Neurofunctional Effects of Methylphenidate and Atomoxetine in Boys with Attention-Deficit/Hyperactivity Disorder During Time Discrimination
Abstract
Background The catecholamine agonists methylphenidate and atomoxetine effectively treat attention-deficit/hyperactivity disorder (ADHD). Furthermore, dopamine agonists have shown to improve time estimation in ADHD, a core cognitive deficit. However, few have compared the effects of methylphenidate and atomoxetine on brain function in ADHD, and none during time estimation. Using single dose challenges, we investigated shared and drug-specific effects in ADHD adolescents on the neural substrates of time discrimination (TD). Methods Twenty ADHD adolescent male subjects were compared in a randomized double-blind cross-over design after single doses of methylphenidate, atomoxetine, and placebo in functional magnetic resonance imaging during TD. Normalization effects were assessed by comparing brain activation under each drug condition with that of 20 healthy age-matched control subjects. Results Relative to control subjects, patients under placebo showed TD deficits and reduced activation of ventrolateral prefrontal cortex (VLPFC)/insula, inferior frontal cortex, and supplementary motor area. Performance differences were normalized only by methylphenidate, relative to both atomoxetine and placebo. Both medications, however, significantly upregulated right VLPFC/insula activation within patients and normalized its underactivation in ADHD boys under placebo relative to control subjects. The supplementary motor area and inferior frontal cortex activation differences that were observe…
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In the authors' four fMRI studies comparing single dosages of methylphenidate and atomoxetine versus placebo on brain activation in children and adolescents with ADHD, reduced activation in frontal, parietal, temporal, and insular-striatal regions during cognitive tasks can be increased (and even normalized) by both stimulant and non-stimulant medications.
“Thus, in our four fMRI studies comparing the effects of single dosages of methylphenidate and atomoxetine versus placebo on brain activation in children and adolescents with ADHD (45, 85–87), we found that reduced activation in frontal, parietal, temporal, and insular-striatal regions during cognitive tasks can be increased (and even normalized) by both stimulant and non-stimulant medications.”
From Differential effects of a single dose of Lisdexamfetamine and Guanfacine on cognitive function in children with ADHD (2025) · cites this paper as [87]
ROI fMRI studies found methylphenidate significantly enhanced right IFC activation during time discrimination together with atomoxetine.
“and during time discrimination together with atomoxetine (24).”
From Effects of stimulants on brain function in attention-deficit/hyperactivity disorder: a systematic review and meta-analysis (2014) · cites this paper as [24]
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 [24]
Acute methylphenidate normalized the underactivation in right IFC in ADHD patients under placebo compared with healthy control subjects during inhibition and timing processes.
“Furthermore, acute methylphenidate normalized the underactivation in right IFC that was observed in ADHD patients under placebo compared with healthy control subjects during inhibition and timing processes [see also 23, 24], which has also been observed previously during interference inhibition (17), motor inhibition 18, 23, WM (72), and TD (4) (Table S2 in Supplement 1).”
From Effects of stimulants on brain function in attention-deficit/hyperactivity disorder: a systematic review and meta-analysis (2014) · cites this paper as [24]
The new whole-brain analysis of three previously published fMRI ROI datasets comparing methylphenidate relative to placebo only was included in the meta-analysis.
“The new whole-brain analysis of our three previously published fMRI ROI datasets 3, 22, 24, comparing methylphenidate relative to placebo only, was included in the meta-analysis.”
From Effects of stimulants on brain function in attention-deficit/hyperactivity disorder: a systematic review and meta-analysis (2014) · cites this paper as [24]
Studies that directly compare the neural bases of stimulants and nonstimulants are limited.
“and studies that directly compare the neural bases of stimulants and nonstimulants are limited”
From Overlapping and differential neuropharmacological mechanisms of stimulants and nonstimulants for attention-deficit/hyperactivity disorder: A comparative neuroimaging analysis (2024) · cites this paper as Smith et al., 2013
It remains unknown whether dissociable therapeutic responses to medications are mediated by shared or distinct neural underpinnings.
“However, it remains unknown whether dissociable therapeutic responses to medications are mediated by shared or distinct neural underpinnings”
From Overlapping and differential neuropharmacological mechanisms of stimulants and nonstimulants for attention-deficit/hyperactivity disorder: A comparative neuroimaging analysis (2024) · cites this paper as Smith et al., 2013
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- Authors
- Smith, A., Cubillo, A., Barrett, N., Giampietro, V., Simmons, A., Brammer, M., & Rubia, K.
- Affiliations
- King's College London (GB)
- National Health Service (GB)
- Corresponding author
- Smith, Anna
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2013-10
- Volume
- 74
- Issue
- 8
- Pages
- 615-622
- ISSN
- 0006-3223 (ISSN-L)
- OpenAlex
- W1990810316
- Cited by
- 53
- References
- 13
- Citations by year
- 2025: 3 · 2024: 4 · 2023: 2 · 2022: 2 · 2021: 2 · 2020: 7 · 2019: 3 · 2018: 6 · 2017: 4 · 2016: 6 · 2015: 5 · 2014: 5 · 2013: 3 · 2012: 1
- FWCI
- 4.49
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Research Portal (King's College London) (submittedVersion)
- 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
- attention deficit hyperactivity disorder, methylphenidate, atomoxetine, temporal discrimination, time estimation, ventrolateral prefrontal cortex, insula, supplementary motor area, inferior frontal cortex, catecholamine agonists, dopamine agonists, stimulants, adolescents
- MeSH terms
- Atomoxetine Hydrochloride, Adolescent, Attention Deficit Disorder with Hyperactivity, Brain, Brain Mapping, Discrimination, Psychological, Double-Blind Method, Humans, Magnetic Resonance Imaging, Male, Methylphenidate, Propylamines, Time Factors, Prefrontal Cortex, Cross-Over Studies
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