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Objective . To develop consensus recommendations for the use of repetitive transcranial magnetic stimulation (rTMS) as an adjunct intervention for upper extremity motor recovery in stroke rehabilitation clinical trials. Participants . The Canadian Platform for Trials in Non-Invasive Brain Stimulation (CanStim) convened a multidisciplinary team of clinicians and researchers from institutions across Canada to form the CanStim Consensus Expert Working Group. Consensus Process . Four consensus themes were identified: (1) patient population, (2) rehabilitation interventions, (3) outcome measures, and (4) stimulation parameters. Theme leaders conducted comprehensive evidence reviews for each theme, and during a 2-day Consensus Meeting, the Expert Working Group used a weighted dot-voting consensus procedure to achieve consensus on recommendations for the use of rTMS as an adjunct intervention in motor stroke recovery rehabilitation clinical trials. Results . Based on best available evidence, consensus was achieved for recommendations identifying the target poststroke population, rehabilitation intervention, objective and subjective outcomes, and specific rTMS parameters for rehabilitation trials evaluating the efficacy of rTMS as an adjunct therapy for upper extremity motor stroke recovery. Conclusions . The establishment of the CanStim platform and development of these consensus recommendations is a first step toward the translation of noninvasive brain stimulation technologies from the laboratory to clinic to enhance stroke recovery.

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.

Introduction: Mild traumatic brain injury (mTBI) outcomes are variable, and 10-15% may suffer from prolonged symptoms beyond 3 months that impair the child's return to normal activities. Neurophysiological mechanisms of mTBI are incompletely understood, particularly in children, but alterations in cortical excitability have been proposed to underlie post-concussion syndrome. Improved understanding is required to advance interventions and improve outcomes., Objective/hypothesis: To determine if cortical excitability is altered in children with mTBI, and its association with clinical symptoms., Methods: This was a cross-sectional controlled cohort study. School-aged children (8-18 years) with mTBI were compared to healthy controls. Cortical excitability was measured using multiple TMS paradigms in children with (symptomatic) and without (recovered) persistent symptoms one-month post-injury. Primary outcome was the cortical silent period (cSP), a potential neurophysiological biomarker of GABAergic inhibition. Secondary outcomes included additional TMS neurophysiology, safety and tolerability. Associations between neurophysiology parameters and clinical symptoms were evaluated., Results: Fifty-three children with mTBI (55% male; mean age 14.1 SD: 2.4 years; 35 symptomatic and 27 asymptomatic participants) and 28 controls (46% male; mean age 14.3 SD: 3.1 years) were enrolled. cSP duration was similar between groups (F (2, 73) = 0.55, p = 0.582). Log 10 long interval intracortical inhibition (LICI) was reduced in symptomatic participants compared to healthy controls (F (2, 59) = 3.83, p = 0.027). Procedures were well tolerated with no serious adverse events., Conclusions: TMS measures of cortical excitability are altered at one month in children with mTBI. Long interval cortical inhibition is decreased in children who remain symptomatic at one month post-injury., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Expressive dysphasia accompanies left inferior frontal gyrus (IFG/Broca) injury. Recovery may relate to interhemispheric balance with homologous, contralesional IFG but is unexplored in children. We evaluated effects of inhibitory rTMS to contralesional IFG combined with intensive speech therapy (SLT). A 15year-old, right-handed male incurred a left middle cerebral artery stroke. After 30months, severe non-fluent dysphasia impacted quality of life. Language networks, neuronal metabolism and white matter pathways were explored using MRI. Language function was measured longitudinally. An intensive SLT program was combined with contralesional inhibitory rTMS of right pars triangularis. Procedures were well tolerated. Language function improved persisting to four months. Post-treatment fMRI demonstrated increased left perilesional IFG activations and connectivity at rest. Bilateral changes in inositol and glutamate metabolism were observed. Contralesional, inhibitory rTMS appears safe in childhood stroke-induced dysphasia. We observed clinically significant improvements after SLT coupled with rTMS. Advanced neuroimaging can evaluate intervention-induced plasticity., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: To determine whether the addition of repetitive transcranial magnetic stimulation (rTMS) and/or constraint-induced movement therapy (CIMT) to intensive therapy increases motor function in children with perinatal stroke and hemiparesis., Methods: A factorial-design, blinded, randomized controlled trial (clinicaltrials.gov/NCT01189058) assessed rTMS and CIMT effects in hemiparetic children (aged 6-19 years) with MRI-confirmed perinatal stroke. All completed a 2-week, goal-directed, peer-supported motor learning camp randomized to daily rTMS, CIMT, both, or neither. Primary outcomes were the Assisting Hand Assessment and the Canadian Occupational Performance Measure at baseline, and 1 week, 2 and 6 months postintervention. Outcome assessors were blinded to treatment. Interim safety analyses occurred after 12 and 24 participants. Intention-to-treat analysis examined treatment effects over time (linear mixed effects model)., Results: All 45 participants completed the trial. Addition of rTMS, CIMT, or both doubled the chances of clinically significant improvement. Assisting Hand Assessment gains at 6 months were additive and largest with rTMS + CIMT (β coefficient = 5.54 [2.57-8.51], p = 0.0004). The camp alone produced large improvements in Canadian Occupational Performance Measure scores, maximal at 6 months (Cohen d = 1.6, p = 0.002). Quality-of-life scores improved. Interventions were well tolerated and safe with no decrease in function of either hand., Conclusions: Hemiparetic children participating in intensive, psychosocial rehabilitation programs can achieve sustained functional gains. Addition of CIMT and rTMS increases the chances of improvement., Classification of Evidence: This study provides Class II evidence that combined rTMS and CIMT enhance therapy-induced functional motor gains in children with stroke-induced hemiparetic cerebral palsy., (© 2016 American Academy of Neurology.)

Objective: We hypothesized an increase in dorsolateral prefrontal cortex (DLPFC) glutamate levels would occur after 3 weeks of repetitive transcranial magnetic stimulation (rTMS) treatment and a decrease in major depressive disorder (MDD) symptoms., Methods: We report 6 patients (4 females) 15 to 21 years of age with treatment-resistant MDD. Participants had a mean (SD) age of 18.7 (1.95) years and a mean (SD) IQ of 102.3 (3.39). Short echo proton magnetic resonance spectroscopy (¹H-MRS) was used to quantify glutamate levels in the left DLPFC (4.5 cc) before and after rTMS treatment. Repetitive transcranial magnetic stimulation was localized to the left DLPFC and applied for 15 consecutive weekdays (120% resting motor threshold; 40 pulses over 4 seconds [10 Hz]; intertrain interval, 26 seconds; 75 trains; 3000 pulses). Treatment response was defined as a greater than 50% reduction in Hamilton Depression Rating Scale scores. Short echo proton magnetic resonance spectroscopy data were analyzed with LCModel to determine glutamate concentration., Results: After rTMS, treatment responders (n = 4) showed an increase (relative to baseline) in left DLPFC glutamate levels (11%), which corresponded to an improvement in depressive symptom severity (68% Hamilton Depression Rating Scale score reduction). Treatment nonresponders (n = 2) had elevated baseline glutamate levels compared to responders in that same region, which decreased with rTMS (-10%). Procedures were generally well tolerated with no adverse events., Conclusions: Repetitive transcranial magnetic stimulation is feasible and possibly efficacious in adolescents with MDD. In responders, rTMS may act by induced elevations in elevating DFPLC glutamate levels in the left DLPFC, thereby leading to symptom improvement.

The permanent nature of motor deficits is a consistent cornerstone of cerebral palsy definitions. Such pessimism is disheartening to children, families, and researchers alike and may no longer be appropriate for it ignores the fantastic plastic potential of the developing brain. Perinatal stroke is presented as the ideal human model of developmental neuroplasticity following distinct, well-defined, focal perinatal brain injury. Elegant animal models are merging with human applied technology methods, including noninvasive brain stimulation for increasingly sophisticated models of plastic motor development following perinatal stroke. In this article, how potential central therapeutic targets are identified and potentially modulated to enhance motor function within these models is discussed. Also, future directions and emerging clinical trials are reviewed., (Copyright © 2013 Elsevier Inc. All rights reserved.)

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: Neurovascular compression (NVC) may cause cranial mononeuropathy but lacks a definitive diagnostic investigation. We hypothesized that the arterial pressure wave (APW) would interact at the neurovascular interface in NVC to inhibit transmission of transcranial magnetic stimulation (TMS) stimuli to affected muscles., Methods: We report a novel neurophysiological method coupling cardiovascular physiology with TMS. The electrocardiogram (ECG) and arterial pressure wave (APW) were coupled to triggering of cortical TMS in a patient with NVC-induced spinal accessory (CNXI) mononeuropathy. Outcome measures included motor evoked potential (MEP) amplitudes and firing probabilities of normal and affected trapezieus (TPZ). Values at intervals in proximity to the APW (40/80/120/160 ms) were compared to baseline (800 ms) using ANOVA and student t-test., Results: Electrocardiogram triggered TMS of CNXI pathways with 100% reliability. MEP amplitudes were decreased in proximity to the APW, particularly at 120 ms (0.21-0.04 mV versus 0.39 +/- 0.10 mV, p=0.003). TPZ firing probabilities were similarly inhibited (43.8% versus 88.2%, p=0.009). No effect of APW proximity was observed on the unaffected side (p=0.868). Procedures were well tolerated., Conclusions: Vascular compression causes CNXI mononeuropathy. Transcranial magnetic stimulation-cardiovascular coupling may evaluate neurovascular junction interactions and non-invasively diagnose NVC.

Pediatric applications of transcranial magnetic stimulation are rapidly expanding, but lack the safety data established for adults. Transcranial magnetic stimulation-induced neurocardiogenic syncope may represent an age-dependent adverse event that is essentially undescribed in the transcranial magnetic stimulation literature. We report on 2 adolescents (of 10 children studied) with transcranial magnetic stimulation-related neurocardiogenic syncope, identify modifiable risk factors, and suggest measures to improve the safety of future pediatric transcranial magnetic stimulation studies.

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.

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Perinatal stroke causes hemiparetic cerebral palsy (HCP) and lifelong disability. Constraint-induced movement therapy (CIMT) and neurostimulation may enhance motor function, but the individual factors associated with responsiveness are undetermined. We explored the clinical and neurophysiological factors associated with responsiveness to CIMT and/or brain stimulation within a clinical trial. PLASTIC CHAMPS was a randomized, blinded, sham-controlled trial (n = 45) of CIMT and neurostimulation paired with intensive, goal-directed therapy. Primary outcome was the Assisting Hand Assessment (AHA). Classification trees created through recursive partitioning suggested clinical and neurophysiological profiles associated with improvement at 6-months. Both clinical (stroke side (left) and age >14 years) and neurophysiological (intracortical inhibition/facilitation and motor threshold) were associated with responsiveness across treatment groups with positive predictive values (PPV) approaching 80%. This preliminary analysis suggested sets of variables that may be associated with response to intensive therapies in HCP. Further modeling in larger trials is required. [ABSTRACT FROM AUTHOR]

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]

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. [ABSTRACT FROM AUTHOR]

Aim: To explore relationships between category classifications for children's rehabilitation goals, outcomes, and participant characteristics. Method: Children with hemiparetic cerebral palsy due to perinatal stroke rated self‐selected goals with the Canadian Occupational Performance Measure (COPM) and completed the Assisting Hand Assessment (AHA) and Box and Block Test (BBT), at baseline and 6 months, in a randomized, controlled 10‐day neuromodulation rehabilitation trial using repetitive transcranial magnetic stimulation. Goals were classified with the Canadian Model of Occupational Performance and Engagement and the International Classification of Functioning, Disability and Health. Analysis included standard linear regression. Results: Data for 45 participants (mean age 11y 7mo, SD 3y 10mo, range 6–19y, 29 males, 16 females) on 186 goals were included. Self‐care goal percentage corresponded with baseline BBT by age (standardized ß=–0.561, p=0.004). Leisure goal percentage corresponded with baseline BBT (standardized ß=0.419, p=0.010). AHA change corresponded with productivity goals (standardized ß=0.327, p=0.029) and age (standardized ß=0.481, p=0.002). COPM change corresponded with baseline COPM and age by AHA change (p<0.05). Interpretation: Younger children with lower motor function were more likely to select self‐care goals while those with better function tended to select leisure goals. Functional improvement corresponded with older age and productivity goals. COPM change scores reflected functional improvement among older children. Children chose functionally and developmentally appropriate goals. Consequently, children should be free to set goals that matter to them. What this paper adds: Children in a brain stimulation trial chose divergent upper extremity functional goals.Younger children with lower ability chose more self‐care goals.Children with higher ability chose more leisure goals.Older children's goal ratings reflected objective functional motor gains.Children chose goals appropriate to their function and level of development. What this paper adds: Children in a brain stimulation trial chose divergent upper extremity functional goals.Younger children with lower ability chose more self‐care goals.Children with higher ability chose more leisure goals.Older children's goal ratings reflected objective functional motor gains.Children chose goals appropriate to their function and level of development. [ABSTRACT FROM AUTHOR]

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. [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]

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Introduction: Symptoms following a mild traumatic brain injury (mTBI) usually resolve quickly but may persist past 3 months in up to 15% of children. Mechanisms of mTBI recovery are poorly understood, but may involve alterations in cortical neurophysiology. Transcranial Magnetic Stimulation (TMS) can non-invasively investigate such mechanisms, but the time course of neurophysiological changes in mTBI are unknown. Objective/Hypothesis: To determine the relationship between persistent post-concussive symptoms (PPCS) and altered motor cortex neurophysiology over time. Methods: This was a prospective, longitudinal, controlled cohort study comparing children (8–18 years) with mTBI (symptomatic vs. asymptomatic) groups to controls. Cortical excitability was measured using TMS paradigms at 1 and 2 months post injury. The primary outcome was the cortical silent period (cSP). Secondary outcomes included short interval intracortical inhibition (SICI) and facilitation (SICF), and long-interval cortical inhibition (LICI). Generalized linear mixed model analyses were used to evaluate the effect of group and time on neurophysiological parameters. Results: One hundred seven participants (median age 15.1, 57% female) including 78 (73%) with symptomatic PPCS and 29 with asymptomatic mTBI, were compared to 26 controls. Cortical inhibition (cSP and SICI) was reduced in the symptomatic group compared to asymptomatic group and tended to increase over time. Measures of cortical facilitation (SICF and ICF) were increased in the asymptomatic group and decreased over time. TMS was well tolerated with no serious adverse events. Conclusions: TMS-assessed cortical excitability is altered in children following mild TBI and is dependent on recovery trajectory. Our findings support delayed return to contact sports in children even where clinical symptoms have resolved. [ABSTRACT FROM AUTHOR]

Background: Major depressive disorder (MDD) is common in youth and treatment options are limited. We evaluated the effectiveness and safety of repetitive transcranial magnetic stimulation (rTMS) in adolescents and transitional aged youth with treatment resistant MDD. Methods: Thirty-two outpatients with moderate to severe, treatment-resistant MDD, aged 13–21 years underwent a three-week, open-label, single center trial of rTMS (ClinicalTrials.gov identifier NCT01731678). rTMS was applied to the left dorsolateral prefrontal cortex (DLPFC) using neuronavigation and administered for 15 consecutive week days (120% rest motor threshold; 40 pulses over 4 s [10 Hz]; inter-train interval, 26 s; 75 trains; 3,000 pulses). The primary outcome measure was change in the Hamilton Depression Rating Scale (Ham-D). Treatment response was defined as a >50% reduction in Ham-D scores. Safety and tolerability were also examined. Results: rTMS was effective in reducing MDD symptom severity (t = 8.94, df = 31, p < 0.00001). We observed 18 (56%) responders (≥ 50% reduction in Ham-D score) and 14 non-responders to rTMS. Fourteen subjects (44%) achieved remission (Ham-D score ≤ 7 post-rTMS). There were no serious adverse events (i.e., seizures). Mild to moderate, self-limiting headaches (19%) and mild neck pain (16%) were reported. Participants ranked rTMS as highly tolerable. The retention rate was 91% and compliance rate (completing all study events) was 99%. Conclusions: Our single center, open trial suggests that rTMS is a safe and effective treatment for youth with treatment resistant MDD. Larger randomized controlled trials are needed. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT01731678 [ABSTRACT FROM AUTHOR]

Applications of non-invasive brain stimulation including therapeutic neuromodulation are expanding at an alarming rate. Increasingly established scientific principles, including directional modulation of well-informed cortical targets, are advancing clinical trial development. However, high levels of disease burden coupled with zealous enthusiasm may be getting ahead of rational research and evidence. Experience is limited in the developing brain where additional issues must be considered. Properly designed and meticulously executed clinical trials are essential and required to advance and optimize the potential of non-invasive neuromodulation without risking the well-being of children and families. Perinatal stroke causes most hemiplegic cerebral palsy and, as a focal injury of defined timing in an otherwise healthy brain, is an ideal human model of developmental plasticity. Advanced models of how the motor systems of young brains develop following early stroke are affording novel windows of opportunity for neuromodulation clinical trials, possibly directing neuroplasticity toward better outcomes. Reviewing the principles of clinical trial design relevant to neuromodulation and using perinatal stroke as a model, this article reviews the current and future issues of advancing such trials in children. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Transcranial direct current stimulation (tDCS) has been investigated mainly in adults and doses may not be appropriate in pediatric applications. In perinatal stroke where potential applications are promising, rational adaptation of dosage for children remains under investigation. Objective: Construct child-specific tDCS dosing parameters through case study within a perinatal stroke tDCS safety and feasibility trial. Methods: 10-year-old subject with a diagnosis of presumed perinatal ischemic stroke and hemiparesis was identified. T1 magnetic resonance imaging (MRI) scans used to derive computerized model for current flow and electrode positions. Workflow using modeling results and consideration of dosage in previous clinical trials was incorporated. Prior ad hoc adult montages vs. de novo optimized montages provided distinct risk benefit analysis. Approximating adult dose required consideration of changes in both peak brain current flow and distribution which further tradeoff between maximizing efficacy and adding safety factors. Electrode size, position, current intensity, compliance voltage, and duration were controlled independently in this process. Results: Brain electric fields modeled and compared to values previously predicted models (Datta et al., 2011; Minhas et al., 2012). Approximating conservative brain current flow patterns and intensities used in previous adult trials for comparable indications, the optimal current intensity established was 0.7 mA for 10 min with a tDCS C3/C4 montage. Specifically 0.7 mA produced comparable peak brain current intensity of an average adult receiving 1.0 mA. Electrode size of 5 × 7 cm² with 1.0 mA and low-voltage tDCS was employed to maximize tolerability. Safety and feasibility confirmed with subject tolerating the session well and no serious adverse events. [ABSTRACT FROM AUTHOR]

Abstract: Perinatal stroke is presented as the ideal human model of developmental neuroplasticity. The precise timing, mechanisms, and locations of specific perinatal stroke diseases provide common examples of well defined, focal, perinatal brain injuries. Motor disability (hemiparetic cerebral palsy) constitutes the primary adverse outcome and the focus of models explaining how motor systems develop in health and after early injury. Combining basic science animal work with human applied technology (functional magnetic resonance imaging, diffusion tensor imaging, and transcranial magnetic stimulation), a model of plastic motor development after perinatal stroke is presented. Potential central therapeutic targets are revealed. The means to measure and modulate these targets, including evidence-based rehabilitation therapies and noninvasive brain stimulation, are suggested. Implications for clinical trials and future directions are discussed. [Copyright &y& Elsevier]

• Combination of 1 Hz rTMS to right IFG together with M−MAT for chronic stroke with aphasia is feasible. • Both sham and rTMS groups showed significant overall improvements in performance. • Large scale trials are warranted to determine efficacy of rTMS plus M−MAT relative to M−MAT alone. • Considerations for future trial methodology and participant selection are offered. Repetitive transcranial magnetic stimulation (rTMS) shows promise in improving speech production in post-stroke aphasia. Limited evidence suggests pairing rTMS with speech therapy may result in greater improvements. Twenty stroke survivors (>6 months post-stroke) were randomized to receive either sham rTMS plus multi-modality aphasia therapy (M−MAT) or rTMS plus M−MAT. For the first time, we demonstrate that rTMS combined with M−MAT is feasible, with zero adverse events and minimal attrition. Both groups improved significantly over time on all speech and language outcomes. However, improvements did not differ between rTMS or sham. We found that rTMS and sham groups differed in lesion location, which may explain speech and language outcomes as well as unique patterns of BOLD signal change within each group. We offer practical considerations for future studies and conclude that while combination therapy of rTMS plus M−MAT in chronic post-stroke aphasia is safe and feasible, personalized intervention may be necessary. [ABSTRACT FROM AUTHOR]

Summary 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Introduction Non-invasive brain stimulation can interrogate neurophysiology and therapeutically modulate brain function. Transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) are the primary modalities. Despite such potential, experience in the developing brain has been limited. We conducted a large, prospective study of children undergoing brain stimulation to determine safety and tolerability across diverse modalities and populations. Methods Our academic pediatric center established a non-invasive brain stimulation laboratory for children in 2008. Multi-disciplinary neurophysiological studies included single- and paired-pulse TMS methods. Therapeutic clinical trials used repetitive TMS (rTMS) and anodal/cathodal standard and high definition (HD) tDCS. Motor mapping used robotic TMS (Axilium). Prospective, standardized safety and tolerability data was obtained on all subjects including a pediatric TMS measure and child and parental interviews. Results From 2008 to 2017, 390 children underwent brain stimulation (median 13.2 years, range 0.7–18). Most common were perinatal stroke/cerebral palsy (80), typically developing (80), and mild traumatic brain injury (73). There were no serious adverse events. Tolerability between single and paired-pulse TMS (459,240 stimulations) and rTMS (2.6 million stimulations) was comparable and rated similar to a long car ride. Even though >100 participants had brain injuries and/or epilepsy, no seizures occurred. Headache following a long TMS neurophysiology protocol was more common in perinatal stroke (40%) than typically developing (13%) participants but was mild and self-limiting. Mild neck pain was reported but comparable between perinatal stroke (22%), depression (19%), and TBI (19%). Tolerability improved over time with rates of all symptoms decreasing by >50% on repeat testing. One of 40 adolescents with depression withdrew from a high-frequency rTMS trial due to discomfort. Following robotic TMS motor mapping, headache was reported by 11%, 20% and 50% of typically developing, perinatal stroke and Tourette syndrome participants. Neck pain appeared to be more common with robotic TMS compared to manual TMS in typically developing children (33% vs 3%). Mean tolerability scores for robotic TMS (4.3 ± 1.5) were comparable to manual TMS (4.2 ± 1.3). Of 65 children receiving tDCS and 9 receiving HD-tDCS, scalp itching in 55% was mild, transient, and comparable to sham. Sensation and tolerability between tDCS and HD-tDCS was comparable. There were no reports of disease-specific outcomes worsening with stimulation. For example, neither low frequency rTMS ( n  = 45) nor cathodal tDCS ( n  = 33) of the non-lesioned motor cortex decreased function of either hand in children with hemiparetic cerebral palsy. Conclusion Non-invasive brain stimulation is safe and well tolerated in children and should be considered minimal risk. Applications in the developing brain should be advanced. [ABSTRACT FROM AUTHOR]