Methylphenidate and cognitive flexibility: Dissociated dose effects in hyperactive children

A randomized, double-blind, placebo-controlled trial was conducted to assess the acute effects of placebo and three doses of methylphenidate (MPH) (0.3, 0.6, 0.9 mg/kg) on cognitive flexibility and overt behavior in 28 children with a confirmed diagnosis of attention deficit-hyperactivity disorder. Two underlying cognitive processes (response inhibition and response reengagement) were assessed by measuring the probability and speed with which subjects could inhibit responses to a primary task (forced-choice letter discrimination) and immediately execute a response to a secondary task (simple reaction time) when given a signal to do so. Results indicated that MPH enhanced cognitive flexibility, although the high dose was less effective than lower doses in enhancing response inhibition. Dissociations of dose effects on cognitive function and behavior were demonstrated: Dose-response functions for changes in behavior were linear, whereas the function for response inhibition was U-shaped. Findings argue against the typical clinical practice of determining the response to stimulant treatment from a single measure such as parent report of child behavior.     

Stimulant Treatment Reduces Lapses in Attention among Children with ADHD: The Effects of Methylphenidate on Intra-Individual Response Time Distributions

Recent research has suggested that intra-individual variability in reaction time (RT) distributions of children with ADHD is characterized by a particularly large rightward skew that may reflect lapses in attention. The purpose of the study was to provide the first randomized, placebo-controlled test of the effects of the stimulant methylphenidate (MPH) on this tail and other RT distribution characteristics. Participants were 49 9- to 12-year-old children with ADHD. Children participated in a 3-day double-blind, placebo-controlled medication assessment during which they received long-acting MPH (Concerta®), with the nearest equivalents of 0.3 and 0.6 mg/kg t.i.d. immediate-release MPH. Children completed a simple two-choice speeded discrimination task on and off of medication. Mode RT and deviation from the mode were used to examine the peak and skew, respectively, of RT distributions. MPH significantly reduced the peak and skew of RT distributions. Importantly, the two medication effects were uncorrelated suggesting that MPH works to improve both the speed and variability in responding. The improvement in variability with stimulant treatment is interpreted as a reduction in lapses in attention. This, in turn, may reflect stimulant enhancement of self-regulatory processes theorized to be at the core of ADHD.     

Single and combined effects of methylphenidate and behavior therapy on the classroom performance of children with attention-deficit hyperactivity disorder

Twenty-four boys with attention deficit-hyperactivity disorder (ADHD) participating in an intensive summer treatment program each received b.i.d. placebo and two doses of methylphenidate (MPH, 0.3 mg/kg and 0.6 mg/kg) crossed with two classroom settings: a behavior modification classroom including a token economy system, time out and daily home report card, and a regular classroom setting not using these procedures. Dependent variables included classroom observations of on-task and disruptive behavior, academic work completion and accuracy, and daily self-ratings of performance. Both MPH and behavior modification alone significantly improved children's classroom behavior, but only MPH improved children's academic productivity and accuracy. Singly, behavior therapy and 0.3 mg/kg PMH produced roughly equivalent improvements in classroom behavior. Further, the combination of behavior therapy and 0.3 mg/kg MPH resulted in maximal behavioral improvements, which were nearly identical to those obtained with 0.6 mg/kg MPH alone.The authors gratefully acknowledge the assistance of Patricia Donovan, Michelle Berry, Mary Ingram, Patricia Wells, Beth Gnagy, Karen Greenslade, Mary Hamilton, and the entire staff of the Western Psychiatric Institute and Clinic ADHD Summer Treatment Program.     

Improving Working Memory in Children with Attention-Deficit/Hyperactivity Disorder: The Separate and Combined Effects of Incentives and Stimulant Medication

Working memory (WM) is considered a core deficit in Attention-Deficit/ Hyperactivity Disorder (ADHD), with numerous studies demonstrating impaired WM among children with ADHD. We tested the degree to which WM in children with ADHD was improved by performance-based incentives, an analog of behavioral intervention. In two studies, WM performance was assessed using a visuo-spatial n-back task. Study 1 compared children (ages 9-12?years) with ADHD-Combined type (n?=?24) to a group of typically developing (TD) children (n?=?32). Study 1 replicated WM deficits among children with ADHD. Incentives improved WM, particularly among children with ADHD. The provision of incentives reduced the ADHD-control group difference by approximately half but did not normalize WM. Study 2 examined the separate and combined effects of incentives and stimulant medication among 17 children with ADHD-Combined type. Both incentives and a moderate dose of long-acting methylphenidate (MPH; ~0.3?mg/kg t.i.d. equivalent) robustly improved WM relative to the no-incentive, placebo condition. The combination of incentives and medication improved WM significantly more than either incentives or MPH alone. These studies indicate that contingencies markedly improve WM among children with ADHD-Combined type, with effect sizes comparable to a moderate dose of stimulant medication. More broadly, this work calls attention to the role of motivation in studying cognitive deficits in ADHD and in testing multifactorial models of ADHD.     

The effect of methylphenidate on three forms of response inhibition in boys with AD/HD

The current study was aimed at (a) investigating the effect of three doses methylphenidate (MPH) and placebo on inhibition of a prepotent response, inhibition of an ongoing response, and interference control in Attention Deficit/Hyperactivity Disorder (AD/HD), and (b) studying dose-response relations for the three forms of response inhibition. To meet these aims, the following tasks were selected: two versions of the Stop Paradigm for inhibition of a prepotent response, a Circle Tracing Task and a recently developed Follow Task for inhibition of an ongoing response, and the Stroop Color-Word Test and an Eriksen Flanker Task for interference control. These tasks were administered to 23 boys with AD/HD during four treatment conditions: 5 mg MPH, 10 mg MPH, 20 mg MPH, and placebo. A pseudorandomized, multiple-blind, placebo-controlled, within-subject design was used. As hypothesized, inhibitory control in children with AD/HD improved under MPH compared to placebo. However, this effect was only significant for inhibition of a prepotent response and inhibition of an ongoing response (as measured by the Follow Task), but not for interference control. The relation between treatment condition and response was linear. However, this linear relation was due to improved inhibitory control under MPH compared to placebo, because no effects of MPH dose were observed for any of the response inhibition measures.     

Stopping eye and hand movements: are the processes independent?

To explore how eye and hand movements are controlled in a stop task, we introduced effector uncertainty by instructing subjects to initiate and occasionally inhibit eye, hand, or eye + hand movements in response to a color-coded foveal or tone-coded auditory stop signal. Regardless of stop signal modality, stop signal reaction time was shorter for eye movements than for hand movements, but notably did not vary with knowledge about which movement to cancel. Most errors on eye + hand stopping trials were combined eye + hand movements. The probability and latency of signal respond eye and hand movements corresponded to predictions of Logan and Cowan's (1984) race model applied to each effector independently.     

Music and Video as Distractors for Boys with ADHD in the Classroom: Comparison with Controls,Individual Differences,and Medication Effects

This study examined the effects of music and video on the classroom behavior and performance of boys with and without attention deficit hyperactivity disorder (ADHD) and examined the effects of 0.3 mg/kg methylphenidate (MPH). In one study, 41 boys with ADHD and 26 controls worked in the presence of no distractor, music, or video. Video produced significant distraction, particularly for the boys with ADHD, and MPH improved the performance of boys with ADHD across distractor conditions.There were individual differences in response to the music such that some boys were adversely affected and others benefited relative to no-distractor.In a second study, music and MPH were assessed in an additional 86 boys with ADHD to examine further the music results. In the presence or absence of music, MPH improved performance relative to placebo. Similar individual differences were found as in Experiment 1.     

Attention-Deficit/Hyperactivity Disorder and methylphenidate: a dose-response analysis and parent-child comparison of somatic complaints

The authors examined parent and child ratings of somatic complaints in 65 children with Attention-Deficit/Hyperactivity Disorder (ADHD) who received four doses (5 mg, 10 mg, 15 mg, 20 mg) of methylphenidate (MPH) in the context of a double-blind, placebo controlled, within-subject (crossover) experimental design. Results indicated that parent and child ratings of somatic complaints decreased in a linear fashion from baseline levels as a function of increasing MPH dose and showed minimal variation across MPH conditions. Statistical comparisons of specific somatic complaints indicated minimal agreement between parents and children in contrast to the nearly identical parent-child dose-response curves. The paradoxical findings of fewer somatic complaints associated with MPH, importance of obtaining children's perceptions of MPH treatment, and implications for measuring somatic complaints are discussed.     

A Dose-Ranging Study of Behavioral and Pharmacological Treatment in Social Settings for Children with ADHD

Placebo and three doses of methylphenidate (MPH) were crossed with 3 levels of behavioral modification (no behavioral modification, NBM; low-intensity behavioral modification, LBM; and high-intensity behavior modification, HBM) in the context of a summer treatment program (STP). Participants were 48 children with ADHD, aged 5–12. Behavior was examined in a variety of social settings (sports activities, art class, lunch) that are typical of elementary school, neighborhood, and after-school settings. Children received each behavioral condition for 3 weeks, order counterbalanced across groups. Children concurrently received in random order placebo, 0.15 mg/kg/dose, 0.3 mg/kg/dose, or 0.6 mg/kg/dose MPH, 3 times daily with dose manipulated on a daily basis in random order for each child. Both behavioral and medication treatments produced highly significant and positive effects on children’s behavior. The treatment modalities also interacted significantly. Whereas there was a linear dose–response curve for medication in NBM, the dose–response curves flattened considerably in LBM and HBM. Behavior modification produced effects as large as moderate doses, and on some measures, high doses of medication. These results replicate and extend to social-recreational settings previously reported results in a classroom setting from the same sample (Fabiano et al., School Psychology Review, 36, 195–216, 2007). Results illustrate the importance of taking dosage/intensity into account when evaluating combined treatments; there were no benefits of combined treatments when the dosage of either treatment was high but combination of the low-dose treatments produced substantial incremental improvement over unimodal treatment.     

Stopping and restarting an unfolding action at various times.

The ability to inhibit an unfolding action is usually investigated using a stop signal (or gostop) task. The data from the stop-signal task are often described using a horse-race model whose key assumption is that each process (i.e., go, stop) exhibits stochastic independence. Using three variations of a coincident-timing task (i.e., go, gostop, and gostopgo) we extend previous considerations of stochastic independence by analysing the go latencies for prior effects of stopping. On random trials in the gostopgo task the signal sweep was paused for various times at various distances before the target. Significant increases in latency errors were reported on those trials on which the signal was paused (p <.005). Further analyses of the pause trials revealed significant effects for both the stopping interval (p <.001) and the pause interval (p <.05). Tukey post hoc analyses demonstrated increased latency errors as a linear function of the stopping interval, as expected, and decreased latency errors as a nonlinear function of the pause interval. These latter results indicate that the latencies of the go process, as reflected in the latency errors, may not exhibit stochastic independence under certain conditions. Various control mechanisms were considered in an attempt to explain these data.     

Effects of methylphenidate on complex cognitive processing in attention-deficit hyperactivity disorder

Three experiments were conducted to explore the effects of methylphenidate (MPH), attention-deficit hyperactivity disorder (ADHD) diagnosis, and age on performance on a complex visual-memory search task. Results showed that the effects of MPH varied with information load. On low-processing loads, all doses of MPH helped children with ADHD to improve accuracy with no cost to reaction time (RT), whereas on high loads, higher MPH doses improved error rates while slowing RT. Without medication, children with ADHD showed high error rates and slow RTs across both low and high loads, as did younger, normal control children. Because MPH slowed performance on only the most difficult, high-load conditions, it is argued that the drug improves self-regulatory ability, enabling children with ADHD to adapt differentially to high and low loads.     

The effect of methylphenidate on very low frequency electroencephalography oscillations in adult ADHD

Altered very low-frequency electroencephalographic (VLF-EEG) activity is an endophenotype of ADHD in children and adolescents. We investigated VLF-EEG case-control differences in adult samples and the effects of methylphenidate (MPH). A longitudinal case-control study was conducted examining the effects of MPH on VLF-EEG (.02–0.2 Hz) during a cued continuous performance task. 41 untreated adults with ADHD and 47 controls were assessed, and 21 cases followed up after MPH treatment, with a similar follow-up for 38 controls (mean follow-up = 9.4 months). Cases had enhanced frontal and parietal VLF-EEG and increased omission errors. In the whole sample, increased parietal VLF-EEG correlated with increased omission errors. After controlling for subthreshold comorbid symptoms, VLF-EEG case-control differences and treatment effects remained. Post-treatment, a time by group interaction emerged; VLF-EEG and omission errors reduced to the same level as controls, with decreased inattentive symptoms in cases. Reduced VLF-EEG following MPH treatment provides preliminary evidence that changes in VLF-EEG may relate to MPH treatment effects on ADHD symptoms; and that VLF-EEG may be an intermediate phenotype of ADHD. Further studies of the treatment effect of MPH in larger controlled studies are required to formally evaluate any causal link between MPH, VLF-EEG and ADHD symptoms.     

The Development of Selective Attention in Children With Attention Deficit Hyperactivity Disorder

The influence of age on a selective attention task was studied in a sample of children with and without Attention Deficit Hyperactivity Disorder (ADHD). The impact of methylphenidate (MPH) treatment on selective attention was also investigated in the children with ADHD. Two age groups of children with ADHD and two age groups of control children were tested using a timed computer task. The task consisted of identifying visual target stimuli under various distracter conditions. Distracters varied on the basis of modality (i.e., visual, auditory, or both) and task relevance (i.e., meaningful or irrelevant). Reaction times and accuracy were measured. Children with ADHD were less efficient on the selective attention task than were children without ADHD, and older children were more efficient than younger children in both groups. Children without ADHD were influenced more by the nature of distracters than were children with ADHD. For children with ADHD, MPH improved performance overall.     

Effects of methylphenidate (Ritalin) on information processing in hyperactive children

The effect of methylphenidate on information-processing efficiency was studied in 12 hyperactive, nonretarded children. Performance on six efficiency tasks (Posner Letter Matching, Reaction Time, Memory Search, Category Verification, Item Identification, and Word-Span) and a general measure of on-task behavior were compared for children receiving methylphenidate or a placebo. The median drug dosage was .38 mg/kg, and it was ingested 1 1/2 hours prior to testing. Children blind to the drug-placebo condition were tested on 4 days. In general, methylphenidate-related improvements in attention to on-task behaviors were found. An overall analysis of processing speed suggested that methylphenidate improved efficiency. Methylphenidate significantly decreased reaction times to simple and complex stimulus arrays; differences due to the drug remained even when on-task attentive behaviors were statistically removed. Significantly fewer identification errors occurred on the Posner task in the methylphenidate condition. Results indicated that methylphenidate improved general attentional behaviors and positively influenced processes that define perceptual efficiency.The first author was supported by NIH Training Grant No. HD 07184. We appreciate the assistance of Dr. Robert Sweeney in carrying out this research and the useful comments of Ellen B. Ryan and Jeanne D. Day.     

The specificity of the effects of stimulant medication on classroom learning-related measures of cognitive processing for Attention Deficit Disorder children

There appear to be beneficial effects of stimulant medication on daily classroom measures of cognitive functioning for Attention Deficit Disorder (ADD) children, but the specificity and origin of such effects is unclear. Consistent with previous results, 0.3 mg/kg methylphenidate improved ADD children's performance on a classroom reading comprehension measure. Using the Posner letting-matching task and four additional measures of phonological processing, we attempted to isolate the effects of methylphenidate to parameter estimates of (a) selective attention, (b) the basic cognitive process of retrieving name codes from permanent memory, and (c) a constant term that represented nonspecific aspects of information processing. Responses to the letter-matching stimuli were faster and more accurate with medication compared to placebo. The improvement in performance was isolated to the parameter estimate that reflected nonspecific aspects of information processing. A lack of medication effect on the other measures of phonological processing supported the Posner task findings in indicating that methylphenidate appears to exert beneficial effects on academic processing through general rather than specific aspects of information processing.     

Methylphenidate and substance abuse: a review of pharmacology,animal, and clinical studies

This article reviews pharmacological, animal, and human evidence regarding the abuse liability of methylphenidate (MPH). Findings are not always consistent, but evidence converges to suggest that although intravenous methylphenidate has some abuse potential, there is very little potential for oral MPH abuse. Furthermore, the available data suggests that children with Attention-Deficit/Hyperactivity Disorder (ADHD) who are treated with MPH are at lower risk for substance use disorder later in life. More longitudinal, prospective studies are needed to assess the long term effects of MPH treatment in ADHD.     

AF-DX 116, a Presynaptic Muscarinic Receptor Antagonist, Potentiates the Effects of Glucose and Reverses the Effects of Insulin on Memory

Male Swiss mice were tested 24 h after training in a one-trial step-through inhibitory avoidance task. Low subeffective doses of -(+)-glucose (10 mg/kg, ip), but not its stereoisomer -(−)-glucose (30 mg/kg, ip), administered immediately after training, and AF-DX 116 (0.3 mg/kg, ip), a presynaptic muscarinic receptor antagonist, given 10 min after training, interact to improve retention. Insulin (8 IU/kg, ip) impaired retention when injected immediately after training, and the effects were reversed, in a dose-related manner, by AF-DX 116 (0.3, 1.0, or 3.0 mg/kg, ip) administered 10 min following insulin. Since AF-DX 116 possibly blocks autoreceptors mediating the inhibition of acetylcholine release from cholinergic nerve terminals, the present data support the view that changes in the central nervous system glucose availability, subsequent to modification of circulating glucose levels, influence the activity of central cholinergic mechanisms involved in memory storage of an inhibitory avoidance response in mice.     

Assessing inhibitory control: a revised approach to the stop signal task

The stop signal task (stop task) is designed to assess inhibitory control and is a frequently used research tool in clinical disorders such as ADHD and schizophrenia. Previous methods of setting stop signal delay and of assessing inhibitory control are problematic. The current study reports two modifications that improve the task as a measure of inhibitory control. The first modification was to set stop signal delays proportional to go mean reaction time (go MRT) to better account for inter-subject variability in go MRT. Twenty-eight normal children were tested, and all standard, stop task dependent measures were obtained when delays were set by this method. The second modification was to calculate a novel dependent measure called the area of inhibition (AOI) which provides a more complete measure of inhibitory control than the slope of the relative finishing time z-scores (ZRFT-slope). Implications for the assessment of inhibitory control in clinical populations are discussed.     

Methylphenidate Does Not Modify the Impact of Response Frequency or Stimulus Sequence on Performance and Event-Related Potentials of Children with Attention Deficit Hyperactivity Disorder

Twenty-six children with attention deficit/hyperactivity disorder (ADHD) participated in a double-blind trial consisting of 2 consecutive weeks each of placebo and methylphenidate (M = 26.92 mg/day = 0.78 mg/kg/day). As expected, stimulant therapy resulted in moderate weight loss, increased somatic complaints, and teacher and parent reports of reduced inattentiveness, aggression, and oppositionality. In both phases of the trial, patients were tested in a choice reaction time task assessing two aspects of the task that presumably affect response selection: response frequency (ratio of targets/nontargets = 25/75 vs. 50/50) and stimulus sequence (alternations vs. repetitions). Both manipulations yielded expected results on performance and event-related potentials (ERPs). Stimulant treatment increased accuracy and speed among younger children and curtailed variability of reaction time for the sample as a whole. However, methylphenidate did not affect ERPs. In combination, the results imply that the enhancement of performance by methylphenidate does not involve the demands of response selection examined in this study.     

The development of selective inhibitory control: The influence of verbal labeling

The role of language in the development of selective inhibitory control was examined in four groups: Children aged 7-9 years, children aged 11-13 years, adults aged 20-27 years, and adults aged 62-76 years. We used a modified stop-signal task in which participants inhibited or executed responses based on a visual signal. Response execution and inhibition were assessed by measurement of reaction times (RTs) and error rates to a go signal and RTs to a stop signal. Four task variations were compared in which subjects named (1) the stimulus, (2) the intended action (go/stop), (3) something irrelevant, or (4) nothing. Results showed different developmental trends for response execution and inhibition across the lifespan. Moreover, response execution was faster and more accurate when subjects named the stimulus instead of the intended action. The increase in response accuracy when naming the stimulus was greatest for children. In contrast to expectations, naming the intended action did not influence response inhibition. Overall, these findings suggest that verbal labeling supports the initiation but not the inhibition of actions.