Mirror movements and brain pathology in children with unilateral cerebral palsy.

AIM: We systematically examined the relationship between mirror movements and brain lesion type, corticospinal tract (CST) organization, and hand function to determine the relevance between mirror movements, brain lesion, the CST pattern, and hand function in children with unilateral cerebral palsy (CP). METHOD: Forty-eight children (mean age 9y 9mo [SD 3y 3mo], range 6-18y; 30 males, 18 females) with unilateral CP participated. Mirror movements, brain lesion type, CST pattern identified by transcranial magnetic stimulation, and clinical outcomes were evaluated. Children performed four unilateral tasks: hand opening/closing, finger opposition, individuation, and finger 'walking'. Mirror movements induced in the contralateral hand were scored using standardized criteria (scores 0-4 using the Woods and Teuber scale). RESULTS: We found that children with periventricular lesion may have stronger mirror movement scores induced in either hand than those with middle cerebral artery lesion (more affected hand: p=0.02; less affected hand: p<0.01). The highest mirror movement score a child exhibits across the tested tasks (i.e. scores of 3-4 using the Woods and Teuber scoring criteria) may potentially be an indicator of an ipsilateral CST connectivity pattern (p=0.03). Significant correlations were observed between higher mirror movement scores when performing hand opening/closing as well as finger walking and better unimanual dexterity (Spearman's rank correlation coefficient rs =0.44, p=0.002; rs =0.46, p=0.002 respectively). INTERPRETATION: Brain lesions may be predictive of the strength of mirror movements in either hand in children with unilateral CP. Our findings warrant further studies to extensively investigate the relationship between mirror movements and the underlying brain pathology. WHAT THIS PAPER ADDS: Brain lesion type may be predictive of mirror movement scores induced in either hand in children with unilateral cerebral palsy. The highest mirror movement score a child exhibits across the tested tasks may indicate corticospinal tract connectivity pattern in children with unilateral cerebral palsy.

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.

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.

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.

Effect of sensory and motor connectivity on hand function in pediatric hemiplegia.

OBJECTIVE: We tested the hypothesis that somatosensory system injury would more strongly affect movement than motor system injury in children with unilateral cerebral palsy (USCP). This hypothesis was based on how somatosensory and corticospinal circuits adapt to injury during development; whereas the motor system can maintain connections to the impaired hand from the uninjured hemisphere, this does not occur in the somatosensory system. As a corollary, cortical injury strongly impairs sensory function, so we hypothesized that cortical lesions would impair hand function more than subcortical lesions. METHODS: Twenty-four children with unilateral cerebral palsy had physiological and anatomical measures of the motor and somatosensory systems and lesion classification. Motor physiology was performed with transcranial magnetic stimulation and somatosensory physiology with vibration-evoked electroencephalographic potentials. Tractography of the corticospinal tract and the medial lemniscus was performed with diffusion tensor imaging, and lesions were classified by magnetic resonance imaging. Anatomical and physiological results were correlated with measures of hand function using 2 independent statistical methods. RESULTS: Children with disruptions in the somatosensory connectivity and cortical lesions had the most severe upper extremity impairments, particularly somatosensory function. Motor system connectivity was significantly correlated with bimanual function, but not unimanual function or somatosensory function. INTERPRETATION: Both sensory and motor connectivity impact hand function in children with USCP. Somatosensory connectivity could be an important target for recovery of hand function in children with USCP. Ann Neurol 2017;82:766-780.

Neurophysiological mechanisms and functional impact of mirror movements in children with unilateral spastic cerebral palsy.

Children with unilateral spastic cerebral palsy (CP) often have mirror movements, i.e. involuntary imitations of unilateral voluntary movements of the contralateral upper extremity. The pathophysiology of mirror movements has been investigated in small and heterogeneous cohorts in the literature. Specific pathophysiology of mirror movements and their impact on upper extremity function require systematic investigation in larger and homogeneous cohorts of children with unilateral spastic CP. Here we review two possible neurophysiological mechanisms underlying mirror movements in children with CP and those with typical development: (1) an ipsilateral corticospinal tract projecting from the contralesional motor cortex (M1) to both upper extremities; (2) insufficient interhemispheric inhibition between the two M1s. We also discuss clinical implications of mirror movements in children with unilateral CP and suggest that a thorough examination of the relationship between the pathophysiology and clinical manifestations of mirror movements is warranted. We suggest two premises: (1) the presence of mirror movements is indicative of an ipsilateral corticospinal tract reorganization; and (2) the corticospinal tract organization may affect patients' responses to certain treatment. If these premises are supported through future research, mirror movements should be clinically evaluated for patient selection to maximize benefits of therapy, hence promoting individualized medicine in this population. WHAT THIS PAPER ADDS: Mirror movements may be indicative of the underlying corticospinal tract reorganization in children with unilateral spastic cerebral palsy (CP). Future research will benefit from systematic investigations of the relationship between mirror movements and its pathophysiology. Mirror movements may be a potential biomarker for individualized medicine in children with unilateral spastic CP.

Using diffusion tensor imaging to identify corticospinal tract projection patterns in children with unilateral spastic cerebral palsy.

AIM: To determine whether diffusion tensor imaging (DTI) can be an independent assessment for identifying the corticospinal tract (CST) projecting from the more-affected motor cortex in children with unilateral spastic cerebral palsy (CP). METHOD: Twenty children with unilateral spastic CP participated in this study (16 males, four females; mean age 9y 2mo [standard deviation (SD) 3y 2mo], Manual Ability Classification System [MACS] level I-III). We used DTI tractography to reconstruct the CST projecting from the more-affected motor cortex. We mapped the motor representation of the more-affected hand by stimulating the more- and the less-affected motor cortex measured with single-pulse transcranial magnetic stimulation (TMS). We then verified the presence or absence of the contralateral CST by comparing the TMS map and DTI tractography. Fisher's exact test was used to determine the association between findings of TMS and DTI. RESULTS: DTI tractography successfully identified the CST controlling the more-affected hand (sensitivity=82%, specificity=78%). INTERPRETATION: Contralateral CST projecting from the lesioned motor cortex assessed by DTI is consistent with findings of TMS mapping. Since CST connectivity may be predictive of response to certain upper extremity treatments, DTI-identified CST connectivity may potentially be valuable for determining such connectivity where TMS is unavailable or inadvisable for children with seizures.

The Role of the Corpus Callosum in Pediatric Dysphagia: Preliminary Findings from a Diffusion Tensor Imaging Study in Children with Unilateral Spastic Cerebral Palsy.

The purpose of this study is to determine the relationship between the structural integrity of the corpus callosum (CC) and clinical feeding/swallowing performance in children with unilateral spastic cerebral palsy (USCP). Twenty children with USCP, (11 males, 5.11-17.6 yoa) were assessed via the Dysphagia Disorder Survey (DDS) and diffusion tensor imaging. Children were grouped into left hemisphere lesion (LHL; n = 13) and right hemisphere lesion (RHL; n = 7) groups. DTI variables analyzed for three CC regions (anterior, middle, posterior) were: fractional anisotropy (FA), radial diffusivity (RD), mean diffusivity (MD), and fibers count. Children with RHL presented with higher clinical dysphagia severity (p = 0.03). Six of seven children with RHL had lesions affecting periventricular/subcortical areas, and 8/13 children with LHL had lesions affecting the sensorimotor cortex. In the LHL group, as FA and fiber count of the anterior CC decreased and RD increased (all indicating reduced CC structural integrity), signs of dysphagia increased (r = -0.667, p = 0.013; r = -0.829, p ≤ 0.001; r = 0.594, p = 0.032, respectively). Reduced fiber count in the middle and posterior CC was also significantly associated with increased DDS scores (r = -0.762, p = 0.002; r = -0.739, p = 0.004, respectively). For the RHL group no significant correlations were observed. We provide preliminary evidence that corpus callosum integrity correlates with feeding/swallowing performance in children with USCP, especially when cortical sensorimotor areas of the left hemisphere are impacted. In this sample, CC integrity appeared to enable interhemispheric cortical plasticity for swallowing, but was not as critical when intrahemispheric connections were disrupted, as seen in the RHL group.

Improvements in hand function after intensive bimanual training are not associated with corticospinal tract dysgenesis in children with unilateral cerebral palsy.

Unilateral cerebral palsy (CP) results from damage to the developing brain that occurs within the first 2 years of life. Previous studies found associations between asymmetry in the size of the corticospinal tract (CST) from the two hemispheres and severity of hand impairments in children with unilateral CP. The extent to which CST damage affects the capacity for hand function improvement is unknown. This study examines the association between an estimate of CST dysgenesis and (1) hand function and (2) the efficacy of intensive bimanual training in improving hand function. Children with unilateral CP, age 3.6-14.9 years, n = 35, received intensive bimanual training. Children engaged in bimanual functional/play activities (6 h/day, 15 days). Peduncle asymmetry, an estimate of CST dysgenesis, was measured on T1-weighted magnetic resonance imaging scans. Hand function was measured pre- and post-treatment using the assisting hand assessment (AHA) and Jebsen-Taylor test of hand function (JTTHF). AHA and JTTHF improved post-treatment (p < 0.001). Peduncle asymmetry was correlated with baseline AHA and JTTHF (p < 0.001) but not with AHA or JTTHF improvement post-training (R(2) < 0.1, p > 0.2). An estimate of CST dysgenesis is correlated with baseline hand function but is a poor predictor of training efficacy, possibly indicating a flexibility of developing motor systems to mediate recovery.

Using motor behavior during an early critical period to restore skilled limb movement after damage to the corticospinal system during development.

This study investigated the requirements for restoring motor function after corticospinal (CS) system damage during early postnatal development. Activity-dependent competition between the CS tracts (CSTs) of the two hemispheres is imperative for normal development. Blocking primary motor cortex (M1) activity unilaterally during a critical period [postnatal week 5 (PW5) to PW7] produces permanent contralateral motor skill impairments, loss of M1 motor map, aberrant CS terminations, and decreases in CST presynaptic sites and spinal cholinergic interneuron numbers. To repair these motor systems impairments and restore function, we manipulated motor experience in three groups of cats after this CST injury produced by inactivation. One group wore a jacket restraining the limb ipsilateral to inactivation, forcing use of the contralateral, impaired limb, for the month after M1 inactivation (PW8-PW13; "restraint alone"). A second group wore the restraint during PW8-PW13 and was also trained for 1 h/d in a reaching task with the contralateral forelimb ("early training"). To test the efficacy of intervention during adolescence, a third group wore the restraint and received reach training during PW20-PW24 ("delayed training"). Early training restored CST connections and the M1 motor map, increased cholinergic spinal interneurons numbers on the contralateral, relative to ipsilateral, side, and abrogated limb control impairments. Delayed training restored CST connectivity and the M1 motor map but not contralateral spinal cholinergic cell counts or motor performance. Restraint alone only restored CST connectivity. Our findings stress the need to reestablish the integrated functions of the CS system at multiple hierarchical levels in restoring skilled motor function after developmental injury.

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.

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.

Improvements in Upper Extremity Function Following Intensive Training Are Independent of Corticospinal Tract Organization in Children With Unilateral Spastic Cerebral Palsy: A Clinical Randomized Trial.

Background/Objectives: Intensive training of the more affected upper extremity (UE) has been shown to be effective for children with unilateral spastic cerebral palsy (USCP). Two types of UE training have been particularly successful: Constraint-Induced Movement Therapy (CIMT) and Bimanual training. Reorganization of the corticospinal tract (CST) early during development often occurs in USCP. Prior studies have suggested that children with an ipsilateral CST controlling the affected UE may improve less following CIMT than children with a contralateral CST. We tested the hypothesis that improvements in UE function after intensive training depend on CST laterality. Study Participants and Setting: Eighty-two children with USCP, age 5 years 10 months to 17 years, University laboratory setting. Materials/Methods: Single-pulse transcranial magnetic stimulation (TMS) was used to determine each child's CST connectivity pattern. Children were stratified by age, sex, baseline hand function and CST connectivity pattern, and randomized to receive either CIMT or Bimanual training, each of which were provided in a day-camp setting (90 h). Hand function was tested before, immediately and 6 months after the intervention with the Jebsen-Taylor Test of Hand Function, the Assisting Hand Assessment, the Box and Block Test, and ABILHAND-Kids. The Canadian Occupational Performance Measure was used to track goal achievement and the Pediatric Evaluation of Disability Inventory was used to assess functioning in daily living activities at home. Results: In contrast to our hypothesis, participants had statistically similar improvements for both CIMT and Bimanual training for all measures independent of their CST connectivity pattern (contralateral, ipsilateral, or bilateral) (p < 0.05 in all cases). Conclusions/Significance: The efficacy of CIMT and Bimanual training is independent of CST connectivity pattern. Children with an ipsilateral CST, previously thought to be maladaptive, have the capacity to improve as well as children with a contralateral or bilateral CST following intensive CIMT or Bimanual training. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT02918890.

Transcranial Static Magnetic Field Stimulation of the Motor Cortex in Children.

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.

Non-Invasive Modulation and Robotic Mapping of Motor Cortex in the Developing Brain.

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

Intervention-Induced Motor Cortex Plasticity in Hemiparetic Children With Perinatal Stroke.

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

Effects of High-Definition and Conventional Transcranial Direct-Current Stimulation on Motor Learning in Children.

Background: Transcranial direct current stimulation (tDCS) can improve motor learning in children. High-definition approaches (HD-tDCS) have not been examined in children. Objectives/Hypothesis: We hypothesized that primary motor cortex HD-tDCS would enhance motor learning but be inferior to tDCS in children. Methods: Twenty-four children were recruited for a randomized, sham-controlled, double-blinded interventional trial (NCT03193580, clinicaltrials.gov/ct2/show/NCT03193580) to receive (1) right hemisphere (contralateral) primary motor cortex (M1) 1 mA anodal conventional 1 × 1 tDCS (tDCS), (2) right M1 1 mA anodal 4 × 1 HD-tDCS (HD-tDCS), or (3) sham. Over five consecutive days, participants trained their left hand using the Purdue Pegboard Test (PPTL). The Jebsen-Taylor Test, Serial Reaction Time Task, and right hand and bimanual PPT were also tested at baseline, post-training, and 6-week retention time (RT). Results: Both the tDCS and HD-tDCS groups demonstrated enhanced motor learning compared to sham with effects maintained at 6 weeks. Effect sizes were moderate-to-large for tDCS and HD-tDCS groups at the end of day 4 (Cohen's d tDCS = 0.960, HD-tDCS = 0.766) and day 5 (tDCS = 0.655, HD-tDCS = 0.851). Enhanced motor learning effects were also seen in the untrained hand. HD-tDCS was well tolerated and safe with no adverse effects. Conclusion: HD-tDCS and tDCS can enhance motor learning in children. Further exploration is indicated to advance rehabilitation therapies for children with motor disabilities such as cerebral palsy. Clinical Trial Registration: clinicaltrials.gov, identifier NCT03193580.

The Relationship Between Hand Function and Overlapping Motor Representations of the Hands in the Contralesional Hemisphere in Unilateral Spastic Cerebral Palsy.

BACKGROUND: In many children with unilateral spastic cerebral palsy (USCP), the corticospinal tract to the affected hand atypically originates in the hemisphere ipsilateral to the affected hand. Such ipsilateral connectivity is on average a predictor of poor hand function. However, there is high variability in hand function in these children, which might be explained by the complexity of motor representations of both hands in the contralesional hemisphere. OBJECTIVE: To measure the link between hand function and the size and excitability of motor representations of both hands, and their overlap, in the contralesional hemisphere of children with USCP. METHODS: We used single-pulse transcranial magnetic stimulation to measure the size and excitability of motor representations of both hands, and their overlap, in the contralesional hemisphere of 50 children with USCP. We correlated these measures with manual dexterity of the affected hand, bimanual performance, and mirror movement strength. RESULTS: The main and novel findings were (1) the large overlap in contralesional motor representations of the 2 hands and (2) the moderate positive associations of the size and excitability of such shared-site representations with hand function. Such functional associations were not present for overall size and excitability of representations of the affected hand. CONCLUSIONS: Greater relative overlap of the affected hand representation with the less-affected hand representation within the contralesional hemisphere was associated with better hand function. This association suggests that overlapping representations might be adaptively "yoked," such that cortical control of the child's less-affected hand supports that of the affected hand.

Combined transcranial direct current stimulation and robotic upper limb therapy improves upper limb function in an adult with cerebral palsy.

BACKGROUND: Robotic therapy can improve upper limb function in hemiparesis. Excitatory transcranial direct current stimulation (tDCS) can prime brain motor circuits before therapy. OBJECTIVE: We tested safety and efficacy of tDCS plus robotic therapy in an adult with unilateral spastic cerebral palsy (USCP). METHODS: In each of 36 sessions, anodal tDCS (2 mA, 20 min) was applied over the motor map of the affected hand. Immediately after tDCS, the participant completed robotic therapy, using the shoulder, elbow, and wrist (MIT Manus). The participant sat in a padded chair with affected arm abducted, forearm supported, and hand grasping the robot handle. The participant controlled the robot arm with his affected arm to move a cursor from the center of a circle to each of eight targets (960 movements). Motor function was tested before, after, and six months after therapy with the Wolf Motor Function Test (WMFT) and Fugl-Meyer (FM). RESULTS: Reaching accuracy on the robot task improved significantly after therapy. The WMFT and FM improved clinically meaningful amounts after therapy. The motor map of the affected hand expanded after therapy. Improvements were maintained six months after therapy. CONCLUSIONS: Combined tDCS and robotics safely improved upper limb function in an adult with USCP.