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Transcranial magnetic stimulation (TMS) motor mapping is a safe, non-invasive method used to study corticomotor organization and intervention-induced plasticity. Reliability of resting maps is well established, but understudied for active maps and unestablished for active maps obtained using robotic TMS techniques. The objective of  this study was to determine the reliability of robotic neuro-navigated TMS motor map measures during active muscle contraction. We hypothesized that map area and volume would show excellent short- and medium-term reliability. Twenty healthy adults were tested on 3 days. Active maps of the first dorsal interosseous muscle were created using a 12 × 12 grid (7 mm spacing). Short- (24 h) and medium-term (3-5 weeks) relative (intra-class correlation coefficient) and absolute (minimal detectable change (MDC); standard error of measure) reliabilities were evaluated for map area, volume, center of gravity (CoG), and hotspot magnitude (peak-to-peak MEP amplitude at the hotspot), along with active motor threshold (AMT) and maximum voluntary contraction (MVC). This study found that AMT and MVC had good-to-excellent short- and medium-term reliability. Map CoG (x and y) were the most reliable map measures across sessions with excellent short- and medium-term reliability (p < 0.001). Map area, hotspot magnitude, and map volume followed with better reliability medium-term than short-term, with a change of 28%, 62%, and 78% needed to detect a true medium-term change, respectively. Therefore, robot-guided neuro-navigated TMS active mapping is relatively reliable but varies across measures. This, and MDC, should be considered in interventional study designs., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Brain stimulation combined with intensive therapy may improve hand function in children with perinatal stroke-induced unilateral cerebral palsy (UCP). However, response to therapy varies and underlying neuroplasticity mechanisms remain unclear. Here, we aimed to characterize robotic motor mapping outcomes in children with UCP. Twenty-nine children with perinatal stroke and UCP (median age 11 ± 2 years) were compared to 24 typically developing controls (TDC). Robotic, neuronavigated transcranial magnetic stimulation was employed to define bilateral motor maps including area, volume, and peak motor evoked potential (MEP). Map outcomes were compared to the primary clinical outcome of the Jebsen-Taylor Test of Hand Function (JTT). Maps were reliably obtained in the contralesional motor cortex (24/29) but challenging in the lesioned hemisphere (5/29). Within the contralesional M1 of participants with UCP, area and peak MEP amplitude of the unaffected map were larger than the affected map. When comparing bilateral maps within the contralesional M1 in children with UCP to that of TDC, only peak MEP amplitudes were different, being smaller for the affected hand as compared to TDC. We observed correlations between the unaffected map when stimulating the contralesional M1 and function of the unaffected hand. Robotic motor mapping can characterize motor cortex neurophysiology in children with perinatal stroke. Map area and peak MEP amplitude may represent discrete biomarkers of developmental plasticity in the contralesional M1. Correlations between map metrics and hand function suggest clinical relevance and utility in studies of interventional plasticity., (© 2022 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Background: Although much is known about cognitive dysfunction in attention-deficit/hyperactivity disorder (ADHD), few studies have examined the pathophysiology of disordered motor circuitry. We explored differences in neurometabolite levels and transcranial magnetic stimulation (TMS)-derived corticomotor representations among children with ADHD and typically developing children., Methods: We used magnetic resonance spectroscopy (MRS) protocols to measure excitatory (glutamate + glutamine [Glx]) and inhibitory (γ-aminobutyric acid [GABA]) neurometabolite levels in the dominant primary motor cortex (M1) and the supplementary motor area (SMA) in children with ADHD and typically developing children. We used robotic neuronavigated TMS to measure corticospinal excitability and create corticomotor maps., Results: We collected data from 26 medication-free children with ADHD (aged 7-16 years) and 25 typically developing children (11-16 years). Children with ADHD had lower M1 Glx ( p = 0.044, d = 0.6); their mean resting motor threshold was lower ( p = 0.029, d = 0.8); their map area was smaller ( p = 0.044, d = 0.7); and their hotspot density was higher ( p = 0.008, d = 0.9). M1 GABA levels were associated with motor map area ( p = 0.036). Limitations: Some TMS data were lost because the threshold of some children exceeded 100% of the machine output. The relatively large MRS voxel required to obtain sufficient signal-to-noise ratio and reliably measure GABA levels encompassed tissue beyond the M1, making this measure less anatomically specific., Conclusion: The neurochemistry and neurophysiology of key nodes in the motor network may be altered in children with ADHD, and the differences appear to be related to each other. These findings suggest potentially novel neuropharmacological and neuromodulatory targets for ADHD., Competing Interests: Competing interests: A. Kirton reports grants or contracts from the Canadian Institutes for Health Research, Alberta Innovates, the Cerebral Palsy Alliance Research Foundation and the Kids Brain Health Network; participation on an advisory board for the PumpKin trial; and membership on the board of the International Pediatric Stroke Organization. No other competing interests were declared., (© 2022 CMA Impact Inc. or its licensors.)

Transcranial magnetic stimulation (TMS) motor mapping is a safe, non-invasive method that can be used to study corticomotor organization. Motor maps are typically acquired at rest, and comparisons to maps obtained during muscle activation have been both limited and contradictory. Understanding the relationship between functional activation of the corticomotor system as recorded by motor mapping is crucial for their use clinically and in research. The present study utilized robotic TMS paired with personalized neuro-navigation to examine the relationship between resting and active motor map measures and their relationship with motor performance. Twenty healthy right-handed participants underwent resting and active robotic TMS motor mapping of the first dorsal interosseous to 10% maximum voluntary contraction. Motor map parameters including map area, volume, and measures of map centrality were compared between techniques using paired sample tests of difference and Bland-Altman plots and analysis. Map area, volume, and hotspot magnitude were larger in the active motor maps, while map center of gravity and hotspot locations remained consistent between both maps. No associations were observed between motor maps and motor performance as measured by the Purdue Pegboard Test. Our findings support previous suggestions that maps scale with muscle contraction. Differences in mapping outcomes suggest rest and active motor maps may reflect functionally different corticomotor representations. Advanced analysis methods may better characterize the underlying neurophysiology of both types of motor mapping., (© 2022 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Perinatal stroke occurs early in life and often leads to a permanent, disabling weakness to one side of the body. To test the hypothesis that non-lesioned hemisphere sensorimotor network structural connectivity in children with perinatal stroke is different from controls, we used diffusion imaging and graph theory to explore structural topology between these populations. Children underwent diffusion and anatomical 3T MRI. Whole-brain tractography was constrained using a brain atlas creating an adjacency matrix containing connectivity values. Graph theory metrics including betweenness centrality, clustering coefficient, and both neighbourhood and hierarchical complexity of sensorimotor nodes were compared to controls. Relationships between these connectivity metrics and validated sensorimotor assessments were explored. Eighty-five participants included 27 with venous stroke (mean age = 11.5 ± 3.7 years), 26 with arterial stroke (mean age = 12.7 ± 4.0 years), and 32 controls (mean age = 13.3 ± 3.6 years). Non-lesioned primary motor (M1), somatosensory (S1) and supplementary motor (SMA) areas demonstrated lower betweenness centrality and higher clustering coefficient in stroke groups. Clustering coefficient of M1, S1, and SMA were inversely associated with clinical motor function. Hemispheric betweenness centrality and clustering coefficient were higher in stroke groups compared to controls. Hierarchical and average neighbourhood complexity across the hemisphere were lower in stroke groups. Developmental plasticity alters the connectivity of key nodes within the sensorimotor network of the non-lesioned hemisphere following perinatal stroke and contributes to clinical disability., (© 2022. The Author(s).)

Introduction: Tourette's syndrome (TS) affects approximately 1% of children. This study will determine the efficacy and safety of paired comprehensive behavioural intervention for tics (CBIT) plus repetitive transcranial magnetic stimulation (rTMS) treatment in children with Tourette's syndrome. We hypothesise that CBIT and active rTMS to the supplementary motor area (SMA) will (1) decrease tic severity, and (2) be associated with changes indicative of enhanced neuroplasticity (eg, changes in in vivo metabolite concentrations and TMS neurophysiology measures)., Methods and Analysis: This study will recruit 50 youth with TS, aged 6-18 for a phase II, double-blind, block randomised, sham-controlled trial comparing active rTMS plus CBIT to sham rTMS plus CBIT in a 1:1 ratio. The CBIT protocol is eight sessions over 10 weeks, once a week for 6 weeks and then biweekly. The rTMS protocol is 20 sessions of functional MRI-guided, low-frequency (1 Hz) rTMS targeted to the bilateral SMA over 5 weeks (weeks 2-6). MRI, clinical and motor assessments and neurophysiological evaluations including motor mapping will be performed 1 week before CBIT start, 1 week after rTMS treatment and 1 week after CBIT completion. The primary outcome measure is Tourette's symptom change from baseline to post-CBIT treatment, as measured by the Yale Global Tic Severity Scale. Secondary outcomes include changes in imaging, neurophysiological and behavioural markers., Ethics and Dissemination: Ethical approval by the Conjoint Health Research Ethics Board (REB18-0220). The results of this study will be published in peer-reviewed scientific journals, on ClinicalTrials.gov and shared with the Tourette and OCD Alberta Network. The results will also be disseminated through the Alberta Addictions and Mental Health Research Hub., Trial Registration: NCT03844919., Competing Interests: Competing interests: FM, CKK, RS, AK, TP, GW, EZ, AH, AN-A and SC have no conflicts of interest. PEC has received research grant support from the National Institute of Mental Health, Brain and Behavior Research Foundation and Pfizer. He has received equipment support from Neuonetics and received supplies and genotyping services from Assurex Health for investigator-initiated studies. He is the primary investigator for a multicentre study funded by Neuronetics and a site primary investigator for a study funded by NeoSync. PEC is a consultant for Procter & Gamble Company and Myriad Neuroscience., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aim: To explore the feasibility and possible effects of low-frequency repetitive transcranial magnetic stimulation (rTMS) delivered to the supplementary motor area (SMA) on tic severity and motor system neurophysiology in children with Tourette syndrome., Method: Ten children with Tourette syndrome (eight males, two females; 9-15y) participated in this open-label, phase 1 clinical trial. Treatment consisted of 1800 low-frequency (1Hz) neuronavigated robotic rTMS (100% resting motor threshold) to the SMA, bilaterally for 15 sessions. The primary outcome was a change in Yale Global Tic Severity Scale (YGTSS) total score from baseline to posttreatment. Secondary outcome measures included changes in magnetic resonance spectroscopy metabolite concentrations, TMS neurophysiology measures, TMS motor maps, and clinical assessments (anxiety, depression) from baseline to the end of treatment., Results: The YGTSS score decreased from baseline after treatment (p<0.001; Cohen's d=2.9). All procedures were well-tolerated., Interpretation: Robot-driven, neuronavigated bilateral rTMS of the SMA is feasible in children with Tourette syndrome and appears to reduce tic severity. What this paper adds Repetitive transcranial magnetic stimulation (rTMS) is feasible to use in children with Tourette syndrome. rTMS is tolerated by children with Tourette syndrome. Precise targeting of the supplementary motor area using functional magnetic resonance imaging is also feasible in these children., (© 2021 Mac Keith Press.)

Introduction: Transcranial magnetic stimulation (TMS) motor mapping can characterize the neurophysiology of the motor system. Limitations including human error and the challenges of pediatric populations may be overcome by emerging robotic systems. We aimed to show that neuronavigated robotic motor mapping in adolescents could efficiently produce discrete maps of individual upper extremity muscles, the characteristics of which would correlate with motor behavior., Methods: Typically developing adolescents (TDA) underwent neuronavigated robotic TMS mapping of bilateral motor cortex. Representative maps of first dorsal interosseous (FDI), abductor pollicis brevis (APB), and abductor digiti minimi (ADM) muscles in each hand were created. Map features including area (primary), volume, and center of gravity were analyzed across different excitability regions (R100%, R75%, R50%, R25%). Correlations between map metrics and validated tests of hand motor function (Purdue Pegboard Test as primary) were explored., Results: Twenty-four right-handed participants (range 12-18 years, median 15.5 years, 52% female) completed bilateral mapping and motor assessments with no serious adverse events or dropouts. Gender and age were associated with hand function and motor map characteristics. Full motor maps (R100%) for FDI did not correlate with motor function in either hand. Smaller excitability subset regions demonstrated reduced variance and dose-dependent correlations between primary map variables and motor function in the dominant hemisphere., Conclusions: Hand function in TDA correlates with smaller subset excitability regions of robotic TMS motor map outcomes. Refined motor maps may have less variance and greater potential to quantify interventional neuroplasticity. Robotic TMS mapping is safe and feasible in adolescents., (© 2021 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Robotic transcranial magnetic stimulation (TMS) is a noninvasive and safe tool that produces cortical motor maps using neuronavigational and neuroanatomical images. Motor maps are individualized representations of the primary motor cortex (M1) topography that may reflect developmental and interventional plasticity. Results of TMS motor map reliability testing have been variable, and robotic measures are undefined. We aimed to determine the short- and long-term reliability of robotic TMS motor maps. Twenty healthy participants underwent motor mapping at baseline, 24 h, and 4 wk. A 12 × 12 grid (7-mm spacing) was placed over the left M1, centered over the hand knob area. Four suprathreshold stimulations were delivered at each grid point. First dorsal interosseous (FDI) motor-evoked potentials (MEPs) were analyzed offline to generate map characteristics of area, volume, center of gravity (COG), and hotspot magnitude. Subsets of each outcome corresponding to 75%, 50%, and 25% of each map were determined. Reliability measures including intraclass correlation coefficient (ICC), minimal detectable change (MDC), and standard error of measure (SEM) were calculated. Map volume, COG, and hotspot magnitude were the most reliable measures (good-to-excellent) over both short- and long-term sessions. Map area reliability was poor-to-moderate for short- and long-term sessions. Smaller map percentile subsets showed decreased variability but only minimal improvements in reliability. MDC for most outcomes was >50%. Procedures were well tolerated with no serious adverse events. Robotic TMS motor mapping is relatively reliable over time, but careful consideration of specific outcomes is required for this method to interrogate plasticity in the human motor system. NEW & NOTEWORTHY Robotic transcranial magnetic stimulation (TMS) is a noninvasive and safe tool that produces cortical motor maps-individualized representations of the primary motor cortex (M1) topography-that may reflect developmental and interventional plasticity. This study is the first to evaluate short- and long-term relative and absolute reliability of TMS mapping outcomes at various M1 excitability levels using novel robotic neuronavigated TMS.

Background: Perinatal stroke often leads to lifelong motor impairment. Two common subtypes differ in timing, location, and mechanism of injury: periventricular venous infarcts (PVI) are fetal white matter lesions while most arterial ischemic strokes (AIS) are cortical injuries acquired near term birth. Both alter motor system development and primary motor cortex (M1) plasticity, often with retained ipsilateral corticospinal fibers from the non-lesioned motor cortex (M1')., Methods: Task-based functional magnetic resonance imaging was used to define patterns of motor cortex activity during paretic and unaffected hand movement. Peak coordinates of M1, M1', and the supplementary motor area in the lesioned and intact hemispheres were compared to age-matched controls. Correlations between displacements and clinical motor function were explored., Results: Forty-nine participants included 14 PVI (12.59 ± 3.7 years), 13 AIS (14.91 ± 3.9 years), and 22 controls (13.91 ± 3.4 years). AIS displayed the greatest M1 displacement from controls in the lesioned hemisphere while PVI locations approximated controls. Peak M1' activations were displaced from the canonical hand knob in both PVI and AIS. Extent of M1 and M1' displacement were correlated (r = 0.50, P = 0.025) but were not associated with motor function. Supplementary motor area activity elicited by paretic tapping was displaced in AIS compared to controls (P = 0.003)., Conclusion: Motor network components may be displaced in both hemispheres after perinatal stroke, particularly in AIS and those with ipsilateral control of the affected limb. Modest correlations with clinical function may support that more complex models of developmental plasticity are needed to inform targets for individualized neuromodulatory therapies in children with perinatal stroke., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Transcranial direct current stimulation (tDCS) is a form of non-invasive brain stimulation that safely modulates brain excitability and has therapeutic potential for many conditions. Several studies have shown that anodal tDCS of the primary motor cortex (M1) facilitates motor learning and plasticity, but there is little information about the underlying mechanisms. Using magnetic resonance spectroscopy (MRS), it has been shown that tDCS can affect local levels of γ-aminobutyric acid (GABA) and Glx (a measure of glutamate and glutamine combined) in adults, both of which are known to be associated with skill acquisition and plasticity; however this has yet to be studied in children and adolescents. This study examined GABA and Glx in response to conventional anodal tDCS (a-tDCS) and high definition tDCS (HD-tDCS) targeting the M1 in a pediatric population. Twenty-four typically developing, right-handed children ages 12-18 years participated in five consecutive days of tDCS intervention (sham, a-tDCS or HD-tDCS) targeting the right M1 while training in a fine motor task (Purdue Pegboard Task) with their left hand. Glx and GABA were measured before and after the protocol (at day 5 and 6 weeks) using a PRESS and GABA-edited MEGA-PRESS MRS sequence in the sensorimotor cortices. Glx measured in the left sensorimotor cortex was higher in the HD-tDCS group compared to a-tDCS and sham at 6 weeks (p = 0.001). No changes in GABA were observed in either sensorimotor cortex at any time. These results suggest that neither a-tDCS or HD-tDCS locally affect GABA and Glx in the developing brain and therefore it may demonstrate different responses in adults., Competing Interests: The authors have declared that no competing interests exist.

Mapping the motor cortex with transcranial magnetic stimulation (TMS) has potential to interrogate motor cortex physiology and plasticity but carries unique challenges in children. Similarly, transcranial direct current stimulation (tDCS) can improve motor learning in adults but has only recently been applied to children. The use of tDCS and emerging techniques like high-definition tDCS (HD-tDCS) require special methodological considerations in the developing brain. Robotic TMS motor mapping may confer unique advantages for mapping, particularly in the developing brain. Here, we aim to provide a practical, standardized approach for two integrated methods capable of simultaneously exploring motor cortex modulation and motor maps in children. First, we describe a protocol for robotic TMS motor mapping. Individualized, MRI-navigated 12x12 grids centered on the motor cortex guide a robot to administer single-pulse TMS. Mean motor evoked potential (MEP) amplitudes per grid point are used to generate 3D motor maps of individual hand muscles with outcomes including map area, volume, and center of gravity. Tools to measure safety and tolerability of both methods are also included. Second, we describe the application of both tDCS and HD-tDCS to modulate the motor cortex and motor learning. An experimental training paradigm and sample results are described. These methods will advance the application of non-invasive brain stimulation in children.

Transcranial direct-current stimulation (tDCS) enhances motor learning in adults. We have demonstrated that anodal tDCS and high-definition (HD) tDCS of the motor cortex can enhance motor skill acquisition in children, but behavioral mechanisms remain unknown. Robotics can objectively quantify complex sensorimotor functions to better understand mechanisms of motor learning. We aimed to characterize changes in sensorimotor function induced by tDCS and HD-tDCS paired motor learning in children within an interventional trial. Healthy, right-handed children (12-18 y) were randomized to anodal tDCS, HD-tDCS, or sham targeting the right primary motor cortex during left-hand Purdue pegboard test (PPT) training over five consecutive days. A KINARM robotic protocol quantifying proprioception, kinesthesia, visually guided reaching, and an object hit task was completed at baseline, posttraining, and six weeks later. Effects of the treatment group and training on changes in sensorimotor parameters were explored. Twenty-four children (median 15.5 years, 52% female) completed all measures. Compared to sham, both tDCS and HD-tDCS demonstrated enhanced motor learning with medium effect sizes. At baseline, multiple KINARM measures correlated with PPT performance. Following training, visually guided reaching in all groups was faster and required less corrective movements in the trained arm ( H (2) = 9.250, p = 0.010). Aspects of kinesthesia including initial direction error improved across groups with sustained effects at follow-up ( H (2) = 9.000, p = 0.011). No changes with training or stimulation were observed for position sense. For the object hit task, the HD-tDCS group moved more quickly with the right hand compared to sham at posttraining ( χ 2 (2) = 6.255, p = 0.044). Robotics can quantify complex sensorimotor function within neuromodulator motor learning trials in children. Correlations with PPT performance suggest that KINARM metrics can assess motor learning effects. Understanding how tDCS and HD-tDCS enhance motor learning may be improved with robotic outcomes though specific mechanisms remain to be defined. Exploring mechanisms of neuromodulation may advance therapeutic approaches in children with cerebral palsy and other disabilities.

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.

Background: Stroke is a leading cause of perinatal brain injury with variable outcomes including cerebral palsy and epilepsy. The biological processes that underlie these heterogeneous outcomes are poorly understood. Alterations in developmental myelination are recognized as a major determinant of outcome in preterm brain injury but have not been explored in perinatal stroke. We aimed to characterize myelination in hemiparetic children after arterial perinatal stroke, hypothesizing that ipsilesional myelination would be impaired, the degree of which would correlate with poor outcome., Methods: Retrospective, controlled cohort study. Participants were identified through the Alberta Perinatal Stroke Project (APSP), a population-based research cohort (n > 400). Inclusion criteria were: 1) MRI-confirmed, unilateral arterial perinatal stroke, 2) T1-weighted MRI after 6 months of age, 3) absence of other neurological disorders, 4) neurological outcome that included at least one of the following tests - Pediatric Stroke Outcome Measure (PSOM), Assisting Hand Assessment (AHA), Melbourne Assessment (MA), neuropsychological evaluation (NPE), and robotic sensorimotor measurements. FreeSurfer software measured hemispheric asymmetry in myelination intensity (primary outcome). A second method using ImageJ software validated the detection of myelination asymmetry. A repeated measures ANOVA was used to compare perilesional, ipsilesional remote, and contralesional homologous region myelination between stroke cases and typically developing controls. Myelination metrics were compared to clinical outcome measures ( t -test, Pearson's correlation)., Results: Twenty youth with arterial stroke (mean age: 13.4 ± 4.2yo) and 27 typically developing controls (mean age: 12.5 ± 3.7yo) were studied in FreeSurfer. Participants with stroke demonstrated lower myelination in the ipsilesional hemisphere (p < 0.0001). Myelination in perilesional regions had lower intensity compared to ipsilesional remote areas (p < .00001) and contralesional homologous areas (p < 0.00001). Ipsilesional remote regions had decreased myelination compared to homologous regions on the contralesional hemisphere (p = 0.016). Contralesional myelination was decreased compared to controls (p < 0.00001). Myelination metrics were not strongly associated with clinical motor, robotic sensorimotor, or neuropsychological outcomes though some complex tests requiring speeded responses had moderate effect sizes., Conclusion: Myelination of apparently uninjured brain in both the ipsilesional and contralesional hemispheres is decreased after perinatal stroke. Differences appear to radiate outward from the lesion. Further study is needed to determine clinical significance.

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.

Perinatal stroke causes hemiparetic cerebral palsy and lifelong motor disability. Bilateral motor cortices are key hubs within the motor network and their neurophysiology determines clinical function. Establishing biomarkers of motor cortex function is imperative for developing and evaluating restorative interventional strategies. Proton magnetic resonance spectroscopy (MRS) quantifies metabolite concentrations indicative of underlying neuronal health and metabolism in vivo. We used functional magnetic resonance imaging (MRI)-guided MRS to investigate motor cortex metabolism in children with perinatal stroke. Children aged 6-18 years with MRI-confirmed perinatal stroke and hemiparetic cerebral palsy were recruited from a population-based cohort. Metabolite concentrations were assessed using a PRESS sequence (3T, TE = 30 ms, voxel = 4 cc). Voxel location was guided by functional MRI activations during finger tapping tasks. Spectra were analysed using LCModel. Metabolites were quantified, cerebral spinal fluid corrected and compared between groups (ANCOVA) controlling for age. Associations with clinical motor performance (Assisting Hand, Melbourne, Box-and-Blocks) were assessed. Fifty-two participants were studied (19 arterial, 14 venous, 19 control). Stroke participants demonstrated differences between lesioned and nonlesioned motor cortex N-acetyl-aspartate [NAA mean concentration = 10.8 ± 1.9 vs. 12.0 ± 1.2, P < 0.01], creatine [Cre 8.0 ± 0.9 vs. 7.4 ± 0.9, P < 0.05] and myo-Inositol [Ins 6.5 ± 0.84 vs. 5.8 ± 1.1, P < 0.01]. Lesioned motor cortex NAA and creatine were strongly correlated with motor performance in children with arterial but not venous strokes. Interrogation of motor cortex by fMRI-guided MRS is feasible in children with perinatal stroke. Metabolite differences between hemispheres, stroke types and correlations with motor performance support functional relevance. MRS may be valuable in understanding the neurophysiology of developmental neuroplasticity in cerebral palsy. Hum Brain Mapp 38:1574-1587, 2017. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Objectives: Transcranial magnetic stimulation (TMS) has been used to measure cortical excitability as a functional measurement of corticomotor pathways. Given its potential application as an assessment tool in stroke, we aimed to analyze the correlation of TMS parameters with clinical features in stroke using data from 10 different centers., Methods: Data of 341 patients with a clinical diagnosis of stroke were collected from studies assessing cortical excitability using TMS. We used a multivariate regression model in which the baseline cortical excitability parameter "resting Motor Threshold (rMT)" was the main outcome and the demographic, anatomic and clinical characteristics were included as independent variables., Results: The variable "severity of motor deficit" consistently remained significant in predicting rMT in the affected hemisphere, with a positive β coefficient, in the multivariate models after sensitive analyses and adjusting for important confounders such as site center. Additionally, we found that the correlations between "age" or "time since stroke" and the rMT in the affected hemisphere were significant, as well as the interaction between "time since stroke" and "severity of motor deficit"., Conclusions: We have shown that severity of motor deficit is an important predictor for rMT in the affected hemisphere. Additionally, time since stroke seems to be an effect modifier for the correlation between motor deficit and rMT. In the unaffected motor cortex, these correlations were not significant. We discuss these findings in the context of stroke rehabilitation., (Copyright © 2016. Published by Elsevier SAS.)

Aim: Brain plasticity mechanisms are probably different in children but remain poorly understood. Paired afferent stimulation (PAS) combines peripheral sensory stimulation with transcranial magnetic stimulation (TMS) of primary motor cortex to induce rapid, reversible, topographically specific increases in primary motor cortex excitability suggestive of long-term potentiation in adults. Our aim was to determine frequency, characteristics, age effects, and reproducibility of PAS in school-age children., Method: Typically developing right-handed children (6-18y) were recruited. Median nerve stimulation was delivered 25ms before suprathreshold primary motor cortex stimulation (0.2Hz, 7.5min). Primary outcome was changed in the amplitude of motor evoked potentials (MEPs) at five time points after PAS (0, 15, 30, 45, 75min) expressed as area under the curve. Reproducibility was evaluated. Secondary outcomes included stimulus response curves and safety/tolerability., Results: Of 28 children (20 males, mean age 12y), 64% demonstrated PAS effects (11 definite, seven probable). PAS effects were sustained across all time points to 75min (p=0.004). Stimulus response curve scores increased after PAS (n=9, p=0.02). PAS effect and age were not correlated. PAS was highly reproducible (p=0.925, r=0.283). Tolerability was favorable without adverse events., Interpretation: PAS effects are present and reproducible in children. Pediatric PAS paradigms appear safe and tolerable. PAS may provide insight into endogenous developmental plasticity, informing future studies in children with cerebral palsy and other motor disorders., (© 2015 Mac Keith Press.)

Objective: Arterial ischemic stroke (AIS) causes disability in children but plastic developmental neurophysiology is unstudied. Imbalance of interhemispheric inhibition (IHI) in adult subcortical stroke is a therapeutic target. We hypothesized that IHI imbalance occurs in childhood AIS and is modifiable by rTMS., Methods: Eligible SickKids Children's Stroke Program patients included children >7years with subcortical AIS (>2years previous) and functional hand impairment. TMS with electromyography over first dorsal interosseous measured baseline motor cortex (M1) rest and 1mV thresholds and stimulus-response curves (100-150%). Paired-pulse TMS studied bidirectional short (SIHI) and long (LIHI) interval IHI. Children were matched for age/weakness and randomized to contralesional inhibitory rTMS or sham (8days) with measures repeated., Results: Ten children (mean 13.9 years) had variable weakness (4 mild/2 moderate/4 severe). Stroke M1 motor thresholds were elevated (75±25% versus 55±14%, p=0.05) and decreased with age. Baseline measures suggested excessive LIHI from non-stroke to stroke side (-46±17% versus -28±23%, p=0.08). Following inhibitory rTMS, increases in stroke side maximal MEP amplitudes were suggested and LIHI from stroke to non-stroke side appeared to increase (-20% to -40%). Procedures were well tolerated., Conclusion: TMS measurement of developmental plastic organization and rTMS interventions are feasible in childhood stroke and IHI imbalance may occur., Significance: Improved understanding of developmental plasticity after childhood stroke will facilitate better rehabilitational therapy., (Copyright © 2010 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

Background: Arterial ischaemic stroke (AIS) can cause disabling hemiparesis in children. We aimed to test whether contralesional, inhibitory repetitive transcranial magnetic stimulation (rTMS) could affect interhemispheric inhibition to improve hand function in chronic subcortical paediatric AIS., Methods: Patients were eligible for this parallel, randomised trial if they were in the SickKids Children's Stroke Program and had subcortical AIS more than 2 years previously, had transcallosal sparing, were more than 7 years of age, had hand motor impairment, had no seizures or dyskinesia, and were taking no drugs that alter cortical excitability. Patients were paired for age and weakness and were randomised within each pair to sham treatment or inhibitory, low-frequency rTMS over contralesional motor cortex (20 min, 1200 stimuli) once per day for 8 days. An occupational therapist did standardised tests of hand function at days 1 (baseline), 5, 10, and 17 (1 week post-treatment), and the primary outcomes were changes in grip strength and the Melbourne assessment of upper extremity function (MAUEF) between baseline and day 10. Patients, parents, and occupational therapists were blinded to treatment allocation. Analysis was per protocol., Findings: Ten patients with paediatric stroke were enrolled (median age 13.25 [IQR 10.08-16.78] years, mean time post-stroke 6.33 [SD 3.56] years): four with mild weakness, two with moderate weakness, and four with severe weakness. A repeated-measures ANOVA showed a significant interaction between time and the effect of treatment on grip strength (p=0.03). At day 10, grip strength was 2.28 (SD 1.01) kg greater than baseline in the rTMS group and 2.92 (1.20) kg less than baseline in the sham group (p=0.009). Benefits in mean grip strength persisted at day 17 (2.63 [0.56] kg greater than baseline with rTMS and 1.00 [0.70] kg less than baseline with sham treatment; p=0.01). Day 10 MAUEF score improved by more in the rTMS group than in the sham group (7.25 [3.8] vs 0.79 [1.3] points greater than baseline; p=0.002), but this benefit did not persist to day 17. Function of the unaffected hand remained stable. rTMS was well tolerated with no serious adverse events., Interpretation: Contralesional inhibitory rTMS was safe and feasible for patients with paediatric subcortical AIS, and seemed to improve hand function in patients with hemiparesis. Further studies are required to confirm the potential role of rTMS in paediatric neurorehabilitation., Funding: Canadian Stroke Consortium; Canadian Institutes of Health Research; American Academy of Neurology Foundation; Alberta Heritage Foundation for Medical Research.

Introduction: Conventional transcranial direct current stimulation (tDCS) and high-definition tDCS (HD-tDCS) may improve motor learning in children. Mechanisms are not understood. Neuronavigated robotic transcranial magnetic stimulation (TMS) can produce individualised maps of primary motor cortex (M1) topography. We aimed to determine the effects of tDCS- and HD-tDCS-enhanced motor learning on motor maps. Methods: Typically developing children aged 12–18 years were randomised to right M1 anodal tDCS, HD-tDCS, or Sham during training of their left-hand on the Purdue Pegboard Task (PPT) over 5 days. Bilateral motor mapping was performed at baseline (pre), day 5 (post), and 6-weeks retention time (RT). Primary muscle was the first dorsal interosseous (FDI) with secondary muscles of abductor pollicis brevis (APB) and adductor digiti minimi (ADM). Primary mapping outcomes were volume (mm2/mV) and area (mm2). Secondary outcomes were centre of gravity (COG, mm) and hotspot magnitude (mV). Linear mixed-effects modelling was employed to investigate effects of time and stimulation type (tDCS, HD-tDCS, Sham) on motor map characteristics. Results: Twenty-four right-handed participants (median age 15.5 years, 52% female) completed the study with no serious adverse events or dropouts. Quality maps could not be obtained in two participants. No effect of time or group were observed on map area or volume. LFDI COG (mm) differed in the medial-lateral plane (x-axis) between tDCS and Sham (p = 0.038) from pre-to-post mapping sessions. Shifts in map COG were also observed for secondary left-hand muscles. Map metrics did not correlate with behavioural changes. Conclusion: Robotic TMS mapping can safely assess motor cortex neurophysiology in children undergoing motor learning and neuromodulation interventions. Large effects on map area and volume were not observed while changes in COG may occur. Larger controlled studies are required to understand the role of motor maps in interventional neuroplasticity in children. [ABSTRACT FROM AUTHOR]

Within the perinatal stroke field, there is a need to establish preclinical models where putative biomarkers for motor function can be examined. In a mouse model of perinatal stroke, we evaluated motor map size and movement latency following optogenetic cortical stimulation against three factors of post-stroke biomarker utility: (1) correlation to chronic impairment on a behavioral test battery; (2) amenability to change using a skilled motor training paradigm; and (3) ability to distinguish individuals with potential to respond well to training. Thy1-ChR2-YFP mice received a photothrombotic stroke at postnatal day 7 and were evaluated on a battery of motor tests between days 59 and 70. Following a cranial window implant, mice underwent longitudinal optogenetic motor mapping both before and after 3 weeks of skilled forelimb training. Map size and movement latency of both hemispheres were positively correlated with impaired spontaneous forelimb use, whereas only ipsilesional hemisphere map size was correlated with performance in skilled reaching. Map size and movement latency did not show groupwise changes with training; however, mice with the smallest pretraining map sizes and worst impairments demonstrated the greatest expansion of map size in response to skilled forelimb training. Overall, motor map size showed utility as a potential biomarker for impairment and training-induced modulation in specific individuals. Future assessment of the predictive capacity of post-stroke motor representations for behavioral outcome in animal models opens the possibility of dissecting how plasticity mechanisms contribute to recovery following perinatal stroke. [ABSTRACT FROM AUTHOR]

Background: Transcranial direct current stimulation (tDCS) has been used extensively in patient populations to facilitate motor network plasticity. However, it has not been studied in patients with brain tumors. We aimed to determine the feasibility of a preoperative motor training and tDCS intervention in patients with glioma. In an exploratory manner, we assessed changes in motor network connectivity following this intervention and related these changes to predicted electrical field strength from the stimulated motor cortex. Methods: Patients with left-sided glioma (n=8) were recruited in an open label proof of concept pilot trial and participated in four consecutive days of motor training combined with tDCS. The motor training consisted of a 60-min period where the subject learned to play the piano with their right hand. Concurrently, they received 40 min of 2 mA anodal tDCS of the left motor cortex. Patients underwent task and resting state fMRI before and after this intervention. Changes in both the connectivity of primary motor cortex (M1) and general connectivity across the brain were assessed. Patient specific finite element models were created and the predicted electrical field (EF) resulting from stimulation was computed. The magnitude of the EF was extracted from left M1 and correlated to the observed changes in functional connectivity. Results: There were no adverse events and all subjects successfully completed the study protocol. Left M1 increased both local and global connectivity. Voxel-wide measures, not constrained by a specific region, revealed increased global connectivity of the frontal pole and decreased global connectivity of the supplementary motor area. The magnitude of EF applied to the left M1 correlated with changes in global connectivity of the right M1. Conclusion: In this proof of concept pilot study, we demonstrate for the first time that tDCS appears to be feasible in glioma patients. In our exploratory analysis, we show preoperative motor training combined with tDCS may alter sensorimotor network connectivity. Patient specific modeling of EF in the presence of tumor may contribute to understanding the dose-response relationship of this intervention. Overall, this suggests the possibility of modulating neural networks in glioma patients. [ABSTRACT FROM AUTHOR]

Background: Non-invasive neuromodulation is an emerging therapy for children with early brain injury but is difficult to apply to preschoolers when windows of developmental plasticity are optimal. Transcranial static magnetic field stimulation (tSMS) decreases primary motor cortex (M1) excitability in adults but effects on the developing brain are unstudied. Objective/Hypothesis: We aimed to determine the effects of tSMS on cortical excitability and motor learning in healthy children. We hypothesized that tSMS over right M1 would reduce cortical excitability and inhibit contralateral motor learning. Methods: This randomized, sham-controlled, double-blinded, three-arm, cross-over trial enrolled 24 healthy children aged 10–18 years. Transcranial Magnetic Stimulation (TMS) assessed cortical excitability via motor-evoked potential (MEP) amplitude and paired pulse measures. Motor learning was assessed via the Purdue Pegboard Test (PPT). A tSMS magnet (677 Newtons) or sham was held over left or right M1 for 30 min while participants trained the non-dominant hand. A linear mixed effect model was used to examine intervention effects. Results: All 72 tSMS sessions were well tolerated without serious adverse effects. Neither cortical excitability as measured by MEPs nor paired-pulse intracortical neurophysiology was altered by tSMS. Possible behavioral effects included contralateral tSMS inhibiting early motor learning (p < 0.01) and ipsilateral tSMS facilitating later stages of motor learning (p < 0.01) in the trained non-dominant hand. Conclusion: tSMS is feasible in pediatric populations. Unlike adults, tSMS did not produce measurable changes in MEP amplitude. Possible effects of M1 tSMS on motor learning require further study. Our findings support further exploration of tSMS neuromodulation in young children with cerebral palsy. [ABSTRACT FROM AUTHOR]

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]