Hyperactivity Disorder

Pediatric Neurology 47 (2012) 177e185

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Original Article

Transcranial Magnetic Stimulation Measures in Attention-Deficit/Hyperactivity Disorder Steve W. Wu MD a, *, Donald L. Gilbert MD, MS a, Nasrin Shahana MBBS a, David A. Huddleston BA a, Stewart H. Mostofsky MD b a

Division of Neurology, Cincinnati Children’s Hospital Medical Center and University of Cincinnati School of Medicine, Cincinnati, Ohio Laboratory for Neurocognitive and Imaging Research, Department of Neurology and Department of Psychiatry, Kennedy Krieger Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland b

article information

abstract

Article history: Received 22 March 2012 Accepted 7 June 2012

Children affected by attention-deficit/hyperactivity disorder demonstrate diminished intrahemispheric inhibition (short interval cortical inhibition), as measured by transcranial magnetic stimulation. This study determined whether interhemispheric inhibition (ipsilateral silent period latency) correlates with clinical behavioral rating and motor control deficits of affected children. In 114 right-handed children (aged 8-12 years; age/sex-matched; 50 affected, 64 controls), we performed comprehensive assessments of behavior, motor skills, and cognition. Transcranial magnetic stimulation reliably elicited ipsilateral silent periods in 54 children (23 affected); all were on average older than those with unobtainable measures. Mean ipsilateral silent period latency was 5 milliseconds longer in the affected group (P ¼ 0.007). Longer latencies correlated with more severe behavioral symptom scores (r ¼ 0.38, P ¼ 0.007), particularly hyperactivity (r ¼ 0.39, P ¼ 0.006), and with worse motor ratings on the Physical and Neurological Examination for Soft Signs (r ¼ 0.27, P ¼ 0.05). Longer latency also correlated with short interval cortical inhibition (r ¼ 0.36, P ¼ 0.008). Longer ipsilateral silent period latencies suggest interhemispheric inhibitory signaling is slower in affected children. The deficit in this inhibitory measure may underlie developmental, behavioral, and motor impairments in children with attention-deficit/hyperactivity disorder. Ó 2012 Elsevier Inc. All rights reserved.

Introduction

Maturations of motor and behavioral control are fundamental processes that occur in parallel throughout childhood. The fine motor control required to manipulate tools and instruments includes the development of independent hand and finger use. Relative delay or dysmaturation of the circuitry permitting motor control results in subtle motor deficits in repetitive and sequential movements, accuracy in rhythm, and suppression of motor overflow [1]. An expanding body of research indicates that these particular motor skills are significantly impaired in children with attention* Communications should be addressed to: Dr. Wu; Division of Neurology; Cincinnati Children’s Hospital Medical Center; 3333 Burnet Avenue, MLC 2015; Cincinnati, OH 45229-3039. E-mail address: [email protected] 0887-8994/$ - see front matter Ó 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pediatrneurol.2012.06.003

deficit/hyperactivity disorder, relative to typically developing peers [1-4]. The temporal association between the development of motor and behavioral control and the consistent statistical associations between deficits in motor skills and attention-deficit/hyperactivity disorder [3-5] suggest that the developing motor system may provide a useful window into neurobiologic mechanisms of behavioral control. A broad aim of our research program has involved identifying easily obtained, quantitative, robust, brainbased markers of behavioral and motor function in children with attention-deficit/hyperactivity disorder. To this end, we recently described, in a large and wellcharacterized matched sample of 104 children aged 8-12 years with attention-deficit/hyperactivity disorder and typically developing control subjects, how physiologic findings in the motor cortex may function as biomarkers of

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attention-deficit/hyperactivity disorder [6]. We used transcranial magnetic stimulation in the motor cortex to measure depolarization motor thresholds, paired pulse facilitation, and two measures of intracortical inhibition: short interval cortical inhibition and the cortical silent period. The most profound difference involved short interval cortical inhibition, which was on average 40% reduced in the group with attention-deficit/hyperactivity disorder [6]. Furthermore, short interval cortical inhibition correlated robustly with the parent-rated severity of attention-deficit/hyperactivity disorder, and moderately with measures of motor skill impairment [6], rated according to the Physical and Neurological Examination for Soft Signs [2,3]. However, as expected in evaluating a behaviorally defined disorder with pathophysiologic heterogeneity, overlap between the attention-deficit/hyperactivity disorder and control groups occurred. The present study was designed to investigate in similar detail the relationships between attention-deficit/ hyperactivity disorder, motor development, short interval cortical inhibition, and a less studied measure of physiologic inhibition in the motor system, i.e., the ipsilateral silent period. This measure involves a period of relative inhibition in ongoing electromyographic activity after the stimulation of the cortex ipsilateral to the target muscle [7]. The ipsilateral silent period may involve both intrahemispheric and interhemispheric inhibitory circuits [7-12], and is altered in persons with lesions of the corpus callosum [9,13]. The ipsilateral silent period may be of particular value as a quantitative physiologic measure, because both qualitative observations and quantitative measures demonstrate that children with attention-deficit/hyperactivity disorder demonstrate increased overflow movements, a motor sign thought to reflect impaired interhemispheric inhibitory control [2,3,5]. Two research groups evaluated ipsilateral silent periods, and reported that children with attention-deficit/hyperactivity disorder manifested longer ipsilateral silent period latencies [14,15]. However, both studies included relatively small sample sizes, totaling 24 [15] and 26 [14] children (patients with attention-deficit/ hyperactivity disorder and control subjects), and could not powerfully assess relationships with other physiologic markers, behavioral severity, or maturation of motor control. Furthermore, in addition to the interhemispheric mechanism, short interval cortical inhibition-like intrahemispheric inhibitory input has also been implicated in the generation of ipsilateral silent periods [11]. We therefore hypothesized that, compared with control subjects, children with attention-deficit/hyperactivity disorder would exhibit longer ipsilateral silent period latencies, and that these latencies would correlate with both attentiondeficit/hyperactivity disorder symptom severity and motor development scores, particularly motor overflow, evaluated according to the Physical and Neurological Examination for Soft Signs. Materials and Methods Participants

This was a 1:1 age-matched and sex-matched case-control study of motor development, motor cortex physiology, and behavioral signs

in right-handed children, aged 8-12 years, with attention-deficit/ hyperactivity disorder vs typically developing control subjects. Participants were recruited from 2006-2011 through a variety of sources, including outpatient clinics at Cincinnati Children’s Hospital Medical Center (Cincinnati, OH) and the Kennedy Krieger Institute (Baltimore, MD), from local chapters of Children and Adolescents with Attention-Deficit/Hyperactivity Disorder, from local schools, pediatricians’ offices, and service organizations (e.g., the Boy Scouts and Girl Scouts), and through fliers posted in the community. Age-matched and sex-matched control subjects were recruited from e-mail and flier advertisements posted at the Cincinnati Children’s Hospital Medical Center, the Kennedy Krieger Institute, and the surrounding communities. Parents who responded were initially screened by telephone. To be included, children had to be otherwise healthy, with no history of psychiatric or developmental disorders other than attention-deficit/ hyperactivity disorder. Children whose parents reported a history of mental retardation, seizures, traumatic brain injury, or other neurologic illnesses were excluded from participation. Psychostimulants, but no other medications, were allowed. For the study, stimulants were withheld on the day before and the day of cognitive and transcranial magnetic stimulation testing. Standard protocol approvals, registrations, and patient consents

Permission for the study was obtained from the Institutional Review Boards of the Cincinnati Children’s Hospital Medical Center and Johns Hopkins University School of Medicine. Written, informed consent was obtained from legal guardians, and assent was obtained from children. Clinical diagnostic and cognitive assessments

All evaluations were performed by research personnel trained to administer psychologic interviews and parent questionnaires, and all data were reviewed and diagnoses confirmed by the physician investigators. These research personnel were blinded to the neurophysiologic data. Socioeconomic status was queried using the Hollingshead Parent History Questionnaire Assessment of Socio Economic Status [16]. Righthandedness was verified using the Edinburgh Handedness Inventory [17]. All children were administered the Basic/Word Reading subtests from the Wechsler Individual Achievement Test II [18] to exclude a learning disability in reading. Intellectual ability was then assessed using the Wechsler Intelligence Scale for Children-IV [19]. Children with full-scale intelligence quotient scores below 80 were excluded from participation. Children were excluded from participation if they demonstrated a statistically significant discrepancy between their full-scale intelligence quotient and a Wechsler Individual Achievement Test II score or Basic/Word Reading subtest score below 85. Diagnostic status (regarding attention-deficit/hyperactivity disorder) was established through the administration of the Diagnostic Interview for Children and Adolescents-IV [20]. Children meeting the criteria for diagnosis of conduct, mood, generalized anxiety, separation anxiety, or obsessive-compulsive disorders according to the Diagnostic Interview for Children and Adolescents-IV interview were excluded. Children with oppositional defiant disorder were not excluded from participation. Although we would have preferred a sample of participants with “pure” attention-deficit/hyperactivity disorder, we did not exclude children with comorbid oppositional defiant disorder because of a high rate of comorbid psychiatric diagnoses that can lead to recruitment difficulties. Although previous studies suggested that attention-deficit/hyperactivity disorder associated with conduct disorder may comprise a distinct subtype, such is not the case for attention-deficit/hyperactivity disorder associated with oppositional defiant disorder [21,22]. Parents and teachers also completed the home and school versions of the Conners’ Parent and Teacher Rating Scales-Revised and the Dupaul Attention-Deficit/Hyperactivity Disorder Rating Scale-IV [23]. Inclusion in the attention-deficit/hyperactivity disorder group was based on three criteria: (1) a diagnosis of attention-deficit/hyperactivity disorder and referral for participation by community clinicians; (2) a Diagnostic and Statistical Manual of Mental Disorders-IV Text Revision diagnosis of attention-deficit/hyperactivity disorder, based on positive scores on at

S.W. Wu et al. / Pediatric Neurology 47 (2012) 177e185 least one of the parent rating scales and (when obtained) one of the teacher rating scales, i.e., a T score of 65 or higher on scale L (Diagnostic and Statistical Manual of Mental Disorders-IV, inattentive) or scale M (Diagnostic and Statistical Manual of Mental Disorders-IV, hyperactive-impulsive) on the Conners’ Parent and Teacher Rating Scales-Revised, or children receiving scores of 2 or 3 on at least six of nine items on the Inattentive or Hyperactivity/Impulsivity scales of the Dupaul Attention-Deficit/ Hyperactivity Disorder Rating Scale; and (3) confirmation of the diagnosis of attention-deficit/hyperactivity disorder according to the Diagnostic Interview for Children and Adolescents-IV psychiatric interview. To meet the inclusion criteria for the control group, parent and teacher reports on Conners’ Parent and Teacher Rating Scales-Revised and the DuPaul Attention-Deficit/Hyperactivity Disorder Rating Scale had to yield scores below the clinical cutoff, and they could not meet the diagnostic criteria for any psychiatric disorder based on the Diagnostic Interview for Children and Adolescents-IV. As with children in the attention-deficit/hyperactivity disorder group, they could not have a history of neurologic disorder or be receiving psychotropic medications. The same intelligence quotient, reading, and achievement discrepancy criteria were also required for inclusion. Motor skill assessments of children with attention-deficit/hyperactivity disorder and control subjects

Study personnel at both sites were trained together for the consistency and reliability of motor assessments. Motor function was assessed comprehensively using the Physical and Neurological Examination for Soft Signs, as recently described in a large cohort of children with attention-deficit/hyperactivity disorder children and control subjects [3]. The Physical and Neurological Examination for Soft Signs measures or rates timed movements, lateral preference, motor overflow, dysrhythmia, coordination, gait, balance, and motor persistence. The main subscale of interest in the Physical and Neurological Examination for Soft Signs was the Motor Overflow subscale, because a deficient control of motor overflow might be expected to correlate with a reduced interhemispheric inhibition/ipsilateral silent period. Motor cortex physiology

Both sites performed single and paired pulse transcranial magnetic stimulation with identical devices, i.e., a Magstim 200 stimulator (Magstim Co., Whitland, Wales, United Kingdom) connected through a Bistim module to a double 70-mm coil. The coil was placed tangential to the skull with handle backward, at 45 degrees to the midline, and its center near the optimal position and orientation for producing a motorevoked potential in the right first dorsal interosseous muscle. Surface electromyography was performed to capture the amplitudes of transcranial magnetic stimulation-evoked motor-evoked potentials. Surface electromyography signals were amplified and filtered (100/1000 Hz; Coulbourn Instruments, Allentown, PA) before being digitized at 2 kHz and stored for analysis, using Signal software and a Micro1401 interface (Cambridge Electronic Design, Cambridge, United Kingdom). For single vs paired pulse studies, all individual tracings were analyzed blinded and offline. More detailed descriptions of single and paired pulse measurements in this study were recently published, including methods to address motion artifacts in hyperkinetic children [6]. Resting motor thresholds and active depolarization motor thresholds were evaluated and defined using conventional criteria [24]. In brief, starting at a low and comfortable intensity of 20% of the stimulator’s output, pulses were administered, and then the stimulation intensities were increased by intervals of 10% until a motor-evoked potential was identified. After adjusting the location and position of the coil to produce a reliable, well-formed motor-evoked potential, the intensity was decreased sequentially until an intensity was reached where three of six trials yielded no motor-evoked potentials, and three trials evoked small motor-evoked potentials (approximately 0.1 mV amplitude motorevoked potentials in resting muscle) [25]. Resting motor thresholds were expressed as percentages of the maximum intensity of the Magstim device. Active motor thresholds were measured according to the standard method [26], and were also approached from above, decreasing the stimulus intensity until the point at which three of six trials yielded no

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motor-evoked potential visible above background electromyography activity, and the other three evoked motor-evoked potentials visible over the background. Transcranial magnetic stimulation pulses were administered at approximately 5-second intervals, and for the active motor threshold, the participant relaxed between trials. The primary physiologic measure of interest was the ipsilateral silent period, obtained using conventional methods [7,14]. The figure-eight transcranial magnetic stimulation coil was placed over the right motor cortex at the optimal location for producing an motor-evoked potential in the first dorsal interosseous muscle of the left hand, and the electromyographic tracing was measured in the right hand for 100 ms before and 400 ms after the transcranial magnetic stimulation pulse. The goal entailed five valid trials. Trials were separated by rest for at least 5 seconds. During each trial, children were instructed to squeeze maximally in each hand simultaneously by squeezing two balls between their thumbs and abducting index fingers. Proper first dorsal interosseous muscle activation while squeezing was verified according to visual and tactile methods, and was confirmed by surface electrophysiology. The children were instructed to maintain muscle contraction until told to “let go” after the completion of each trial. Trials where children released the balls or did not maintain muscle contraction were observed in real time, and were repeated to ensure adequate trials. Invalid trials were excluded from analysis. The onset and offset of ipsilateral silent periods were defined visually by researchers blinded to diagnosis, using the rectified average from the valid ipsilateral silent period trials. Ipsilateral silent period latency involves the time interval from the transcranial magnetic stimulation pulse to the onset of the ipsilateral silent period. The duration of the ipsilateral silent period involves the time interval between the onset and offset of the ipsilateral silent period (Fig 1A). The study of children with ipsilateral silent periods posed some unique challenges, of which we had partial expectations based on previous experience with measuring ipsilateral silent periods in children. We did anticipate that this stimulus would be noxious for some children. We always performed this measurement last, after other measures. If children wished to discontinue after the first pulse, we allowed this and did not record any data. Because the device is set at 100% stimulation and both hands (and hemispheres) are activated, a large and diffuse motor response is elicited, including some direct spread in some children, perhaps attributable to a smaller head size or temporalis muscle, causing a jaw jerk. We also anticipated that even some cooperative children would not elicit an ipsilateral silent period, in part because the maximal intensity of the machine would be just at or slightly above the resting motor threshold for some young participants. Durations of silent periods are strongly affected (lengthened) by higher intensities relative to resting motor thresholds [27]. Short interval cortical inhibition was measured using standard methods [28]. In brief, 20 single pulse trials were performed with the intensity set at 15-30% above the resting motor thresholds (test pulse) to produce a motor-evoked potential of amplitude of approximately 1 mV. The paired pulse trials used a conditioning pulse intensity set at 60% of resting motor thresholds, because 70% of resting motor threshold conditioning pulses yielded stronger inhibition in children with attention-deficit/hyperactivity disorder and in control subjects. Based on this experience, on trial and error at other intensities, and on a published conditioning pulse “dose” intensity study in healthy adults [29], we determined that a slightly less efficient condition pulse would disperse the ratios in children more widely, with a greater opportunity for evaluating group differences and correlations of interest. The conditioning pulse preceded the test pulse by either 3 ms (inhibitory interval; short interval cortical inhibition) or 10 ms (excitatory interval; intracortical facilitation). Trials were generated in random order, separated by 6 seconds (5%). Short interval cortical inhibition was expressed as a ratio of mean paired pulse to mean single pulse amplitudes so that, for example, a ratio of 0.55 would indicate 45% inhibition. Lower ratios indicate greater inhibition. Statistical analyses Primary analysis: Sample size calculation

Group (attention deficit/hyperactivity disorder vs. control children) difference in ipsilateral silent period latency comprised the primary

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S.W. Wu et al. / Pediatric Neurology 47 (2012) 177e185 was obtained after all other measures because of the likelihood of discomfort, insofar as this measure is obtained at 100% of stimulator output. Discomfort at higher intensities led 15 children (10 with attention-deficit/hyperactivity disorder) to discontinue or decline measurements after feeling the higher-intensity transcranial magnetic stimulation pulses. Even in cases where experiments were completed, a silent period was not always consistently reproducible (i.e., clearly identified in at least three of five individual tracings). Therefore, the first analysis we performed identified the clinical and demographic features of children in whom an ipsilateral silent period was present vs those in whom an ipsilateral silent period was not identified, using c2 and unpaired t tests. The loss of participants because of discomfort or high thresholds potentially led to a case control sample that was less well matched, thereby creating potential bias. Therefore, attention-deficit/hyperactivity disorder vs control group differences were assessed statistically using t and c2 tests, as appropriate. In the final analysis, the primary outcome of interest, i.e., ipsilateral silent period according to diagnostic group, was also regressed over sex and any other factors identified at P < 0.1, to evaluate for confounders. Assessment of normality

All continuous data were assessed for normality using Kolmogorov Smirnov testing. Attention-deficit/hyperactivity disorder rating scales were not normative. Therefore, correlations with the severity of attention-deficit/hyperactivity disorder based on scales were evaluated according to nonparametric (Spearman) correlations. All other analyses used parametric statistics. Univariate analyses of children with attention-deficit/hyperactivity disorder vs control subjects: Ipsilateral silent period, behavior, motor function, motor physiology, and clinical/demographic variables

Figure 1. (A) A surface electromyographic tracing from one participant indicates the rectified average of five ipsilateral silent period (ISP) trials. As described in Materials and Methods, the participant maintains muscle activity throughout, as demonstrated on the y axis. The first arrow at 0.00 seconds represents the transcranial magnetic stimulation (TMS) pulse artifact. In this case, the ipsilateral silent period, a decrement of electromyographic activity, begins 38 ms (ipsilateral silent period latency) after the transcranial magnetic stimulation pulse. The duration of the ipsilateral silent period is 19 ms. (B) Ipsilateral silent period latencies in seconds, comparing children with attention deficit/hyperactivity disorder (ADHD) to typically developing (TD) children. Each dot represents the ipsilateral silent period latency for one participant. The reference line represents the mean for the entire sample. outcome of interest. We assumed this would be normally distributed, and planned a two-sample t test. Estimated means and standard deviations (S.D.s) of ipsilateral silent periods were obtained from two previous studies in small samples of children with attention-deficit/hyperactivity disorder and control subjects [14,15]. A sample size of 30 children per group was calculated to yield 80% power, with a ¼ 0.05, to detect a 4-ms (approximately 10%) group difference, with an estimated S.D. of 6 ms. Analysis of groups based on presence of clear ipsilateral silent period

Reproducible ipsilateral silent periods were difficult to obtain in children. Participation was voluntary, and an ipsilateral silent period

The primary dependent variable of interest for all analyses in this study comprised the ipsilateral silent period latency. Ipsilateral silent period duration was analyzed but of secondary interest, for several reasons. First, the most robust age-related effect and difference previously identified in children with attention-deficit/hyperactivity disorder vs control subjects involved the ipsilateral silent period latency [15]. Second, durations of silent periods are likely confounded by resting motor thresholds. This effect occurs because ipsilateral silent periods are conventionally measured at maximum stimulator intensity, and are not indexed to resting motor thresholds, as is the case with cortical silent periods. Therefore, for each individual, the relative intensity applied during measures of ipsilateral silent periods would differ as a proportion of their resting motor thresholds, so that duration might actually reflect and be confounded by resting motor thresholds, rather than being related to a diagnosis of attention-deficit/hyperactivity disorder. Motor and behavioral rating scales scores were treated as continuous variables. Demographics and intelligence quotients were compared across groups, and clinical and experimental data were compared across the two sites (Cincinnati and Baltimore), using t and c2 tests as appropriate. Group comparisons

Behavior (i.e., attention-deficit/hyperactivity disorder total scores, inattention, and hyperactivity), motor physiology (i.e., thresholds, ipsilateral silent periods, and short interval cortical inhibition), and motor function (i.e., total and subscale scores of the Physical and Neurological Examination for Soft Signs) were characterized (means  S.D.s) and compared between children with attention-deficit/hyperactivity disorder and control subjects, using t tests. Correlations for attention-deficit/hyperactivity disorder severity: Motor skills

Correlations of behavior with ipsilateral silent period latency were of primary interest. Nonparametric (Spearman) correlations of total attention-deficit/hyperactivity disorder symptom severity and of inattention vs hyperactive/impulsive subscales were calculated. Parametric correlations (Pearson) were used for motor function (Physical and Neurological Examination for Soft Signs, plus Motor Overflow subscales)

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and for short interval cortical inhibition and other transcranial magnetic stimulation measures.

Primary outcome: Ipsilateral silent period latency in children with attention-deficit/hyperactivity disorder vs control subjects

Results

Group differences in motor physiology and function are presented in Table 2. The primary measure of interest evoked by transcranial magnetic stimulation, ipsilateral silent period latency, was significantly longer in the children with attention-deficit/hyperactivity disorder compared with control subjects (P ¼ 0.007) (Fig 1B). The duration of ipsilateral silent periods did not differ (Table 2) and was not included in further analyses. A post hoc analysis within the group with attention-deficit/hyperactivity disorder was performed in children currently receiving versus not receiving psychostimulants. The ipsilateral silent period latency did not differ between these two groups (P ¼ no significance).

Participants

Transcranial magnetic stimulation motor physiology and ratings of motor function did not differ across sites (Cincinnati and Baltimore). The recruited sample included 114 children (50 with attention-deficit/hyperactivity disorder). Ipsilateral silent period data were considered evaluable in 54 children (23 with attention-deficit/hyperactivity disorder). Group differences: Measurable vs unmeasurable ipsilateral silent periods

Of the total sample, the proportions of children with attention-deficit/hyperactivity disorder vs control subjects (P ¼ 0.8) and the DuPaul Attention-Deficit/Hyperactivity Disorder Rating Scale symptom scores (P ¼ 0.8) did not differ between the groups in which the ipsilateral silent period was obtainable or unobtainable. Full-scale intelligence quotient (P ¼ 1.0) and total Physical and Neurological Examination for Soft Signs (motor skill) scores (P ¼ 0.7) also did not differ. Children in whom an ipsilateral silent period was clearly obtained were older on average (mean age, 11.0 years; S.D., 1.4 years) than those in whom an ipsilateral silent period was not clearly present (mean age, 10.5 years; S.D., 1.4 years; P ¼ 0.03). As expected, both active (P ¼ 0.006) and resting (P ¼ 0.01) motor thresholds were lower in the children in whom an ipsilateral silent period was obtainable. The remainder of analyses was performed only in those children with an identifiable ipsilateral silent period. Their clinical and demographic features are listed in Table 1.

Multivariate correlations: Ipsilateral silent period latency in children with attention-deficit/hyperactivity disorder vs control subjects, assessing for possible confounders and interactions

When sex and diagnosis were included as covariates in the multivariate analysis, there was no primary sex effect (P ¼ 0.50) or sex-diagnosis interaction effect (P ¼ 0.12) on the ipsilateral latency. Factors that differed between groups (Table 1) were also assessed via linear regression. Neither Hollingshead family social status (P ¼ 0.82) nor any of the cognitive subtests (all P ¼ 0.5) were associated with ipsilateral silent period latency. Univariate correlations between ipsilateral silent period latency, age, attention-deficit/hyperactivity disorder symptom severity, and motor function

Exploratory univariate correlations of interest are described in Table 3. As expected, the ipsilateral silent period latency shortened with age. More severe parent-rated signs

Table 1. Demographic, clinical, and cognitive data in children with ADHD vs typically developing children

Demographics Male/female Age in years Hollingshead Parent History Questionnaire total scores ADHD ratings ADHD-RS-IV Home Version, total scores CPRS, total T scores Cognitive assessments Verbal comprehension index Perceptual reasoning index Working memory index Processing speed index Full-scale intelligence quotient Word reading index

Typically Developing Children

Children With ADHD

(n ¼ 31)

(n ¼23)

19/12 11.10 (1.38) 51.71 (8.52)

10/13 10.93 (1.48) 40.80 (11.22)

0.19 0.68 0.006

4.33 (4.51) 46.00 (6.24)

35.95 (9.11) 79.13 (12.61)

<0.001 <0.001

109.80 107.33 105.10 101.23 109 110.06

(16.94) (12.05) (13.11) (13.29) (12.92) (10.75)

99.56 104.57 101.09 93.55 100.57 100

(14.86) (10.38) (13.3) (11.62) (10.81) (11.12)

Abbreviations: ADHD ¼ Attention-deficit/hyperactivity disorder ADHD-RS-IV ¼ Attention-deficit/hyperactivity disorder rating scale, version 4 CPRS ¼ Conners’ parent and teacher rating scales Scores for the Conners’ Parent and Teacher Rating Scales were normed at T ¼ 50; scores above 70 were consistent with attention-deficit/hyperactivity disorder. Demographic, clinical, and cognitive data were applied in the final sample of children for whom an ipsilateral silent period was reliably obtained. The Attention-Deficit/Hyperactivity Disorder Rating Scale, version 4, contains possible scores from 0-54; percentiles are based on age and sex norms. The Hollingshead Parent History Questionnaire measures the socioeconomic status of families.

P Value

0.03 0.40 0.29 0.04 0.02 0.002

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Table 2. Motor physiology and motor function in children with ADHD vs typically developing children

Typically Developing Children With P Children ADHD Value

Motor physiology ISP latency (ms) ISP duration (ms) SICI ratio RMT AMT ICF CSP (ms) Motor function PANESS total score Overflow right Overflow left Overflow total Gait and station Timed tasks

Mean

S.D.

Mean

S.D.

40.9 10.5 0.46 60.9 40.0 1.05 60.2

6.1 6.2 0.18 12.5 9.9 0.17 40.4

45.9 9.0 0.67 62.2 40.8 1.16 73.0

6.9 7.0 0.24 10.4 8.2 0.18 52.0

0.007 0.41 0.0007 0.61 0.47 0.02 0.34

8.6 2.8 2.6 5.3 3.4 6.7

28.6 4.7 4.7 9.9 8.0 20.7

10.1 2.4 2.4 5.4 4.9 8.0

0.0001 0.02 0.01 0.01 0.001 0.0003

16.6 3.0 2.2 6.1 3.9 12.7

Abbreviations: ADHD ¼ Attention-deficit/hyperactivity disorder AMT ¼ Active motor threshold CSP ¼ Cortical silent period ICF ¼ Intracortical facilitation ratio ISP ¼ Ipsilateral silent period ms ¼ Milliseconds PANESS ¼ Physical and Neurological examination for Soft Signs RMT ¼ Resting motor threshold S.D. ¼ Standard deviation SICI ¼ Short interval cortical inhibition The short interval cortical inhibition ratio is relative to “1.0,” or no inhibition. Therefore, 0.46 indicates 54% relative inhibition, and lower ratios indicate more inhibition. Higher scores on the Physical and Neurological Examination for Soft Signs indicate more significant delays.

of attention-deficit/hyperactivity disorder (with both the DuPaul and the Conners’ scale) were correlated with longer ipsilateral silent period latencies and with less transcranial magnetic stimulation-evoked motor cortex inhibition (i.e., higher short interval cortical inhibition ratios). Longer ipsilateral silent period latencies were correlated at the trend or marginally significant level with total scores on the Physical and Neurological Examination for Soft Signs, and more specifically with Overflow and Gait subscale ratings. Discussion

This study identified significantly longer ipsilateral silent periods in children aged 8-12 years with attention-deficit/ hyperactivity disorder, compared with their typically developing peers. We identified this finding after very comprehensive assessments of cognition, learning, and behavior, including screening for and statistically analyzing intelligence quotients, reading ability, and socioeconomic status, in a cohort where other neurologic, psychiatric, developmental, or medical problems that might act as confounders were excluded. This finding was statistically robust, and builds on our previous findings that transcranial magnetic stimulation can be used to identify measures in motor cortex that reflect signs of attention-deficit/hyperactivity disorder, the severity of behavioral signs, and anomalies in motor development. The findings in our study confirm and extend those of two smaller studies also reporting that the onset latency of the ipsilateral silent period is longer in children with attentiondeficit/hyperactivity disorder [14,15]. The present study’s

detailed motor and behavioral characterizations strongly support the validity of those previous studies. In addition, much more detailed clinical phenotyping allowed not only for the exclusion of potential statistical confounders, but more importantly for evaluating correlations of clinical and scientific interest. In support of this relationship, one research group subsequently reported that methylphenidate shortens (in the direction of normal) the ipsilateral silent period latency in children with attention-deficit/ hyperactivity disorder [30]. This study contains three novel, correlational results. First, we detected a correlation between longer ipsilateral silent period latency and higher parent-rated severity of signs in attention-deficit/hyperactivity disorder, particularly for ratings of hyperactivity/impulsivity. This result is in concordance with our previous findings that reduced short interval cortical inhibition correlates more strongly with severity of hyperactivity/impulsivity in children with attention-deficit/hyperactivity disorder [6,31] and in children and adults with Tourette syndrome [31-33]. This finding appears robust and consistent across two different rating scales of attention-deficit/hyperactivity disorder. Second, longer ipsilateral silent period latency also correlated with more impaired motor development, as assessed with the Physical and Neurological Examination for Soft Signs. Third, and perhaps most interestingly, we also identified a correlation between longer (interhemispheric) ipsilateral silent period latency and reduced (intrahemispheric) short interval cortical inhibition. We and others previously identified reduced short interval cortical inhibition as a robust marker of the presence and severity of signs in attention-deficit/hyperactivity disorder [6,33-35]. However, to the best of our knowledge, short interval cortical inhibition had not been evaluated previously for correlations with other quantitative measures evoked by transcranial magnetic stimulation. Here we demonstrated a correlation between reduced short interval cortical inhibition and prolonged ipsilateral silent period latency. Both of these transcranial magnetic stimulation-evoked measures suggest that children with attention-deficit/hyperactivity disorder manifest deficits in inhibitory control. Mechanistically, these two inhibitory measures exhibit some similarities and differences. For example, interhemispheric inhibition, as measured by ipsilateral silent period, clearly depends on transcallosal pathways, which should not affect short interval cortical inhibition. However, several groups reported that intrahemispheric cortical circuits can affect interhemispheric inhibition in a fashion similar to that of short interval cortical inhibition [11,36,37]. This mechanistic similarity between short interval cortical inhibition and ipsilateral silent period may explain why these measures are both different in children with attention-deficit/hyperactivity disorder compared with control subjects. With regard to anomalous motor development in attention-deficit/hyperactivity disorder, we were particularly interested in evaluating the relationship between previously characterized subtle signs [3,4] and ipsilateral silent period latencies, because interhemispheric signaling may underlie the commonly observed increased motor overflow in attention-deficit/hyperactivity disorder. Our findings relating scores on the Physical and Neurological

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Table 3. Correlations between ISP latency and behavioral ratings, motor ratings, and motor cortex inhibition

ISP Latency

Age Behavioral ratings DuPaul ADHD Rating Scale Inattention Hyperactive/impulsivity Conners’ Parent and Teacher Rating Scales ADHD total T score Inattention T score Hyperactive/impulsive T score Motor ratings PANESS total score Overflow total Overflow right Overflow left Gait Timed tasks Motor cortex physiology RMT AMT SICI

r

P Value

0.256

0.062

0.327 0.272 0.342 0.376 0.347 0.385

0.017 0.049 0.012 0.007 0.013 0.006

0.252 0.283 0.305 0.250 0.329 0.154

0.075 0.044 0.030 0.077 0.018 0.280

0.192 0.147 0.362

0.168 0.288 0.008

Abbreviations: ADHD ¼ Attention-deficit/hyperactivity disorder AMT ¼ Active motor threshold ISP ¼ Ipsilateral silent period PANESS ¼ Physical and Neurological Examination for Soft Signs RMT ¼ Resting motor threshold SICI ¼ Short interval cortical inhibition Larger short interval cortical inhibition ratios indicate less inhibition. Raw scores on the Physical and Neurological Examination for Soft Signs are provided. Higher scores indicate more significant delays.

Examination for Soft Signs to ipsilateral silent period suggest that the inhibitory mechanisms underlying the ipsilateral silent period also reflect those underlying anomalous motor development in attention-deficit/ hyperactivity disorder. These findings, along with the age correlation we identified, are broadly consistent with those of Garvey et al., who also identified correlations between younger age, slower finger-tapping speed, and longer ipsilateral silent period latencies [15]. Finger speed was not significant in our analysis. However, the comprehensive assessments in the Physical and Neurological Examination for Soft Signs identified several other correlated subscales. In evaluating right/left/total and subscale differences, we emphasize that these values are ordinal and observational, and thus likely to be less robust in general than global scores in the Physical and Neurological Examination for Soft Signs. Higher motor cortex depolarization thresholds in younger children substantially reduced our final sample size. Features of our equipment, including the coil configuration and thickness of insulation, may have contributed to differences in the yield of our study, because in our entire sample, the resting motor threshold was more than 20% higher than reported in previous studies [14,15,38]. Because intensity strongly influences silent period duration [27], these differences in our equipment may also explain why silent periods were shorter on average in our study and why, in contrast with previous studies, we did not detect significantly shorter durations of ipsilateral silent periods in children with attention-deficit/hyperactivity disorder (Table 2). A broader applicability of ipsilateral silent periods to young children may require changes in coil design or

perhaps alternate techniques permitting lower-intensity stimulations, or in which the ipsilateral silent period is indexed to the participant’s resting motor threshold, as most often occurs in studies of cortical silent period. An additional potential limitation involves the effects of medication. The use of stimulant medication in our sample may be substantially higher than in European pediatric populations. Based on the pharmacokinetics of stimulant medications, our washout period should have been adequate. Post hoc analyses of currently treated vs currently untreated children with attention-deficit/hyperactivity disorder have not identified any differences in transcranial magnetic stimulation-evoked inhibitory responses. This case-control study was cross-sectional, and thus results must be interpreted cautiously. A longitudinal study may provide more readily interpretable insights into the relationship between age-related motor development, motor physiology, and attention-deficit/hyperactivity disorder. Longitudinal studies, perhaps combining ipsilateral silent periods with not only short interval cortical inhibition but also imaging studies of motor cortex volume and thickness [39-41], cortical studies of neurotransmitters [42], or callosal volume [43-45] or diffusion [46], may clarify the extent to which differences in ipsilateral silent period latency reflect transsynaptic vs structural processes. Combining measures of ipsilateral silent periods and short interval cortical inhibition with functional studies of behavioral factors such as reward delay aversion and response inhibition may help disentangle forms of inhibitory dysfunction, and in turn help delineate meaningful long-term neurodevelopmental profiles that aid in the development of more effective treatments [47].

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This research was funded by National Institutes of Health grants R01 MH078160 and MH085328, by the Institute for Clinical and Translational Research at the Johns Hopkins University School of Medicine, and by National Institutes of Health/National Center for Research Resources/Clinical and Translational Science Awards Program grant UL1-RR025005. The authors thank Martha Denckla, MD, for inspiration and guidance, Marjorie Garvey, MB, BCh, for helpful discussions in planning our experiments and interpreting our results, our research coordinators for technical assistance, and the children and parents for their time and participation. S.W.W. receives research support from the Tourette Syndrome Association and the National Institutes of Health-National Institute of Neurological Disorders and Stroke Pediatric Research Loan Repayment Program. He is also involved in clinical trials conducted by the Genzyme Corporation, Otsuka Pharmaceuticals, Inc., and Psyadon Pharmaceuticals, Inc. D.L.G. has received honoraria from the Tourette Syndrome Association/ Centers for Disease Control, the American Academy of Neurology, and the American Academy of Pediatrics. He serves on the Medical Advisory Board for the Tourette Syndrome Association, writes board review questions for PREP Self-Assessment (American Academy of Pediatrics), and has received research support from Psyadon Pharmaceuticals and Otsuka Pharmaceuticals. S.H.M. has received funding from the Autism Speaks Foundation and the Simons Foundation. He has received honoraria from the National Association of Neuropsychologists.

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