Effects of methylphenidate, desipramine, and L-dopa on attention and inhibition in children with Attention Deficit Hyperactivity Disorder.

The objective of this study was to investigate the effects of methylphenidate (MPH) on attention and inhibition in children with Attention Deficit Hyperactivity Disorder (ADHD) and to establish what the relative contributions of the noradrenergic and dopaminergic systems to this effect were. In addition to MPH, two other drugs were administered in order to affect both transmitter systems more selectively, L-dopa (dopamine (DA) agonist) and desipramine (DMI) (noradrenaline (NA) re-uptake inhibitor). Sixteen children with ADHD performed a stop-task, a laboratory task that measures the ability to inhibit an ongoing action, in a double-blind randomized within-subjects design. Each child received an acute clinical dose of MPH, DMI, L-dopa, and placebo; measures of performance and plasma were determined. The results indicated that inhibition performance was improved under DMI but not under MPH or L-dopa. The response-time to the stop-signal was marginally shortened after intake of DMI. MPH decreased omission and choice-errors and caused faster reaction times to the trials without the stop-tone. No effects of L-dopa whatsoever were noted. Prolactin levels were increased and 5-HIAA levels were lowered under DMI relative to placebo. It is suggested that the effects of MPH on attention are due to a combination of noradrenergic and dopaminergic mechanisms. The improved inhibition under DMI could be serotonergically mediated.

Attentional capacity, a probe ERP study: differences between children with attention-deficit hyperactivity disorder and normal control children and effects of methylphenidate.

In the present study it was investigated whether the smaller P3s in attention-deficit hyperactivity disorder (ADHD) children are caused by a shortage of capacity underlying P3 processes or whether they are due to a capacity allocation problem. Also, effects of methylphenidate on these processes were investigated. Performance and event-related potentials (ERPs) of 14 ADHD and 14 control children were measured using an irrelevant-probe technique. Three types of task irrelevant visual probes (standards, deviants, and novels) were presented against the background of two visual tasks that varied in task difficulty. The parietal P3 wave was measured in response to task stimuli and probes. ADHD subjects made significantly fewer correct detections than normal controls in both the easy and the hard tasks. Controls showed an enhanced P3 to task-relevant stimuli in the hard task, whereas ADHD children did not. Probe (novel) P3 amplitudes decreased from the easy to the hard task to the same extent in both groups. Methylphenidate enhanced the percentage of correct responses and task P3 amplitudes in both the easy and the hard task but probe P3 amplitudes were not influenced by methylphenidate. It was concluded that ADHD children do not suffer from a shortage in attentional capacity; rather, the evidence is in favor of a problem with capacity allocation. Furthermore, methylphenidate had enhancing effects on performance and ERPs, but did not improve the capacity-allocation deficit.

Perceptual and response interference in children with attention-deficit hyperactivity disorder, and the effects of methylphenidate.

Fourteen children with attention-deficit hyperactivity disorder (ADHD) and 14 normal control children were compared with respect to stimulus- and response-related processes. Subjects with ADHD took part in two additional sessions under methylphenidate or placebo. In both experiments, performance and electrophysiological measures such as the P2, N2, and P3 components of event-related potential and electromyogram (EMG) activity were measured during an Eriksen flanker task. In both groups of children, reaction times (RTs) to arrow stimuli incongruent with the target were longer than those to neutral stimuli (response interference), which were again slower than RTs to target-alone stimuli (perceptual interference). Children with ADHD made more errors to incongruent stimuli and showed more response interference. For correct responses, no differences between the groups in response interference effects on reaction time, P2, N2, and P3 latency, or EMG onset were found. Methylphenidate had a general enhancing effect on accuracy but did not specifically reduce interference from the flanking stimuli. Methylphenidate had no effects on RT, N2 and P2 latency, P3 amplitude or latency, or EMG activity. The conclusion that methylphenidate did not influence response processes contrasts sharply with findings reported by authors using the Sternberg memory search task.

Associations between event-related potentials and measures of attention and inhibition in the Continuous Performance Task in children with ADHD and normal controls.

OBJECTIVES: First, to differentiate between inattention and impulsivity based on type of errors made in the AX version of the Continuous Performance Task (CPT), and second, to investigate whether differences in performance between children with attention-deficit hyperactivity disorder (ADHD) and normal controls also occur in specific forms of brain activity, namely event-related potentials (ERPs), presumably related to inattention and impulsivity or inhibition. METHOD: Sixteen ADHD and 16 normal control children performed the CPT-AX. ERPs were recorded at occipital (Oz), parietal (Pz), central (Cz), and frontal (Fz) leads. RESULTS: The ADHD children had a higher CPT-Inattention score and showed smaller parietal positive waves at a latency of approximately 300 msec in reaction to target stimuli, target P3s, likewise indicating less attention. In contrast, they showed neither higher CPT-Impulsivity nor a smaller frontocentral negative wave at about 200 msec (N2); the N2 is generally seen as reflecting inhibition. A subgroup of children with ADHD and oppositional defiant disorder (n = 6) had smaller N2 waves than controls, however. CONCLUSIONS: The ADHD group studied showed deficits in attention but not in impulsivity (or inhibition).

Differences in plasma concentrations of the D- and L-threo methylphenidate enantiomers in responding and non-responding children with attention-deficit hyperactivity disorder.

Children with attention-deficit hyperactivity disorder who are categorized as responders or non-responders to methylphenidate (MPH) on the basis of their electrophysiological P3 response in a selective attention task differ in metabolic patterns of the D- and L-threo MPH enantiomers. Non-responders showed significantly higher plasma concentrations of both D- and L-threo MPH enantiomers.

Are abnormal event-related potentials specific to children with ADHD? A comparison with two clinical groups.

Children with attention deficit disorder and hyperactivity (ADHD) were compared with two other clinical groups, namely, children with autism and children with dyslexia, with respect to several peaks of the ERP. By using these other clinical groups, it was studied whether amplitude differences between children and ADHD and normal control children, which were found in an earlier study, were specific to children with ADHD. ERPs were measured in response to stimuli in an auditory and a visual oddball task. Only with respect to the P3 and Pz, measured in response to deviant auditory stimuli, did the children with ADHD show smaller amplitudes than both autistic children and those with dyslexia. It was concluded that a smaller amplitude of this peak is specific to children with ADHD.

Event-related potentials and performance of attention-deficit hyperactivity disorder: children and normal controls in auditory and visual selective attention tasks.

Attention-deficit hyperactivity disorder (ADHD) children and normal controls (7-13 yrs old) performed an auditory and visual selective attention task. Subjects were instructed to respond to the infrequent (10%) stimuli in the relevant channel. Processing negativity (PN) and several other ERP peaks were scored at the midline electrodes. In the auditory task, controls had more correct detections (hits), less false alarms, larger P3b amplitudes to nontarget stimuli (but not to hits), a larger central PN and larger early frontal positivity (100-250 ms) to target stimuli than ADHD subjects. In the visual modality, controls had more correct detections, less false alarms, larger P3b amplitudes to nontarget stimuli (but not to hits), and larger frontal P3(1) amplitudes to infrequent than to frequent stimuli. It was hypothesized that in ADHD children in both the auditory and the visual task, there is a deficit in the activation of the P3b process. Incorrect triggering of the P3b process might be caused by disturbances in other aspects of the attention process, preceding the P3b.

Effects of methylphenidate on event-related potentials and performance of attention-deficit hyperactivity disorder children in auditory and visual selective attention tasks.

Attention-deficit hyperactivity disorder (ADHD) children participated in a double-blind placebo-controlled study in which the effects of a dosage of 15 mg methylphenidate (MPH) on auditory and visual selective attention tasks was determined by presenting frequent (90%) and infrequent (10%) stimuli in both relevant and irrelevant input channels. The subject's task was to respond to the infrequent tones in the relevant input channel. Processing activity (negativity and positivity) was assessed for both tasks. N1, P2, N2, and P3b peaks were scored in the auditory task and N1, P1, N2, P2, P3(1), and P3b peaks were scored in the visual task. Effects of MPH were more prevalent in the visual than in the auditory condition. In the visual condition MPH enhanced the percentage of hits, caused higher central, parietal, and occipital P3b amplitudes to attended stimuli (both standards and deviants), and also enhanced the frontal processing negativity (PN). In the auditory task MPH did not influence performance, but it enhanced the frontal PN as well as the parietal and occipital P3b amplitudes to all stimulus types. In ADHD children, MPH ameliorates some, but not all, deficits and also improves processing where no differences with normal children are present.

Event-related brain potentials in children with attention-deficit and hyperactivity disorder: effects of stimulus deviancy and task relevance in the visual and auditory modality.

It has frequently been reported that in so-called oddball tasks, children with attention-deficit and hyperactivity disorder (ADDH) show small P3 peaks of the event-related potential (ERP) in response to "targets" (task-relevant deviant stimuli) than normal children. It is not clear, however, whether this smaller P3 is due to abnormal processing of infrequent stimuli per se and/or of task-relevant stimuli and whether it is preceded by abnormalities in earlier peaks, especially those thought to be related to automatic deviancy detection [mismatch negativity (MMN) in the auditory modality and P2N2 in the visual modality]. ERPs of ADDH and normal children in response to visual and auditory stimuli were studied in a condition without task relevance as well as in a task-relevant condition. ADDH children showed smaller P3 amplitudes and (marginally) smaller MMN to auditory deviant stimuli, irrespective of task relevance, so smaller P3s in ADDH children are due to stimulus deviancy per se. In the visual modality the P3 effect failed to reach significance. Because the smaller P3s were also found in a condition not requiring task-related motivation, recent motivational interpretations of differences with normal children are not supported. ADDH children also showed smaller P1 amplitudes than normal children to all stimuli except visual novels. The ERP differences were unrelated to performance, since both groups performed equally well.

Effects of oxazepam on event-related brain potentials, EEG frequency bands, and vigilance performance.

Eighteen males performed two vigilance tasks with static and dynamic stimuli under the influence of oxazepam (20 and 40 mg) in a placebo-controlled, double blind, crossover design. Oxazepam dose-dependently impaired overall level of performance and aggravated the decrement with time in measures of accuracy and sensitivity relative to placebo. The drug reduced the amplitudes of the P1, N1, P2N2, and P3 (dose-dependently) waves of event-related potentials (ERPs). Oxazepam aggravated the linear decline with time of the P3 amplitude only. Oxazepam impaired accuracy was related to deterioration of central processing involved in stimulus discrimination (P2N2). Impairment of response-related performance measures (RT and RI) was associated with processing manifest in the P1, N1, and P3 waves. Oxazepam effects on the amplitudes of N1 and P3 correlated with drug effects on power in alpha 1 (8-10 Hz). Drug effects on overall performance and alpha were also related; the drug effect on response speed correlated only with the drug effect on beta 1 (12.5-21 Hz). Effects of time-on-task on performance and EEG were unrelated, but oxazepam induced performance declines with time may have been caused by declines in resource allocation, as manifest in the amplitude of P3. Time effects on EEG power bands and ERP amplitudes were not significantly related to the time course of oxazepam activity. A curious dissociation emerged: both oxazepam and time-on-task impaired performance, but the drug induced a decrease of theta and alpha 1 power, whereas time-on-task increased power. Various processes play a role in performance decrements with time, and various aspects of processing may be involved in signal-detection measures which makes terms such as sensitivity quite meaningless. So-called computational processing was indistinguishable from energetic processes, which questions the validity of the distinction between these two domains. Explanations of EEG activity in terms of a unidimensional theory of arousal are untenable.

Is the Continuous Performance Task useful in research with ADHD children? Comments on a review.

A recent review of the Continuous Performance Task (CPT) as a research tool by Corkum and Siegel, Journal of Child Psychology and Psychiatry, 34, 1217-1239, 1993, is criticized for insufficient covering of the relevant literature, disregard of the question of differentiation among clinical groups, and inadequacy of explanations of Attention-Deficit-Hyperactivity Disorder (ADHD) in terms of arousal, activation, and effort. An attention-deficit in ADHD children cannot be inferred from poor performance on a CPT. Impaired performance is anything but specific to ADHD children and is caused by a host of variables among which "attention" probably plays a minor role.

Alcohol and vigilance performance: a review.

In the literature on the effects of alcohol on driving-related skills, it is sometimes claimed that vigilance tasks are insensitive instruments whereas divided-attention tasks are extremely sensitive to the effects of alcohol. The results of the present review, based on the analysis of 38 comparisons of alcohol and placebo in vigilance tasks, require that these claims be restated. Both types of attentional task (concentrated and divided) are indispensable in test batteries, although not all types of vigilance and divided-attention task are equally sensitive, e.g. some types of vigilance task, using spatial stimuli, were sensitive to BAC levels of 0.03% whereas other types were insensitive to levels of 0.10%. In contrast, the usefulness of tasks of questionable validity and/or low sensitivity (such as the DSST, CFF, digit span, simple RT and choice RT) is questioned. Apart from issues of validity and sensitivity of tests, the ways in which alcohol may affect performance are also discussed. The main effect of moderate doses of alcohol is on attention and information processing. The capacity to divide and sustain attention is already impaired at BAC levels of 0.02-0.03%. Further, alcohol effects appear to some extent to be time-dependent, and are greatest during periods of sleepiness (the early afternoon and after midnight). Some current BAC levels concerning drinking and driving are far too generous. There is sufficient evidence from the literature on performance indicating that the BAC standard for driving should be lowered to 0.02% for driving after midnight and for special risk groups (young and less experienced drivers).

Effects of oxazepam on performance and event-related brain potentials in vigilance tasks with static and dynamic stimuli.

Eighteen males performed two vigilance tasks with static and dynamic stimuli under the influence of oxazepam (20 and 40 mg) in a placebo-controlled, double blind, crossover design. Oxazepam (40 mg) caused impaired performance in the early part of a task with stimuli inducing frequent saccadic eye movements (dynamic task), relative to a task in which the stimuli remained at the same location (static task). This could not be explained by effects of the drug on oculomotor behavior. A larger diameter of the pupil in the dynamic task indicated that performance on this task may have required more effort. Stimulus processing requirements were higher in the dynamic task, as suggested by event-related brain potentials (ERPs), in particular the P3 wave; i.e., more resources had to be allocated in this task. This (additional) investment of resources appeared impossible after administration of oxazepam (40 mg). The conclusion was that tasks eliciting frequent eye movements require more effort and processing resources.

Methylphenidate influences on both early and late ERP waves of ADHD children in a continuous performance test.

Although it has frequently been reported that hyperactive children have abnormally small P3 amplitudes of the event-related potential (ERP), which are normalized by the stimulant drug methylphenidate (MPH), the literature is inconsistent concerning earlier ERP waves. The aim of the present study was to investigate whether the normalizing effect of a 10-mg dose of MPH was also apparent on earlier waves, such as the N1, the P2, and the N2, besides the P3. Twelve attention deficit with hyperactivity disorder (ADHD) children performed a Continuous Performance Test involving a button-press response to the letter X (CPT-X) under the influence of MPH in a double-blind placebo controlled acute dosage design. ERPs were recorded at Oz, Pz, Cz, and Fz. The expected increase of the parietal P3, both to targets and nontargets, was apparent, as well as a significant increase in percentage of hits. There also was a significant increase of an earlier, negative going, wave, the N2, with a frontal maximum, under the influence of MPH. This wave was probably a manifestation of an increase in processing negativity for target stimuli only, after the intake of the stimulant drug. No effect of MPH was found on the N1 or the P2.

Effects of oxazepam on eye movements and performance in vigilance tasks with static and dynamic stimuli.

The aim of the present study was to determine whether in a task with stimuli inducing frequent saccadic eye movements, ingestion of oxazepam impairs performance more than in a task in which the stimuli remained fixed at the same location, due to effects of oxazepam on the ocular system. Eighteen males performed a vigilance task with static and dynamic stimuli under the influence of oxazepam (20 and 40 mg) in a placebo-controlled, double blind, crossover design. Oxazepam (40 mg) had a larger effect on vigilance performance in the first part of the dynamic task, relative to its static counterpart. Oxazepam also had an effect on oculomotor behavior, but this effect was unrelated to impaired performance. There were dose-dependent effects of oxazepam on absolute, overall level of performance but not on the decrement with time. The non-dose-dependent aggravation of the decrement in correct detections, caused by the drug, could only partly be accounted for by pharmacokinetics and increased eyelid closures, and was also caused by pharmacodynamic effects of the drug, such as those on attention. Different effects were noted for the two signal detection measures of response behavior, B" and RI.

Prepubescent children may have specific deficits in olfactory sensitivity.

In three age groups (mean ages 9, 15, and 20 years, ns = 58, 58, 112) olfactory sensitivity to 5 odorants was assessed. The prepubescent children showed no loss in sensitivity to the odor of amyl acetate but were inferior in detection of the other 4 odorants, in particular, in detection of 2 musk odors. The results suggest odorant-specific receptor development during puberty. However, it is emphasized that several factors should be better controlled before it can be concluded that changes with age can be used as a model to increase knowledge of olfactory function.

Sex differences in olfactory sensitivity and the problem of the generality of smell acuity.

Sex differences in olfactory sensitivity are not an invariably recurring phenomenon. In the present study some factors, possibly involved in inconsistent findings, are investigated. Sensitivity to 5 different odorants was assessed in 112 subjects on 4 different occasions. Sex differences emerged for some odors but not for others, and some explanations for this state of affairs were suggested. There was no effect of the personality dimension of extraversion-introversion. Low correlations among the 5 measures of detectability question the existence of a general factor of sensitivity.

Diurnal variations in olfactory sensitivity and the relationship to food intake.

At least a dozen studies have investigated the effects of food intake on olfactory sensitivity. Most studies reported the existence of food-related changes in sensitivity but the findings are highly discrepant. In the present study, earlier studies are reviewed, their shortcomings discussed, and the results of an experiment are reported. Using an air-dilution olfactometer, sensitivity to the odor of acetophenone was assessed throughout the day in seven subjects on four consecutive days, both with and without lunch. In the group data no consistent pattern of changes in sensitivity related to food intake was found, although some individual subjects showed a diurnal variation. Some suggestions are made enhancing the possibility that in the future a relationship between food intake and olfactory sensitivity may be observed.

Stimulant drugs and vigilance performance: a review.

The literature on the effects of some stimulant drugs (amphetamine, methylphenidate, caffeine, and nicotine) on vigilance performance is reviewed. Improvement of overall level of performance (both accuracy and speed) after the intake of amphetamine, caffeine, and nicotine has often been reported, and the decrement in performance with time has been shown to be prevented especially with amphetamine and nicotine. Effects on false alarms are negligible. In studies where a test battery was employed, vigilance tasks appeared to be the most sensitive performance tests in detecting the effects of stimulants; however, different vigilance tasks may measure different aspects of mental functions. There is no support for earlier conclusions that improvements are noticed only in fatigued subjects in protracted sessions. Evidence from several studies does not support the hypothesis that improvements are only a recovery of withdrawal-induced impairment. Because positive effects have been obtained with drugs possessing different mechanisms of action, there is as yet no clear support for a noradrenergic, dopaminergic, or cholinergic theory of sustained attention. Simple neurotransmitter theories of attention and information processing may be untenable.

Time effects on event-related brain potentials and vigilance performance.

A review of the literature showed that in vigilance or oddball tasks, changes over time in event-related potentials (ERPs) and performance measures often seem to be unrelated, but a number of studies had some shortcomings. In the present study a visual vigilance experiment was carried out, in which single-trial ERPs and performance data of 40 males were obtained. A relationship between time trends in behavioral and ERP measures was found: an early P3 amplitude and response latency (RT) showed an inversely varying relation over time. Analysis of covariance showed that the two linear trends tap the same aspect of processing: both trends became insignificant when adjusted for common variance. A negative correlation between mean values of P3 amplitude and RT rather than for change scores has been observed in previous studies, but has been ignored in the literature. However, correlations with RT have also been reported for other ERP deflections. Although there were several correlations between mean scores, most time-induced changes in ERP parameters appeared to be unrelated to worsening performance, for which several explanations are advanced. The ERP results do not support the hypothesis that a decrement in performance is caused by increasing difficulty discriminating targets from nontargets. A gradual decline in effort or resources allocated to the task might be an alternative explanation of performance deterioration. However, an effort-hypothesis cannot easily be tested. Effort is often invoked post hoc, and has previously been associated with many ERP components. The relationship between ERPs and the signal detection measures "sensitivity" d' and "response bias" beta is discussed.