Acute Effects Of Methylphenidate Research Articles

MicroPET/CT assessment of neurochemical effects in the brain after long-term methylphenidate treatment in nonhuman primates

Methylphenidate (MPH) is a psychostimulant approved by the FDA to treatment Attention-Deficit Hyperactivity Disorder (ADHD). MPH is believed to exert its pharmacological effects via preferential blockade of the dopamine transporter (DAT) and the norepinephrine transporter (NET), resulting in increased monoamine levels in the synapse. We used a quantitative non-invasive PET imaging technique to study the effects of long-term methylphenidate use on the central nervous system (CNS). We conducted microPET/CT scans on young adult male rhesus monkeys to monitor changes in the dopaminergic system. We used [18F] AV-133, a ligand for the vesicular monoamine transporter 2 (VMAT2), and [18F]FESP a ligand for the D2 and 5HT2 receptors. In this study we evaluated the effects if chronic MPH treatment in the nonhuman primates (NHP). Two-year-old, male rhesus monkeys were orally administered MPH diluted in the electrolyte replenisher, Prang, twice a day, five days per week (M-F) over an 8-year period. The dose of MPH was gradually escalated from 0.15 mg/kg initially to 2.5 mg/kg/dose for the low dose group, and 1.5 mg/kg to 12.5 mg/kg/dose for the high dose group (Rodriguez et al., 2010). Scans were performed on Mondays, about 60 h after their last treatment, to avoid the acute effects of MPH. Tracers were injected intravenously ten minutes before microPET/CT scanning. Sessions lasted about 120 min. The Logan reference tissue model was used to determine the Binding Potential (BP) of each tracer in the striatum with the cerebellar cortex time activity curve as an input function. Both MP treatment groups had a lower [18F] AV-133 BP, although this failed to reach statistical significance. MPH treatment did not have a significant effect on The BP of [18F] FESP in the striatum. Long-term administration of MPH did not significant change any of the marker of monoamine function used here. These data suggest that, despite lingering concerns, long-term use of methylphenidate does not negatively impact monoamine function. This study also demonstrates that microPET imaging can distinguish differences in binding potentials of a variety of radiotracers in the CNS of NHPs. This approach may provide minimally-invasive biomarkers of neurochemical processes associated with chronic exposure to CNS medications. (Supported by NCTR).

Effects of methylphenidate on executive functioning in children and adolescents with ADHD after long-term use: a randomized, placebo-controlled discontinuation study.

BackgroundMethylphenidate may improve executive functioning in children with attention‐deficit/hyperactivity disorder (ADHD). However, it is unclear if there are still acute effects of methylphenidate on executive functioning after long‐term use.MethodsIn a randomized double‐blind, placebo‐controlled discontinuation study, 94 children and adolescents (ages 8–18 years) who used methylphenidate beyond two years were either assigned to seven weeks of continued treatment with 36 or 54 mg of extended‐release methylphenidate or to gradual withdrawal over three weeks to placebo for four weeks. Performance on neuropsychological tasks, measuring working memory, response inhibition, attentional flexibility and psychomotor speed was compared between both groups using mixed models for repeated measures. Additionally, we investigated within the discontinuation group if a deterioration on the investigator‐rated Clinical Global Impressions Improvement scale after withdrawing to placebo was related to a worse performance on the neuropsychological tasks. This study was registered in the Netherlands Trial Register (www. Trialregister.nl) with identifier 5252.ResultsAfter withdrawal of methylphenidate, the discontinuation group made more errors on working memory (β = −1.62, SD = 0.56, t = −2.88, p = .01, Cohen’s f2 = .14), independent from reaction time compared to baseline, in contrast to the continuation group. We did not find differences in changes in response inhibition, attentional flexibility and psychomotor speed between the two groups. Also, there were no significant differences in task measures between the participants who deteriorated clinically and those who did not.ConclusionsOur study shows that methylphenidate has a beneficial effect on working memory after two years of use. Future studies should explore whether cognitive outcomes may aid clinical decision‐making on the continued use of methylphenidate, given dissociation between cognitive and behavioural effects of stimulant medication.

The interactive effects of test-retest and methylphenidate administration on cognitive performance in youth with ADHD: A double-blind placebo-controlled crossover study

Studies have shown that Methylphenidate (MPH) affects cognitive performance on the neuropsychological tests and clinical symptoms of individuals diagnosed with attention deficit/hyperactivity disorder (ADHD). This study investigated the acute effects of MPH on neuropsychological tests to explore the interaction between MPH and test-retest effects. Twenty youths with ADHD were tested before and after MPH intake in a double-blind placebo-controlled crossover design and compared to twenty matched controls. Participants were tested on a range of standardized tasks including sustained attention to response, N-Back, and Word/Color Stroop. Identical tasks were administered twice each testing day, before and 1 hour after MPH/Placebo administration. Healthy controls were tested similarly with no intervention. Decreases in response time (RT) variability across tasks and in commission errors were found in ADHD after MPH. Conversely, a significant increase in RT variability and increase in omission errors were observed after the placebo. In the control group, RT variability and omission errors increased whereas commission errors decreased, suggesting fatigue and practice effects, respectively. Test-retest reliability was higher in controls than ADHD. It is suggested that cognitive tests are sensitive objective measures for the assessment of responses to MPH in ADHD but are also affected by repetition and fatigue.

Acute Effects of MPH on the Parent–Teen Interactions of Adolescents With ADHD

This study explored the nature of interactions between adolescent males with ADHD and their mothers, and the effects of methylphenidate (MPH) on an analogue parent–teen interaction task. Twenty-five adolescent males with ADHD (M = 13.6 years) and their mothers and 14 non-ADHD adolescent males (M = 13.4 years) and their mothers completed ratings of perceived dyadic conflict. Behavioral observations of dyads during 10-min conflict-resolution tasks were also collected. The ADHD dyads completed these tasks twice, with adolescents receiving either 0.3 mg/kg MPH or placebo. Videotaped sessions were coded using the Parent–Adolescent Interaction Rating Scale. Following the conflict-resolution task, participants rated their perceived conflict and affect during the interaction. Findings indicated higher conflict in the ADHD dyads, and minimal MPH effects on parent–teen interactions during the analogue task. Results suggest that stimulant medication does not produce meaningful acute effects on parent–teen interactions.

MicroPET/CT assessment of FDG uptake in brain after long-term methylphenidate treatment in nonhuman primates

Methylphenidate (MPH) is a psychostimulant commonly used for the treatment of Attention-Deficit Hyperactivity Disorder (ADHD). Since the long-term effects of this drug on the central nervous system (CNS) are not well understood, we conducted microPET/CT scans on young adult male rhesus monkeys (n=4/group) to gather information on brain metabolism using the uptake of [18F]Fluoro-2-deoxy-2-d-glucose (FDG) as a marker. Approximately two-year old, male rhesus monkeys were treated orally with MPH twice per day, five days per week (M-F) over a 6-year period. Subjects received MPH at either 2.5 or 12.5mg/kg/dose or vehicle (Prang). To minimize the acute effects of MPH on FDG uptake, microPET/CT scans were scheduled on Mondays before their first daily dosing of the week (approximately 68h since their last treatment). FDG (370±8.88MBq) was injected intravenously and 30min later microPET/CT images were obtained over 60min. Radiolabeled tracer accumulation in regions of interest (ROIs) in the prefrontal cortex, temporal cortex, striatum and cerebellum were converted into Standard Uptake Values (SUVs). Compared to the control group, the uptake of FDG in the cerebellum was significantly decreased in both the low and high dose groups. These preliminary data demonstrate that microPET imaging is capable of distinguishing differences in retention of FDG in the brains of NHPs treated chronically with MPH and suggests that this approach may provide a minimally invasive biomarker for exploring the effects of chronic MPH treatment on aspects of brain function.

Evaluation of acute cardiovascular effects of immediate-release methylphenidate in children and adolescents with attention-deficit hyperactivity disorder.

Attention-deficit hyperactivity disorder is a frequent condition in children and often extends into adulthood. Use of immediate-release methylphenidate (MPH) has raised concerns about potential cardiovascular adverse effects within a few hours after administration. This study was carried out to investigate acute effects of MPH on electrocardiogram (ECG) in a pediatric population. A total of 54 consecutive patients with attention-deficit hyperactivity disorder (51 males and 3 females; mean age =12.14±2.6 years, range 6–19 years), receiving a new prescription of MPH, underwent a standard ECG 2 hours before and after the administration of MPH 10 mg per os. Basal and posttreatment ECG parameters, including mean QT (QT interval when corrected for heart rate [QTc]), QTc dispersion (QTd) interval duration, T-peak to T-end (TpTe) intervals, and TpTe/QT ratio were compared. Significant modifications of both QTc and QTd values were not found after drug administration. QTd fluctuated slightly from 25.7±9.3 milliseconds to 25.1±8.4 milliseconds; QTc varied from 407.6±12.4 milliseconds to 409.8±12.7 milliseconds. A significant variation in blood pressure (systolic blood pressure 105.4±10.3 vs 109.6±11.5; P<0.05; diastolic blood pressure 59.2±7.1 vs 63.1±7.9; P<0.05) was observed, but all the data were within normal range. Heart rate moved from 80.5±15.5 bpm to 87.7±18.8 bpm. No change in TpTe values was found, but a statistically significant increase in TpTe/QTc intervals was found with respect to basal values (0.207±0.02 milliseconds vs 0.214±0.02 milliseconds; P<0.01). The findings of this study show no significant changes in ECG parameters. TpTe values can be an additional parameter to evaluate borderline cases.

Effects of methylphenidate in children with attention deficit hyperactivity disorder: a near-infrared spectroscopy study with CANTAB®

BackgroundA wide range of evidence supports the methylphenidate (MPH)-induced enhancement of prefrontal cortex (PFC) functioning and improvements in behavioral symptoms in patients with attention deficit hyperactivity disorder (ADHD). Although working memory (WM) has been hypothesized to be impaired in patients with ADHD, no pharmacological studies have examined visuospatial WM (VSWM) with near-infrared spectroscopy (NIRS).Study aimThe present study was designed to investigate the acute effects of MPH on neuropsychological performance and hemodynamic activation in children with ADHD during VSWM tasks.MethodsThe subject group included 10 boys and 1 girl previously diagnosed with ADHD. Two VSWM tasks of differing degrees of difficulty were conducted. This is the first study on the pharmacological effects of MPH in children with ADHD to evaluate hemodynamic responses in the PFC with simultaneous NIRS.ResultsNo significant differences were found in the scores for both spatial working memory (SWM) and score of spatial span (SSP) tasks between the MPH-off and MPH–on conditions. However, a significant MPH-effect on changes in oxy-hemoglobin levels in the PFC was found only in the SWM task.ConclusionThese findings suggest that PFC activation might be affected by MPH, depending on the degree of difficulty of the particular task. Although the MPH-induced change on behavior may or may not be obvious, NIRS measurements might be useful for assessing the psychological effects of MPH even when performance changes were not observed in the cognitive tasks.

P.7.d.012 Effects of methylphenidate on cognition in ADHD across the lifespan: preliminary results of a meta-regression analysis

Purpose: Stimulants like methylphenidate (MPH) are the first choice of pharmacological interventions for children and adults with attention-deficit hyperactivity disorder [1]. However, the human brain is in development until the early 20’s [2], and different behavioral responses to MPH have been shown for younger compared to older children [3]. This raises the question whether cognitive effects of MPH are related to the developmental stage of individuals with ADHD, and whether MPH effect might be associated with medication history of participants. Thus, the aims of the present meta-analysis were to determine whether the effect of MPH on cognitive functions is age-related, and whether medication naivety is associated with MPH effect. Methods: Double-blind, placebo controlled trials, reporting data on the effects of MPH on response inhibition, working memory and sustained attention, were included in a meta-regression analysis. Only samples with an ADHD diagnosis were included. In order to ensure comparability of effect sizes across study designs, an estimated correlation between measurements of 0.5 was taken into account when calculating effect sizes of crossover designs. Age and medication naivety were included in the analysis as moderators. Preliminary results: Forty-five studies (n = 1534) with 61 data points were included in the analyses, resulting in mean effect sizes of 0.41 for response inhibition (95%CI [0.22–0.61]), 0.27 for working memory (95%CI [−0.01–0.55]), and 0.45 for sustained attention (95%CI [0.26–0.63]). Effects of MPH on response inhibition and sustained attention were significant (both p< 0.0001). The mean effect size for working memory was not significant (p= 0.021). Overall, age did not significantly moderate the effect of MPH (QM = 0.02, df = 1, p= 0.90), but an age– response relationship was found for working memory (QM = 4.42, df = 1, p= 0.04). The influence of medication naivety was assessed with single dose trials in which the population was either described as 100% naive (5 studies), or as 0% naive (8 studies). Medication naivety of samples was not a significant moderator of MPH effect (QM = 0.34, df = 1, p= 0.56). Discussion: The present analysis shows moderate positive effects of MPH on response inhibition and sustained attention. The mean effect size for working memory studies was not significant. Interestingly, an age–response relationship was only found for working memory studies, with adult studies demonstrating larger effects. It is uncertain whether this reflects a heightened sensitivity to MPH of adult working memory, as this analysis only comprised two studies with adults and no studies with adolescents. This stresses the need for additional MPH trials with adolescents and adults. In addition, no relationship between naivety to stimulants and MPH effect was found, indicating that acute effects of MPH might be independent of treatment history.

Descending glutamatergic pathways of PFC are involved in acute and chronic action of methylphenidate

Progressive augmentation of behavioral response following repeated psychostimulant administrations is known as behavioral sensitization, and is an indicator of a drug's liability for abuse. It is known that methylphenidate (MPD) (also known as Ritalin), a drug used to treat attention-deficit hyperactivity disorder (ADHD), induces sensitization in animals following repeated injections. It was recently reported that bilateral electric (non-specific) lesion of prefrontal cortex (PFC) prevented MPD elicited behavioral sensitization. Since PFC sends glutamatergic afferents to both ventral tegmental area (VTA) and nucleus accumbens (NAc), sites that are involved in induction and expression of behavioral sensitization respectively and glutamate from PFC is known to modulate dopamine cell activity in VTA and NAc, this study investigated the role of descending glutamate from PFC in MPD elicited behavioral sensitization. Locomotor activity of three groups of rats–control, sham operated and group with specific chemical lesion of glutamate neurons of PFC–was recorded using an open-field assay. On experimental day (ED) 1, the locomotor activity was recorded post a saline injection. The sham and lesion groups underwent respective surgeries on ED 2, and were allowed to recover for 5 days (from ED 3 to ED 7). The post-surgery baseline was recorded on ED 8 following a saline injection. On ED's 9 through 14, 2.5 mg/kg MPD was given, followed by a 4-day washout period (ED 15 -18). All three groups received a rechallenge injection of 2.5 mg/kg on ED 19 and their locomotor activity on various days was analyzed. It was found that ibotenic acid lesion modulated the acute and chronic effects of MPD and hence suggests that PFC glutamatergic afferents are involved in the acute effect of MPD as well as in its chronic effects such as behavioral sensitization to MPD.

Dopaminergic modulates task performance and learning-induced plasticity via distinct D1 and D2 receptors

Event Abstract Back to Event Dopaminergic modulates task performance and learning-induced plasticity via distinct D1 and D2 receptors Kay Tye1*, Lynne Tye2, Jackson Cone1, Patricia Janak1 and Antonello Bonci1 1 Gallo Center at UCSF, United States 2 MIT, United States Dopamine is thought to contribute to many behavioral actions, including those related to motivation and reward. Methylphenidate (MPH), also known as Ritalin, is currently the most commonly prescribed psychostimulant, but despite prevalent use in children, adolescents and adults, the neural mechanisms by which MPH modifies behavioral performance are unknown for two main reasons. First, MPH is typically administered systemically, thereby altering the function of multiple neural circuits, making it difficult to identify the brain changes that influence behavior. Second, MPH has multiple pharmacological targets, including the dopamine, norepinephrine and serotonin transporters. Previously, we have demonstrated that the lateral amygdala shows a robust, linear relationship between learning performance and synaptic strength. Furthermore, dopamine receptor activation has been shown to enhance amygdala-mediated behaviors. To investigate the acute effects of MPH on behavior as well as learning-induced plasticity, we infused MPH into the amygdala immediately prior to training in a cue-reward task for a natural reward. We found that MPH locally administered in the lateral amygdala enhances learning performance in a similar manner to a selective DAT inhibitor. Additionally, we show that MPH enhances performance both by facilitating the ability to acquire a cue-reward association, via a dopamine D1 receptor-dependent mechanism, as well as by suppressing task-irrelevant behavior, via D2 receptor-dependent mechanisms. Furthermore, we demonstrate that treatment with either MPH or a selective DAT inhibitor elevates levels of DA which gate learning-induced plasticity at cortico-amygdala synapses. This represents a novel mechanism by which MPH enhances learning performance. Conference: 41st European Brain and Behaviour Society Meeting, Rhodes Island, Greece, 13 Sep - 18 Sep, 2009. Presentation Type: Oral Presentation Topic: Symposia lectures Citation: Tye K, Tye L, Cone J, Janak P and Bonci A (2009). Dopaminergic modulates task performance and learning-induced plasticity via distinct D1 and D2 receptors. Conference Abstract: 41st European Brain and Behaviour Society Meeting. doi: 10.3389/conf.neuro.08.2009.09.058 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 05 Jun 2009; Published Online: 05 Jun 2009. * Correspondence: Kay Tye, Gallo Center at UCSF, Emeryville, United States, ktye@gallo.ucsf.edu Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Kay Tye Lynne Tye Jackson Cone Patricia Janak Antonello Bonci Google Kay Tye Lynne Tye Jackson Cone Patricia Janak Antonello Bonci Google Scholar Kay Tye Lynne Tye Jackson Cone Patricia Janak Antonello Bonci PubMed Kay Tye Lynne Tye Jackson Cone Patricia Janak Antonello Bonci Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Acute effects of methylphenidate on neuropsychological parameters in adults with ADHD: possible relevance for therapy

Recent research has demonstrated that attention-deficit/hyperactivity disorder (ADHD), one of the most common mental disorders in childhood, continues into adulthood. In adulthood, however, pharmacotherapy with psychostimulants still is an off-label treatment. Because of this we routinely administer a test dose of methylphenidate (MPH) prior to a continuous medication and measure MPH effects quantitatively and repeatedly employing a neuropsychological test battery. To probe if the acute effects of MPH are indeed helpful in predicting longer-term efficacy of MPH treatment we retrospectively analyzed the neuropsychological test results of 34 patients on continuous MPH medication. Two testing sessions had been performed without MPH (at baseline and 24 h after a single dose intake to control possible training effects), one after a single dose and one after 3-6 months of regular intake of MPH. A significant improvement of performance in tests assessing attentional, memory and executive functions after single medication was maintained on long term medication in those 23 patients available for follow-up. These results indicate that beneficial short term effects of MPH predict longer-term effects and may thus be helpful in the decision for an off-label treatment. Controlled prospective studies are now necessary.

Methylphenidate sensitization is prevented by prefrontal cortex lesion

Methylphenidate (MPD), also known as Ritalin, is a widely used treatment for Attention Deficit Hyperactivity Disorder. Repeated administration of MPD causes dose-dependent sensitization. MPD binds to dopamine (DA) transporters, and DA, therefore, remain in the synaptic cleft for longer time, resulting in an indirect DA agonist effect. MPD affects neurotransmission in brain regions including the prefrontal cortex (PFC). The mechanisms of sensitization to MPD are not clear. The aim of this study was to investigate the role of prefrontal cortex in effects of acute and chronic MPD administration, using the open field assay and male Sprague–Dawley rats with bilateral electrolytic lesions of PFC. After 1 day of control recording, following saline injection, the animals were divided randomly into three groups, (1) an intact control group, (2) a sham group, and (3) a lesion group. Then, groups 2 and 3 underwent surgery, followed by 5 days of recovery. Recordings were resumed following 1 day of saline injection and following six consecutive daily injections of 2.5 mg/kg MPD, 3 days of washout period, and another day of re-challenge injection of 2.5 mg/kg MPD. Acute MPD elicited increases in locomotor activity, similar to those observed from intact animals, in both sham and lesion groups. The sham group was behaviorally sensitized while the PFC lesion group failed to exhibit behavioral sensitization. These results suggest that the PFC does not interfere with the acute effects of MPD on locomotor activity but is required for development of behavioral sensitization to MPD.

Methylphenidate Enhances the Abuse-Related Behavioral Effects of Nicotine in Rats: Intravenous Self-Administration, Drug Discrimination, and Locomotor Cross-Sensitization

Stimulant drugs, including D-amphetamine, cocaine, and methylphenidate, increase cigarette smoking in controlled human laboratory experiments. Although the mechanism(s) underlying this effect are unknown, it is possible that stimulants may enhance directly the abuse-related effects of nicotine. In the present study, we characterized the behavioral pharmacological interactions between methylphenidate and nicotine in the intravenous self-administration, drug discrimination, and locomotor cross-sensitization procedures. Adult male Sprague-Dawley rats were trained to respond for intravenous nicotine (0.01 or 0.03 mg/kg/infusion) or sucrose, and the acute effects of methylphenidate (1.25-10 mg/kg) were determined; in addition, separate groups of rats were treated with methylphenidate (2.5 mg/kg) or saline before 12 consecutive nicotine (0.03 mg/kg/infusion) self-administration sessions. Next, the discriminative stimulus effects of nicotine (0.03-0.3 mg/kg) and methylphenidate (1.25-10 mg/kg), alone and in combination with a low nicotine dose (0.056 mg/kg), were tested in nicotine-trained rats. Finally, the locomotor effect of repeated methylphenidate (2.5 mg/kg) was tested in rats previously treated with nicotine (0.2-0.8 mg/kg). Results indicated that acute methylphenidate increased the rate of nicotine self-administration at doses that reduced sucrose-maintained responding; furthermore, tolerance to this effect was not apparent following repeated methylphenidate. Methylphenidate, while not substituting for nicotine alone, dose-dependently enhanced the discriminative stimulus effect of a low nicotine dose. In addition, repeated nicotine exposure promoted the development of locomotor sensitization to methylphenidate. Taken together with recent clinical findings, these results suggest that methylphenidate may enhance the abuse-related behavioral effects of nicotine, perhaps increasing vulnerability to tobacco dependence.

Acute effect of methylphenidate on QT interval duration and dispersion in children with attention deficit hyperactivity disorder

Among childhood psychiatric disorders, attention deficit hyperactivity disorder (ADHD) is of greatest interest to practitioners. Methylphenidate (MPH) is a drug that is widely used in the treatment of children in whom ADHD has been diagnosed. Although this treatment has been used for years, its effects on the heart remain the subject of debate. The QT interval comprises the ventricular activation and recovery periods as seen on electrocardiogram (ECG). The acute effect of MPH on QT interval dispersion is unknown. Researchers in the present study sought to investigate the acute effects of MPH on QT interval as seen on ECG. A total of 25 patients with ADHD (mean age, 9.4+/-2.1 y) who were treated with MPH were enrolled in the study. Twelve-lead derivation ECGs were taken before and 2 h after administration of 10 mg of MPH. Maximum QT interval, minimum QT interval, and interval durations were measured, and QT dispersion was calculated, for each ECG. QT dispersion measured after medication administration decreased significantly from 59.6+/-16.3 ms to 50.8+/-10.9 ms (P=.016); corrected QT dispersion decreased significantly from 70.9+/-17.6 ms to 61.3+/-13.3 ms (P=.011). Maximum QT interval duration decreased from 73.7+/-21.8 ms to 361.8+/-29.0 ms (P=.006); minimum QT interval duration rose from 317.0+/-23.3 ms to 322.3+/-21.6 ms (P=.312). In conclusion, the findings of this study show that MPH reduces QT dispersion during the acute period shortly after its administration.

Methylphenidate and Flexible Thinking in ADHD

The acute effects of methylphenidate (MPH) in 3 dosages (0.3, 0.6, and 0.9 mg/kg) on the performance of 17 ADHD children in tests of cognitive flexibility were evaluated at the Departments of Psychology and Pediatrics, McGill University-Montreal Children’s Hospital Research Institute, Canada.