Aim The aim of this study was to determine the feasibility and efficacy of five treatments of 6Hz primed, low-frequency, repetitive transcranial magnetic stimulation (rTMS) combined with constraint-induced movement therapy (CIMT) to promote recovery of the paretic hand in children with congenital hemiparesis. Method Nineteen children with congenital hemiparesis aged between 8 and 17 years (10 males, nine females; mean age 10y 10mo, SD 2y 10mo; Manual Ability Classification Scale levels I-III) underwent five sessions of either real rTMS (n=10) or sham rTMS (n=9) alternated daily with CIMT. CIMT consisted of 13 days of continuous long-arm casting with five skin-check sessions. Each child received a total of 10 hours of one-to-one therapy. The primary outcome measure was the Assisting Hand Assessment (AHA) and the secondary outcome variables were the Canadian Occupational Performance Measure (COPM) and stereognosis. A Wilcoxon signed-rank sum test was used to analyze differences between pre- and post-test scores within the groups. Analysis of covariance was used to compute mean differences between groups adjusting for baseline. Fisher’s exact test was used to compare individual change in AHA raw scores with the smallest detectable difference (SDD) of 4 points. Results All participants receiving treatment finished the study. Improvement in AHA differed significantly between groups (p=0.007). No significant differences in the secondary outcome measures were found. Eight out of 10 participants in the rTMS/CIMT group showed improvement greater than the SDD, but only two out of nine in the sham rTMS/CIMT group showed such improvement (p=0.023). No serious adverse events occurred. Interpretation Primed, low-frequency rTMS combined with CIMT appears to be safe, feasible, and efficacious in pediatric hemiparesis. Larger clinical trials are now indicated.

Clinicaltrials.govNCT 02250092.

Objective We investigated the preliminary efficacy of cathodal transcranial direct current stimulation (tDCS) combined with bimanual training in children and young adults with unilateral cerebral palsy based on the principle of exaggerated interhemispheric inhibition (IHI). Methods Eight participants with corticospinal tract (CST) connectivity from the lesioned hemisphere participated in an open-label study of 10 sessions of cathodal tDCS to the nonlesioned hemisphere (20 minutes) concurrently with bimanual, goal-directed training (120 minutes). We measured the frequency of adverse events and intervention efficacy with performance (bimanual—Assisting Hand Assessment (AHA)—and unimanual—Box and Blocks), self-report (Canadian Occupational Performance Measure (COPM), ABILHAND), and neurophysiologic (motor-evoked potential amplitude, cortical silent period (CSP) duration, and motor mapping) assessments. Results All participants completed the study with no serious adverse events. Three of 8 participants showed gains on the AHA, and 4 of 8 participants showed gains in Box and Blocks (more affected hand). Nonlesioned CSP duration decreased in 6 of 6 participants with analyzable data. Cortical representation of the first dorsal interosseous expanded in the nonlesioned hemisphere in 4 of 6 participants and decreased in the lesioned hemisphere in 3 of 4 participants with analyzable data. Conclusions While goal achievement was observed, objective measures of hand function showed inconsistent gains. Neurophysiologic data suggests nonlinear responses to cathodal stimulation of the nonlesioned hemisphere. Future studies examining the contributions of activity-dependent competition and cortical excitability imbalances are indicated.

Background Neurorehabilitation interventions in children with unilateral cerebral palsy (UCP) target motor abilities in daily life yet deficits in hand skills persist. Limitations in the less-affected hand may impact overall bimanual hand skills. Objective To compare hand function, by timed motor performance on the Jebsen-Taylor Test of Hand Function (JTTHF) and grip strength of children with UCP to children with typical development (CTD), ages 8–18 years old. Exploratory analyses compared hand function measures with respect to neurophysiological outcomes measured by transcranial magnetic stimulation and between group comparisons of hemispheric motor threshold. Methods Baseline hand skills were evaluated in 47 children (21 UCP; 26 CTD). Single-pulse transcranial magnetic stimulation testing assessed corticospinal tract and motor threshold. Results The mean difference of the less-affected hand of children with UCP to the dominant hand of CTD on the JTTHF was 21.4 seconds [95% Confidence Interval = 9.32, 33.46, p=0.001]. The mean difference in grip strength was −30.8 N [−61.9, 0.31, p = 0.052]. Resting motor thresholds between groups were not significant, but age was significantly associated with RMT (p<0.001; p=0.001). Children with UCP ipsilateral pattern of motor representation demonstrated greater mean differences between hands than children with contralateral pattern of motor representation (p<0.001). All results adjusted for age and sex. Conclusions The less-affected hand in children with UCP underperformed the dominant hand of CTD. Limitations were greater in children with UCP ipsilateral motor pattern. Rehabilitation in the less-affected hand may be warranted. Bilateral hand function in future studies may help identify the optimal rehabilitation and neuromodulatory intervention.

Non-invasive brain stimulation has been increasingly investigated, mainly in adults, with the aims of influencing motor recovery after stroke. However, a consensus on safety and optimal study design has not been established in pediatrics. The low incidence of reported major adverse events in adults with and without clinical conditions has expedited the exploration of NIBS in children with paralleled purposes to influence motor skill development after neurological injury. Considering developmental variability in children, with or without a neurologic diagnosis, adult dosing and protocols may not be appropriate. The purpose of this paper is to present recommendations and tools for the prevention and mitigation of adverse events (AEs) during NIBS in children with unilateral cerebral palsy (UCP). Our recommendations provide a framework for pediatric NIBS study design. The key components of this report on NIBS AEs are (a) a summary of related literature to provide the background evidence and (b) tools for anticipating and managing AEs from four international pediatric laboratories. These recommendations provide a preliminary guide for the assessment of safety and risk mitigation of NIBS in children with UCP. Consistent reporting of safety, feasibility, and tolerability will refine NIBS practice guidelines contributing to future clinical translations of NIBS.

Objective To investigate the safety of combining 6-Hz primed low-frequency repetitive transcranial magnetic stimulation (rTMS) intervention in the contralesional hemisphere with a modified constraint-induced movement therapy (mCIMT) program in children with congenital hemiparesis. Design Phase 1 randomized, double-blinded, placebo-controlled pretest/posttest trial. Setting University academic facility and a pediatric specialty hospital. Participants Nineteen subjects aged 8 to 17 years with congenital hemiparesis due to ischemic stroke or periventricular leukomalacia. No subject withdrew due to adverse events. All subjects included completed the study. Interventions Subjects were randomized to one of two groups: either rTMSreal with mCIMT (n = 10) or rTMSsham with mCIMT (n = 9). Main Outcome Measures Adverse events, physician assessment, ipsilateral hand function, stereognosis, cognitive function, subject report of symptoms assessment and subject questionnaire. Results No major adverse events occurred. Minor adverse events were found in both groups. The most common were headaches (real: 50%, sham: 89%, p=0.14) and cast irritation (real: 30%, sham: 44%, p = 0.65). No differences between groups in secondary cognitive and unaffected hand motor measures were found. Conclusions Primed rTMS can be used safely with mCIMT in congenital hemiparesis. We provide new information on the use of rTMS in combination with mCIMT in children. These findings could be useful in research and future clinical applications in advancing function in congenital hemiparesis.

Combined non-invasive brain stimulation (NIBS) and rehabilitation interventions have the potential to improve function in children with unilateral cerebral palsy (UCP), however their effects on developing brain function are not well understood. In a proof-of-principle study, we used single-pulse transcranial magnetic stimulation (TMS) to measure changes in corticospinal excitability and relationships to motor performance following a randomized controlled trial consisting of 10 days of combined constraint-induced movement therapy (CIMT) and cathodal transcranial direct current stimulation (tDCS) applied to the contralesional motor cortex. Twenty children and young adults (mean age = 12 years, 9 months, range = 7 years, 7 months, 21 years, 7 months) with UCP participated. TMS testing was performed before, after, and 6 months after the intervention to measure motor evoked potential (MEP) amplitude and cortical silent period (CSP) duration. The association between neurophysiologic and motor outcomes and differences in excitability between hemispheres were examined. Contralesional MEP amplitude decreased as hypothesized in five of five participants receiving active tDCS immediately after and 6 months after the intervention, however no statistically significant differences between intervention groups were noted for MEP amplitude [mean difference = −323.9 μV, 95% CI = (−989, 341), p = 0.34] or CSP duration [mean difference = 3.9 ms, 95% CI = (−7.7, 15.5), p = 0.51]. Changes in corticospinal excitability were not statistically associated with improvements in hand function after the intervention. Across all participants, MEP amplitudes measured in the more-affected hand from both contralesional (mean difference = −474.5 μV) and ipsilesional hemispheres (−624.5 μV) were smaller compared to the less-affected hand. Assessing neurophysiologic changes after tDCS in children with UCP provides an understanding of long-term effects on brain excitability to help determine its potential as a therapeutic intervention. Additional investigation into the neurophysiologic effects of tDCS in larger samples of children with UCP are needed to confirm these findings.

Mirror movements (MM) can be a clinical manifestation of unilateral cerebral palsy (UCP) causing involuntary movements when attempting to use either hand for functional activities. Atypical development of the corticospinal tract (CST) contributes to impairments in observed motor movements and functional activities. However, little is known about the underlying neurophysiology and contribution of the CST to MM. The current case study characterizes MM in 13 children and young adults with UCP ranging in age from 7 to 19 years and includes clinical and neurophysiologic variables. Clinical profiles included MM of each hand (ie, Woods and Teuber), bimanual coordination and hand use (Assisting Hand Assessment [AHA]), and perception of performance (Canadian Occupational Performance Measure [COPM]). We measured the strength of motor-evoked potentials (MEP) elicited from single-pulse transcranial magnetic stimulation (TMS) of each hemisphere to create a ratio of hemispheric responses. Our sample included three types of CST circuitry: ipsilateral (n = 5), bilateral (n = 3), and contralateral (n = 4). The MEP ratio ranged from 0 to 1.45 (median 0.11) with greater MM observed in participants with ratios greater than 0.5. We observed a positive relationship between the MEP ratio and the more-affected MM score, meaning participants with larger ipsilateral responses from contralesional stimulation (eg, the contralesional hemisphere was stimulated with TMS resulting in an ipsilateral MEP response), as compared with contralateral responses, displayed greater MM than those that did not. There was no relationship between MM and function as measured by the AHA or COPM. These findings suggest a role of the contralesional hemisphere to MM, which could serve as a therapeutic target for interventions.