Reliability of active robotic neuro-navigated transcranial magnetic stimulation motor maps.

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.

Robotic mapping of motor cortex in children with perinatal stroke and hemiparesis.

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.

Can Children With Perinatal Stroke Use a Simple Brain Computer Interface?

Background and Purpose: Perinatal stroke is the leading cause of hemiparetic cerebral palsy resulting in lifelong disability for millions of people worldwide. Options for motor rehabilitation are limited, especially for the most severely affected children. Brain computer interfaces (BCIs) sample brain activity to allow users to control external devices. Functional electrical stimulation enhances motor recovery after stroke, and BCI-activated functional electrical stimulation was recently shown to improve upper extremity function in adult stroke. We aimed to determine the ability of children with perinatal stroke to operate a simple BCI. Methods: Twenty-one children with magnetic resonance imaging­confirmed perinatal stroke (57% male, mean [SD] 13.5 [2.6] years, range 9­18) were compared with 24 typically developing controls (71% male, mean age [SD] 13.7 [3.7] years, range 6­18). Participants trained on a simple EEG-based BCI over 2 sessions (10 trials each) utilizing 2 different mental imagery strategies: (1) motor imagery (imagine opening and closing of hands) and (2) goal oriented (imagine effector object moving toward target) to complete 2 tasks: (1) drive a remote controlled car to a target and (2) move a computer cursor to a target. Primary outcome was Cohen Kappa with a score >0.40 suggesting BCI competence. Results: BCI performance was comparable between stroke and control participants. Mean scores were 0.39 (0.18) for stroke versus 0.42 (0.18) for controls (t[42]=0.478, P=0.94). No difference in performance between venous (M=0.45, SD=0.29) and arterial (M=0.34, SD=0.22) stroke (t[82]=1.89, P=0.090) was observed. No effect of task or strategy was observed in the stroke participants. Over 90% of stroke participants demonstrated competency on at least one of the 4 task-strategy combinations. Conclusions: Children with perinatal stroke can achieve proficiency in basic tasks using simple BCI systems. Future directions include exploration of BCI-functional electrical stimulation systems for rehabilitation for children with hemiparesis and other forms of cerebral palsy.

Reliability of robotic transcranial magnetic stimulation motor mapping.

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.

Bilateral transcranial magnetic stimulation of the supplementary motor area in children with Tourette syndrome.

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.

Bilateral actigraphic quantification of upper extremity movement in hemiparetic children with perinatal stroke: a case control study.

BACKGROUND: Hemiparetic cerebral palsy impacts millions of people worldwide. Assessment of bilateral motor function in real life remains a major challenge. We evaluated quantification of upper extremity movement in hemiparetic children using bilateral actigraphy. We hypothesized that movement asymmetry correlates with standard motor outcome measures. METHODS: Hemiparetic and control participants wore bilateral wrist Actiwatch2 (Philips) for 48 h with movement counts recorded in 15-s intervals. The primary outcome was a novel statistic of movement asymmetry, the Actigraphic Movement Asymmetry Index (AMAI). Relationships between AMAI and standard motor outcomes (Assisting Hand Assessment, Melbourne Assessment, and Box and Block Test [BB]) were explored with Pearson or Spearman correlation. RESULTS: 30 stroke (mean 11 years 2 months (3 years 10 months); 13 female, 17 male) and 23 control (mean 11 years 1 month (4 years 5 months); 8 female, 15 male) were enrolled. Stroke participants demonstrated higher asymmetry. Correlations between AMAI and standard tests were moderate and strongest during sleep (BB: r = 0.68, p < 0.01). CONCLUSIONS: Standard tests may not reflect the extent of movement asymmetry during daily life in hemiparetic children. Bilateral actigraphy may be a valuable complementary tool for measuring arm movement, potentially enabling improved evaluation of therapies with a focus on child participation.

Fatigue in children with perinatal stroke: clinical and neurophysiological associations.

AIM: To characterize fatigue in children with hemiparesis with perinatal stroke and explore associations with measures of motor performance and corticospinal excitability. METHOD: Forty-five children (16 females, 29 males), aged 6 to 18 years (mean [SD] 12y [4]), with magnetic resonance imaging-confirmed perinatal stroke participated. Associations between fatigue (Pediatric Quality of Life Inventory Version 3.0 cerebral palsy module fatigue subscale), motor performance (Assisting Hand Assessment [AHA], Box and Blocks Test, grip strength), and excitability of corticospinal projections to both hands were examined using ranked tests of correlation, robust regression, and the Mann-Whitney U test. RESULTS: Nearly half of the participants (n=21) reported experiencing fatigue in the previous month. Function in the less affected hand (Box and Blocks Test, grip strength) was correlated with fatigue scores. Participants with preserved ipsilateral projections to the more affected hand had less fatigue, and scores correlated with the excitability of these projections. Fatigue scores were not associated with age, sex, or AHA score. INTERPRETATION: Fatigue is common in children with hemiparesis with perinatal stroke and is associated with motor performance and the presence and excitability of ipsilateral corticospinal projections from the contralesional hemisphere to the more affected hand. WHAT THIS PAPER ADDS: Fatigue is common in children with hemiparesis with perinatal stroke. Fatigue was associated with motor performance and strength in the less affected, but not the more affected, hand. Fatigue was associated with the presence and excitability of ipsilateral corticospinal projections from the contralesional hemisphere.

Clinician awareness of brain computer interfaces: a Canadian national survey.

BACKGROUND: Individuals with severe neurological disabilities but preserved cognition, including children, are often precluded from connecting with their environments. Brain computer interfaces (BCI) are a potential solution where advancing technologies create new clinical opportunities. We evaluated clinician awareness as a modifiable barrier to progress and identified eligible populations. METHODS: We executed a national, population-based, cross-sectional survey of physician specialists caring for persons with severe disability. An evidence- and experience-based survey had three themes: clinician BCI knowledge, eligible populations, and potential impact. A BCI knowledge index was created and scored. Canadian adult and pediatric neurologists, physiatrists and a subset of developmental pediatricians were contacted. Secure, web-based software administered the survey via email with online data collection. RESULTS: Of 922 valid emails (664 neurologists, 253 physiatrists), 137 (15%) responded. One third estimated that ≥10% of their patients had severe neurological disability with cognitive capacity. BCI knowledge scores were low with > 40% identifying as less than "vaguely aware" and only 15% as "somewhat familiar" or better. Knowledge did not differ across specialties. Only 6 physicians (4%) had patients using BCI. Communication and wheelchair control rated highest for potentially improving quality of life. Most (81%) felt BCI had high potential to improve quality of life. Estimates suggested that > 13,000 Canadians (36 M population) might benefit from BCI technologies. CONCLUSIONS: Despite high potential and thousands of patients who might benefit, BCI awareness among clinicians caring for disabled persons is poor. Further, functional priorities for BCI applications may differ between medical professionals and potential BCI users, perhaps reflecting that clinicians possess a less accurate understanding of the desires and needs of potential end-users. Improving knowledge and engaging both clinicians and patients could facilitate BCI program development to improve patient outcomes.

Mirror movements in children with unilateral cerebral palsy due to perinatal stroke: clinical correlates of plasticity reorganization.

AIM: We aimed to determine if the mirror movements that often result in children with unilateral cerebral palsy (CP) after perinatal stroke represent a clinical biomarker of developmental plasticity. METHOD: This was a prospective, controlled cohort study. Mirror movements in children with unilateral CP from a population-based cohort were compared to those of typically developing controls. The population with stroke was assessed further via electromyography (EMG), motor function, and corticospinal organization investigations. Mirror movements were quantified (0-5) bidirectionally. EMG mirror movements were quantified during voluntary contraction. Motor function was quantified by validated measures including the Assisting Hand Assessment (AHA). Corticospinal organization was categorized as ipsilateral or contralateral using transcranial magnetic stimulation (TMS). The relationships between mirror movements, function, and corticospinal organization were assessed (t-tests, Pearson rank correlation coefficients). RESULTS: Ninety-two participants were scored (55 males, 37 females, mean [SD] 12y [5y 6mo], range 4-17y), 63 with complete motor outcomes and 39 with TMS data. EMG ratios correlated with clinical mirror movements (r=0.562, p=0.008). Mild mirror activity in controls declined with age (r=-0.459, p<0.001). Mirroring was stronger with tasks performed by the affected hand (p<0.001). Mirror movements correlated with AHA scores (r=-0.255, p=0.04) and poor motor outcome (p<0.001). Unaffected hand mirror activity was higher in children with ipsilateral corticospinal tract arrangements (p<0.001). INTERPRETATION: Clinical mirror movements correlate with disability and corticospinal organization in children with unilateral CP with perinatal stroke. This simple bedside biomarker could facilitate patient selection for personalized rehabilitation. WHAT THIS PAPER ADDS: Mirror movements are a clinical indicator of corticospinal organization in children with unilateral cerebral palsy with perinatal stroke. Mirroring is strongest in children with ipsilateral corticospinal tract reorganization. The concept of a 'directionality factor' to mirror movements highlights additional, clinically relevant functional correlations.

MOVIMIENTOS EN ESPEJO EN NIÑOS CON PARÁLISIS CEREBRAL UNILATERAL DEBIDO A UN ACCIDENTE CEREBROVASCULAR PERINATAL: CORRELATOS CLÍNICOS DE REORGANIZACIÓN DE LA PLASTICIDAD: OBJETIVO: Nuestro objetivo fue determinar si los movimientos en espejo que a menudo presentan niños con parálisis cerebral unilateral después de un accidente cerebrovascular perinatal representan un biomarcador clínico de la plasticidad del desarrollo. MÉTODO: Este fue un estudio prospectivo de cohorte controlado. Los movimientos en espejo en niños con parálisis cerebral unilateral de una cohorte basada en la población se compararon con los de los controles. La población con accidente cerebrovascular se evaluó más a fondo mediante electromiografía (EMG), función motora e investigaciones de organización corticoespinal. Los movimientos en espejo se cuantificaron (0-5) bidireccionalmente. Los movimientos en espejo EMG fueron cuantificados durante la contracción voluntaria. La función motora se cuantificó mediante medidas validadas, incluida la Evaluación de la Mano Auxiliar (AHA). La organización corticoespinal se clasificó como ipsilateral o contralateral utilizando estimulación magnética transcraneal (SMT). Se evaluaron las relaciones entre los movimientos de espejo, la función y la organización corticoespinal (pruebas t, coeficientes de correlación de rango de Pearson). RESULTADOS: Noventa y dos participantes fueron calificados (55 masculinos, 37 femeninos, media [DE] 12 años de edad [5 años y 6 meses], rango 4-17 años), 63 con resultados motores completos y 39 con datos de TMS. Las proporciones de EMG se correlacionaron con los movimientos en espejo clínico (r = 0.562, p = 0.008). La actividad del espejo leve en los controles disminuyó con la edad (r = −0.459, p < 0.00001). El reflejo fue más fuerte con las tareas realizadas por la mano afectada (p < 0,001). Los movimientos en espejo se correlacionaron con las puntuaciones del AHA (r = −0.255, p = 0.04) y el resultado motor deficiente (p < 0.001). La actividad en espejo de la mano no afectada fue mayor en niños con disposiciones del tracto corticoespinal ipsilateral (p < 0,001). INTERPRETACIÓN: Los movimientos en espejo clínico se correlacionan con la función motora y la organización corticoespinal en niños con parálisis cerebral unilateral con accidente cerebrovascular perinatal. Este biomarcador simple junto a la cama podría facilitar la selección de pacientes para una rehabilitación personalizada.

MOVIMENTOS EM ESPELHO EM CRIANÇAS COM PARALISIA CEREBRAL UNILATERAL DEVIDO A ACIDENTE VASCULAR CEREBRAL PERINATAL: CORRELATOS CLÍNICOS DA REORGANIZAÇÃO POR PLASTICIDADE: OBJETIVO: Visamos determinar se os movimentos em espelho frequentemente observados em crianças com paralisia cerebral unilateral após acidente vascular cerebral perinatal representam um biomarcardor clínico da plasticidade do desenvolvimento MÉTODO: Tratou-se de um estudo de coorte prospectivo controlado. Movimentos em espelho em crianças com paralisia cerebral unilateral de uma coorte populacional foram comparados com os de controles. A população com acidente vascular cerebral foi adicionalmente avaliada com investigações de eletromiografia (EMG), função motora, e organização córtico-espinhal. Os movimentos em espelho foram quantificados (0-5) bidirecionalmente. Movimentos em espelho ao EMG foram quantificados durante a contração voluntária. A função motora foi quantificada por meio de medidas validadas incluindo a Assisting Hand Assessment (AHA). A organização córtico-espinhal foi categorizada como ipsilateral ou contralateral usando estimulação magnética transcraniana (EMT). As relações entre movimentos em espelho, função, e organização córtico-espinhal foram avaliadas (testes t, coeficientes de correlação de Pearson). RESULTADOS: Noventa e dois participantes foram pontuados (55 do sexo masculino, 37 do sexo feminino, média [DP] 12a [5a 6m], variação 4-17a), 63 com resultados motores completos e 39 com dados de EMT. As razões do EMG se correlacionaram com movimentos em espelho clínicos (r = 0,562, p = 0,008). A atividade em espelho leve nos controles diminuiu com a idade (r = −0,459, p < 0,00001). O espelhamento foi mais forte com tarefas realizadas pela mão afetada (p < 0,001). Movimentos em espelho correlacionaram com escores da AHA (r = -0,255, p = 0,04) e com pobre resultado motor (p < 0,001). Atividade em espelho na mão não afetada foi maior em crianças com arranjos ipsilaterais do trato córtico-espinhal (p < 0,001). INTERPRETAÇÃO: Movimentos em espelho clínicos se corelacionaram com a incapacidade e com a organização córtico-espinhal em crianças com paralisia cerebral unilateral com acidente vascular cerebral perinatal. Este simples biomarcador pode facilitar a seleção de pacientes para reabilitação personalizada.

Developmental profile of motor cortex transcallosal inhibition in children and adolescents.

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.

Long-latency, inhibitory spinal pathway to ankle flexors activated by homonymous group 1 afferents.

Inhibitory feedback from sensory pathways is important for controlling movement. Here, we characterize, for the first time, a long-latency, inhibitory spinal pathway to ankle flexors that is activated by low-threshold homonymous afferents. To examine this inhibitory pathway in uninjured, healthy participants, we suppressed motor-evoked potentials (MEPs), produced in the tibialis anterior (TA), by a prior stimulation to the homonymous common peroneal nerve (CPN). The TA MEP was suppressed by a triple-pulse stimulation to the CPN, applied 40, 50, and 60 ms earlier and at intensities of 0.5-0.7 times motor threshold (average suppression of test MEP was 33%). Whereas the triple-pulse stimulation was below M-wave and H-reflex threshold, it produced a long-latency inhibition of background muscle activity, approximately 65-115 ms after the CPN stimulation, a time period that overlapped with the test MEP. However, not all of the MEP suppression could be accounted for by this decrease in background muscle activity. Evoked responses from direct activation of the corticospinal tract, at the level of the brain stem or thoracic spinal cord, were also suppressed by low-threshold CPN stimulation. Our findings suggest that low-threshold muscle and cutaneous afferents from the CPN activate a long-latency, homonymous spinal inhibitory pathway to TA motoneurons. We propose that inhibitory feedback from spinal networks, activated by low-threshold homonymous afferents, helps regulate the activation of flexor motoneurons by the corticospinal tract.

BCI-activated electrical stimulation in children with perinatal stroke and hemiparesis: A pilot study.

Background: Perinatal stroke (PS) causes most hemiparetic cerebral palsy (CP) and results in lifelong disability. Children with severe hemiparesis have limited rehabilitation options. Brain computer interface- activated functional electrical stimulation (BCI-FES) of target muscles may enhance upper extremity function in hemiparetic adults. We conducted a pilot clinical trial to assess the safety and feasibility of BCI-FES in children with hemiparetic CP. Methods: Thirteen participants (mean age = 12.2 years, 31% female) were recruited from a population-based cohort. Inclusion criteria were: (1) MRI-confirmed PS, (2) disabling hemiparetic CP, (3) age 6-18 years, (4) informed consent/assent. Those with neurological comorbidities or unstable epilepsy were excluded. Participants attended two BCI sessions: training and rehabilitation. They wore an EEG-BCI headset and two forearm extensor stimulation electrodes. Participants' imagination of wrist extension was classified on EEG, after which muscle stimulation and visual feedback were provided when the correct visualization was detected. Results: No serious adverse events or dropouts occurred. The most common complaints were mild headache, headset discomfort and muscle fatigue. Children ranked the experience as comparable to a long car ride and none reported as unpleasant. Sessions lasted a mean of 87 min with 33 min of stimulation delivered. Mean classification accuracies were (M = 78.78%, SD = 9.97) for training and (M = 73.48, SD = 12.41) for rehabilitation. Mean Cohen's Kappa across rehabilitation trials was M = 0.43, SD = 0.29, range = 0.019-1.00, suggesting BCI competency. Conclusion: Brain computer interface-FES was well -tolerated and feasible in children with hemiparesis. This paves the way for clinical trials to optimize approaches and test efficacy.

Establishing a Clinical Brain-Computer Interface Program for Children With Severe Neurological Disabilities.

BACKGROUND: Children with severe motor impairment but intact cognition are deprived of fundamental human rights. Quadriplegic cerebral palsy is the most common scenario where rehabilitation options remain limited. Brain-computer interfaces (BCI) represent a potential solution, but pediatric populations have been neglected. Direct engagement of children and families could provide meaningful opportunities while informing program development. We describe a patient-centered, clinical, non-invasive pediatric BCI program. METHODS: Eligible children were identified within a population-based, tertiary care children's hospital. Criteria included 1) age six to 18 years, 2) severe physical disability (non-ambulatory, minimal hand use), 3) severely limited speech, and 4) evidence of grade 1 cognitive capacity. After initial screening for BCI competency, participants attended regular sessions, attempting commercially available and customized systems to play computer games, control devices, and attempt communication. RESULTS: We report the first 10 participants (median 11 years, range 6-16, 60% male). Over 334 hours of participation, there were no serious adverse events. BCI training was well tolerated, with favorable feedback from children and parents. All but one participant demonstrated the ability to perform BCI tasks. The majority performed well, using motor imagery based tasks for games and entertainment. Difficulties were most significant using P300, visual evoked potential based paradigms where maintenance of attention was challenging. Children and families expressed interest in continuing and informing program development. CONCLUSIONS: Patient-centered clinical BCI programs are feasible for children with severe disabilities. Carefully selected participants can often learn quickly to perform meaningful tasks on readily available systems. Patient and family motivation and engagement appear high.

Exploring Clinical and Neurophysiological Factors Associated with Response to Constraint Therapy and Brain Stimulation in Children with Hemiparetic Cerebral Palsy.

BACKGROUND: 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. OBJECTIVE: We explored the clinical and neurophysiological factors associated with responsiveness to CIMT and/or brain stimulation within a clinical trial. METHODS: 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. RESULTS: 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%. CONCLUSION: 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.

Robotic Rehabilitation and Transcranial Direct Current Stimulation in Children With Bilateral Cerebral Palsy.

Aim: To identify challenges of combining robotic upper extremity rehabilitation with tDCS in children with upper extremity bilateral cerebral palsy (CP) by assessing feasibility, tolerability and safety. Methods: This was an unblinded, open-label, pilot clinical trial. Participants completed 10 × 1 h sessions of robotic rehabilitation combined with motor cortex anodal tDCS. Feasibility, acceptability and practicality, were assessed including the number of participants completing the protocol, factors limiting participation, time required for sessions, and completion of functional assessments and tolerability scales. To assess safety, standardized clinical and robotic measures of sensorimotor function were performed. The trial was registered at clinicaltrials.gov (NCT04233710). Results: Eight children were recruited (mean age 8y ± 1.8y, range 6-11 years) and 5 completed the intervention. There were no serious adverse events. One child developed focal seizures 6 weeks after the trial that were deemed to be unrelated. Barriers to completion included time and scheduling demands and patient factors, specifically cognitive/behavioral impairments and dyskinesia. No decline in clinical function was appreciated. Conclusions: Robotic upper extremity rehabilitation combined with tDCS may be feasible in children with bilateral CP. Careful participant selection, family engagement, and protocol adaptations are recommended to better understand the feasibility and tolerability of future trials.

Active versus resting neuro-navigated robotic transcranial magnetic stimulation motor mapping.

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.

Effects of Transcranial Direct Current Stimulation and High-Definition Transcranial Direct Current Stimulation Enhanced Motor Learning on Robotic Transcranial Magnetic Stimulation Motor Maps in Children.

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.

Robotic transcranial magnetic stimulation motor maps and hand function in adolescents.

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.

Perinatal stroke: mapping and modulating developmental plasticity.

Most cases of hemiparetic cerebral palsy are caused by perinatal stroke, resulting in lifelong disability for millions of people. However, our understanding of how the motor system develops following such early unilateral brain injury is increasing. Tools such as neuroimaging and brain stimulation are generating informed maps of the unique motor networks that emerge following perinatal stroke. As a focal injury of defined timing in an otherwise healthy brain, perinatal stroke represents an ideal human model of developmental plasticity. Here, we provide an introduction to perinatal stroke epidemiology and outcomes, before reviewing models of developmental plasticity after perinatal stroke. We then examine existing therapeutic approaches, including constraint, bimanual and other occupational therapies, and their potential synergy with non-invasive neurostimulation. We end by discussing the promise of exciting new therapies, including novel neurostimulation, brain-computer interfaces and robotics, all focused on improving outcomes after perinatal stroke.

Targeted Interventions in Tourette's using Advanced Neuroimaging and Stimulation (TITANS): study protocol for a double-blind, randomised controlled trial of transcranial magnetic stimulation (TMS) to the supplementary motor area in children with Tourette's syndrome.

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.