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Background: Clinical trials are suggesting efficacy of intensive therapy combined with brain stimulation to improve hand function in hemiparetic children with perinatal stroke. However, individual variability exists and the underlying neuroplasticity mechanisms are unknown. Exploring primary motor cortex (M1) neurophysiology, and how it changes with such interventions, may provide valuable biomarkers for advancing personalized neurorehabilitation., Methods: Forty-five children (age 6-19 years) with hemiparesis participated in PLASTIC CHAMPS, a blinded, sham-controlled, factorial clinical trial. All received 80 hours of goal-directed intensive upper extremity therapy. They were randomized into 4 groups: repetitive transcranial magnetic stimulation (rTMS) of contralesional M1, constraint therapy, both, or neither. Stimulus recruitment curves (SRC), short-interval intracortical inhibition (SICI), and intracortical facilitation (ICF) for lesioned and contralesional M1 were investigated using TMS. Clinical assessments including the Assisting Hand Assessment (AHA) and Canadian Occupational Performance Measure (COPM) were conducted pre- and postintervention., Results: All children completed the intervention and both function (AHA) and goal performance (COPM) improved with additive effects of rTMS and constraint ( P < .01). After intervention, motor-evoked potential (MEP) amplitudes from the contralesional M1 to the less-affected hand increased (n = 16, P < .02). SRC from the contralesional M1 to the less-affected hand increased (n = 25, P < .01). SICI of the contralesional M1 to the less-affected hand decreased (n = 30, P < .04). No changes were observed for ICF in either hemisphere ( P > .12)., Conclusion: TMS applied before/after intensive neuromodulation therapies can explore M1 neurophysiology and plasticity in children with cerebral palsy. Increased MEP sizes and decreased SICI may reflect mechanisms of interventional plasticity and be potential biomarkers of individualized medicine.

Objective: Brain stimulation and constraint therapy may enhance function after perinatal stroke but mechanisms are unknown. We characterized interhemispheric interactions (IHI) in hemiparetic children and explored their relationship to motor function and neuromodulation., Methods: Forty-five hemiparetic perinatal stroke subjects aged 6-19 years completed a clinical trial of repetitive-transcranial magnetic stimulation (rTMS) and constraint therapy. Paired-pulse TMS measured IHI in cases and normal controls. Suprathreshold conditioning stimuli preceded contralateral test stimuli bidirectionally: stroke to non-stroke (SNS) and non-stroke to stroke (NSS). Primary outcome was the interhemispheric ratio (IHR) between conditioned and test only MEP amplitudes X100 (<100 implied inhibition). Motor outcomes at baseline and post-intervention were compared to IHR., Results: Procedures were well tolerated. IHI occurred bidirectionally in controls. Eighteen stroke participants had complete data. IHR were increased in stroke participants in both directions. SNS IHR was >100 (facilitation) in 39% of measurements and correlated with better motor function. NSS IHR correlated with poorer motor function. Intervention-induced clinical change was not associated with IHR., Conclusions: Interhemispheric interactions are altered and related to clinical function, but not necessarily neuromodulation, in children with perinatal stroke., Significance: Adding interhemispheric interactions to evolving models of developmental plasticity following early injury may advance neuromodulation strategies., (Copyright © 2017 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Background: Perinatal stroke causes lifelong motor disability, affecting independence and quality of life. Non-invasive neuromodulation interventions such as transcranial direct current stimulation (tDCS) combined with intensive therapy may improve motor function in adult stroke hemiparesis but is under-explored in children. Measuring cortical metabolites with proton magnetic resonance spectroscopy (MRS) can inform cortical neurobiology in perinatal stroke but how these change with neuromodulation is yet to be explored., Methods: A double-blind, sham-controlled, randomized clinical trial tested whether tDCS could enhance intensive motor learning therapy in hemiparetic children. Ten days of customized, goal-directed therapy was paired with cathodal tDCS over contralesional primary motor cortex (M1, 20 min, 1.0 mA, 0.04 mA/cm 2 ) or sham. Motor outcomes were assessed using validated measures. Neuronal metabolites in both M1s were measured before and after intervention using fMRI-guided short-echo 3T MRS., Results: Fifteen children [age(range) = 12.1(6.6-18.3) years] were studied. Motor performance improved in both groups and tDCS was associated with greater goal achievement. After cathodal tDCS, the non-lesioned M1 showed decreases in glutamate/glutamine and creatine while no metabolite changes occurred with sham tDCS. Lesioned M1 metabolite concentrations did not change post-intervention. Baseline function was highly correlated with lesioned M1 metabolite concentrations (N-acetyl-aspartate, choline, creatine, glutamate/glutamine). These correlations consistently increased in strength following intervention. Metabolite changes were not correlated with motor function change. Baseline lesioned M1 creatine and choline levels were associated with clinical response., Conclusions: MRS metabolite levels and changes may reflect mechanisms of tDCS-related M1 plasticity and response biomarkers in hemiparetic children with perinatal stroke undergoing intensive neurorehabilitation., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Recent changes in surgical training environments may have limited opportunities for trainees to gain proficiency in skill. Complex skills such as neurosurgery require extended periods of training. Methods to enhance surgical training are required to overcome duty-hour restrictions, to ensure the acquisition of skill proficiency. Transcranial direct-current stimulation (tDCS) can enhance motor skill learning, but is untested in surgical procedural training. We aimed to determine the effects of tDCS on simulation-based neurosurgical skill acquisition., Methods: Medical students were trained to acquire tumor resection skills using a virtual reality neurosurgical simulator. The primary outcome of change in tumor resection was scored at baseline, over 8 repetitions, post-training, and again at 6 weeks. Participants received anodal tDCS or sham over the primary motor cortex. Secondary outcomes included changes in brain resected, resection effectiveness, duration of excessive forces (EF) applied, and resection efficiency. Additional outcomes included tDCS tolerability., Results: Twenty-two students consented to participate, with no dropouts over the course of the trial. Participants receiving tDCS intervention increased the amount of tumor resected, increased the effectiveness of resection, reduced the duration of EF applied, and improved resection efficiency. Little or no decay was observed at 6 weeks in both groups. No adverse events were documented, and sensation severity did not differ between stimulation groups., Conclusions: The addition of tDCS to neurosurgical training may enhance skill acquisition in a simulation-based environment. Trials of additional skills in high-skill residents, and translation to nonsimulated performance are needed to determine the potential utility of tDCS in surgical training., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Transcallosal fibers facilitate interhemispheric networks involved in motor tasks. Despite their clinical relevance, interhemispheric motor control systems have not been completely defined in the developing brain. The objective of this study was to examine the developmental profile of transcallosal inhibition in healthy children and adolescents. Nineteen typically developing right-handed participants were recruited. Two transcranial magnetic stimulation (TMS) paradigms assessed transcallosal inhibition: ipsilateral silent periods (iSP) and paired-pulse interhemispheric inhibition (IHI). TMS was applied to the motor hotspot of the first dorsal interosseous muscle. Resting motor threshold (RMT), iSP latency, duration and suppression strength, and paired-pulse IHI were measured from both hemispheres. The Purdue Pegboard Test assessed unimanual motor function. Hemispheric differences were evident for RMT and iSP latency and suppression strength, where the left hemisphere had a lower RMT, prolonged latency, and greater suppression strength. iSP duration showed hemispheric symmetry. RMT and iSP latency decreased with age, whereas iSP suppression strength increased. Girls showed shorter iSP latency. Children typically displayed IHI, although hemispheric differences were observed. iSP suppression strength was uniquely associated with IHI within individuals. iSP duration correlated with motor performance. TMS can characterize transcallosal inhibition in normal children and adolescents with effects of age, directionality, sex, and motor performance. Establishing this developmental profile of interhemispheric interactions may advance understanding and therapeutic strategies for pediatric motor disorders such as cerebral palsy. NEW & NOTEWORTHY Here we demonstrate that transcranial magnetic stimulation can characterize transcallosal inhibition in normal children and adolescents with effects of age, directionality, handedness, and motor performance. Interestingly, we also demonstrated sex effects, possibly related to the differing developmental profiles of boys and girls. Establishing this developmental profile of interhemispheric interactions may advance understanding and therapeutic strategies for pediatric motor disorders such as cerebral palsy., (Copyright © 2017 the American Physiological Society.)

This study aims to determine the effects of transcranial direct-current stimulation (tDCS) on motor learning in healthy school-aged children. Safety, tolerability, and translation of effects to untrained tasks were also explored. We recruited 24 right-handed children for a randomized, sham-controlled, double-blinded trial to receive: right primary motor cortex (M1) 1 mA anodal (1A-tDCS), left M1 1 mA cathodal (1C-tDCS), left M1 2 mA cathodal tDCS (2C-tDCS), or sham tDCS over 3 consecutive days of motor task practice. Participants trained their left hand to perform the Purdue Pegboard Test (PPT) during tDCS application. Right hand and bimanual PPT, the Jebsen-Taylor Test (JTT), and the Serial Reaction Time Task (SRTT) were tested at baseline and post-training. All measures were retested 6 weeks later. Active tDCS montages enhanced motor learning compared with sham (all P < 0.002). Effects were sustained at 6 weeks. Effect sizes were large and comparable across montages: contralateral 1A-tDCS (Cohen's d = 2.58) and ipsilateral 1C-tDCS (3.44) and 2C-tDCS (2.76). Performance in the untrained hand PPT, bilateral JTT, and SRTT often improved with tDCS. tDCS was well-tolerated and safe with no adverse events. These first principles will advance the pairing of tDCS with therapy to enhance rehabilitation for disabled children such as those with cerebral palsy., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: Perinatal stroke causes most hemiparetic cerebral palsy. Ipsilateral connections from nonlesioned hemisphere to affected hand are common. The nonlesioned primary motor cortex (M1) determines function and is a potential therapeutic target but its neurophysiology is poorly understood., Objective: We aimed to characterize the neurophysiological properties of the nonlesioned M1 in children with perinatal stroke and their relationship to clinical function., Methods: Fifty-two participants with hemiparetic cerebral palsy and magnetic resonance imaging-confirmed perinatal stroke and 40 controls aged 8 to 18 years completed the same transcranial magnetic stimulation (TMS) protocol. Single-pulse TMS to nonlesioned M1 determined rest and active motor thresholds (RMT/AMT), motor-evoked potential (MEP) latencies, and stimulus recruitment curves (SRC: 100%-150% RMT). Paired-pulse TMS evaluated short-latency intracortical inhibition (SICI) and intracortical facilitation (ICF). Ipsilateral (IP) participants (ipsilateral MEP ≥0.05 mV in ≥5/20 trials) were compared with contralateral MEP only, nonipsilateral (NI) participants. Assisting Hand and Melbourne assessments quantified clinical function., Results: Twenty-five IP were compared with 13 NI (n = 38, median age 12 years, 66% male). IP had lower motor function. SRC to unaffected hand were comparable between IP and NI while IP had smaller ipsilateral SRC. Ipsilateral MEP latencies were prolonged (23.5 ± 1.8 vs 22.2 ± 1.5 ms contra, P < .001). Contralateral SICI was different between IP (-42%) and NI (-20%). Ipsilateral SICI was reduced (-20%). Contralateral ICF was comparable between groups (+43%) and ipsilaterally (+43%). Measures correlated between contralateral and ipsilateral sides., Conclusion: Neurophysiology of nonlesioned M1 and its relationship to motor function is measureable in children with perinatal stroke. Correlation of excitability and intracortical circuitry measures between contralateral and ipsilateral sides suggests common control mechanisms.

Introduction Perinatal stroke is the leading cause of hemiparetic cerebral palsy (CP). We have shown non-invasive brain stimulation enhances motor learning in healthy and hemiparetic children using transcranial-direct-current-stimulation (tDCS). High-definition (HD-tDCS) may offer additional potential but is unstudied in pediatrics. Motor maps are individualized representations of primary motor cortex (M1) topography measurable with single pulse TMS. Advances in MRI-guided imaging and robotic TMS may facilitate rapid and accurate motor mapping. How motor maps are altered by motor learning and tDCS are unknown. We aimed to determine the effects of tDCS/HD-tDCS enhanced motor learning on motor maps in children, hypothesizing tDCS-enhanced learning is associated with motor map enlargement. Methods AMPED (Accelerated Motor learning in PEDiatrics) is a randomized, sham-controlled trial (NCT03193580). Participants are healthy, right handed children aged 12–18 years. TMS motor mapping is performed using neuronavigated (Brainisght2), robotic (Axilum) TMS. A 10 × 10, 7 mm grid is placed over M1 with 4 stimulations per point generating motor evoked potentials (MEP) of individual hand muscles. Primary outcome is motor map area (volume, center of gravity, cortical excitability are secondary). Motor function is assessed with Purdue Pegboard (primary), Jebsen-Taylor Test, and Serial Reaction Time Task. Participants are randomized into three groups: right M1 1 mA tDCS, HD-tDCS, or sham. All practiced the PPT daily (8 trails) during stimulation with the left hand for 5 consecutive days. Safety and tolerability is assessed daily. All outcomes are repeated on day 5 and at 6 weeks. Two-way repeated measure ANOVA examined changes in performance and motor maps across groups and sessions. Results Fifteen of 24 participants have completed the study (median age 16.4, 67% female). Blinded interim analysis grouped interventions as A, B, or C. PPT scores improved across all groups (p < 0.001) mean improvement was 3.93(SD:1.3) and comparable across groups: A 4.3(SD 1.7), B 3.1(SD 1.2), C 3.7(SD 1.2). Motor maps were obtained without complication except two subjects could not complete bi-hemispheric mapping due to time constraints. Motor map outcomes differed at baseline between hemispheres −109.31 mm 2 (SD 675.46). Following intervention, map area decreased in group C(−147 ± 65.7), p < 0.04) but change in area was not different between groups. Similar findings were observed for secondary outcomes. Procedures were well tolerated with no adverse events. Conclusion Trials combining tDCS or HD-tDCS enhanced motor learning with robotic TMS motor mapping are feasible in children. Completion of the sample will determine how HD-tDCS enhancement of motor learning compares to tDCS, with potential to advance therapeutic applications in children with CP. [ABSTRACT FROM AUTHOR]