Acute effects of methylphenidate on performance during the Test of Variables of Attention in children with attention deficit/hyperactivity disorder

Authors


Chih-Ken Chen, MD, PhD, Department of Psychiatry, Chang Gung Memorial Hospital, 222 Mai-Chin Road, Keelung, Taiwan. Email: kenchen@cgmh.org.tw

Abstract

Abstract  This study attempted to determine the acute effects of methylphenidate (MPH) on cognitive performance using the Test of Variables of Attention (TOVA) in children with attention deficit/hyperactivity disorder (ADHD). The study subjects comprised 57 children diagnosed with ADHD aged 6–13 years. Diagnoses of ADHD and other comorbid psychiatric disorders were based on Diagnostic and Statistical Manual of Mental Disorders-fourth edition criteria following a standard interview with the Schedule for Affective Disorder and Schizophrenia for School-Age Children, epidemiologic version. The subjects' performance on the TOVA was compared before and 1 h after administration of MPH. After administration of MPH, commission scores, response time and ADHD scores improved significantly, however, there were no significant changes in omission scores, response time variability or response sensitivity. The authors concluded that administration of one dose of MPH (0.5–1.0 mg/kg) produced more effects on impulsivity than on attention deficiency in children with ADHD, and that the second half section of the TOVA could be more sensitive than the first half in determining the acute effects of MPH therapy in children with ADHD. However, the effects of different MPH doses on the TOVA results need further investigation.

INTRODUCTION

Attention deficit/hyperactivity disorder (ADHD) is a clinical disorder characterized by persistent over-activity, inattention and impulsivity that are severe, developmentally inappropriate and cause impaired function at home and school. Children with ADHD are at increased risk for low educational attainment, income, and underemployment.1 Moreover, children with ADHD generally have learning difficulties, beha-vioral problems, lack peer acceptance, low self-esteem and high risk for adult criminality and substance abuse.1–3 Longitudinal studies have indicated that 30–50% of children with ADHD develop significant behavior and psychiatric problems in adulthood.4 A variety of adverse environments, many which involve parent–child relationships, are associated with ADHD.5 Despite the seriousness of ADHD, little is known about its cause. ADHD is highly heritable but is likely a complex disorder involving multiple genes of moderate effect.6,7 Twin studies support the view that genetic factors are the major influence on familial risk with heritability estimates for ADHD symptom scores consistently reported to be in the region of 60–90%.8 Results of molecular genetic studies have highly suggested that dopamine plays a central role in ADHD.9–12

Psychostimulant therapy is the most common treatment for ADHD. Psychostimulants exert their pharmacological effects in part by inhibiting the dopamine transporter and, therefore, retaining a larger quantity of dopamine activity in the synaptic cleft for longer periods.13 Methylphenidate (MPH), a kind of psychostimulamt, is the most frequently prescribed medication for ADHD, and its clinical efficacy is well established.14 The effects of MPH on attention result from a combination of noradrenergic and dopaminergic mechanisms.15 The two principal problems in children with ADHD are attention deficiency and impulsivity/hyperactivity. The Diagnostic and Statistical Manual of Mental Disorders–fourth edition (DSM-IV)16 classified ADHD into three subtypes: inattentive, hyperactive-impulsive and combined. Methylphenidate is assumed to ameliorate both. However, the question remains whether MPH exerts its effects on these two problems to the same degree.

Typically, ADHD is diagnosed based on behavior ratings which are highly subjective and susceptible to bias. A frequently employed objective measure for inattention and impulsivity is the continuous performance test.17 Despite continued usage of continuous performance test (CPT) in studying children with ADHD, the studies on type of CPT errors committed by children with ADHD or the studies on effects of MPH on children with ADHD revealed inconsistent results.18 The Test of Variables of Attention (TOVA) is a computerized continuous performance test with minimal language demands,19 which can be given after a single challenge dose of medication to reliably predict treatment response. The TOVA has been reported to have good discriminating validity and can be a useful tool in diagnosing ADHD cases in Japanese children with ADHD.20 The TOVA can also be applied to titrate the dose of medication for attention variables and to monitor medication efficacy over time.17 The aim of this study was to determine the acute effects of MPH on cognitive performance using the TOVA in children with ADHD. The authors also studied the differences in TOVA performance between children with subtypes of ADHD.

METHODS

Study participants

A total of 60 subjects were recruited from children diagnosed with and/or treated for ADHD at the Department of Child Psychiatry, Chang Gung Children's Hospital, Taiwan. Study approval was obtained from the Institutional Review Board of Chang Gung Memorial Hospital. Written informed consent was obtained from the parents of each child following an explanation of the study. The diagnoses of ADHD and comorbid disorders were performed by two senior child psychiatrists and based on the DSM-IV criteria after structured interviews with the Chinese version21 of the Schedule for Affective Disorder and Schizophrenia for School-Age Children, epidemiologic version (K-SADS-E22). Subjects with ADHD were classified into three types: inattentive, hyperactive-impulsive, and combined inattentive and hyperactive-impulsive. The authors excluded children who had comorbid pervasive developmental disorders or mental retardation, and who had a history of bipolar disorder, psychosis, epilepsy, or brain injury.

Measurements

Experienced child psychologists conducted neuro-psychological tests with individual subjects in a dedicated room to reduce variability in testing conditions. The tests employed were as follows: (i) Wechsler Intelligence Scale for Children, third edition,23 which is a standardized intelligence test and is appropriate for children and adolescents aged 6–16; and (ii) Test of Variables of Attention-Visual24 (TOVA-V), which is a computerized continuous performance test comprising a target stimulus and a non-target stimulus. Before the present study, the authors have conducted a study to examine the validity of the TOVA in Chinese children with ADHD. Comparing TOVA performance of 39 children with ADHD and 30 normal controls, the authors found that the ADHD group had significantly higher means than the control group in omission errors, commission errors, response time variability, response sensitivity and ADHD scores, and concluded that the TOVA had good ability to distinguish Chinese children with ADHD from normal Chinese controls.

In the TOVA-V, stimuli appear individually and are randomly presented according to a determined ratio. The tested subject is required to immediately press a button after seeing a target. The duration of the test is 22.6 min. Two kinds of visual stimuli appear a total of 648 times. The variables measured are omissions, commissions, response time, response time variability and response sensitivity (d′). An omission is scored when a target stimulus appears and the participant does not press the button. The score represents the subject's degree of inattention. A commission, which is scored when a target stimulus does not appear but the participant presses the button, represents the participant's inability to control impulses. Response time is the time taken (measured in ms) to respond to each trial. Response time variability is calculated based on deviation from the mean time for giving a correct response. An evaluation of the response sensitivity (d′), which represents the ratio of hit frequency to frequency of false responses, measures the ability to accurately distinguish a target from a non-target and is interpreted as a measure of perceptual sensitivity. Response sensitivity (d′) is derived from signal detection theory, which measures how quickly one's performance worsens (deteriorates) over the time of testing. People with ADHD ‘lose it’ much more quickly than others. An ADHD score is derived from the total subscores. The ADHD score is a comparison of the person's TOVA performance to an age/gender-specific group with ADHD. All of the other measures tell how different this person's performance is when compared to others who do not have ADHD. The ADHD score tells how similar this person's performance is to others with ADHD. The advantage of TOVA is that it is not influenced by cultural biases and results can be compared worldwide. The TOVA results, compared to the normal same gender, same age and average intelligence quotient group, are reported as standard deviations from the norm.

Each subject performed the TOVA twice. All subjects were free from any medication for at least 1 week prior to the first TOVA. The second TOVA was performed 1 h after administration of MPH. A dose of 0.5–1.0 mg/kg MPH was determined with dosage modifications based on the subjects' dosages of MPH before medication washout.

Data analysis

The results of TOVA were reported as standard deviations which indicated the extent of deviation from the norm. The anova, χ2 test, Student's t-tests and Mann–Whitney U-tests were applied for group comparisons, and paired t-tests were used for repeated measures. A two-tailed value of P < 0.05 was considered statistically significant.

RESULTS

Three recruited subjects had extremely poor performance on TOVA and were excluded from analysis. Therefore, the final sample comprised 57 children with ADHD. Subject ages ranged from 6 to 13 years old (mean age, 8.5 ± 2.2 years). Of the 57 subjects, 50 were male and seven were female. A total of 14 subjects had learning disorders (24.6%). Five (8.8%) had comorbid oppositional defiant disorders, three (5.3%) had tic disorders, and two (3.5%) had conduct disorders.

The subjects were classified into three subtypes of ADHD: inattentive (N = 21), hyperactive-impulsive (N = 6), and combined (N = 30). No meaningful differences in age between these three groups were identified, F (2, 54) = 1.0, P = 0.4. Table 1 shows the TOVA results for these three subtypes. There were significant differences in response time variability and ADHD scores between these three subtypes. Post-hoc tests indicated that subjects with inattentive ADHD had a significantly better performance in response time variability than those with combined ADHD, 95% confidence interval = 0.02–1.38, P = 0.04.

Table 1.  Test of Variables of Attention results for attention deficit/hyperactivity disorder subtypes before methylphenidate treatment
 Inattentive (n = 21)Hyperactive (n = 6)Combined (n = 30)Statistic
  1. Test of Variables of Attention results are reported as standard deviations from the norm.

  2. Data are expressed as mean ± SD.

  3. ADHD, attention deficit/hyperactivity disorder.

Omission−0.56 ± 1.290.33 ± 2.62−0.92 ± 1.40F (2, 54) = 2.4, P = 0.1
Commission0.26 ± 0.570.43 ± 0.93−0.05 ± 1.23F (2, 54) = 0.5, P = 0.6
Response time−0.27 ± 1.37−0.59 ± 0.99−0.88 ± 0.89F (2, 54) = 1.8, P = 0.2
Response time variability−0.20 ± 1.26−0.12 ± 0.98−0.90 ± 0.75F (2, 54) = 3.8, P = 0.03
Response sensitivity (d′)−0.24 ± 1.27−0.01 ± 0.75−0.43 ± 0.98F (2, 54) = 1.7, P = 0.2
ADHD score−1.17 ± 2.13−0.57 ± 2.08−1.77 ± 1.89F (2, 45) = 3.4, P = 0.04

The mean dosage of MPH was 15.5 ± 4.2 mg. Table 2 presents the changes in TOVA scores before and after administration of MPH. After administration of MPH, there were significant improvements in ADHD scores, commission errors, response time and response time variability, however, there was no significant improvement in omission errors or d′. The improvements in the variables of attention were different between the first half and the second half sections of the TOVA test. In the first half section of the TOVA, the subjects had significant improvement only in response time but not in other variables. In the second half section, there were also significant improvements in commission errors, response time, response time variability and d′ but not in omission.

Table 2.  Test of Variables of Attention results for attention deficit/hyperactivity disorder before and after methylphenidate treatment
 Before treatmentAfter treatmentStatistic
  1. Test of Variables of Attention results are reported as standard deviations from the norm.

  2. Data are expressed as mean ± SD.

  3. ADHD, attention deficit/hyperactivity disorder.

Omission
 Total−0.66 ± 1.33−0.49 ± 1.37t (56) = −1.13, P = 0.3
 First half−0.49 ± 1.27−0.50 ± 1.46t (56) = −0.23, P = 0.98
 Second half−0.66 ± 1.33−0.43 ± 1.28t (56) = −1.50, P = 0.1
Commission
 Total0.17 ± 1.000.45 ± 1.07t (56) = −2.19, P = 0.03
 First half−0.004 ± 0.94−0.08 ± 1.17t (56) = 0.46, P = 0.6
 Second half0.22 ± 1.080.74 ± 1.17t (56) = −4.68, P < 0.001
Response time
 Total−0.62 ± 1.12−0.34 ± 1.16t (56) = −2.68, P = 0.003
 First half−0.58 ± 1.01−0.18 ± 1.10t (56) = −3.64, P = 0.001
 Second half−0.61 ± 1.16−0.37 ± 1.16t (56) = −2.10, P = 0.04
Response time variability
 Total−0.56 ± 1.03−0.12 ± 1.10t (56) = −3.60, P = 0.001
 First half−0.56 ± 1.18−0.42 ± 1.08t (56) = −0.75, P = 0.5
 Second half−0.52 ± 1.08−0.11 ± 1.13t (55) = −3.12, P = 0.003
Response sensitivity (d′)
 Total−0.43 ± 0.98−0.34 ± 1.16t (56) = −0.48, P = 0.6
 First half−0.46 ± 1.07−0.39 ± 1.19t (56) = −0.54, P = 0.6
 Second half−0.62 ± 0.93−0.05 ± 1.31t (56) = −5.75, P < 0.001
 ADHD score−1.69 ± 1.86−0.26 ± 2.29t (45) = −5.76, P < 0.001

There was no significant difference in TOVA scores between males and females. The rates of inattentive type, hyperactive type and mixed type were 34.0%, 12.0%, 54.0% for males, and 57.1%, 0%, 42.9% for females, respectively. There was no significant gender difference (P = 0.391) in the distribution of ADHD subtypes. Table 3 presents comparisons of the changes in TOVA scores between males and females after MPH treatment. Male scores were significantly more improved for commission errors, response time variability and d′ than were those of females. The children with hyperactivity type or combined type of ADHD had significantly more improvement for commission errors than those with inattentive type of ADHD (Table 4).

Table 3.  Comparison of changes between males and females in Test of Variables of Attention performance after methylphenidate treatment
 Males (n = 50)Females (n = 7)Statistic
  1. Test of Variables of Attention results are reported as standard deviations from the norm.

  2. Data are expressed as mean ± SD.

  3. ADHD, attention deficit/hyperactivity disorder.

Omission0.19 ± 1.14−0.07 ± 0.59Z = 1.18, P = 0.2
Commission0.39 ± 0.92−0.49 ± 1.07Z = 2.09, P = 0.04
Response time0.30 ± 0.810.16 ± 0.62Z = 0.56, P = 0.6
Response time variability0.53 ± 0.92−0.23 ± 0.65Z = 2.02, P = 0.04
Response sensitivity (d′)0.44 ± 0.63−0.03 ± 0.34Z = 2.06, P = 0.04
ADHD score1.44 ± 1.671.18 ± 2.11Z = 0.29, P = 0.8
Table 4.  Comparison of changes in Test of Variables of Attention performance between subjects with and without hyperactivity after methylphenidate treatment
 Inattentive (n = 21)Hyperactive + combined (n = 36)Statistic
  1. Test of Variables of Attention results are reported as standard deviations from the norm.

  2. Data are expressed as mean ± SD.

  3. ADHD, attention deficit/hyperactivity disorder.

Omission0.14 ± 0.940.18 ± 1.18t (55) = 0.14, P = 0.9
Commission−0.13 ± 0.900.52 ± 0.95t (55) = 2.54, P = 0.01
Response time0.42 ± 0.630.20 ± 0.87t (55) = 0.99, P = 0.3
Response time variability0.32 ± 0.910.51 ± 0.93t (55) = 0.77, P = 0.4
Response sensitivity (d′)0.28 ± 0.600.45 ± 0.63t (55) = 1.00, P = 0.3
ADHD score1.38 ± 1.721.45 ± 1.68t (44) = 0.13, P = 0.9

DISCUSSION

This study demonstrated that one dose of MPH significantly enhanced subjects' TOVA performance in commission errors, response time and ADHD scores, but not in omission errors, response time variability or d′. The findings of previous MPH studies25–31 on cognitive performance in ADHD children are inconsistent. Michael et al. reported significant improvement for both omission and commission errors,30 while Coons et al. reported no beneficial effects.31 Hastings and Barkley reported that omission errors and response time improved when MPH were given to individuals with ADHD.27 The present study reported significant improvements in commission errors only but not omission errors, which were consistent with findings of Klorman et al.25 and Aggarwal et al.28 In terms of effects on ADHD information process, previous studies have demonstrated that MPH does not affect short-term memory, visual retention, baseline motor speed or encoding,32 and that this drug increases the decision and selection process of a timed task.33 Although impulsiveness is only one of the features of ADHD, it forms a core deficit from which the other associated deficits emerge.34 Impulsivity, a primary problem for children with ADHD, was operationalized in the TOVA as commissions. Commissions are scored when a target stimulus does not appear but the participant reacts by pressing the button. Therefore, a commission represents the participant's inability to control impulses. Impulsivity is predominant in subjects with hyperactivity. Therefore, it makes sense that the present study also found subjects with hyperactive type or combined type of ADHD showed significantly more improvement in commission errors than those with inattentive ADHD.

The diversity of results from studies mentioned above may reflect variations in methodology, including different MPH dosages, stimulus durations, interstimuli intervals, time on task and numbers of trials.18 Different MPH dosages may lead to various effects on attention functions.29,35,36 For the TOVA, the stimulus duration is 100 ms, which is relatively short compared to those (50–800 ms) in other studies. The target stimuli are presented 22.5% of the time during the first half (the boring session) and 77.5% of the time during the second half (the stimulating session) of the TOVA test. A meta-analytic study has shown that the effects of MPH on the CPT tests are greater in experiments using shorter stimulus duration, smaller number of trials and higher probability of a target.18 The finding of the present study that there were significant improvements in the second half, but not in the first half, of the commission scores, response time variability and response sensitivity could be explained by higher probability of a target in the second half than the first half of the test. Based on this finding, the authors propose that the second half section of the TOVA is more sensitive than the first half in determining the acute effects of MPH therapy in children with ADHD. However, it can not be ruled out that timing of performing the TOVA may influence the test results. In this study, the second half of the TOVA was performed 1.5 h after administration of MPH while the first half was performed 1 h after administration of MPH. It is possible that performing TOVA test 1.5 h after administration of MPH provides better sensitivity in determining the effects of MPH therapy in children with ADHD than doing that 1 h after.

This study identified that males had significantly more improvement in commission errors, response time variability and d′ than females. However, this finding may be confounded by gender differences in ADHD symptoms or in distributions of ADHD subtypes. Therefore, this preliminary finding requires further study with a larger sample before concluding that males with ADHD respond better to MPH than females. Indeed, research has shown that there are gender-based differences in ADHD symptoms. For example, Greenberg and Waldman suggested that males make more omission, commission and anticipatory errors and have a faster mean reaction time than females.17 In this study, there was no significant difference in TOVA scores between males and females. However, the sample comprised only seven females and, therefore, there was insufficient statistical power to detect small or moderate gender differences in symptom presentations.

This work must be considered within the context of its methodological limitations. This study is not placebo-controlled and order is not counter-balanced. All subjects were tested first without medication and then with medication, therefore, practice effects, produced by repeated testing, could not be ruled out. This study assessed the acute effects of MPH on performance during TOVA. This study's findings, which were based on one dose of MPH, cannot be generalized as representative of its long-term effects. Finally, this present study used visual presentation of TOVA stimuli. Most people are concordant for visual and auditory information processing. However, a small proportion (estimated at 12%) of individuals are discordant and process visual and auditory information differently. Therefore, to have a more comprehensive assessment of information processing in patients with ADHD, TOVA-visual and TOVA-auditory may be applied in the forthcoming studies of this field. Despite these limitations, analytical results of this study elucidated differentially the significant effects of MPH on various attention functions of children with ADHD, and concluded that administration of one dose of MPH (0.5–1.0 mg/kg) produced more acute effects on impulsivity than on attention deficiency in children with ADHD. However, the effects of different MPH doses on the TOVA results need further investigation.

ACKNOWLEDGMENTS

This study was supported by research grants from the Chang Gung Memorial Hospital, Taiwan (CMRPG32015, CMRPG260121). The authors wish to express their deepest gratitude to all the children and their parents who participated in this study.

Ancillary