Safety and efficacy of non-invasive brain stimulation for the upper extremities in children with cerebral palsy: A systematic review.

AIM: To evaluate available evidence examining safety and efficacy of non-invasive brain stimulation (NIBS) on upper extremity outcomes in children with cerebral palsy (CP). METHOD: We electronically searched 12 sources up to May 2023 using JBI and Cochrane guidelines. Two reviewers selected articles with predetermined eligibility criteria, conducted data extraction, and assessed risk of bias using the Cochrane Risk of Bias criteria. RESULTS: Nineteen studies were included: eight using repetitive transcranial magnetic stimulation (rTMS) and 11 using transcranial direct current stimulation (tDCS). Moderate certainty evidence supports the safety of rTMS and tDCS for children with CP. Very low to moderate certainty evidence suggests that rTMS and tDCS result in little to no difference in upper extremity outcomes. INTERPRETATION: Evidence indicates that NIBS is a safe and feasible intervention to target upper extremity outcomes in children with CP, although it also indicates little to no significant impact on upper extremity outcomes. These findings are discussed in relation to the heterogeneous participants' characteristics and stimulation parameters. Larger studies of high methodological quality are required to inform future research and protocols for NIBS.

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.

Estimating and examining the costs of inpatient diabetes care in an Irish Public Hospital.

AIM: To estimate and examine hospitalisation costs of Type 1 and Type 2 diabetes in an Irish public hospital. METHODS: A retrospective audit of hospital inpatient admissions over a 5-year period was undertaken, and a wide range of admission-related data were collected for a sample of 7,548 admissions. Hospitalisations were costed using the diagnosis-related group methodology. A series of descriptive, univariate and multivariate regression analyses were undertaken. RESULTS: The mean hospitalisation cost for Type 1 diabetes was €4,027 and for Type 2 diabetes was €5,026 per admission. Sex, admission type and length of stay were significantly associated with hospitalisation costs for admissions with a primary diagnosis of Type 1 diabetes. Age, admission type, diagnosis status, complications status, discharge destination, length of stay and year were significantly associated with hospitalisation costs for admissions with a primary diagnosis of Type 2 diabetes. Length of stay was associated with higher mean costs, with each additional day increasing Type 1 diabetes costs by €260 (p = 0.001) and Type 2 diabetes by €216 (p < 0.001). Unscheduled admissions were associated with significantly lower costs than elective admissions; €1,578 (p = 0.035) lower for Type 1 diabetes and €2,108 (p < 0.001) lower for Type 2 diabetes. CONCLUSIONS: This study presents estimates of the costs of diabetes care in the Irish public hospital system and identifies the factors which influence costs for Type 1 and Type 2 diabetes. These findings may be of interest to patients, the public, researchers and those with influence over diabetes policy and practice in Ireland and internationally.

Intensive Bimanual Intervention for Children Who Have Undergone Hemispherectomy: A Pilot Study.

PURPOSE: To conduct a pilot study to assess the feasibility and effectiveness of an intensive bimanual intervention on upper limb function in children who have undergone hemispherectomy. METHODS: Thirteen children received 90 hours of intensive bimanual training (Hand-Arm Bimanual Intensive Therapy, HABIT). The Jebsen-Taylor Test of Hand Function (JTTHF), Box and Block Test (BBT), Assisting Hand Assessment (AHA), ABILHAND-Kids, and Canadian Occupational Performance Measure (COPM) were assessed by a masked clinician twice before, immediately, and 6 months after treatment. RESULTS: Significant improvements over time were found in the JTTHF, AHA, ABILHAND-Kids, and COPM. CONCLUSION: Completion of HABIT was feasible for children with hemispherectomy. Improvement of bimanual function and functional goals can be related to the nature of the activities prioritized in HABIT training.

Intensive Unimanual Training Leads to Better Reaching and Head Control than Bimanual Training in Children with Unilateral Cerebral Palsy.

AIMS: To quantify the changes in joint movement control and motor planning of the more-affected upper extremity (UE) during a reach-grasp-eat task in children with Unilateral Spastic Cerebral Palsy (USCP) after either constraint-induced movement therapy (CIMT) or hand-arm bimanual intensive therapy (HABIT). METHODS: Twenty children with USCP (average age 7.7; MACS levels I-II) were randomized into either a CIMT or HABIT group. Both groups received intensive training 6 h a day for 15 days. Children performed a reach-grasp-eat task before and after training with their more-affected hand using 3D kinematic analysis. RESULTS: Both groups illustrated shorter movement time during reaching, grasping, and eating phases after training (p < 0.05). Additionally, both intensive training approaches improved joint control with decreased trunk involvement, greater elbow, and wrist excursions during the reaching phase, and greater elbow excursion during the eating phase (p < 0.05). However, only the CIMT group decreased hand curvature during reaching, lowered hand position at grasp, and decreased head rotation during the eating phase (p < 0.05). CONCLUSIONS: The current findings showed that both CIMT and HABIT improved UE joint control, but there were greater effects of CIMT on the more-affected UE motor planning and head control for children with USCP.

Reliability and responsiveness of the Jebsen-Taylor Test of Hand Function and the Box and Block Test for children with cerebral palsy.

AIM: To assess the reliability and to evaluate the responsiveness of both the Jebsen-Taylor Test of Hand Function (JTTHF) and the Box and Block Test (BBT) in children with cerebral palsy (CP). METHOD: In this retrospective study, the reliability analyses were conducted with paired t-tests considering a short (mean 14d) and a long (mean 120d) time in between two assessment periods. In addition, an intraclass correlation coefficient (ICC) was used to assess the level of congruency. The responsiveness to therapy was conducted with a paired t-test in the whole sample regarding the age, the manual ability level as classified with the Manual Ability Classification System (MACS), and the topography. RESULTS: Our main results confirmed the tests' reliability in a short time period for the JTTHF in both hands and for the BBT on the less affected hand. These results were consistent with the ICC. The responsiveness was confirmed, except on the less affected hand for the JTTHF, with similar results for age, MACS, and topography approach. INTERPRETATION: This study supports the use of the JTTHF and the BBT to examine changes after short-term interventions for children with CP. These results should be interpreted with association to normative values or with a control group when used over long assessment periods. WHAT THIS PAPER ADDS: The Box and Block Test (BBT) is reliable in a brief period of assessment in children with cerebral palsy (CP). The Jebsen-Taylor Test of Hand Function (JTTHF) is reliable in a brief period of assessment in children with CP. The JTTHF and BBT are responsive to changes in a brief period of intensive therapy in children with CP. The reliability and responsiveness of the JTTHF and BBT are weak over long assessment periods.

CONFIABILIDAD Y SENSIBILIDAD DE LA PRUEBA JEBSEN-TAYLOR TEST OF HAND FUNCTIÓN Y LA PRUEBA BOX AND BLOCK TEST EN NIÑOS CON PARÁLISIS CEREBRAL: OBJETIVO: Evaluar la confiabilidad y la sensibilidad de las pruebas Jebsen-Taylor Test of Hand Function (JTTHF) y Box and Block Test (BBT) en niños con parálisis cerebral (PC). MÉTODO: En este estudio retrospectivo, los análisis de confiabilidad fueron realizados con pruebas t para muestras relacionadas, considerando un tiempo corto (media de 14 días) y largo (media de 120 días) entre dos períodos de evaluación. Además, se utilizó el coeficiente de correlación intraclase (CCI) para evaluar el grado de congruencia. La sensibilidad de la terapia fue evaluada con prueba t en toda la muestra, respecto a la edad, nivel de habilidad manual, según el sistema de clasificación de la habilidad manual (MACS), y la topografía. RESULTADOS: Nuestros principales resultados confirman la confiabilidad a corto plazo para la prueba JTTHF en ambas manos y para la prueba BBT en la mano menos afectada. Estos resultados fueron consistentes, de acuerdo con el CCI. La sensibilidad fue confirmada, excepto en la mano menos afectada para la prueba JTTHF, con resultados similares respecto a la edad, MACS y topografía. INTERPRETACIÓN: Este estudio sustenta el uso de las pruebas JTTFH y BBT para evaluar cambios luego de intervenciones de corto plazo para niños con PC. Estos resultados debieran ser interpretados en asociación a valores de normalidad o con un grupo control cuando sean utilizados para evaluar períodos de intervención de largo plazo.

CONFIABILIDADE E RESPONSIVIDADE DO TESTE DA FUNÇÃO MANUAL DE JEBSEN-TAYLOR E DO TESTE DA CAIXA E BLOCOS PARA CRIANÇAS COM PARALISIA CEREBRAL: OBJETIVO: Avaliar a confiabilidade e a responsividade do Teste da Função Manual de Jebsen-Taylor (TFMJT) e do Teste da Caixa e Blocos (TCB) para crianças com paralisia cerebral (PC). MÉTODO: Neste estudo retrospectivo, análises de confiabilidade foram realizadas com testes t pareados considerando um tempo curto (média 14d) e longo (média 120d) entre dois períodos de avaliação. Adicionalmente, coeficiente de correlacão intraclasse (CCI) foi usado para avaliar o nível de conguência. A responsividade a terapia foi conduzida com um teste t pareado em uma amostra considerando a idade, o nível de habilidade manual classificado pelo Sistema de Classificação da Habilidade Manual (MACS), e a topografia. RESULTADOS: Nossos principais resultados confirmaram a confiabilidade dos testes em um curto período de tempo para o TFMJT em ambas as mãos e para o TCB na mão menos afetada. Estes resultados foram consistentes com o CCI. A responsividade foi confirmada, exceto na mão menos afetada para o TFMJT, com resultados similares para a abordagem por idade, MACS e topografia. INTERPRETAÇÃO: Este estudo apóia o uso do TFMJT e do TCB para examinar mudanças após intervenções de curto prazo em crianças com PC. Estes resultados devem ser interpretados em associação com valores normativos ou um grupo controle quando usados em longos períodos de avaliação.

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.

Transcranial Direct Current Stimulation (tDCS) Paired with Occupation-Centered Bimanual Training in Children with Unilateral Cerebral Palsy: A Preliminary Study.

Objective: We investigated the preliminary efficacy of cathodal transcranial direct current stimulation (tDCS) combined with bimanual training in children and young adults with unilateral cerebral palsy based on the principle of exaggerated interhemispheric inhibition (IHI). Methods: Eight participants with corticospinal tract (CST) connectivity from the lesioned hemisphere participated in an open-label study of 10 sessions of cathodal tDCS to the nonlesioned hemisphere (20 minutes) concurrently with bimanual, goal-directed training (120 minutes). We measured the frequency of adverse events and intervention efficacy with performance (bimanual-Assisting Hand Assessment (AHA)-and unimanual-Box and Blocks), self-report (Canadian Occupational Performance Measure (COPM), ABILHAND), and neurophysiologic (motor-evoked potential amplitude, cortical silent period (CSP) duration, and motor mapping) assessments. Results: All participants completed the study with no serious adverse events. Three of 8 participants showed gains on the AHA, and 4 of 8 participants showed gains in Box and Blocks (more affected hand). Nonlesioned CSP duration decreased in 6 of 6 participants with analyzable data. Cortical representation of the first dorsal interosseous expanded in the nonlesioned hemisphere in 4 of 6 participants and decreased in the lesioned hemisphere in 3 of 4 participants with analyzable data. Conclusions: While goal achievement was observed, objective measures of hand function showed inconsistent gains. Neurophysiologic data suggests nonlinear responses to cathodal stimulation of the nonlesioned hemisphere. Future studies examining the contributions of activity-dependent competition and cortical excitability imbalances are indicated.

Impairments of Visuospatial Attention in Children with Unilateral Spastic Cerebral Palsy.

Aim: This observational study aimed at assessing the prevalence of visuospatial attention deficits in children with unilateral spastic cerebral palsy (USCP), taking into consideration the affected hemibody and the localization of the brain lesion. Method: Seventy-five children with USCP were assessed with four visuospatial attention tests: star cancellation, Ogden figure copy, line bisection, and proprioceptive pointing. Results: A majority (64%) of children with USCP presented a deficit in at least one test compared to the reference values. The alterations observed in children with left or right USCP were related to egocentric or allocentric neglect, respectively. Children with cortico/subcortical lesion presented more often visuospatial attention deficits than children with periventricular lesion. Visuospatial attention deficits were not associated with brain lesion locations. Interpretation: Visuospatial attention deficits are prevalent in children with USCP and should be taken into account during their rehabilitation process. The present results shed new light on the interpretation of motor impairments in children with USCP as they may be influenced by the frequent presence of visuospatial deficits.

Intensive upper- and lower-extremity training for children with bilateral cerebral palsy: a quasi-randomized trial.

AIM: An approach that simultaneously engages both the upper and lower extremities, hand-arm bimanual intensive therapy including lower extremity (HABIT-ILE), has recently demonstrated improvements in upper and lower extremities in children with unilateral cerebral palsy (CP). It is not known whether children with bilateral CP would benefit from this approach. The aim of this study was to examine the efficacy of HABIT-ILE in children with bilateral CP. METHOD: A quasi-randomized trial design was used, whereby 20 participants (age 6-15y, Gross Motor Function Classification System levels II-IV, Manual Ability Classification System levels I-III) were assigned to a treatment (HABIT-ILE) or a comparison group in the order in which they were enrolled. Children in the HABIT-ILE group were assessed before and after 84 hours of intervention over 13 days, as well as at 3 months' follow-up. Children in the comparison group were assessed at the same time points. Children in both groups were assessed using the Gross Motor Function Measure (GMFM-66) and ABILHAND-Kids (primary measures), and six secondary measures. RESULTS: A group×test session interaction indicated significant improvements in the HABIT-ILE group as assessed by the GMFM-66, lower-extremity performance (6-Minute Walk Test; Pediatric Balance Scale), functional upper-extremity abilities (ABILHAND-Kids/Pediatric Evaluation of Disability Inventory), and the dexterity of the less affected upper extremity. CONCLUSION: HABIT-ILE is efficacious for improving both upper- and lower-extremity function in children with bilateral 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.

Feasibility of Using an Arm Weight-Supported Training System to Improve Hand Function Skills in Children With Hemiplegia.

OBJECTIVE: This investigation was a pilot feasibility trial evaluating the use of an arm-weight-supported training device to improve upper-extremity function in children with hemiplegia. METHOD: A single-group within-subject design was used. Participants were 6 children ages 7-17 yr with upper-extremity weakness secondary to hemiplegia. The intervention consisted of 15-18 treatment sessions using an arm-weight-supported training device with the affected upper extremity. Fine motor function was assessed using the Jebsen-Taylor Hand Function Test, the Box and Block Test, and the Assisting Hand Assessment. We examined participants' interactions with the device and assessment scores pre- and postintervention. RESULTS: Five of the 6 children exhibited some changes after the therapy. The system required significant modifications to ensure appropriate positioning. CONCLUSION: The arm-weight-supported system may be viable for therapeutic use. Future studies should use randomized controlled designs and compare effectiveness of weight-supported training with that of other rehabilitation strategies.

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.