Abstract
Background Transcranial direct current stimulation (tDCS) is a form of noninvasive brain stimulation that has shown improved adult stroke outcomes. Applying tDCS in children with congenital hemiparesis has not yet been explored.
Objective The primary objective of this study was to explore the safety and feasibility of single-session tDCS through an adverse events profile and symptom assessment within a double-blind, randomized placebo-controlled preliminary study in children with congenital hemiparesis. A secondary objective was to assess the stability of hand and cognitive function.
Design A double-blind, randomized placebo-controlled pretest/posttest/follow-up study was conducted.
Setting The study was conducted in a university pediatric research laboratory.
Participants Thirteen children, ages 7 to 18 years, with congenital hemiparesis participated.
Measurements Adverse events/safety assessment and hand function were measured.
Intervention Participants were randomly assigned to either an intervention group or a control group, with safety and functional assessments at pretest, at posttest on the same day, and at a 1-week follow-up session. An intervention of 10 minutes of 0.7 mA tDCS was applied to bilateral primary motor cortices. The tDCS intervention was considered safe if there was no individual decline of 25% or group decline of 2 standard deviations for motor evoked potentials (MEPs) and behavioral data and no report of adverse events.
Results No major adverse events were found, including no seizures. Two participants did not complete the study due to lack of MEP and discomfort. For the 11 participants who completed the study, group differences in MEPs and behavioral data did not exceed 2 standard deviations in those who received the tDCS (n=5) and those in the control group (n=6). The study was completed without the need for stopping per medical monitor and biostatisticial analysis.
Limitations A limitation of the study was the small sample size, with data available for 11 participants.
Conclusions Based on the results of this study, tDCS appears to be safe, feasible, and well tolerated in most children with hemiparesis. Future investigations of serial sessions of tDCS in conjunction with rehabilitation in pediatric hemiparesis are indicated to explore the benefit of a synergistic approach to improving hand function.
Noninvasive brain stimulation (NIBS) has been investigated for benefits in recovery of motor function in adults1,2 and more recently in children.3–5 One form, transcranial magnetic stimulation (TMS), can be used either to test cortical excitability or as an intervention aimed at identifying or influencing cortical excitability.6 In the evaluation of potential clinical application of NIBS, however, TMS has associated reports of seizures in adults.7,8 Although no seizures were reported in a 2005 review of TMS in children, TMS has the capacity to induce seizure to investigate pathophysiology,9 whereas another form of NIBS, transcranial direct current stimulation (tDCS), does not. Transcranial direct current stimulation modulates cortical excitability in the brain by influencing the resting membrane potential.10 If such an excitatory environment is created, it may allow for further improvements in voluntary motor control through rehabilitation.11,12
Additionally, tDCS is not as costly as TMS, is more portable, and has the potential for use simultaneously with rehabilitation as a means to enhance neurorecovery.13–15 For example, in human research, tDCS trials in adult neurologic and psychiatric diagnoses have revealed promising results in motor and cognitive improvements, with no serious adverse events reported.11,16–18 The application of tDCS in adults with hemiparesis due to stroke also has demonstrated improvements in hand function in conjunction with no major adverse events.19,20 Such neuroenhancement could be explored at an earlier stage in disease or neurorecovery. In particular, applying tDCS in children with congenital hemiparesis not only could benefit children at the time of stimulation but also might extend this benefit throughout neurodevelopment and across the life span. Studies incorporating the use of tDCS in children are few, however, with the majority in psychiatric disorders.21–24
To understand the mechanism of tDCS, it is important to appreciate the interconnections between the cortical hemispheres. The balance of function and influence of one hemisphere on another is called interhemispheric inhibition (IHI).25 For example, in a typically developing brain, one hemisphere mainly controls contralateral movement and sends inhibitory signals to the contralateral motor cortex, allowing for unilateral limb movement. When the brain is damaged, an exaggeration may develop in the normal ability of one hemisphere to inhibit the other for purposes of unilateral function. The nonlesioned hemisphere may overinhibit the viable yet dormant neuronal activity of the lesioned hemisphere. Therefore, application of a tDCS protocol may be intended to decrease the exaggerated inhibition of the nonlesioned hemisphere and increase neuronal activity of viable neurons in the lesioned hemisphere with the aim of improving function of the affected extremity. With appropriate electrode configuration, simultaneous bihemispheric stimulation may then be applied with the aim to (1) inhibit this exaggerated IHI from the nonlesioned (healthy) hemisphere and (2) facilitate activity within the lesioned (injured) hemisphere.
The purpose of this preliminary study was to investigate the safety and feasibility of a one-time application of tDCS in children with congenital hemiparesis. Although this form of NIBS has no reported serious adverse events, including seizure, in adults with stroke or children with other diagnoses, its application has not been investigated in children with congenital hemiparesis. It is unknown if a TMS-triggered seizure in a child who has had a stroke could contribute to the occurrence of additional unprovoked seizure activity or progress to the development of epilepsy. We hypothesized that children involved in a one-time application of tDCS would not experience any serious adverse events, including seizure, and would exhibit no decline in cognitive or motor function as measured by safety symptoms, adverse events, hand function in both hands, and cognitive status. Based on previous literature, no serious adverse events, such as seizure, were anticipated.26,27 However, due to the mechanism of tDCS, electrical currents are passed through the head, and minor adverse events could have occurred. Adverse effects associated with tDCS are suggested to be minimal and may include itching, tingling, a burning sensation in the area of the electrodes, headache, neck pain, scalp pain, skin redness, fatigue, trouble concentrating, and acute mood change. Using the information gleaned from this preliminary study, future clinical efficacy trials may further investigate the influence on motor function and improved outcomes.
Method
Design Overview
This preliminary study evaluated the safety of a single tDCS session through adverse events and behavioral assessment with a double-blind, randomized placebo-controlled study in children with congenital hemiparesis performed in an academic university setting. The study was advertised by website, social media, and letters to families interested in research as identified through affiliated hospital systems. Participants were initially screened by telephone to review inclusion and exclusion criteria. Verbal consent and signed HIPAA forms were obtained to proceed with a medical record and magnetic resonance imaging (MRI) review.
The inclusion and exclusion criteria assessment was conducted by the study medical director and a pediatric neurologist. The inclusion criteria were: (1) congenital hemiparesis confirmed by most recent MRI or computed tomography radiologic report of hemispheric stroke or periventricular leukomalacia (if the MRI lesion matched the damage associated with the clinical status reported in medical records and if perinatal recognition of impairment was documented, a congenitally related stroke was assumed to have occurred); (2) ages 7 to 18 years, attaining an age wherein IHI is typically established28,29; (3) 10 degrees or more of active motion at the second-digit metacarpophalangeal joint of the paretic hand to measure any potential changes from baseline; (4) adequate receptive language function and cognitive processing to follow two-step commands as evidenced by 75% accuracy of performance on the Token test of intelligence30; (5) no evidence of seizure activity within the previous 2 years; and (6) ability to give informed assent along with the informed consent of the legal guardian.
The exclusion criteria were: (1) metabolic disorders; (2) neoplasm; (3) epilepsy; (4) disorders of cellular migration and proliferation; (5) acquired traumatic brain injury; (6) expressive aphasia; (7) currently pregnant as evidenced by testing in all female participants; (8) indwelling metal or medical devices incompatible with NIBS; (9) evidence of skin disease or skin abnormalities; and (10) botulinum toxin or phenol intramuscular block within 6 months preceding tDCS.
A blinded investigator performed the testing during the pretest/posttest/follow-up study design, which included 2 on-site visits, 1 week apart. The first visit consisted of a pretest immediately before and posttest immediately after the tDCS intervention. The pretest comprised assessments to determine the feasibility and safety of the intervention. The same battery of assessments was performed on the same day at posttest and 1 week later in a follow-up session to assess for any change in motor and cognitive function or adverse events (further described below).
Setting and Participants
Thirteen children and adolescents, ages 7 to 18 years, with congenital hemiparesis due to hemispheric stroke initially participated in this study at an academic institution (Tab. 1). Eleven children completed the study procedures. Their mean age was 14.0 years (SD=3.5, range=7.8–18.5, median=14.7). Five children were randomly assigned in a nonstratified manner to the intervention group, and 6 children were randomly assigned to the control group.
Demographic Data and Baseline Characteristics of Participants With Pediatric Hemiparesis (n=11)a
At pretest, participants were assigned a Manual Ability Classification System (MACS) score31 (I–IV, with I representing functioning at highest level) and Gross Motor Function Classification System (GMFCS) score (I–IV, with I representing functioning at highest level).32 The medical director completed these assessments at each testing period.
Due to the small sample size and nonstratified randomization, balance was not achieved between the groups for age, side of lesion, and sex. However, for the purpose of evaluating safety, baseline differences in these variables were not felt to compromise the results of this study. The average age was 11 years in the intervention group and 17 years in the control group. With future studies of efficacy, however, age-matched controls would allow for a more representative comparison of age-appropriate activity.
Written informed assent with consent was obtained from all participants and their legal guardians before inclusion in the study. The NIBS was performed at the Clinical and Translational Science Institute (University of Minnesota, Minneapolis, Minnesota) to ensure medical safety and accessibility to appropriate response to potential adverse events.
Assessments
The primary purpose of this study was to investigate feasibility and safety of tDCS in pediatric hemiparesis. We hypothesized that there would be no serious adverse events, including seizure. Also, as a component of safety, we hypothesized that there would be no decline in cognitive or motor function and, therefore, included the assessments to allow us to investigate that hypothesis. Testing was performed on 2 separate days, with pretesting and posttesting occurring on day 1 and follow-up testing on day 7, by 4 investigators blinded to the group assignment (principal investigator, medical director, and 2 testing investigators).
Safety.
The blinded medical director assessed each participant with the Modified Pediatric Stroke Outcome Measure.33 The Token test of intelligence, initially used as a determination of eligibility, was performed to assess any change in receptive language and ability to follow verbal commands, with a maximum score of 46 points.30 Hand function was assessed for both the affected (hemiparetic) and unaffected hands using grip-strength dynamometry34 (measured in pounds) and the Box and Blocks Test.35 Mean intrarater and interrater reliability for the grip-strength dynamometer have been found to vary between .75 and .98 in youth, with a mean concurrent validity of .78 to .93.36 For the Box and Blocks Test, the intraclass correlation coefficient has been found to be .85 for test-retest reliability and .99 for interrater reliability,37 and correlation with the Fugl-Meyer Test and Action Research Arm Test was very high (rho >.92).38 Higher scores on these measures indicate improved performance.
The same blinded testing investigator administered the Token test, grip-strength dynamometry, and Box and Blocks Test and assessed vital signs, including blood pressure and heart rate, at each testing session with direct supervision from the principal investigator. Single-pulse TMS has been used as a tool for analysis of cortical excitability. No serious adverse events have been reported in children.9 The TMS was delivered by a 70-mm, figure-of-eight coil in a Magstim 200 TMS unit (Magstim Company Ltd, Dyfed, United Kingdom) to identify bilateral primary motor (M1) “hotspots,” or cortical regions showing the greatest excitability, for the first dorsal interosseous (FDI) muscles and the ipsilesional and contralesional motor thresholds of the M1 locations as determined by published guidelines.39 From these hotspots, the resting motor threshold was measured as the output of the percentage of machine maximum. If a resting motor threshold could not be elicited, an active motor threshold was recorded.40 Motor evoked responses from the FDI musculature were assessed using electrodes connected to a Cadwell Sierra Wedge electromyography (EMG) amplifier (Cadwell Laboratories, Kennewick, Washington). The M1 FDI hotspot locations, identified by TMS, were used as the electrode site for tDCS. The skin was lightly cleaned with an alcohol swab, and the participant's hair was optimally parted from the site of stimulation to increase conductance.
Upon evaluation of symptoms at pretest, posttest, and follow-up, each child was queried in both open- and closed-question formats. The open question “How are you feeling today?” was followed by the closed-format questioning. After each closed question regarding symptoms was answered, the testing investigator queried the child on the relation of the symptom to the tDCS application and assigned an ordinal scale score of 1 (“none”) to 5 (“definite”). The study medical monitor then determined the relative likelihood of this relationship based on the child's status. For example, one child at pretest described the “redness” on her arm due to a mosquito bite as “possibly” related to the tDCS application, and the medical monitor deemed this relation as “none.”
Participant feedback.
The participants also completed a tDCS symptom survey consisting of a report of symptoms at pretest, posttest, and follow-up testing. Adapted from Garvey et al,41 a separate posttest participant survey of tDCS application was performed to assess subjective participant reactions in receiving tDCS. Both were conducted by the principal investigator.
Medical monitor.
A physician monitor reviewed the scores on assessments to analyze safety and study stopping as described below. Responses for each participant were analyzed after day 1 and day 7.
Randomization and Interventions
Participants were randomly assigned by the study biostatistician, who was not involved in the outcomes testing, into intervention and control groups (Fig. 1). This randomization was achieved by assigning participants to either the intervention or control group with equal probability within randomly permuted blocks of size 2, 4, and 8, which also were selected with equal probability. Due to the preliminary nature of the study, stratification in grouping was not performed.
Flow diagram of participants through the study. MRI=magnetic resonance imaging, CT=computed tomography, MEP=motor evoked potential.
A bihemispheric tDCS montage was used with ipsilesional-anodal and contralesional-cathodal electrode positioning (described below). This application of tDCS is known to be polarity-specific, with anodal tDCS facilitating excitability while cathodal tDCS inhibits excitability.20,42 Another important consideration with the use of tDCS is to incorporate knowledge on dosing parameters and current flow, density, intensity, duration, and location from previous adult and pediatric modeling.43–46
Before the tDCS intervention, skin integrity assessments were performed.47 With the participants sitting in a comfortable chair, the scalp was measured using the conventional 10/20 electroencephalography (EEG) system with the C3/C4 EEG location indicating the area over the motor cortex.48
For the tDCS intervention, all instructions were the same based on the testing instructions delivered at a third grade reading level, and all children verbalized understanding of instructions. All participants were advised to report immediately if the stimulation was intolerable and to give feedback on their tolerance of the tDCS throughout. Sanitized and disinfected 5- × 7-cm2 rubber electrodes with clean, single-use sponges dampened with normal saline (sodium chloride) were placed over the stimulation sites and held against the head with a wide rubber headband that covered the entire surface of the electrode to ensure firm and even contact with the skin. The cathode rubber electrode was placed over the M1 FDI hotspot of the nonlesioned hemisphere, and the anode rubber electrode was placed over the M1 FDI hotspot of the lesioned hemisphere. A 15- to 30-second preliminary stimulation of up to 0.7 mA was administered for familiarity with the stimulation, and once complete, stimulation formally commenced. Bihemispheric tDCS was delivered by a Soterix Limited Energy 1×1 (LTE) tDCS Stimulator (Soterix Medical Inc, New York, New York) using two 9-V batteries with a limit of up to 1.5 mA and 20 minutes maximum duration of stimulation.49 In this study, participants in the intervention group received stimulation for 10 minutes at 0.7 mA. Unblinded intervention investigators administered the tDCS while shielding the settings from view of the child and legal guardian and the blinded investigators.
To influence potential bias, all participants experienced a gradual ramp-up sensation for the first 30 seconds, regardless of the group assignment. A placebo control setting on the tDCS device for participants in the control group allowed for administration of the ramp-up/ramp-down stimulation, yet no interim stimulation. The sensation then abated for participants in the control group until the end of the 10 minutes, when they received a 30-second ramp-down sensation until the machine turned off. Continuous assessment of safety was incorporated. In order to assess resting motor activity and identify potential pre-ictal activity, EMG monitoring of bilateral extensor digitorum and biceps brachii ipsilateral musculature was continually assessed during the tDCS intervention. This approach allowed both the testing investigators and intervention investigators to monitor for seizure activity without revealing group assignment. At the end of the stimulation, the skin around the electrode site was immediately checked for redness or damage.
Data Analysis
Baseline and demographic information was summarized using means, standard deviations, medians, and ranges for continuous variables and the number and percentage of participants in each category for categorical variables. The mean and standard deviation are presented for future research for computing power and sample size. The range and median are presented to assess safety. The same summary statistics were computed for the change from pretest to posttest, from pretest to follow-up, and from posttest to follow-up for safety symptoms and adverse events, hand function in both hands, and cognitive status. Due to the small size of the study, comparisons between the intervention and control groups were evaluated using the Wilcoxon rank sum test for continuous variables. The Fisher exact test was used to compare categorical variables between the 2 groups. In addition, longitudinal plots were created with a line for each participant to evaluate any changes that may warrant a safety concern at the individual level.
The safety of each participant was assessed on an individual basis throughout his or her involvement with the study, regardless of group assignment. Any decline in function or participant responses that indicated a potential adverse effect was reviewed individually. In addition, a prespecified interim analysis for the continuation of the entire study was completed after the first 10 participants completed the trial using the as-treated study population. The mean changes between the 2 groups were then compared. The stopping criteria were defined as a mean difference between groups exceeding 2 standard deviations. Had this occurred, the study would have been stopped for full review by the medical monitor or revising the protocol before proceeding. A mean difference of less than 2 standard deviations was considered adequate for continuation of the study together with the individual stopping criterion. Stopping rules were established within the study protocol and institutional review board application and incorporated direct feedback from the medical monitor. No difference between the mean change scores exceeded the safety boundary, and the medical monitor recommended continuation of the study.
Role of the Funding Source
The research reported was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health (Award Number UL1TR000114) to the University of Minnesota Clinical and Translational Science Institute (CTSI), by the CTSI Biostatistical Design and Analysis Center, and by the Minnesota Medical Foundation.
Results
Two children who were enrolled did not complete the study due to cortical excitability or discomfort. One child (aged 8 years 8 months) was excluded prior to randomization due to inability to elicit a motor evoked potential (MEP) in either hemisphere using TMS. Without this value, guidance for tDCS electrode location and a TMS postassessment after tDCS would have been incomplete. A second child (aged 9 years 8 months), who was assigned to the intervention group, withdrew during the 30-second ramp-up to 0.1 mV of tDCS due to an “uncomfortable feeling.” The 10-minute tDCS intervention did not occur. This child did not want to complete posttesting except for answering the Participant Report of Symptoms at posttest and 1-week follow-up questions.
Symptom Survey
No serious adverse events, including seizure, occurred. Among the 11 participants who completed the study, minor adverse events reported were the sensations of itchiness (n=1, intervention group) and burning (n=1, control group) under the area of the electrodes, which stopped immediately after cessation of the tDCS intervention. Also, reports of sleepiness (n=3, control group; n=1, intervention group) and difficulty concentrating (n=1, intervention group; n=1, control group) resolved within 24 hours. Posttest symptoms are reported in Table 2.
Reported Symptoms at Posttest Assessment After Transcranial Direct Current Stimulationa
Upon follow-up testing, only one participant in the control group reported mild sleepiness, which was reported to have no relation to the study. No other symptom was reported by any participant at follow-up. At pretest, the one participant who withdrew during the 30-second ramp-up reported mild sleepiness due to waking up for camp early that day, with no relation to tDCS. After this child withdrew from the study, she reported mild itching under the site of the electrodes, which she described as “definitely” related to the tDCS and persistent mild sleepiness, which was “possibly” related to the tDCS. This participant was willing to be interviewed by telephone 1 week later for follow-up and reported no persistent symptoms.
Participant Survey of tDCS Application
The overall average rating of the participants' satisfaction with being involved in the study was 8.2 (SD=1.9) on a 0- to 10-point ordinal scale (0=worst, 10=best). Importantly, the mean for the intervention group alone was 8.3 (SD=1.6), similar to the mean of 8.1 (SD=2.4) for the control group. Only one participant (intervention group) stated that he or she would not be involved in the study again, nor would he or she recommend it to a friend. The most common narrative response on the “best liked” aspect of the study was “helping other kids by participating,” followed by the interest in the activities they performed during the study: “testing skills on games, watching the computer screens, watching the study going on.” Two participants disliked the wetness of the tDCS sponges, and 2 reported dislike of the sensation of the TMS assessment through statements about the TMS stimulation as the “strong-feeling, clicky-thing” and “tapping thing.”
Safety Outcomes: Behavioral and Electrophysiologic Responses
Vital sign values for blood pressure and heart rate for each participant remained within age-appropriate guidelines at each testing session.50 The physicians who administered the Modified Pediatric Stroke Outcome Measure at each testing session observed no changes in performance that raised a safety concern. Functional and cognitive status did not reveal changes of greater than 25% decline for each participant or 2 standard deviations in the group analysis; therefore, the study was continued without stopping (Tab. 3, Fig. 2). Of the 11 children who had an MEP with TMS assessment, 10 had resting motor thresholds, and 1 had an active motor threshold wherein a maintained active contraction elicited an MEP, while at rest an MEP was not elicited (Tab. 3).
Behavioral Outcomes and Motor Threshold Changes Between Testing Sessionsa
Effects of transcranial direct current stimulation (tDCS) on behavioral and electrophysiologic outcome measures in intervention and control groups. (A) Box and Blocks Test score for unaffected hand. (B) Box and Blocks Test score for affected hand. Overall stability in scores or slight improvements noted in both groups. (C) Grip strength for unaffected hand. Some improvement noted in intervention group's tDCS scores at posttest, which returned to baseline level at follow-up. (D) Grip strength for affected hand. Small decline in some values in the control group at follow-up. (E) Primary motor cortex (M1) motor threshold values using transcranial magnetic stimulation (TMS) in the ipsilesional hemisphere. Overall values declined in both groups at follow-up. (F) Primary motor cortex motor threshold values using TMS in the contralesional hemisphere. Decline in control group noted in a few participants at follow-up. Overall lack of significant difference noted between groups on all outcomes measures.
Discussion
This preliminary study was conducted to investigate the safety and feasibility of a tDCS intervention for application in pediatric hemiparesis. Eleven children with congenital hemiparesis completed a 10-minute session of bihemispheric tDCS over the primary motor cortex. Two additional participants did not complete the study due to a lack of MEP in the ipsilesional cortex in one case and discomfort in the other case. No seizures or other serious adverse events occurred. The most common side effects reported were sleepiness and concentration difficulties, which resolved within 24 hours. Less commonly noted were sensations of itching and burning, which immediately resolved after the termination of tDCS. Safety of serial tDCS application has been supported in a recent study of children, ages 5 to 12 years, with language disorders.21 After 10 sessions of tDCS at 1 to 2 mA with the anode positioned over Broca's area and the cathode over the right supraorbital region, the authors noted resultant participant complaints of tingling, itching, and burning sensations, with immediate resolution after tDCS application. Difficulty concentrating also was reported. In a study by Lindenberg et al20 of 20 patients with stroke, 5 sessions of tDCS at 1.5 mA for 30 minutes in combination with physical therapy and occupational therapy resulted in no adverse events. However, the participants in that study reported mild tingling at the electrode sites. Such reports were similar to the minor adverse event complaints we observed in our study. Additionally, a study of serial bihemispheric tDCS to the motor cortex in combination with constraint-induced movement therapy in adults with stroke showed improvements in motor performance, with no adverse events.11 We similarly found that this one-time application of tDCS was a safe and feasible intervention that exhibited minor and short-duration adverse events in children with hemiparesis. As future investigations study the effect of tDCS on outcomes, the clinical cost would be comparable to present neuromuscular electrical stimulation sessions.
In developing pediatric trials, participant reports and feedback are important. When queried, 100% (6 of 6) of the participants in the control group and 75% (3 of 4) of those in the intervention group reported they would perform the study again. One child in the intervention group responded that he or she “didn't know.” In regard to recommending the study to others, 100% (5 of 5) of the participants in the control group and 75% (3 of 4) of those in the intervention group said they would. One child in the control group and one child in the intervention group said they “didn't know.” These results are similar to those found in childrens' subjective reactions to TMS application.41,51 Participant mean rating of the study overall was high (average score of 8.2 on a scale of 0 [dislike] to 10 [like]), and children from both groups reported items they liked about the tDCS. Meaningfully, children in both groups also shared subjective reflections on their dislikes in performing the study, such as the work involved and the sensations themselves. Two forms of NIBS were utilized: TMS for cortical excitability measurement and tDCS for intervention. As 2 participants remarked specifically on the sensation of receiving TMS, future tolerance assessment to each form of stimulation may be beneficial. This observation acknowledges the value of information retrieved in working with children. At the same time, however, appropriate construct of questioning also must be established to thoroughly understand the relationship of symptoms to tDCS. Carefully planned questioning allowed us the important opportunity to assess each participant's comfort with and responses to involvement in the study. As described, we incorporated a medical monitor to evaluate and determine the symptom and tDCS relationship. Continued development of such monitoring will create a framework to adapt the study design to the needs of the child in future studies.
While the average age in the intervention and control groups was 11 years and 17 years, respectively, the primary aim of evaluating safety and not efficacy was deemed acceptable. With future studies of efficacy, however, age-matched controls and group stratification would allow for a more representative comparison of age-appropriate activity. With a larger sample size, evaluation of behavioral outcome measure scores and responses can occur. Our assessment of behavioral outcomes related directly to the safety of tDCS and was used to examine a possible decline in score, which did not exceed 2 standard deviations of difference.
Motor threshold values also allowed for assessment of potential change in cortical excitability. If the cathodal site inhibits excitation and the anodal site facilitates excitation, a possible finding might have been an increase in overall contralesional hemispheric motor thresholds and, more to be expected, a decrease in ipsilesional hemispheric motor thresholds. A lower threshold, therefore, may be indicative of increased cortical excitability and decreased TMS energy output to elicit an MEP, thus an indication of a reduction in existing exaggerated IHI.52 These changes in TMS-deduced cortical excitability were inconsistent in this one-time tDCS application. In the ipsilesional hemisphere, the motor threshold generally declined in both groups, with increases found in one child in the intervention group and one child in the control group. In the contralesional hemisphere, the motor threshold values for most children either remained the same or varied in either direction slightly from baseline. Knowledge of each participant's cortical excitability is necessary to address the unanswered questions regarding the influence of NIBS interventions. For example, in the case of the young child who did not reveal an MEP using TMS, exclusion was indicated because we would not have had a measure with which to compare potential cortical excitability changes. In addition, the application of a bihemispheric montage may not have been optimal, as other tDCS montage configurations exist.53
The value of NIBS in pediatric clinical research is vital not only for its effect during childhood but also for the potential impact that a change in function can have across the life span. The finding in this investigation of safety and feasibility of the use of tDCS allows for further investigations of serial tDCS sessions in combination with rehabilitation interventions, which could reduce rehabilitation-related costs in ongoing therapy for a child with congenital hemiparesis. Future research incorporating cautious investigation of optimal tDCS responders and parameters in the pediatric population has the potential to advance neurorehabilitation beyond current boundaries, further improving motor function and affecting large numbers of children with hemiparesis at a time in development ripe for neuroplastic change and lasting benefit.
Footnotes
All authors provided concept/idea/project design. Dr Gillick, Mr Menk, Dr Krach, Dr Usset, Dr Vaith, Dr Wood, and Dr Worthington provided writing and data collection. Dr Gillick, Mr Menk, Dr Usset, Dr Vaith, Dr Wood, and Dr Worthington provided data analysis. Dr Gillick provided project management, fund procurement, facilities/equipment, and institutional liaisons. Dr Gillick and Dr Krach provided study participants. Dr Gillick, Dr Feyma, Dr Krach, Dr Usset, Dr Vaith, Dr Wood, and Dr Worthington provided consultation (including review of manuscript before submission). The authors acknowledge Nanette Aldahondo, MD, and Nik Sell for their participation in child assessments and sessions. They thank Ms Sally Jones, Ms Maureen Boxrud, and Lisa Rohrer, PhD, for their assistance in manuscript review and pediatric-specific study coordination and design. They are grateful for the involvement of the children and families in this study.
The project was previously presented at: NYC Neuromodulation Conference; November 22–24, 2013; New York, New York; American Academy for Cerebral Palsy and Developmental Medicine Annual Conference; October 16–19, 2013; Milwaukee, Wisconsin; Minnesota Chapter APTA Conference; April 20, 2013; Minneapolis, Minnesota; Translational Science Symposium; April 18, 2013; Washington, DC; and University of Minnesota Clinical and Translational Science Institute Conference; September 12, 2012; Minneapolis, Minnesota.
This study was approved by the University of Minnesota Institutional Review Board.
The research reported was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health Award Number UL1TR000114 of the National Institutes of Health (NIH) to the University of Minnesota Clinical and Translational Science Institute (CTSI), and CTSI Biostatistical Design and Analysis Center as well as the Minnesota Medical Foundation. REDCap Study data were collected and managed using REDCap52 electronic data capture tools hosted at the University of Minnesota.
The study is registered at ClinicalTrials.gov: NCT01636661.
- Received November 22, 2013.
- Accepted November 5, 2014.
- © 2015 American Physical Therapy Association
References
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