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Hyperactivity Disorder
Methylphenidate Improves Visual-Spatial Memory in Children With Attention-Deficit/Hyperactivity Disorder ANNE-CLAUDE BEDARD, M.SC., RHONDA MARTINUSSEN, M.ED., ABEL ICKOWICZ, M.D., ROSEMARY TANNOCK, PH.D.
AND
ABSTRACT Objective: To investigate the effect of methylphenidate (MPH) on visual-spatial memory, as measured by subtests of the Cambridge Neuropsychological Testing Automated Battery (CANTAB), in children with attention-deficit/hyperactivity disorder (ADHD). Visual-spatial memory is a core component of working memory that has been shown to be impaired in ADHD, irrespective of comorbid reading and/or language problems. Method: A clinic-referred sample of school-age children with a confirmed DSM-IV diagnosis of ADHD (n = 26) completed tests of visual-spatial memory, planning ability, and recognition memory in an acute, randomized, placebo-controlled, crossover trial with three single fixed doses of MPH. MPH effects on right-handed and left-handed motor control were also assessed. Results: MPH significantly improved performance on a self-ordered, updating visual-spatial working memory task and on maintenance of visualspatial information but had no effects on measures of visual-spatial planning ability or recognition memory. Also, MPH significantly improved left-handed motor control. Conclusions: Beneficial effects of MPH on visual-spatial processing in ADHD are selective and restricted to visual-spatial memory. J. Am. Acad. Child Adolesc. Psychiatry, 2004;43(3):260– 268. Key Words: attention-deficit/hyperactivity disorder, methylphenidate, working memory, cognition.
Attention-deficit/hyperactivity disorder (ADHD) is a common developmental disorder that affects 3% to 7% of school-age children (American Psychiatric Association, 2000). Current models of ADHD are founded on neuropsychological theories of impaired functioning of the frontal lobes, in particular the prefrontal cortex (Goldman-Rakic, 1987; Shallice, 1982). It has been suggested that the cognitive difficulties experienced by children with ADHD are accounted for by deficits in the executive functions (Barkley, 1997). Executive functions are a set of cognitive control processes that Accepted October 7, 2003. From The Institute of Medical Science, University of Toronto (Ms. Bedard, Ms. Martinussen, Dr. Tannock), Brain & Behaviour Research Program and Department of Psychiatry, The Hospital for Sick Children (Ms. Bedard, Ms. Martinussen, Drs. Ickowicz and Tannock). Work on this paper was supported by the Psychiatry Department at The Hospital for Sick Children and CIHR Doctoral Awards (Ms. Bedard, Ms. Martinussen). The authors thank Min-Na Hockenberry for her contribution. Correspondence to Dr. Tannock, Brain & Behaviour Research, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8; e-mail: [email protected]. 0890-8567/04/4303–0260©2004 by the American Academy of Child and Adolescent Psychiatry. DOI: 10.1097/01.chi.0000106850.88132.5a
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serve to optimize performance in complex tasks and include processes such as the allocation of attention, working memory, and inhibition (e.g., Fuster, 1999). Working memory serves to maintain temporary, active representations of information for further processing or recall (Baddeley, 1996). It plays a crucial role in reducing distraction and controlling attention during complex cognitive activities such as mental calculation and language comprehension (Baddeley, 1996; de Fockert et al., 2001; Miyake and Shaw, 1999). There are several competing theoretical models of working memory (Miyake and Shaw, 1999), but most differentiate between two processes: maintenance and manipulation of information. Domain-specific models, such as that proposed by Baddeley (1996), also distinguish between the different modalities of information (e.g., auditory-verbal, visual-spatial). Prevailing models of ADHD suggest that working memory impairments are central to ADHD (Barkley, 1997; Castellanos and Tannock, 2002; Rapport et al., 2001), but findings are equivocal and previous reviews have concluded that there is no robust evidence of impairments in ADHD (Pennington and Ozonoff, 1996; Welsh, 2002). Notably, these conclusions were J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 43:3, MARCH 2004
MPH AND VISUAL-SPATIAL MEMORY IN ADHD
based primarily on the findings from studies of auditory-verbal working memory, many of which did not control for reading or language disorders that are themselves associated with impairments in auditory-verbal working memory. The most recent review concluded that there is growing evidence for impairments in visual-spatial working memory (in both maintenance and manipulation processes) in ADHD (Martinussen et al., unpublished, 2003). The evidence for visual-spatial working memory deficits in ADHD is consistent with neuropsychological and imaging studies that implicate mainly right frontal-striatal circuitry in ADHD (reviewed by Giedd et al., 2001). If visual-spatial working memory is impaired in ADHD, then it is important to determine whether treatment that targets the behavioral symptoms of ADHD also improves this important cognitive control process. Psychostimulant medication, such as methylphenidate (MPH), is the primary treatment approach for ADHD (e.g., NIH Consensus Statement, 1998). Accumulating evidence of structural and functional abnormalities in prefrontal and striatal brain regions in ADHD, which are modulated by catecholaminergic neurotransmitters, provides the theoretical basis for neuropharmacological treatment of this disorder. One pathway of MPH action in the brain is through blocking dopamine reuptake, increasing the amount of extracellular dopamine available to bind to its receptors (Volkow et al., 2001). Dopamine is an important neurotransmitter involved in executive control processing (see review by Nieoullon, 2002), and there is a high density of dopamine receptors in the prefrontal cortex and basal ganglia (reviewed by Solanto, 1998). These brain structures, which are intricately involved in working memory and are catecholamine modulated (Braver et al., 2001, Carlson et al., 1998), have been shown to be deficient in ADHD (reviewed by Castellanos and Swanson, 2002). MPH-induced increases in dopamine levels in the synaptic clefts of these structures are believed to enhance several aspects of cognitive processing, including working memory (Mehta et al., 2000a). Stimulants have been found to enhance performance of tests of visual-spatial working memory and planning in healthy adult volunteers (Elliott et al., 1997; Mattay et al., 2000). However, the lack of stimulant effects on visual-spatial memory in ADHD is due primarily to lack of data rather than inconsistency in findings. Three studies suggest that stimulants may enhance visual-spatial working memory; two of them were uncontrolled (Barnett et al., 2001; Kempton et al., 1999) J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 43:3, MARCH 2004
and the third involved a randomized controlled design but was a case study of an adult with ADHD (Mehta et al., 2000b). In a previous randomized, placebocontrolled study, MPH improved the ability of nonanxious children with ADHD to update verbal information in a paced auditory serial addition task (Tannock et al., 1995). No study to date has examined the impact of MPH on visual-spatial processing in children with ADHD in a randomized, placebo-controlled, crossover design. The purpose of this study was to examine the effects of stimulant medication on various components of visual-spatial processes in children with ADHD. We used several of the well-validated tests from the Cambridge Neuropsychological Testing Automated Battery (CANTAB; reviewed by Luciana, 2003) that assess psychomotor speed/accuracy, visual-spatial processing, such as recognition memory, spatial planning ability, and both the maintenance and manipulation components of visual-spatial working memory. We predicted that MPH would improve measures of visual-spatial working memory in children with ADHD. METHOD SUBJECTS Sample characteristics are presented in Table 1. All children had a confirmed DSM-IV diagnosis of ADHD and were consecutive referrals for evaluation of their response to stimulant treatment. The majority of subjects were right-handed and medication naïve. Most were white (90%), and the remainder were Asian (10%). Exclusionary criteria included a full-scale IQ score of less than 80; evidence of neurological dysfunction, poor physical health, uncorrected sensory impairments, history of psychosis (based on physician inquiry); or the primary language spoken at home was not English. DIAGNOSTIC ASSESSMENT Clinical diagnosis of ADHD, using DSM-IV criteria, was based upon information from semistructured interviews conducted with parents (Parent Interview for Child Symptoms [PICS]) (Ickowicz et al., 2002) and the child’s classroom teacher (Teacher Telephone Interview [TTI]) (Tannock et al., 2000). Trained clinicians blind to other aspects of the child’s assessment conducted interviews independently. Both interviews require the clinician rather than the informant to rate the presence and severity of each symptom, based upon descriptive information of the child’s behavior in prescribed contexts, using prespecified scoring criteria. Reliability and validity for the DSM-III-R version of both interviews are high (Schachar et al., 1995); evaluation of the psychometric properties of the DSMIV versions is underway. Parent and teacher ratings of the child’s behavior were gathered using the Conners Rating Scale-Revised (CRS-R) (Conners, 1997). Diagnosis of conduct disorder and oppositional defiant disorder was based on information from the PICS and TTI interviews. The Wechsler Intelligence Scale for Children-
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TABLE 1 Sample Characteristics Total Sample Age, mean (SD) Range, years Gender (male/female) WISC-III Full Scale IQ, mean (SD) Teacher-based on TTI-IVa No. of inattentive symptoms No. of hyp/imp symptoms Teacher-based on Connersb No. of inattentive symptoms No. of hyp/imp symptoms Parent-based on PICS No. of inattentive symptoms No. of hyp/imp symptoms Parent-based on Conners No. of inattentive symptoms No. of hyp/imp symptoms DSM-IV ADHD subtype (%) ADHD-combined ADHD-inattentive ADHD-hyp/imp Comorbid diagnosesc (% subjects) Reading disorder Conduct disorder Oppositional defiant disorder Generalized anxiety disorder Separation anxiety disorderd
8.69 (1.56) 6.92–12.08 23/3 104.58 (12.71) 6.26 (2.25) 4.92 (2.61) 4.65 (2.92) 2.83 (2.69) 6.04 (1.73) 6.69 (2.31) 4.32 (2.94) 2.64 (2.53) 88 8 4 4 27 23 9 14
Note: Data unavailable for: a2 children; b3 children; c1 child; d4 children. TTI = Teacher Telephone Interview; Hyp/Imp = hyperactive/impulsive; PICS = Parent Interview for Child Symptoms; ADHD = attention-deficit/hyperactivity disorder. Third Edition (WISC-III) (Wechsler, 1991) was used to assess intellectual functioning, and three tests were used to assess reading ability: the Reading subtest of the Wide Range Achievement Test3rd edition (WRAT-3) (Wilkinson, 1993) and the Word Attack and Word Identification subtests of the Woodcock Reading Mastery Test-Revised (Woodcock, 1987). Each child’s clinical diagnostic profile as defined by the preceding research criteria was confirmed by a child psychiatrist, based upon review of the information gathered during the assessment. APPARATUS AND STIMULI Subjects were administered selected computerized subtests from the CANTAB, which has been successfully used in school-age children (Luciana, 2003). The subtests were presented on a highresolution IBM Advantech monitor with a touch-sensitive screen. For the computer tasks, all subjects were seated approximately 60 cm away from the computer screen, reported previous computer experience, and were tested with the same computer unit. All CANTAB tasks require use of the subject’s dominant hand. Visual-Spatial Working Memory Tasks CANTAB Spatial Working Memory. This is a self-ordered search task that measures the ability to continually update information
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about spatial locations in working memory. This task requires subjects to search through boxes to find a hidden token. Subjects are told that once a token has been found, that box will not be used to hide another token. Once found, the next token is hidden and a new trial commences. Following practice trials, subjects complete four test trials with each of four, six, and eight boxes. Performance is measured according to indices of errors committed, which indicate failures in the updating process. A “within search error” (WSE) is committed when a subject returns to a box already opened and found to be empty earlier in the same search sequence; Returning to an “empty” box that already contained a token in a previous trial constitutes a “between search error” (BSE). A “strategy” score is calculated to reflect a systematic approach to the search task: low scores represent efficient strategy use and higher scores represent low strategy use. CANTAB Spatial Span. This task assesses maintenance of visualspatial information and is based on the Corsi Block Task (Milner, 1971). White squares are presented, some of which momentarily change in color in a variable sequence. The subject must touch each of the boxes in the same order as they were colored by the computer. The number of boxes that change color (i.e., difficulty level) in the sequence is increased from two to a maximum of nine. If the subject fails to replicate the correct sequence, the next trial remains at the same difficulty level. The spatial span is calculated as the highest level at which the subject reproduces at least one correct sequence and can range from a score of 0 to 9. Unfortunately, this task was not administered to the first group of subjects, so only 40% (n = 10) of the sample completed this task. There were no demographic/diagnostic differences between those who were and were not administered this task. Finger Windows. The Finger Windows task from the Wide Range Assessment of Memory and Learning (WRAML) (Adams and Sheslow, 1990) was used as a second measure of maintenance and manipulation of visual-spatial working memory. In the standardized version (Finger Windows Forward), the examiner points to an increasingly longer series of locations on a card and the subject is asked to reproduce the sequence exactly. One point is given for each correctly recalled sequence. After three consecutive errors the test is discontinued. A novel version (Finger Windows Backward) of this task was developed whereby the subject must reproduce the demonstrated spatial sequence in reverse order of presentation. The scoring and discontinue rules are the same for both versions. Tasks requiring forward recall are thought to assess maintenance, whereas reverse recall tasks assess spatial working memory as both maintenance and manipulation (i.e., reordering) of information is required (Owen, 2000). Visual-Spatial Cognitive Control Tasks CANTAB Stockings of Cambridge Planning Task. This is a visualspatial planning test based on the Tower of London task (Shallice, 1982). Two sets of three colored balls are presented, with each set arranged in vertical “stockings” hanging in three pockets. The balls of both sets are shown in different positions for each trial. The subject must use the balls in the lower display to replicate the pattern shown in the upper display. This involves working out an optimal set of moves (i.e., the fewest moves possible) and then executing them by moving one ball at a time. Task difficulty increases from one to five move solutions. Performance is measured by the number of trials completed within the minimum number of moves. CANTAB Spatial Recognition Memory. This task involves a twochoice forced discrimination paradigm in which subjects must recognize the spatial locations of target stimuli. Subjects are presented with a square that moves to five different target locations. In the
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recognition phase, the subject sees a series of five square pairs and must touch the square in each pair that is in a previously seen location. This is repeated three more times, each time with five new locations. Performance is defined as the overall percentage of correct responses, and the mean latency for correct responses assesses recognition speed. Motor Control Tasks CANTAB Motor Screening. This is a simple pointing task that measures psychomotor speed. This task introduces the subject to the touch-screen and is used to ensure that the subject can touch the screen accurately and can hear, understand, and follow instructions. The task consists of a serious of crosses shown in different locations. The subject must touch the crosses as they appear on the screen as quickly and as accurately as possible. The mean latency to touch a cross is measured. Clicker Task. This is a behavioral measure of relative motor proficiency of the left and right hands and is based on the task used by Bishop (2001). Subjects are instructed to hold a tally counter in the palm of their right hand, and after a brief demonstration, they are instructed to tap with their right thumb as quickly as possible for 30 seconds and then to repeat the task using their left thumb. Following these practice trials, two test trials are performed using the right and left hands. The number of thumb presses per hand is recorded. DRUG PROTOCOL All 26 children participated in a 4-day randomized, doubleblind, placebo-controlled, crossover trial of MPH conducted in a pediatric hospital laboratory. Testing occurred over a period of 5 consecutive days for 3 hours per session. After baseline measures were obtained on the first day, each child received a single challenge with each of three fixed doses of MPH (5 mg, 10 mg, and 15 mg for children who weighed <25 kg; 10 mg, 15 mg, and 20 mg for those who weighed ≥25 kg) and a placebo dose. This translated to the following mean mg/kg for each of the MPH dose levels: low (mean = 0.28, SD = 0.06); medium (mean = 0.43, SD = 0.08); high (mean = 0.59, SD = 0.11). Nine (35%) of the 26 children weighed <25 kg. Fixed doses of MPH were used because there is no clear evidence that response to medication is dependent on body weight, and statistical analyses showed that there were no differences in drug response between the children who were in either weight group. The doses were administered in a counterbalanced order so that approximately equal numbers of children received each of the possible drug condition orders. The two exceptions to this rule were that no directly ascending or descending medication orders were permitted because they would have made it difficult to interpret drug effects for individual children. The examiner, psychiatrist, child, and child’s family were not informed about the child’s randomization order or daily medication status until trial completion. Placebo and active medication was prepared by the hospital pharmacist and was powdered and packaged in an opaque gelatin capsule to prevent identification of contents by color, taste, or volume. Each child’s medication was placed in an individually named and dated envelope to ensure accurate administration. ADMINISTRATION PROCEDURE Parents gave written consent for their children and all children gave verbal assent to participate in this study, approved by the institutional Ethics Review Board. Each subject was tested individually. The examiner remained in the testing room with the subject, read a uniform set of instructions, operated the computer, and monitored progress from start to completion for each task.
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Five parallel versions of the Spatial Recognition Memory CANTAB task and the Finger Windows tasks were administered (one on each of baseline and 4 testing days) to minimize practice effects; parallel versions of the other CANTAB tests were not available at the time of the study. All tasks were administered 60 to 180 minutes after ingestion of the capsule and were completed in the same order each day. STATISTICAL ANALYSES A four-stage approach to data analysis was used. First, the data were checked for outliers. Some individuals displayed extreme performance on individual tasks on certain trial days but were within a normal range on others. The data from these univariate outliers were included in the analyses. Tabachnik and Fidell’s (1989) most conservative score-changing option was selected for only those tasks on which these individuals deviated extremely (i.e., >3 SD from the group mean). Each deviant score was changed to equal the next highest score in the distribution, plus one unit. Thus, the score remained as the most extreme in the distribution while at the same time minimized the skew it created in the sample. This procedure was applied to 0.7% (14/2,165) of data points: Motor Screening (0.77% [1/130]) and Spatial Working Memory (1.11% [13/1,170]). Second, correlational analyses of baseline data using Pearson product moment correlations were performed to examine interrelationships among tests off drug. Third, drug effects were examined using multivariate repeated measures analyses of variance with dose (four levels: placebo, low, medium, and high) as a repeated factor and experimental task manipulation as either another repeated factor or as separate entered measures. Trend analyses and post hoc Sidak pairwise comparisons followed for any significant effects to determine the overall shape of the dose-response curve and significant differences between dose levels. All analyses were repeated with weight group (low versus high) as a between-subjects factor to ensure that weight group did not influence results. Analyses were also repeated excluding the left-handed subjects to ensure that handedness did not influence results. Data analysis was performed using the Statistical Package for the Social Science (SPSS/PC). All statistical tests were two-tailed. RESULTS
Baseline correlations among measures are presented in Table 2. There were significant correlations between measures of visual-spatial manipulation of information (i.e., Finger Windows Backward and BSE) and between measures of visual-spatial maintenance of information (i.e., Finger Windows Forward and CANTAB Spatial Span span length). Furthermore, measures of visual-spatial maintenance were correlated with both measures of visual-spatial manipulation and visualspatial recognition memory. Also, performance on the left-handed motor control task was positively correlated with performance on a task of visual-spatial manipulation of information. Means, standard deviations, and repeated-measures multivariate analyses of variance results for all test measures at baseline and for each drug condition are presented in Table 3. 263
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TABLE 2 Task Correlations Measured at Baseline Visual-Spatial Working Memory Tasks Spatial Span Spatial Working Memory
Total BSE Total WSE Strategy score Finger Windows Backward Finger Windows Forward Span length Total errors Min no. move solutions Correct responses Mean correct latency Right thumb Left thumb Latency
Total BSE
Total WSE
Strategy Score
—
0.704* —
0.599* 0.204 —
Finger Windows Backward
Finger Windows Forward
Span Length
Total Errors
−0.470* −0.248 −0.340 —
−0.311 −0.095 −0.120 0.667* —
−0.711* −0.372 −0.404 0.509 0.700* —
−0.771* −0.477 −0.323 0.560 0.659* 0.923* —
Cognitive Control Tasks Stockings of Cambridge Min No. Move Solutions
Correct Responses
Mean Correct Latency
−0.289 −0.207 −0.369 0.250 0.381 0.456 0.197 —
0.121 0.336 −0.092 0.243 0.520* −0.045 −0.197 0.047 —
0.293 0.349 0.172 0.056 0.109 0.141 0.142 −0.176 0.151 —
Total BSE Total WSE Strategy score Finger Windows Backward Finger Windows Forward Span length Total errors Min no. move solutions Correct responses Mean correct latency Right thumb Left thumb Latency
Motor Control Tasks
Spatial Recognition Memory
Thumb Press
Motor Screening
Right Thumb
Left Thumb
Latency
−0.357 −0.174 −0.419* 0.178 0.173 0.258 0.302 0.046 0.155 −0.249 —
−0.306 −0.092 −0.437* 0.390* 0.314 0.124 0.185 0.133 0.214 −0.270 0.804* —
0.142 0.122 0.011 −0.183 −0.008 −0.202 −0.105 0.095 0.056 0.100 −0.316 −0.208 —
Note: BSE = between search error; WSE = within search error. * Correlation is significant at the .05 level (two-tailed).
Visual-Spatial Working Memory
There was a significant overall effect of MPH on errors committed during the CANTAB Spatial Working Memory task (Wilks λ = 0.05). Univariate statistics showed that MPH significantly reduced both WSE (F3,75 = 6.59, p = .001, eta-square [η2] = 0.21) and BSE (F3,75 = 2.63, p = .05, η2 = 0.10). Trend analysis indicated that both error types were linearly reduced with increasing dose (WSE: F1,25 = 12.89, p = .001, η2 = 0.34; BSE: F1,25 = 6.53, p = .02, η2 = 0.21). In addition, WSEs were significantly reduced with MPH 264
in a quadratic function with increasing dose (F1,25 = 4.36, p = .05, η2 = 0.15). Post hoc pairwise comparisons revealed that subjects made significantly fewer WSEs on all MPH doses compared to placebo (p < .02). Further inspection of WSE revealed a significant interaction between dose and difficulty level (F6,150 = 2.82, p = .05, η2 = 0.10) such that significant drug effects were limited to the highest difficulty level (i.e., eight-box problems) (F3,75 = 4.25, p = .02, η2 = 0.15). Post hoc pairwise comparisons of BSE indicated that only the high dose of MPH reduced BSE compared to J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 43:3, MARCH 2004
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TABLE 3 Group Means and Standard Deviations for the Dependent Variables Measured in the Baseline and Four Treatment Conditions Measure Visual-spatial working memory tasks Spatial working memory (n = 26) Total BSE Total WSE Strategy score Spatial span (n = 10) Span length Total errors Finger Windows (n = 26) Foward Backward Cognitive control tasks Stockings of Cambridge (n = 23) Minimum no. move solutions Spatial recognition memory (n = 21) Correct responses (%) Mean correct latency (ms) Motor control tasks Thumb press (n = 26) Right thumb Left thumb Motor screening (n = 26) Latency (ms)
Baseline
Placebo
Low
Medium
High
Mean (SD)
Mean (SD)
Mean (SD)
Mean (SD)
Mean (SD)
51.5 (14.5) 2.2 (2.6) 37.9 (3.8)
46.8 (21.0) 4.2 (3.2) 36.3 (4.9)
43.0 (15.1) 2.5 (2.5) 35.8 (3.9)
42.0 1.8 35.4
(17.0) (2.2) (5.5)
38.5 (18.7) 1.8 (1.7) 34.9 (5.4)
4.0 11.2
(1.6) (6.2)
4.3 9.5
(1.0) (3.7)
4.5 9.7
(1.0) (4.6)
4.6 13.4
(1.2) (7.0)
5.5 15.7
(1.5) (9.6)
10.1 5.4
(3.5) (3.6)
9.9 8.6
(5.1) (4.5)
10.7 8.9
(5.9) (5.3)
11.7 9.1
(5.3) (5.2)
12.7 9.7
(5.0) (5.5)
5.4
(2.1)
7.4
(2.1)
8.0
(1.4)
7.9
(1.9)
7.8
(2.1)
72.6 (10.9) 2,673 (906)
66.4 (15.3) 1,959 (959)
67.9 (14.5) 1,767 (549)
63.6 (14.3) 2,074 (1,061)
65 (17.4) 1,957 (754)
87 77
(16) (15)
92 77
(22) (18)
98 87
(20) (15)
98 87
(18) (16)
97 89
(19) (17)
903
(295)
814
(222)
780
(238)
825
(214)
823
(187)
Note: Data from baseline (day 1) provided for comparison purposes only and are not included in drug analyses. BSE = between search error; WSE = within search error.
placebo (p = .01) and that there was no difficulty level by drug-dose interaction (F6,150 = 0.72, p = .56, η2 = 0.03). Finally, MPH had no effect on subjects’ strategy score on this task (F3,75 = 1.13, p = .34, η2 = 0.04). MPH also significantly improved span length on the CANTAB Spatial Span task (Wilks λ < 0.05). Univariate analyses revealed a significant main effect for dose on span length (F3,24 = 3.77, p = .024, η2 = 0.32) with a significantly linear trend (F1,8 = 8.49, p = .019), and post hoc analysis revealed that the mean span length on high dose was significantly higher than on placebo or low and medium doses (p < .05). There was also a significant overall effect of MPH on correctly recalled items for the Finger Windows tasks (Wilks λ = 0.05). Univariate analyses revealed a significant main effect for MPH dose on correctly recalled items for the Finger Windows Forward task (F3,75 = 4.93, p = .004, η2 = 0.17), but no significant drug effects were found for correctly recalled items for the Finger Windows Backward task (F3,75 = 1.09, p = .36, η2 = 0.04). Although inspection of the data revealed that subjects recalled a greater number of correct sequences with MPH compared to placebo, the effects of J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 43:3, MARCH 2004
MPH were much stronger on the Forward (i.e., indexing span) compared to the Backward (i.e., indexing manipulation) task version. The number of correctly recalled items on the Finger Windows Forward task increased linearly with dose (F1,25 = 12.67, p = .002, η2 = 0.34), and post hoc pairwise comparisons indicated that although the mean number of correct items recalled for Finger Windows Forward was higher on high dose compared to placebo, the difference was not significant (p = .07). Visual-Spatial Cognitive Control Tasks
There were no MPH effects on spatial planning as indicated by the lack of drug effects on number of problems solved in minimum moves on the CANTAB Stockings of Cambridge Task. Moreover, there were no drug effects on the CANTAB Spatial Recognition Memory Task (accuracy: F3,60 = 0.64, p = .60, η2 = 0.03; latency: F3,60 = 1.05, p = .38, η2 = 0.05). Motor Control
MPH did not effect motor speed on the CANTAB Motor Screening test (F3,75 = 0.71, p = .55). By con265
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trast, there was an overall effect of MPH on thumb pressing rate in the clicker task (Wilks λ = 0.55, F = 2.68, p = .045). Univariate analyses demonstrated that drug significantly increased left thumb presses (F3,75 = 7.91, p < .001, η2 = 0.24), with no significant effects on right thumb pressing (F3,75 = 2.58, p = .08, η2 = 0.09). Specifically, left thumb presses linearly improved F3,75 = 17.97, p < .001) with MPH dose, and post hoc analyses demonstrated a significantly greater number of left thumb presses made on all MPH doses compared to placebo (low, p < .003; medium, p < .008; high, p < .001). Lastly, MPH effects did not differ between weight groups or when the analyses were repeated on the righthanded subjects only. DISCUSSION
This is the first controlled study of stimulant effects (MPH) on visual-spatial memory in children with ADHD. MPH reduced errors on a self-ordered, computerized visual-spatial working memory task and also improved the capacity to store visual-spatial information as measured by performance on both computerized and pencil-and-paper span capacity tasks. MPH did not influence visual-spatial planning as measured by the Stockings of Cambridge task or visual-spatial recognition memory as measured by the Spatial Recognition task. Collectively, these findings indicate that stimulant medication selectively enhances discrete visual-spatial processes in children with ADHD— specifically components of visual-spatial working memory. The results from the self-ordered spatial working memory test identified significant MPH effects on task performance as measured by the decrease in committed errors with increasing dose. Both types of errors measured in this task represent failure to update working memory in terms of the locations already searched, thus resulting in poorer task performance. MPH significantly decreased errors caused by subjects returning to a box already opened either during the same search (WSE) or during a search for subsequent tokens (BSE). Previous research has demonstrated stimulant effects on this spatial working memory task both in healthy adult volunteers (Elliott et al., 1997; Mehta et al., 2000a) and in children with ADHD (Barnett et al., 2001; Kempton et al., 1999), with stimulant effects being restricted to decreasing the number of BSEs. However, we demonstrated additional MPH improve266
ments in WSE restricted to the highest difficulty level. Several factors may explain the discrepant findings. First, our use of a within-subject design may have reduced the WSE variance and afforded greater statistical power to detect drug effects, compared to the uncontrolled and parallel-group design used in previous studies (e.g., Barnett et al., 2001; Kempton et al., 1999). Second, the subjects in the current study exhibited many more WSEs across all testing days than reported in an earlier study (Barnett et al., 2001), leaving greater room for drug-related improvements. However, consistent with previous research findings (Barnett et al., 2001; Kempton et al., 1999), we found no effects of stimulants on strategy, suggesting that drug effects were specific to the working memory processes and not attributable to any generalized improvement in attention or strategy use. The fact that MPH improved performance on two different tasks of spatial span affords greater confidence that the findings reflect drug effects on the cognitive function itself and are not simply task-dependent effects. The two tasks are similar in terms of stimuli and response demand but differ in that they have slightly different scoring methods, and Finger Windows is examiner-administered whereas CANTAB Spatial Span is computerized. Also, the baseline data revealed that performance on the two tasks are positively correlated. The discrepancy in drug effects on the two tasks measuring the manipulation of visual-spatial working memory may be a result of differing task demands. For example, CANTAB Spatial Working Memory requires updating memory of locations but not of sequence (except as reflected in an effective strategy that was not influenced by drug) whereas Finger Windows Backward requires both maintenance and manipulation (reverse) of the sequence of locations. No drug effects were discernible on either the CANTAB Spatial Recognition Memory or Stockings of Cambridge tasks. On the one hand, findings are consistent with those from the only other study of drug effects on spatial recognition memory in ADHD (Kempton et al., 1999), which found that children with ADHD performed more poorly than matched controls regardless of whether they were receiving stimulant treatment. On the other hand, previous uncontrolled studies of drug effects on spatial planning in children with ADHD on and off medication have yielded inconsistent findings (Kempton et al., 1999). A comment is warranted on the seemingly discordant findings for drug effects on motor control. MPH J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 43:3, MARCH 2004
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did not improve motor latency on the motor screening task (simple touching reaction time task) or correct response latency on the spatial recognition memory task. By contrast, positive drug effects were found on the thumb-clicker task but were restricted to the lefthand performance. Notably, the CANTAB tasks were performed with the dominant hand (which was the right hand for most children [88%]), whereas the clicker task was performed by both right and left hands separately. The fact that MPH improved performance on left-handed thumb pressing but not on righthanded thumb pressing insinuates asymmetrical brain hemispheric MPH effects, consistent with previous research (e.g., Campbell et al., 1996; Malone et al., 1988, 1994a,b). Converging evidence from drug and neuroimaging of cognitive function studies indicates that MPH affects right hemisphere brain structures to a greater extent than left hemisphere structures and that visual-spatial working memory is right hemispheredependent (Curtis et al., 2000; Kim et al., 2001; O’Reilly et al., 1999; Owen et al., 1999; Smith and Jonides, 1998). Findings from this study indicate selectivity of MPH effects on visual-spatial processing and motor control. Specifically, MPH appears to have enhanced right-hemisphere brain processes such as components of visual-spatial working memory and leftsided motor control but not measures of right-sided motor control, visual-spatial strategy, planning, or problem solving. This selectivity of MPH action was also reported by Gao and Goldman-Rakic (2003), who demonstrated that dopamine actions are highly focused and constrained to a particular role on specific local circuits, indicating that dopaminergic action cannot be regarded as general and nonspecific.
is known about practice/carryover effects on the tasks used over a brief time. Finally, only single measures of spatial planning and spatial recognition memory were used in this study. Several measures of each of these constructs are recommended to determine whether present findings are task-specific or due to lack of drug sensitivity of the cognitive constructs. Despite these limitations, our findings are consistent with the empirical and theoretical work from which our initial hypotheses and study objectives were drawn. Moreover, the findings support recent arguments that stimulants act selectively on visual-spatial processing in children with ADHD. Clinical Implications
Growing evidence indicates that visual-spatial working memory in particular is impaired in ADHD. Findings from this study indicate that MPH, which is known to be effective on behavioral symptoms of ADHD, also has some beneficial effects on visualspatial working memory. On the other hand, drug effects are highly heterogeneous: not all benefit and not on all tasks of visual-spatial processing. Furthermore, heterogeneity in cognitive response to MPH was evident in this study, as reflected by the increases with MPH in between-subject standard deviation for several measures. Thus some deficits may remain unaltered by MPH and may require adjunctive or alternative treatment. Disclosure: Dr. Rosemary Tannock is a consultant and an Advisory Board Member and has research funding from Eli Lilly. She also has research funding from Novartis Pharmaceuticals. REFERENCES
Limitations
Several methodological limitations of the present study need to be considered when interpreting results. First, findings are based on a small sample that demands verification in a larger sample. This would permit an examination of possible differential drug effects as a function of age, gender, and/or DSM-IV subtypes. Also, only the acute effects of single challenge with each of the MPH doses were investigated, so it is unknown whether the effects on visual-spatial memory would be similar with extended treatment. As well, there may have been a waning of drug effect at the 180-minute mark, which would have generated an order effect in terms of performance on the tests that were administered toward the end of the fixed sequence. Also, little J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 43:3, MARCH 2004
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Mehta MA, Calloway P, Sahakian BJ (2000b), Amelioration of specific working memory deficit by methylphenidate in a case of adult attention-deficit/hyperactivity disorder. Psychopharmacology 14:299– 302 Milner B (1971), Interhemispheric differences in the localization of psychological processes in man. Br Med Bull 27:272–277 Miyake A, Shaw P (1999), Models of Working Memory: Mechanisms of Active Maintenance and Executive Control. New York: Cambridge University Press Nieoullon A (2002), Dopamine and the regulation of cognition and attention. Prog Neurobiol 67:53–83 NIH Consensus Statement (1998), NIH Consensus Development Conference on Diagnosis and Treatment of Attention Deficit Hyperactivity Disorder. Bethesda, MD O’Reilly R, Braver TS, Cohen JD (1999), A biologically based computational model of working memory. In: Models of Working Memory, Miyake A, Shah P, eds. New York: Cambridge University Press, pp 375– 411 Owen AM (2000), The role of the lateral frontal cortex in mnemonic processing: the contribution of functional imaging. Exp Brain Res 133:33–43 Owen AM, Herrod NJ, Menon DK et al. (1999), Redefining the functional organization of working memory processes within human lateral prefrontal cortex. Eur J Neurosci 11:567–574 Pennington BF, Ozonoff S (1996), Executive functions and developmental psychopathology. J Child Psychol Psychiatry 37:51–87 Rapport MD, Chung K-M, Shore G, Isaacs P (2001), A conceptual model of child psychopathology: implications for understanding attention deficit hyperactivity disorder and treatment efficacy. J Clin Child Psychol 30:48–58 Schachar R, Tannock R, Marriott M, Logan G (1995), Deficient inhibition in attention deficit hyperactivity disorder. J Abnorm Child Psychol 23:411–437 Shallice T (1982), Specific impairment in planning: In: The Neuropsychology of Cognitive Function. Broadbent DE, Weiskrantz L, eds. London: Royal Society, pp 109–209 Smith EE, Jonides J (1998), Neuroimaging analyses of working memory. Proc Natl Acad Sci U S A 95:12061–12068 Solanto MV (1998), Neuropsychopharmacological mechanisms of stimulant drug action in attention-deficit hyperactivity disorder: a review and integration. Behav Brain Res 94:127–152 Tabachnik BG, Fidell LS (1989), Using Multivariate Statistics, 2nd ed. New York: Harper & Row Tannock R, Hum M, Masellis M, Humphries T, Schachar R (2000), Interviewing teachers about children’s classroom behavior and academic performance. In: Proceedings of the 47th Annual Meeting of the American Academy of Child and Adolescent Psychiatry, New York, October 24–29 Tannock R, Ickowicz A, Schachar R (1995), Differential effects of methylphenidate on working memory in ADHD children with or without comorbid anxiety. J Am Acad Child Adolesc Psychiatry 34:886–896 Volkow ND, Wang GJ, Fowler JS et al. (2001), Therapeutic doses of oral methylphenidate significantly increase extracellular dopamine in the human brain. J Neurosci 21:1–5 Wechsler D (1991), Wechsler Intelligence Scale for Children. New York: Psychological Corporation Welsh MC (2002), Developmental and clinical variations in executive function. In: Developmental Variations in Learning: Applications to Social, Executive Function, Language, and Reading Skills, Molfese DL, Molfese VJ, eds. Mahwah, NJ: Erlbaum, pp 139–185 Wilkinson GS (1993), The Wide Range Achievement Test-Third Edition (WRAT3) San Antonio, TX: Psychological Corporation Woodcock RW (1987), Woodcock Reading Mastery Test-Revised. Circle Pines, MN: American Guidelines Services
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ABSTRACT Objective: To investigate the effect of methylphenidate (MPH) on visual-spatial memory, as measured by subtests of the Cambridge Neuropsychological Testing Automated Battery (CANTAB), in children with attention-deficit/hyperactivity disorder (ADHD). Visual-spatial memory is a core component of working memory that has been shown to be impaired in ADHD, irrespective of comorbid reading and/or language problems. Method: A clinic-referred sample of school-age children with a confirmed DSM-IV diagnosis of ADHD (n = 26) completed tests of visual-spatial memory, planning ability, and recognition memory in an acute, randomized, placebo-controlled, crossover trial with three single fixed doses of MPH. MPH effects on right-handed and left-handed motor control were also assessed. Results: MPH significantly improved performance on a self-ordered, updating visual-spatial working memory task and on maintenance of visualspatial information but had no effects on measures of visual-spatial planning ability or recognition memory. Also, MPH significantly improved left-handed motor control. Conclusions: Beneficial effects of MPH on visual-spatial processing in ADHD are selective and restricted to visual-spatial memory. J. Am. Acad. Child Adolesc. Psychiatry, 2004;43(3):260– 268. Key Words: attention-deficit/hyperactivity disorder, methylphenidate, working memory, cognition.
Attention-deficit/hyperactivity disorder (ADHD) is a common developmental disorder that affects 3% to 7% of school-age children (American Psychiatric Association, 2000). Current models of ADHD are founded on neuropsychological theories of impaired functioning of the frontal lobes, in particular the prefrontal cortex (Goldman-Rakic, 1987; Shallice, 1982). It has been suggested that the cognitive difficulties experienced by children with ADHD are accounted for by deficits in the executive functions (Barkley, 1997). Executive functions are a set of cognitive control processes that Accepted October 7, 2003. From The Institute of Medical Science, University of Toronto (Ms. Bedard, Ms. Martinussen, Dr. Tannock), Brain & Behaviour Research Program and Department of Psychiatry, The Hospital for Sick Children (Ms. Bedard, Ms. Martinussen, Drs. Ickowicz and Tannock). Work on this paper was supported by the Psychiatry Department at The Hospital for Sick Children and CIHR Doctoral Awards (Ms. Bedard, Ms. Martinussen). The authors thank Min-Na Hockenberry for her contribution. Correspondence to Dr. Tannock, Brain & Behaviour Research, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8; e-mail: [email protected]. 0890-8567/04/4303–0260©2004 by the American Academy of Child and Adolescent Psychiatry. DOI: 10.1097/01.chi.0000106850.88132.5a
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serve to optimize performance in complex tasks and include processes such as the allocation of attention, working memory, and inhibition (e.g., Fuster, 1999). Working memory serves to maintain temporary, active representations of information for further processing or recall (Baddeley, 1996). It plays a crucial role in reducing distraction and controlling attention during complex cognitive activities such as mental calculation and language comprehension (Baddeley, 1996; de Fockert et al., 2001; Miyake and Shaw, 1999). There are several competing theoretical models of working memory (Miyake and Shaw, 1999), but most differentiate between two processes: maintenance and manipulation of information. Domain-specific models, such as that proposed by Baddeley (1996), also distinguish between the different modalities of information (e.g., auditory-verbal, visual-spatial). Prevailing models of ADHD suggest that working memory impairments are central to ADHD (Barkley, 1997; Castellanos and Tannock, 2002; Rapport et al., 2001), but findings are equivocal and previous reviews have concluded that there is no robust evidence of impairments in ADHD (Pennington and Ozonoff, 1996; Welsh, 2002). Notably, these conclusions were J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 43:3, MARCH 2004
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based primarily on the findings from studies of auditory-verbal working memory, many of which did not control for reading or language disorders that are themselves associated with impairments in auditory-verbal working memory. The most recent review concluded that there is growing evidence for impairments in visual-spatial working memory (in both maintenance and manipulation processes) in ADHD (Martinussen et al., unpublished, 2003). The evidence for visual-spatial working memory deficits in ADHD is consistent with neuropsychological and imaging studies that implicate mainly right frontal-striatal circuitry in ADHD (reviewed by Giedd et al., 2001). If visual-spatial working memory is impaired in ADHD, then it is important to determine whether treatment that targets the behavioral symptoms of ADHD also improves this important cognitive control process. Psychostimulant medication, such as methylphenidate (MPH), is the primary treatment approach for ADHD (e.g., NIH Consensus Statement, 1998). Accumulating evidence of structural and functional abnormalities in prefrontal and striatal brain regions in ADHD, which are modulated by catecholaminergic neurotransmitters, provides the theoretical basis for neuropharmacological treatment of this disorder. One pathway of MPH action in the brain is through blocking dopamine reuptake, increasing the amount of extracellular dopamine available to bind to its receptors (Volkow et al., 2001). Dopamine is an important neurotransmitter involved in executive control processing (see review by Nieoullon, 2002), and there is a high density of dopamine receptors in the prefrontal cortex and basal ganglia (reviewed by Solanto, 1998). These brain structures, which are intricately involved in working memory and are catecholamine modulated (Braver et al., 2001, Carlson et al., 1998), have been shown to be deficient in ADHD (reviewed by Castellanos and Swanson, 2002). MPH-induced increases in dopamine levels in the synaptic clefts of these structures are believed to enhance several aspects of cognitive processing, including working memory (Mehta et al., 2000a). Stimulants have been found to enhance performance of tests of visual-spatial working memory and planning in healthy adult volunteers (Elliott et al., 1997; Mattay et al., 2000). However, the lack of stimulant effects on visual-spatial memory in ADHD is due primarily to lack of data rather than inconsistency in findings. Three studies suggest that stimulants may enhance visual-spatial working memory; two of them were uncontrolled (Barnett et al., 2001; Kempton et al., 1999) J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 43:3, MARCH 2004
and the third involved a randomized controlled design but was a case study of an adult with ADHD (Mehta et al., 2000b). In a previous randomized, placebocontrolled study, MPH improved the ability of nonanxious children with ADHD to update verbal information in a paced auditory serial addition task (Tannock et al., 1995). No study to date has examined the impact of MPH on visual-spatial processing in children with ADHD in a randomized, placebo-controlled, crossover design. The purpose of this study was to examine the effects of stimulant medication on various components of visual-spatial processes in children with ADHD. We used several of the well-validated tests from the Cambridge Neuropsychological Testing Automated Battery (CANTAB; reviewed by Luciana, 2003) that assess psychomotor speed/accuracy, visual-spatial processing, such as recognition memory, spatial planning ability, and both the maintenance and manipulation components of visual-spatial working memory. We predicted that MPH would improve measures of visual-spatial working memory in children with ADHD. METHOD SUBJECTS Sample characteristics are presented in Table 1. All children had a confirmed DSM-IV diagnosis of ADHD and were consecutive referrals for evaluation of their response to stimulant treatment. The majority of subjects were right-handed and medication naïve. Most were white (90%), and the remainder were Asian (10%). Exclusionary criteria included a full-scale IQ score of less than 80; evidence of neurological dysfunction, poor physical health, uncorrected sensory impairments, history of psychosis (based on physician inquiry); or the primary language spoken at home was not English. DIAGNOSTIC ASSESSMENT Clinical diagnosis of ADHD, using DSM-IV criteria, was based upon information from semistructured interviews conducted with parents (Parent Interview for Child Symptoms [PICS]) (Ickowicz et al., 2002) and the child’s classroom teacher (Teacher Telephone Interview [TTI]) (Tannock et al., 2000). Trained clinicians blind to other aspects of the child’s assessment conducted interviews independently. Both interviews require the clinician rather than the informant to rate the presence and severity of each symptom, based upon descriptive information of the child’s behavior in prescribed contexts, using prespecified scoring criteria. Reliability and validity for the DSM-III-R version of both interviews are high (Schachar et al., 1995); evaluation of the psychometric properties of the DSMIV versions is underway. Parent and teacher ratings of the child’s behavior were gathered using the Conners Rating Scale-Revised (CRS-R) (Conners, 1997). Diagnosis of conduct disorder and oppositional defiant disorder was based on information from the PICS and TTI interviews. The Wechsler Intelligence Scale for Children-
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TABLE 1 Sample Characteristics Total Sample Age, mean (SD) Range, years Gender (male/female) WISC-III Full Scale IQ, mean (SD) Teacher-based on TTI-IVa No. of inattentive symptoms No. of hyp/imp symptoms Teacher-based on Connersb No. of inattentive symptoms No. of hyp/imp symptoms Parent-based on PICS No. of inattentive symptoms No. of hyp/imp symptoms Parent-based on Conners No. of inattentive symptoms No. of hyp/imp symptoms DSM-IV ADHD subtype (%) ADHD-combined ADHD-inattentive ADHD-hyp/imp Comorbid diagnosesc (% subjects) Reading disorder Conduct disorder Oppositional defiant disorder Generalized anxiety disorder Separation anxiety disorderd
8.69 (1.56) 6.92–12.08 23/3 104.58 (12.71) 6.26 (2.25) 4.92 (2.61) 4.65 (2.92) 2.83 (2.69) 6.04 (1.73) 6.69 (2.31) 4.32 (2.94) 2.64 (2.53) 88 8 4 4 27 23 9 14
Note: Data unavailable for: a2 children; b3 children; c1 child; d4 children. TTI = Teacher Telephone Interview; Hyp/Imp = hyperactive/impulsive; PICS = Parent Interview for Child Symptoms; ADHD = attention-deficit/hyperactivity disorder. Third Edition (WISC-III) (Wechsler, 1991) was used to assess intellectual functioning, and three tests were used to assess reading ability: the Reading subtest of the Wide Range Achievement Test3rd edition (WRAT-3) (Wilkinson, 1993) and the Word Attack and Word Identification subtests of the Woodcock Reading Mastery Test-Revised (Woodcock, 1987). Each child’s clinical diagnostic profile as defined by the preceding research criteria was confirmed by a child psychiatrist, based upon review of the information gathered during the assessment. APPARATUS AND STIMULI Subjects were administered selected computerized subtests from the CANTAB, which has been successfully used in school-age children (Luciana, 2003). The subtests were presented on a highresolution IBM Advantech monitor with a touch-sensitive screen. For the computer tasks, all subjects were seated approximately 60 cm away from the computer screen, reported previous computer experience, and were tested with the same computer unit. All CANTAB tasks require use of the subject’s dominant hand. Visual-Spatial Working Memory Tasks CANTAB Spatial Working Memory. This is a self-ordered search task that measures the ability to continually update information
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about spatial locations in working memory. This task requires subjects to search through boxes to find a hidden token. Subjects are told that once a token has been found, that box will not be used to hide another token. Once found, the next token is hidden and a new trial commences. Following practice trials, subjects complete four test trials with each of four, six, and eight boxes. Performance is measured according to indices of errors committed, which indicate failures in the updating process. A “within search error” (WSE) is committed when a subject returns to a box already opened and found to be empty earlier in the same search sequence; Returning to an “empty” box that already contained a token in a previous trial constitutes a “between search error” (BSE). A “strategy” score is calculated to reflect a systematic approach to the search task: low scores represent efficient strategy use and higher scores represent low strategy use. CANTAB Spatial Span. This task assesses maintenance of visualspatial information and is based on the Corsi Block Task (Milner, 1971). White squares are presented, some of which momentarily change in color in a variable sequence. The subject must touch each of the boxes in the same order as they were colored by the computer. The number of boxes that change color (i.e., difficulty level) in the sequence is increased from two to a maximum of nine. If the subject fails to replicate the correct sequence, the next trial remains at the same difficulty level. The spatial span is calculated as the highest level at which the subject reproduces at least one correct sequence and can range from a score of 0 to 9. Unfortunately, this task was not administered to the first group of subjects, so only 40% (n = 10) of the sample completed this task. There were no demographic/diagnostic differences between those who were and were not administered this task. Finger Windows. The Finger Windows task from the Wide Range Assessment of Memory and Learning (WRAML) (Adams and Sheslow, 1990) was used as a second measure of maintenance and manipulation of visual-spatial working memory. In the standardized version (Finger Windows Forward), the examiner points to an increasingly longer series of locations on a card and the subject is asked to reproduce the sequence exactly. One point is given for each correctly recalled sequence. After three consecutive errors the test is discontinued. A novel version (Finger Windows Backward) of this task was developed whereby the subject must reproduce the demonstrated spatial sequence in reverse order of presentation. The scoring and discontinue rules are the same for both versions. Tasks requiring forward recall are thought to assess maintenance, whereas reverse recall tasks assess spatial working memory as both maintenance and manipulation (i.e., reordering) of information is required (Owen, 2000). Visual-Spatial Cognitive Control Tasks CANTAB Stockings of Cambridge Planning Task. This is a visualspatial planning test based on the Tower of London task (Shallice, 1982). Two sets of three colored balls are presented, with each set arranged in vertical “stockings” hanging in three pockets. The balls of both sets are shown in different positions for each trial. The subject must use the balls in the lower display to replicate the pattern shown in the upper display. This involves working out an optimal set of moves (i.e., the fewest moves possible) and then executing them by moving one ball at a time. Task difficulty increases from one to five move solutions. Performance is measured by the number of trials completed within the minimum number of moves. CANTAB Spatial Recognition Memory. This task involves a twochoice forced discrimination paradigm in which subjects must recognize the spatial locations of target stimuli. Subjects are presented with a square that moves to five different target locations. In the
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recognition phase, the subject sees a series of five square pairs and must touch the square in each pair that is in a previously seen location. This is repeated three more times, each time with five new locations. Performance is defined as the overall percentage of correct responses, and the mean latency for correct responses assesses recognition speed. Motor Control Tasks CANTAB Motor Screening. This is a simple pointing task that measures psychomotor speed. This task introduces the subject to the touch-screen and is used to ensure that the subject can touch the screen accurately and can hear, understand, and follow instructions. The task consists of a serious of crosses shown in different locations. The subject must touch the crosses as they appear on the screen as quickly and as accurately as possible. The mean latency to touch a cross is measured. Clicker Task. This is a behavioral measure of relative motor proficiency of the left and right hands and is based on the task used by Bishop (2001). Subjects are instructed to hold a tally counter in the palm of their right hand, and after a brief demonstration, they are instructed to tap with their right thumb as quickly as possible for 30 seconds and then to repeat the task using their left thumb. Following these practice trials, two test trials are performed using the right and left hands. The number of thumb presses per hand is recorded. DRUG PROTOCOL All 26 children participated in a 4-day randomized, doubleblind, placebo-controlled, crossover trial of MPH conducted in a pediatric hospital laboratory. Testing occurred over a period of 5 consecutive days for 3 hours per session. After baseline measures were obtained on the first day, each child received a single challenge with each of three fixed doses of MPH (5 mg, 10 mg, and 15 mg for children who weighed <25 kg; 10 mg, 15 mg, and 20 mg for those who weighed ≥25 kg) and a placebo dose. This translated to the following mean mg/kg for each of the MPH dose levels: low (mean = 0.28, SD = 0.06); medium (mean = 0.43, SD = 0.08); high (mean = 0.59, SD = 0.11). Nine (35%) of the 26 children weighed <25 kg. Fixed doses of MPH were used because there is no clear evidence that response to medication is dependent on body weight, and statistical analyses showed that there were no differences in drug response between the children who were in either weight group. The doses were administered in a counterbalanced order so that approximately equal numbers of children received each of the possible drug condition orders. The two exceptions to this rule were that no directly ascending or descending medication orders were permitted because they would have made it difficult to interpret drug effects for individual children. The examiner, psychiatrist, child, and child’s family were not informed about the child’s randomization order or daily medication status until trial completion. Placebo and active medication was prepared by the hospital pharmacist and was powdered and packaged in an opaque gelatin capsule to prevent identification of contents by color, taste, or volume. Each child’s medication was placed in an individually named and dated envelope to ensure accurate administration. ADMINISTRATION PROCEDURE Parents gave written consent for their children and all children gave verbal assent to participate in this study, approved by the institutional Ethics Review Board. Each subject was tested individually. The examiner remained in the testing room with the subject, read a uniform set of instructions, operated the computer, and monitored progress from start to completion for each task.
J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 43:3, MARCH 2004
Five parallel versions of the Spatial Recognition Memory CANTAB task and the Finger Windows tasks were administered (one on each of baseline and 4 testing days) to minimize practice effects; parallel versions of the other CANTAB tests were not available at the time of the study. All tasks were administered 60 to 180 minutes after ingestion of the capsule and were completed in the same order each day. STATISTICAL ANALYSES A four-stage approach to data analysis was used. First, the data were checked for outliers. Some individuals displayed extreme performance on individual tasks on certain trial days but were within a normal range on others. The data from these univariate outliers were included in the analyses. Tabachnik and Fidell’s (1989) most conservative score-changing option was selected for only those tasks on which these individuals deviated extremely (i.e., >3 SD from the group mean). Each deviant score was changed to equal the next highest score in the distribution, plus one unit. Thus, the score remained as the most extreme in the distribution while at the same time minimized the skew it created in the sample. This procedure was applied to 0.7% (14/2,165) of data points: Motor Screening (0.77% [1/130]) and Spatial Working Memory (1.11% [13/1,170]). Second, correlational analyses of baseline data using Pearson product moment correlations were performed to examine interrelationships among tests off drug. Third, drug effects were examined using multivariate repeated measures analyses of variance with dose (four levels: placebo, low, medium, and high) as a repeated factor and experimental task manipulation as either another repeated factor or as separate entered measures. Trend analyses and post hoc Sidak pairwise comparisons followed for any significant effects to determine the overall shape of the dose-response curve and significant differences between dose levels. All analyses were repeated with weight group (low versus high) as a between-subjects factor to ensure that weight group did not influence results. Analyses were also repeated excluding the left-handed subjects to ensure that handedness did not influence results. Data analysis was performed using the Statistical Package for the Social Science (SPSS/PC). All statistical tests were two-tailed. RESULTS
Baseline correlations among measures are presented in Table 2. There were significant correlations between measures of visual-spatial manipulation of information (i.e., Finger Windows Backward and BSE) and between measures of visual-spatial maintenance of information (i.e., Finger Windows Forward and CANTAB Spatial Span span length). Furthermore, measures of visual-spatial maintenance were correlated with both measures of visual-spatial manipulation and visualspatial recognition memory. Also, performance on the left-handed motor control task was positively correlated with performance on a task of visual-spatial manipulation of information. Means, standard deviations, and repeated-measures multivariate analyses of variance results for all test measures at baseline and for each drug condition are presented in Table 3. 263
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TABLE 2 Task Correlations Measured at Baseline Visual-Spatial Working Memory Tasks Spatial Span Spatial Working Memory
Total BSE Total WSE Strategy score Finger Windows Backward Finger Windows Forward Span length Total errors Min no. move solutions Correct responses Mean correct latency Right thumb Left thumb Latency
Total BSE
Total WSE
Strategy Score
—
0.704* —
0.599* 0.204 —
Finger Windows Backward
Finger Windows Forward
Span Length
Total Errors
−0.470* −0.248 −0.340 —
−0.311 −0.095 −0.120 0.667* —
−0.711* −0.372 −0.404 0.509 0.700* —
−0.771* −0.477 −0.323 0.560 0.659* 0.923* —
Cognitive Control Tasks Stockings of Cambridge Min No. Move Solutions
Correct Responses
Mean Correct Latency
−0.289 −0.207 −0.369 0.250 0.381 0.456 0.197 —
0.121 0.336 −0.092 0.243 0.520* −0.045 −0.197 0.047 —
0.293 0.349 0.172 0.056 0.109 0.141 0.142 −0.176 0.151 —
Total BSE Total WSE Strategy score Finger Windows Backward Finger Windows Forward Span length Total errors Min no. move solutions Correct responses Mean correct latency Right thumb Left thumb Latency
Motor Control Tasks
Spatial Recognition Memory
Thumb Press
Motor Screening
Right Thumb
Left Thumb
Latency
−0.357 −0.174 −0.419* 0.178 0.173 0.258 0.302 0.046 0.155 −0.249 —
−0.306 −0.092 −0.437* 0.390* 0.314 0.124 0.185 0.133 0.214 −0.270 0.804* —
0.142 0.122 0.011 −0.183 −0.008 −0.202 −0.105 0.095 0.056 0.100 −0.316 −0.208 —
Note: BSE = between search error; WSE = within search error. * Correlation is significant at the .05 level (two-tailed).
Visual-Spatial Working Memory
There was a significant overall effect of MPH on errors committed during the CANTAB Spatial Working Memory task (Wilks λ = 0.05). Univariate statistics showed that MPH significantly reduced both WSE (F3,75 = 6.59, p = .001, eta-square [η2] = 0.21) and BSE (F3,75 = 2.63, p = .05, η2 = 0.10). Trend analysis indicated that both error types were linearly reduced with increasing dose (WSE: F1,25 = 12.89, p = .001, η2 = 0.34; BSE: F1,25 = 6.53, p = .02, η2 = 0.21). In addition, WSEs were significantly reduced with MPH 264
in a quadratic function with increasing dose (F1,25 = 4.36, p = .05, η2 = 0.15). Post hoc pairwise comparisons revealed that subjects made significantly fewer WSEs on all MPH doses compared to placebo (p < .02). Further inspection of WSE revealed a significant interaction between dose and difficulty level (F6,150 = 2.82, p = .05, η2 = 0.10) such that significant drug effects were limited to the highest difficulty level (i.e., eight-box problems) (F3,75 = 4.25, p = .02, η2 = 0.15). Post hoc pairwise comparisons of BSE indicated that only the high dose of MPH reduced BSE compared to J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 43:3, MARCH 2004
MPH AND VISUAL-SPATIAL MEMORY IN ADHD
TABLE 3 Group Means and Standard Deviations for the Dependent Variables Measured in the Baseline and Four Treatment Conditions Measure Visual-spatial working memory tasks Spatial working memory (n = 26) Total BSE Total WSE Strategy score Spatial span (n = 10) Span length Total errors Finger Windows (n = 26) Foward Backward Cognitive control tasks Stockings of Cambridge (n = 23) Minimum no. move solutions Spatial recognition memory (n = 21) Correct responses (%) Mean correct latency (ms) Motor control tasks Thumb press (n = 26) Right thumb Left thumb Motor screening (n = 26) Latency (ms)
Baseline
Placebo
Low
Medium
High
Mean (SD)
Mean (SD)
Mean (SD)
Mean (SD)
Mean (SD)
51.5 (14.5) 2.2 (2.6) 37.9 (3.8)
46.8 (21.0) 4.2 (3.2) 36.3 (4.9)
43.0 (15.1) 2.5 (2.5) 35.8 (3.9)
42.0 1.8 35.4
(17.0) (2.2) (5.5)
38.5 (18.7) 1.8 (1.7) 34.9 (5.4)
4.0 11.2
(1.6) (6.2)
4.3 9.5
(1.0) (3.7)
4.5 9.7
(1.0) (4.6)
4.6 13.4
(1.2) (7.0)
5.5 15.7
(1.5) (9.6)
10.1 5.4
(3.5) (3.6)
9.9 8.6
(5.1) (4.5)
10.7 8.9
(5.9) (5.3)
11.7 9.1
(5.3) (5.2)
12.7 9.7
(5.0) (5.5)
5.4
(2.1)
7.4
(2.1)
8.0
(1.4)
7.9
(1.9)
7.8
(2.1)
72.6 (10.9) 2,673 (906)
66.4 (15.3) 1,959 (959)
67.9 (14.5) 1,767 (549)
63.6 (14.3) 2,074 (1,061)
65 (17.4) 1,957 (754)
87 77
(16) (15)
92 77
(22) (18)
98 87
(20) (15)
98 87
(18) (16)
97 89
(19) (17)
903
(295)
814
(222)
780
(238)
825
(214)
823
(187)
Note: Data from baseline (day 1) provided for comparison purposes only and are not included in drug analyses. BSE = between search error; WSE = within search error.
placebo (p = .01) and that there was no difficulty level by drug-dose interaction (F6,150 = 0.72, p = .56, η2 = 0.03). Finally, MPH had no effect on subjects’ strategy score on this task (F3,75 = 1.13, p = .34, η2 = 0.04). MPH also significantly improved span length on the CANTAB Spatial Span task (Wilks λ < 0.05). Univariate analyses revealed a significant main effect for dose on span length (F3,24 = 3.77, p = .024, η2 = 0.32) with a significantly linear trend (F1,8 = 8.49, p = .019), and post hoc analysis revealed that the mean span length on high dose was significantly higher than on placebo or low and medium doses (p < .05). There was also a significant overall effect of MPH on correctly recalled items for the Finger Windows tasks (Wilks λ = 0.05). Univariate analyses revealed a significant main effect for MPH dose on correctly recalled items for the Finger Windows Forward task (F3,75 = 4.93, p = .004, η2 = 0.17), but no significant drug effects were found for correctly recalled items for the Finger Windows Backward task (F3,75 = 1.09, p = .36, η2 = 0.04). Although inspection of the data revealed that subjects recalled a greater number of correct sequences with MPH compared to placebo, the effects of J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 43:3, MARCH 2004
MPH were much stronger on the Forward (i.e., indexing span) compared to the Backward (i.e., indexing manipulation) task version. The number of correctly recalled items on the Finger Windows Forward task increased linearly with dose (F1,25 = 12.67, p = .002, η2 = 0.34), and post hoc pairwise comparisons indicated that although the mean number of correct items recalled for Finger Windows Forward was higher on high dose compared to placebo, the difference was not significant (p = .07). Visual-Spatial Cognitive Control Tasks
There were no MPH effects on spatial planning as indicated by the lack of drug effects on number of problems solved in minimum moves on the CANTAB Stockings of Cambridge Task. Moreover, there were no drug effects on the CANTAB Spatial Recognition Memory Task (accuracy: F3,60 = 0.64, p = .60, η2 = 0.03; latency: F3,60 = 1.05, p = .38, η2 = 0.05). Motor Control
MPH did not effect motor speed on the CANTAB Motor Screening test (F3,75 = 0.71, p = .55). By con265
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trast, there was an overall effect of MPH on thumb pressing rate in the clicker task (Wilks λ = 0.55, F = 2.68, p = .045). Univariate analyses demonstrated that drug significantly increased left thumb presses (F3,75 = 7.91, p < .001, η2 = 0.24), with no significant effects on right thumb pressing (F3,75 = 2.58, p = .08, η2 = 0.09). Specifically, left thumb presses linearly improved F3,75 = 17.97, p < .001) with MPH dose, and post hoc analyses demonstrated a significantly greater number of left thumb presses made on all MPH doses compared to placebo (low, p < .003; medium, p < .008; high, p < .001). Lastly, MPH effects did not differ between weight groups or when the analyses were repeated on the righthanded subjects only. DISCUSSION
This is the first controlled study of stimulant effects (MPH) on visual-spatial memory in children with ADHD. MPH reduced errors on a self-ordered, computerized visual-spatial working memory task and also improved the capacity to store visual-spatial information as measured by performance on both computerized and pencil-and-paper span capacity tasks. MPH did not influence visual-spatial planning as measured by the Stockings of Cambridge task or visual-spatial recognition memory as measured by the Spatial Recognition task. Collectively, these findings indicate that stimulant medication selectively enhances discrete visual-spatial processes in children with ADHD— specifically components of visual-spatial working memory. The results from the self-ordered spatial working memory test identified significant MPH effects on task performance as measured by the decrease in committed errors with increasing dose. Both types of errors measured in this task represent failure to update working memory in terms of the locations already searched, thus resulting in poorer task performance. MPH significantly decreased errors caused by subjects returning to a box already opened either during the same search (WSE) or during a search for subsequent tokens (BSE). Previous research has demonstrated stimulant effects on this spatial working memory task both in healthy adult volunteers (Elliott et al., 1997; Mehta et al., 2000a) and in children with ADHD (Barnett et al., 2001; Kempton et al., 1999), with stimulant effects being restricted to decreasing the number of BSEs. However, we demonstrated additional MPH improve266
ments in WSE restricted to the highest difficulty level. Several factors may explain the discrepant findings. First, our use of a within-subject design may have reduced the WSE variance and afforded greater statistical power to detect drug effects, compared to the uncontrolled and parallel-group design used in previous studies (e.g., Barnett et al., 2001; Kempton et al., 1999). Second, the subjects in the current study exhibited many more WSEs across all testing days than reported in an earlier study (Barnett et al., 2001), leaving greater room for drug-related improvements. However, consistent with previous research findings (Barnett et al., 2001; Kempton et al., 1999), we found no effects of stimulants on strategy, suggesting that drug effects were specific to the working memory processes and not attributable to any generalized improvement in attention or strategy use. The fact that MPH improved performance on two different tasks of spatial span affords greater confidence that the findings reflect drug effects on the cognitive function itself and are not simply task-dependent effects. The two tasks are similar in terms of stimuli and response demand but differ in that they have slightly different scoring methods, and Finger Windows is examiner-administered whereas CANTAB Spatial Span is computerized. Also, the baseline data revealed that performance on the two tasks are positively correlated. The discrepancy in drug effects on the two tasks measuring the manipulation of visual-spatial working memory may be a result of differing task demands. For example, CANTAB Spatial Working Memory requires updating memory of locations but not of sequence (except as reflected in an effective strategy that was not influenced by drug) whereas Finger Windows Backward requires both maintenance and manipulation (reverse) of the sequence of locations. No drug effects were discernible on either the CANTAB Spatial Recognition Memory or Stockings of Cambridge tasks. On the one hand, findings are consistent with those from the only other study of drug effects on spatial recognition memory in ADHD (Kempton et al., 1999), which found that children with ADHD performed more poorly than matched controls regardless of whether they were receiving stimulant treatment. On the other hand, previous uncontrolled studies of drug effects on spatial planning in children with ADHD on and off medication have yielded inconsistent findings (Kempton et al., 1999). A comment is warranted on the seemingly discordant findings for drug effects on motor control. MPH J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 43:3, MARCH 2004
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did not improve motor latency on the motor screening task (simple touching reaction time task) or correct response latency on the spatial recognition memory task. By contrast, positive drug effects were found on the thumb-clicker task but were restricted to the lefthand performance. Notably, the CANTAB tasks were performed with the dominant hand (which was the right hand for most children [88%]), whereas the clicker task was performed by both right and left hands separately. The fact that MPH improved performance on left-handed thumb pressing but not on righthanded thumb pressing insinuates asymmetrical brain hemispheric MPH effects, consistent with previous research (e.g., Campbell et al., 1996; Malone et al., 1988, 1994a,b). Converging evidence from drug and neuroimaging of cognitive function studies indicates that MPH affects right hemisphere brain structures to a greater extent than left hemisphere structures and that visual-spatial working memory is right hemispheredependent (Curtis et al., 2000; Kim et al., 2001; O’Reilly et al., 1999; Owen et al., 1999; Smith and Jonides, 1998). Findings from this study indicate selectivity of MPH effects on visual-spatial processing and motor control. Specifically, MPH appears to have enhanced right-hemisphere brain processes such as components of visual-spatial working memory and leftsided motor control but not measures of right-sided motor control, visual-spatial strategy, planning, or problem solving. This selectivity of MPH action was also reported by Gao and Goldman-Rakic (2003), who demonstrated that dopamine actions are highly focused and constrained to a particular role on specific local circuits, indicating that dopaminergic action cannot be regarded as general and nonspecific.
is known about practice/carryover effects on the tasks used over a brief time. Finally, only single measures of spatial planning and spatial recognition memory were used in this study. Several measures of each of these constructs are recommended to determine whether present findings are task-specific or due to lack of drug sensitivity of the cognitive constructs. Despite these limitations, our findings are consistent with the empirical and theoretical work from which our initial hypotheses and study objectives were drawn. Moreover, the findings support recent arguments that stimulants act selectively on visual-spatial processing in children with ADHD. Clinical Implications
Growing evidence indicates that visual-spatial working memory in particular is impaired in ADHD. Findings from this study indicate that MPH, which is known to be effective on behavioral symptoms of ADHD, also has some beneficial effects on visualspatial working memory. On the other hand, drug effects are highly heterogeneous: not all benefit and not on all tasks of visual-spatial processing. Furthermore, heterogeneity in cognitive response to MPH was evident in this study, as reflected by the increases with MPH in between-subject standard deviation for several measures. Thus some deficits may remain unaltered by MPH and may require adjunctive or alternative treatment. Disclosure: Dr. Rosemary Tannock is a consultant and an Advisory Board Member and has research funding from Eli Lilly. She also has research funding from Novartis Pharmaceuticals. REFERENCES
Limitations
Several methodological limitations of the present study need to be considered when interpreting results. First, findings are based on a small sample that demands verification in a larger sample. This would permit an examination of possible differential drug effects as a function of age, gender, and/or DSM-IV subtypes. Also, only the acute effects of single challenge with each of the MPH doses were investigated, so it is unknown whether the effects on visual-spatial memory would be similar with extended treatment. As well, there may have been a waning of drug effect at the 180-minute mark, which would have generated an order effect in terms of performance on the tests that were administered toward the end of the fixed sequence. Also, little J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 43:3, MARCH 2004
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