central

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Cites

Research works printed but not linked: 2

  1. Rubia, 2010, “Cool” inferior frontostriatal dysfunction in attention deficit hyperactivity disorder (ADHD) versus “hot” ventromedial orbitofronto-limbic dysfunction in conduct disorder: A review [published online ahead of print November 20]
  2. Rubia, 2010, Disorder-specific inferior frontal dysfunction in boys with pure attention-deficit/hyperactivity disorder compared to boys with pure CD during cognitive flexibility, Hum Brain Mapp, 31, 1823, 10.1002/hbm.20975 · DOI · Paper page

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Metadata

Authors
Rubia, K., Halari, R., Mohammad, A.-M., Taylor, E., & Brammer, M.
Affiliations
King's College London (GB)
Corresponding author
Rubia, Katya
Venue
Biological Psychiatry
Publisher
Elsevier BV
Published
2011-08
Volume
70
Issue
3
Pages
255-262
ISSN
0006-3223 (ISSN-L)
OpenAlex
W2050444644
Cited by
171
References
92
Citations by year
2026: 7 · 2025: 7 · 2024: 8 · 2023: 7 · 2022: 5 · 2021: 10 · 2020: 8 · 2019: 5 · 2018: 8 · 2017: 14 · 2016: 12 · 2015: 14 · 2014: 19 · 2013: 20 · 2012: 25
FWCI
14.53
Type
journal article
Language
en
Open access
Locations
  • Biological Psychiatry (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Research Portal (King's College London) (submittedVersion)
Funders
  • Medical Research Council (G9900839)
  • PPP Healthcare UK (1206/1140)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Attention Deficit Hyperactivity Disorder
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Neural and Behavioral Psychology Studies
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Keywords
methylphenidate, attention deficit hyperactivity disorder, error processing, performance monitoring, ventrolateral prefrontal cortex, dorsomedial prefrontal cortex, stop-signal task, inhibition, catecholamine agonists
MeSH terms
Adolescent, Central Nervous System Stimulants, Attention, Attention Deficit Disorder with Hyperactivity, Child, Double-Blind Method, Frontal Lobe, Gyrus Cinguli, Humans, Magnetic Resonance Imaging, Male, Methylphenidate, Neuropsychological Tests, Psychomotor Performance

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