Neurofunctional Effects of Methylphenidate and Atomoxetine in Boys with Attention-Deficit/Hyperactivity Disorder During Time Discrimination

doi:10.1016/j.biopsych.2013.03.030

Biological Psychiatry

Volume 74, Issue 8, 15 October 2013, Pages 615-622

https://doi.org/10.1016/j.biopsych.2013.03.030 Get rights and content

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 observed under placebo were reduced by methylphenidate and atomoxetine, respectively, but neither survived rigorous testing for normalization.

Conclusions

While only methylphenidate had a drug-specific effect of improving TD performance deficits, both drugs significantly upregulated and normalized right VLPFC underactivation in ADHD boys under placebo relative to control subjects, suggesting shared effects of stimulants and nonstimulants on a key prefrontal dysfunction during timing.

Section snippets

Participants

Twenty-eight primarily medication-naive, right-handed adolescent boys between 10 and 17 years old (mean age of final sample: 12 years, 11 months [SD: 1 year, 7 months]) with a clinical diagnosis of inattentive/hyperactive-impulsive combined ADHD, as assessed by an experienced child psychiatrist using the standardized Maudsley diagnostic interview (29), which assesses ADHD according to DSM-IV-Text Revision criteria (30), were recruited from clinics. One patient had a brief medication trial of

Task Performance

Repeated measures ANOVAs within ADHD under each medication condition were significant for TD errors (F_2,39 = 4.8; p < .02), due to fewer TD errors in ADHD patients during the methylphenidate condition relative to placebo (p < .06) and atomoxetine (p < .03), but not for TOJ errors (F_2,39 = .1, p = .48) (Table 1).

A series of ANOVAs comparing errors between control and ADHD boys under each medication condition revealed for the ADHD placebo-control comparison, a significant effect of condition (F

Discussion

This study demonstrates a relatively superior effect of a single dose of methylphenidate compared with placebo and atomoxetine on TD performance in ADHD boys but shared effects on the underlying neurofunctional networks of TD. Compared with control subjects, ADHD boys under placebo made significantly more TD but not TOJ errors and had reduced activation in typical areas of TD in right VLPFC/insula, right IFC, and SMA/ACC. Methylphenidate relative to atomoxetine and placebo significantly

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Meta-analysis: Altered Perceptual Timing Abilities in Attention-Deficit/Hyperactivity Disorder
2022, Journal of the American Academy of Child and Adolescent Psychiatry
We meta-analyzed studies comparing perceptual timing abilities in the range of milliseconds to several seconds in persons with attention-deficit/hyperactivity disorder (ADHD) and neurotypical participants, using the well-established time discrimination, time estimation, time production, and time reproduction paradigms.
We searched PubMed, OVID databases, and Web of Knowledge through September 17, 2020. From 2,266 records, 55 studies were retained and meta-analyzed with random effects models. We conducted meta-regression analyses to explore moderating effects of task parameters and neuropsychological measures of working memory, attention, and inhibition on timing performance.
Compared with persons without ADHD, those with ADHD had significantly more severe difficulties in discriminating stimuli of very brief durations, especially in the sub-second range. They also had more variability in estimating the duration of stimuli lasting several seconds. Moreover, they showed deficits in time estimation and time production accuracy, indicative of an accelerated internal clock. Additional deficits in persons with ADHD were also found in the time reproduction paradigm, involving attentional (slower counting at short time intervals due to distraction) and motivational (faster counting at long time intervals due to increased delay aversion) functions.
There is meta-analytic evidence of a broad range of timing deficits in persons with ADHD. Results have implications for advancing our knowledge in the field (eg, for refinement of recent timing models in ADHD) and clinical practice (eg, testing timing functions to characterize the clinical phenotype of the patient and implementation of interventions to improve timing abilities).
Systematic Review: Medication Effects on Brain Intrinsic Functional Connectivity in Patients With Attention-Deficit/Hyperactivity Disorder
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Resting-state functional magnetic resonance imaging (R-fMRI) studies of the neural correlates of medication treatment in attention-deficit/hyperactivity disorder (ADHD) have not been systematically reviewed. Our objective was to systematically identify, assess and summarize within-subject R-fMRI studies of pharmacological-induced changes in patients with ADHD. We critically appraised strengths and limitations, and provide recommendations for future research.
Systematic review of published original reports in English meeting criteria in pediatric and adult patients with ADHD up to July 1, 2020. A thorough search preceded selection of studies matching prespecified criteria. Strengths and limitations of selected studies, regarding design and reporting, were identified based on current best practices.
We identified and reviewed 9 studies (5 pediatric and 4 adult studies). Sample sizes were small-medium (16–38 patients), and included few female participants. Medications were methylphenidate, amphetamines, and atomoxetine. Wide heterogeneity was observed in designs, analyses and results, which could not be combined quantitatively. Qualitatively, the multiplicity of brain regions and networks identified, some of which correlated with clinical improvements, do not support a coherent mechanistic hypothesis of medication effects. Overall, reports did not meet current standards to ensure reproducibility.
In this emerging field, the few studies using R-fMRI to analyze the neural correlates of medications in patients with ADHD suggest a potential modulatory effect of stimulants and atomoxetine on several intrinsic brain activity metrics. However, methodological heterogeneity and reporting issues need to be addressed in future research to validate findings which may contribute to clinical care. Such a goal is not yet at hand.
Increased left inferior fronto-striatal activation during error monitoring after fMRI neurofeedback of right inferior frontal cortex in adolescents with attention deficit hyperactivity disorder
2020, NeuroImage: Clinical
Attention Deficit/Hyperactivity Disorder (ADHD) is a self-regulation disorder, with impairments in error monitoring associated with underactivation of the related brain network(s). Psychostimulant medication improves ADHD symptoms and can upregulate brain function, but has side effects, with limited evidence for longer-term effects. Real-time functional magnetic resonance neurofeedback (fMRI-NF) has potential longer-term neuroplastic effects. We previously reported the effects of 11 runs of 8.5 min of fMRI-NF of the right inferior frontal cortex (rIFC) in adolescents with ADHD. This resulted in improvement of clinical symptom and enhanced rIFC activation post-pre treatment during response inhibition, when compared to a control group receiving fMRI-NF of the left parahippocampal gyrus (lPHG).
In the current study we applied a novel analysis to the existing data by investigating the effects of fMRI-NF of rIFC in 16 adolescents with ADHD compared to fMRI-NF of lPHG in 11 adolescents with ADHD on the neurofunctional correlates of error monitoring during the same fMRI tracking stop task and potential associations with cognitive and clinical measures. We found stronger performance adjustment to errors in the rIFC-NF compared to the control lPHG-NF group. At the brain function level, fMRI-NF of rIFC compared to that of lPHG was associated with increased activation in error monitoring regions of the left IFC, premotor cortex, insula and putamen. The increased activation in left IFC-insular-striatal error monitoring regions in the rIFC-NF relative to the lPHG-NF group was furthermore trend-wise correlated with NF-induced ADHD symptom improvements.
The findings of this study show, that during error monitoring, fMRI-NF training of rIFC upregulation elicited improvement in post-error behavioural adjustments and concomitant increased activation in left hemispheric fronto-insular-striatal and premotor regions mediating self-control and self-monitoring functions. This suggests that the administration of fMRI-NF of the rIFC may have had an impact on wider networks of self-regulation and self-monitoring in adolescents with ADHD.
Methylphenidate and atomoxetine normalise fronto-parietal underactivation during sustained attention in ADHD adolescents
2019, European Neuropsychopharmacology
Citation Excerpt :
Given that both drugs improve behavioural and cognitive inattention, and the evidence that both drugs can upregulate/normalise underactivation in IFC and parietal regions, which are part of the ventral attention system, during related executive function tasks (Cubillo et al., 2014a, 2014b; Rubia et al., 2014; Smith et al., 2013), we hypothesised that both drugs would normalise and/or upregulate IFC-parietal regions. Based on evidence from previous comparative fMRI studies of single-dose methylphenidate and atomoxetine effects during other functions, we further predicted that there would be drug-specific effects of methylphenidate on normalisation and/or upregulation of striato-thalamic regions (Cubillo et al., 2014a, 2014b; Rubia et al., 2011a, 2009b; Smith et al., 2013) and drug-specific or stronger effects of atomoxetine on DLPFC upregulation/normalisation (Cubillo et al., 2014a). Seventeen medication-naïve right-handed boys (10–17 years old) with a clinical diagnosis of combined type ADHD (including both inattentive and hyperactive/impulsive symptoms) as assessed by an experienced child psychiatrist using the standardized Maudsley diagnostic interview (DSM-IV-TR criteria) (Goldberg and Murray, 2002), were recruited from South London clinics.
Problems with sustained attention are a key clinical feature of Attention Deficit/Hyperactivity Disorder (ADHD) which also manifests in poor performance and abnormal fronto-striato-parietal activation during sustained attention. Methylphenidate and atomoxetine improve attention functions and upregulate abnormal fronto-cortical activation during executive function tasks in ADHD patients. Despite this, no functional Magnetic Resonance Imaging (fMRI) study has compared the effects of methylphenidate and atomoxetine on the neurofunctional substrates of sustained attention in ADHD. This randomised, double-blind, placebo-controlled, cross-over study investigated the comparative normalisation effects of methylphenidate and atomoxetine on fMRI correlates and performance in 14 ADHD adolescents relative to 27 age-matched healthy controls during a parametric sustained attention/vigilance task with progressively increasing load of sustained attention. ADHD patients were scanned three times under a single clinical dose of either methylphenidate, atomoxetine, or placebo in pseudo-randomised order. Healthy controls were scanned once and compared to patients under each drug condition to test for potential drug-normalisation effects. Relative to controls, ADHD boys under placebo were impaired in performance and had underactivation in predominantly right-hemispheric fronto-parietal, and striato-thalamic regions. Both drugs normalised all underactivations, while only methylphenidate improved performance deficits. Within patients, methylphenidate had a drug-specific effect of upregulating left ventrolateral prefrontal/superior temporal activation relative to placebo and atomoxetine, while both drugs increased activation of right middle/superior temporal cortex, posterior cingulate, and precuneus relative to placebo. The study shows shared normalisation effects of methylphenidate and atomoxetine on fronto-striato-thalamo-parietal dysfunction in ADHD during sustained attention but a drug-specific upregulation effects of methylphenidate on ventral fronto-temporal regions.
Frontal brain injury chronically impairs timing behavior in rats
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Citation Excerpt :
Adults with ADHD exhibit similar errors, and increased variability in their temporal judgments [15]. Moreover, psychostimulant treatment of ADHD reduces symptoms related to timing behaviors whereas nonstimulant treatments do not [16], suggesting a strong role for dopamine signaling in the control of interval timing. This may be specifically relevant to brain injury as dopamine release is severely attenuated after focal experimental injury [17], and dopamine transporters and receptor levels are altered in patients with TBI [18,19].
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Attention-Deficit/Hyperactivity Disorder (ADHD) is a common neurodevelopmental disorder associated with a range of mental health, neurocognitive and functional problems. Although the diagnosis is based on descriptions of behaviour, individuals with ADHD characteristically describe excessive spontaneous mind wandering (MW). MW in individuals with ADHD reflects constant mental activity which lacks topic stability and content consistency. Based on this review of the neural correlates of ADHD and MW, we outline a new perspective on ADHD: the MW hypothesis. We propose that altered deactivation of the default mode network, and dysfunctional interaction with the executive control network, leads to excessive and spontaneous MW, which underpins symptoms and impairments of ADHD. We highlight that processes linked to the normal neural regulation of MW (context regulation, sensory decoupling, salience thresholds) are deficient in ADHD. MW-related measures could serve as markers of the disease process, as MW can be experimentally manipulated, as well as measured using rating scales, and experience sampling during both cognitive tasks and daily life. MW may therefore be a potential endophenotype.

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: Authors ASm and AC contributed equally to this work.

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Archival ReportNeurofunctional Effects of Methylphenidate and Atomoxetine in Boys with Attention-Deficit/Hyperactivity Disorder During Time Discrimination

Background

Methods

Results

Conclusions

Section snippets

Participants

Task Performance

Discussion

Biol Psychiatry

Neurosci Biobehav Rev

Biol Psychiatry

Med Hypotheses

Neuropsychology

Neuropharmacology

Biol Psychiatry

Value Health

Neuropsychopharmacology

Biol Psychiatry

Biol Psychiatry

Neuroimage

Behav Brain Res

Magn Reson Imaging

Neuroimage

Neuroimage

Biol Psychiatry

Neuroimage

J Am Acad Child Adolesc Psychiatry

Neuropharmacology

Biol Psychiatry

J Am Acad Child Adolesc Psychiatry

Impulsiveness as a timing disturbance: Neurocognitive abnormalities in attention-deficit hyperactivity disorder during temporal processes and normalization with methylphenidate

Phil Trans R Soc Lond B Biol Sci

Timing deficits in attention-deficit/hyperactivity disorder (ADHD): Evidence from neurocognitive and neuroimaging studies

Neuropsycholia

Temporal processing in children with ADHD: Evidence for a pure time perception deficit in ADHD

J Child Psychol Psychiatry

Performance of children with ADHD on a test battery of impulsiveness

Child Neuropsychol

Reduced activation in right lateral prefrontal cortex and anterior cingulate cortex in medication-naïve adolescents with attention deficit hyperactivity disorder during time discrimination

J Child Psychol Psychiatry

Motor timing deficits in community and clinical boys with hyperactive behaviour: The effect of methylphenidate on motor timing

J Abnorm Child Psychol

Effect of methylphenidate on time perception in children with attention-deficit/hyperactivity disorder

Exp Clin Psychopharmacol

Methylphenidate normalizes fronto-striatal underactivation during interference inhibition in medication-naive boys with attention-deficit hyperactivity disorder

Neuropsychopharmacology

Evaluation of atomoxetine for first-line treatment of newly diagnosed, treatment-naive children and adolescents with attention deficit/hyperactivity disorder

Curr Med Res Opin

Atomoxetine and osmotically released methylphenidate for the treatment of attention deficit hyperactivity disorder: Acute comparison and differential response

Am J Psychiatry

Archival Report
Neurofunctional Effects of Methylphenidate and Atomoxetine in Boys with Attention-Deficit/Hyperactivity Disorder During Time Discrimination