Methylphenidate Normalizes Frontocingulate Underactivation During Error Processing in Attention-Deficit/Hyperactivity Disorder
Open accessAbstract
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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Randomized placebo-controlled fMRI studies of acute methylphenidate effects in medication-naïve ADHD boys found increased activation in the cerebellum during attention, time discrimination, and interference inhibition.
“the cerebellum during attention, TD, and interference inhibition 4, 16, 18”
From Effects of stimulants on brain function in attention-deficit/hyperactivity disorder: a systematic review and meta-analysis (2014) · cites this paper as [18]
The Methods describe a randomized, placebo-controlled fMRI study in medication-naïve boys with ADHD, and the Abstract Results report normalization of cerebellar underactivation during successful inhibition. But this study used a motor-response stop task, not attention, time-discrimination, or interference-inhibition tasks. The within-patient comparison found no significant activation difference between methylphenidate and placebo during successful stopping, so it does not establish the claimed cerebellar increase. (LLM, conf=0.86)
Experimental — accuracy not yet measuredRandomized placebo-controlled fMRI studies of acute methylphenidate effects in medication-naïve ADHD boys found increased activation in striatum during reward and response inhibition.
“and striatum during reward and response inhibition 16, 18.”
From Effects of stimulants on brain function in attention-deficit/hyperactivity disorder: a systematic review and meta-analysis (2014) · cites this paper as [18]
The Methods describe a randomized, double-blind, placebo-controlled fMRI study in 12 medication-naïve boys with ADHD. The Brain Activation results report greater putamen and caudate activation with methylphenidate during failed stopping, supporting the response-inhibition portion. This paper did not study reward, and it found no significant medication-related activation difference during successful stopping. The supplied copy gives no page numbers for these sections. (LLM, conf=0.87)
Experimental — accuracy not yet measuredRandomized placebo-controlled fMRI studies of acute methylphenidate effects in medication-naïve ADHD boys found increased activation in predominantly right, but also left, IFC during tasks of sustained attention, inhibition, and time discrimination.
“Randomized placebo-controlled fMRI studies of acute methylphenidate effects in medication-naïve ADHD boys using whole-brain image analyses found increased activation in predominantly right, but also left, IFC during tasks of sustained attention, inhibition, and time discrimination (TD) 4, 16, 17, 18”
From Effects of stimulants on brain function in attention-deficit/hyperactivity disorder: a systematic review and meta-analysis (2014) · cites this paper as [18]
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredTen datasets compared methylphenidate with placebo on brain function in medication-naïve patients in randomized controlled designs.
“Ten datasets compared methylphenidate with placebo on brain function in medication-naïve patients in randomized controlled designs 4, 16, 17, 18”
From Effects of stimulants on brain function in attention-deficit/hyperactivity disorder: a systematic review and meta-analysis (2014) · cites this paper as [18]
Randomized placebo-controlled fMRI studies of acute methylphenidate effects in medication-naïve ADHD boys found increased activation in parietal regions during sustained attention, error monitoring, and interference inhibition.
“in parietal regions during sustained attention, error monitoring, and interference inhibition 16, 17, 18”
From Effects of stimulants on brain function in attention-deficit/hyperactivity disorder: a systematic review and meta-analysis (2014) · cites this paper as [18]
Most fMRI studies found methylphenidate to have a positive effect on brain activation, but only some observed performance improvement.
“While most fMRI studies found methylphenidate to have a positive effect on brain activation, only some studies observed performance improvement 18, 21, 24, 25, 26, 74, 75, likely reflecting the superior sensitivity of fMRI relative to behavior to detect pharmacologic effects or the relatively small subject numbers of fMRI studies, underpowered for performance effects.”
From Effects of stimulants on brain function in attention-deficit/hyperactivity disorder: a systematic review and meta-analysis (2014) · cites this paper as [18]
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- [11]Rubia K. “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] Biol Psychiatry 2010 21094938
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Hart, H., Radua, J., Nakao, T., Mataix-Cols, D., & Rubia, K. (2013) · JAMA Psychiatry · doi:10.1001/jamapsychiatry.2013.277 · Cited by 764 · see citing works
Self-citationNeuroimaging of child abuse: a critical review
Hart, H., & Rubia, K. (2012) · Frontiers in Human Neuroscience · doi:10.3389/fnhum.2012.00052 · Cited by 660 · see citing works
Self-citationRubia, K. (2018) · Frontiers in Human Neuroscience · doi:10.3389/fnhum.2018.00100 · Cited by 384 · see citing works
“Thus, during cognitive control tasks, IFC was found to be disorder-specifically reduced compared to OCD patients in individual fMRI studies (Rubia et al., 2010a, 2011a), as well as in a comparative fMRI meta-analysis of cognitive control functions, including motor and interference inhibition and…”
Self-citationNoreika, V., Falter, C. M., & Rubia, K. (2013) · Neuropsychologia · doi:10.1016/j.neuropsychologia.2012.09.036 · Cited by 339 · see citing works
Self-citationRubia, K., Alegria, A. A., Cubillo, A. I., Smith, A. B., Brammer, M. J., & Radua, J. (2014) · Biological Psychiatry · doi:10.1016/j.biopsych.2013.10.016 · Cited by 315 · see citing works
Self-citationBeauchaine, T. P., & McNulty, T. (2013) · Development and Psychopathology · doi:10.1017/s0954579413000746 · Cited by 288 · see citing works
Measurement and Reliability of Response Inhibition
Congdon, E. L., Mumford, J. A., Cohen, J. R., Galván, A., Canli, T., & Poldrack, R. A. (2012) · Frontiers in Psychology · doi:10.3389/fpsyg.2012.00037 · Cited by 298 · see citing works
Coghill, D. R., Seth, S., Pedroso, S., Usala, T., Currie, J., & Gagliano, A. (2014) · Biological Psychiatry · doi:10.1016/j.biopsych.2013.10.005 · Cited by 271 · see citing works
Cortese, S. (2012) · European Journal of Paediatric Neurology · doi:10.1016/j.ejpn.2012.01.009 · Cited by 335 · see citing works
Meta-analysis of fMRI studies of timing in attention-deficit hyperactivity disorder (ADHD)
Hart, H., Radua, J., Mataix-Cols, D., & Rubia, K. (2012) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2012.08.003 · Cited by 258 · see citing works
Self-citationLukito, S., Norman, L., Carlisi, C., Radua, J., Hart, H., Simonoff, E., & Rubia, K. (2020) · Psychological Medicine · doi:10.1017/s0033291720000574 · Cited by 248 · see citing works
Self-citationFusar-Poli, P., Rubia, K., Rossi, G., Sartori, G., & Balottin, U. (2012) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2011.11060940 · Cited by 260 · see citing works
Self-citationRos, T., Théberge, J., Frewen, P., Kluetsch, R. C., Densmore, M., Calhoun, V. D., & Lanius, R. A. (2012) · NeuroImage · doi:10.1016/j.neuroimage.2012.09.046 · Cited by 251 · see citing works
Trait Impulsivity and the Externalizing Spectrum
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McCarthy, H., Skokauskas, N., & Frodl, T. (2014) · Psychological Medicine · doi:10.1017/s0033291713001037 · Cited by 156 · see citing works
Response Inhibition and Interference Control in Obsessive–Compulsive Spectrum Disorders
van Velzen, L. S., Vriend, C., de Wit, S. J., & van den Heuvel, O. A. (2014) · Frontiers in Human Neuroscience · doi:10.3389/fnhum.2014.00419 · Cited by 159 · see citing works
Alegria, A. A., Wulff, M., Brinson, H., Barker, G. J., Norman, L. J., Brandeis, D., Stahl, D., David, A. S., Taylor, E., Giampietro, V., et al. (2017) · Human Brain Mapping · doi:10.1002/hbm.23584 · Cited by 151 · see citing works
Self-citationIntegration of an EEG biomarker with a clinician's ADHD evaluation
Snyder, S. M., Rugino, T. A., Hornig, M., & Stein, M. A. (2015) · Brain and Behavior · doi:10.1002/brb3.330 · Cited by 165 · see citing works
Imaging the ADHD brain: disorder-specificity, medication effects and clinical translation
Rubia, K., Alegria, A., & Brinson, H. (2014) · Expert Review of Neurotherapeutics · doi:10.1586/14737175.2014.907526 · Cited by 146 · see citing works
Self-citationEffect of Psychostimulants on Brain Structure and Function in ADHD
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Rubia, K., Lim, L., Ecker, C., Halari, R., Giampietro, V., Simmons, A., Brammer, M., & Smith, A. (2013) · NeuroImage · doi:10.1016/j.neuroimage.2013.06.078 · Cited by 133 · see citing works
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Hart, H. C., Chantiluke, K. C., Cubillo, A., Smith, A. B., Simmons, A., Brammer, M. J., Marquand, A. F., & Rubia, K. (2013) · Human Brain Mapping · doi:10.1002/hbm.22386 · Cited by 135 · see citing works
Self-citationPandolfo, P., Machado, N. J., Köfalvi, A., Takahashi, R. N., & Cunha, R. A. (2013) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2012.04.011 · Cited by 118 · see citing works
Cubillo, A., Smith, A. B., Barrett, N., Giampietro, V., Brammer, M. J., Simmons, A., & Rubia, K. (2014) · Cerebral Cortex · doi:10.1093/cercor/bhs296 · Cited by 116 · see citing works
Self-citationImproving Response Inhibition in Parkinson’s Disease with Atomoxetine
Ye, Z., Altena, E., Nombela, C., Housden, C. R., Maxwell, H., Rittman, T., Huddleston, C., Rae, C. L., Regenthal, R., Sahakian, B. J., et al. (2014) · Biological Psychiatry · doi:10.1016/j.biopsych.2014.01.024 · Cited by 104 · see citing works
Brain abnormalities in attention-deficit hyperactivity disorder: a review.
Rubia, K., Alegría, A. A., & Brinson, H. (2014) · PubMed · Cited by 96 · see citing works
Self-citationSchweren, L., de Zeeuw, P., & Durston, S. (2012) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2012.10.014 · Cited by 95 · see citing works
Neurobiology of ADHD From Childhood to Adulthood
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Neurotherapeutics for Attention Deficit/Hyperactivity Disorder (ADHD): A Review
Rubia, K., Westwood, S. J., Aggensteiner, P.-M., & Brandeis, D. (2021) · Cells · doi:10.3390/cells10082156 · Cited by 88 · see citing works
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Self-citationPutting the brakes on inhibitory models of frontal lobe function
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Kowalczyk, O. S., Cubillo, A. I., Smith, A., Barrett, N., Giampietro, V., Brammer, M., Simmons, A., & Rubia, K. (2019) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2019.07.139 · Cited by 63 · see citing works
Self-citationMethylphenidate Effects on Neural Activity During Response Inhibition in Healthy Humans
Costa, A. C. L., Riedel, M. J., Pogarell, O. M., Menzel-Zelnitschek, F., Schwarz, M., Reiser, M. F., Möller, H., Rubia, K., Meindl, T., & Ettinger, U. (2012) · Cerebral Cortex · doi:10.1093/cercor/bhs107 · Cited by 69 · see citing works
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Chantiluke, K., Barrett, N., Giampietro, V., Santosh, P., Brammer, M., Simmons, A., Murphy, D. G., & Rubia, K. (2015) · Psychopharmacology · doi:10.1007/s00213-014-3837-2 · Cited by 63 · see citing works
Self-citationLim, L. L., Chantiluke, K. C., Cubillo, A., Smith, A. B., Simmons, A., Mehta, M. A., & Rubia, K. (2014) · Psychological Medicine · doi:10.1017/s0033291714001974 · Cited by 61 · see citing works
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Self-citationTreatment biomarkers for ADHD: Taking stock and moving forward
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Methylphenidate Effects on Prefrontal Functioning During Attentional-Capture and Response Inhibition
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Precision Medicine Care in ADHD: The Case for Neural Excitation and Inhibition
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Anomalías cerebrales en el trastorno por déficit de atención/hiperactividad: una revisión
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Neural Correlates of Treatment in Adolescents with Bipolar Depression During Response Inhibition
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Exercise Improves Cognitive Control: Evidence from the Stop Signal Task
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Functional imaging changes in the medial prefrontal cortex in adult ADHD
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Anterior insula hyperactivation in ADHD when faced with distracting negative stimuli
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Self-citationSegregating sustained attention from response inhibition in ADHD: An fMRI study
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What happens when children encounter an error?
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The Neural Effects of Psychotropic Medications in Children and Adolescents
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From neurons to brain networks, pharmacodynamics of stimulant medication for ADHD
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Reduced Neural Error Signaling in Left Inferior Prefrontal Cortex in Young Adults With ADHD
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Integrative genomic analysis of methylphenidate response in attention-deficit/hyperactivity disorder
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Decreased Cingulate Cortex activation during cognitive control processing in bipolar disorder
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Pre-trauma Methylphenidate in rats reduces PTSD-like reactions one month later
Ritov, G., & Richter‐Levin, G. (2017) · Translational Psychiatry · doi:10.1038/tp.2016.277 · Cited by 17 · see citing works
Manza, P., Hu, S., Ide, J. S., Farr, O. M., Zhang, S., Leung, H., & Li, C. R. (2016) · Journal of Psychopharmacology · doi:10.1177/0269881115625102 · Cited by 15 · see citing works
- 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)
- PMC
- PMC3139835
- 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
- hybrid
- doi.org
- 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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