Ephrem Zewdie

Short-interval intracortical inhibition with incomplete spinal cord injury

OBJECTIVE Short-interval intracortical inhibition (SICI) in leg and hand muscles was characterized in individuals with incomplete spinal cord injury (SCI) to understand how such inhibition limits corticospinal drive after spinal insult. METHODS We compared SICI during a voluntary contraction in 16 SCI and 14 control subjects, the latter group tested over a larger range of conditioning and test stimulus (CS and TS) intensities to best match the SCI data. RESULTS The average peak SICI in the tibialis anterior muscle was typically 3-4 times lower in the SCI subjects compared to controls. When matched for absolute TS intensity, in terms of maximum stimulator output, both U-shaped SICI recruitment curves were produced by similar CS intensities. SICI in the first dorsal interosseous muscle of the hand tended to be larger than in the ankle flexor. CONCLUSIONS Incomplete SCI reduces SICI compared to controls, but the absolute CS intensities that produce the U-shaped SICI recruitment curves are unchanged. SIGNIFICANCE These findings suggest that although the relative excitability profile of cortical SICI networks is unchanged after SCI, the effective inhibition of corticospinal tract output by these neurons is reduced.

Training to Enhance Walking in Children With Cerebral Palsy: Are We Missing the Window of Opportunity?

The objective of this paper is to (1) identify from the literature a potential critical period for the maturation of the corticospinal tract (CST) and (2) report pilot data on an intensive, activity-based therapy applied during this period, in children with lesions to the CST. The best estimate of the CST critical period for the legs is when the child is younger than 2 years of age. Previous interventions for walking in children with CST damage were mainly applied after this age. Our preliminary results with training children younger than 2 years showed improvements in walking that exceeded all previous reports. Further, we refined techniques for measuring motor and sensory pathways to and from the legs, so that changes can be measured at this young age. Previous activity-based therapies may have been applied too late in development. A randomized controlled trial is now underway to determine if intensive leg therapy improves the outcome of children with early stroke.

Transcranial direct current stimulation for children with perinatal stroke and hemiparesis

Objective: To determine whether the addition of transcranial direct current stimulation (tDCS) to intensive therapy increases motor function in children with perinatal stroke and hemiparetic cerebral palsy. Methods: This was a randomized, controlled, double-blind clinical trial. Participants were recruited from a population-based cohort with MRI-classified unilateral perinatal stroke, age of 6 to 18 years, and disabling hemiparesis. All completed a goal-directed, peer-supported, 2-week after-school motor learning camp (32 hours of therapy). Participants were randomized 1:1 to 1 mA cathodal tDCS over the contralesional primary motor cortex (M1) for the initial 20 minutes of daily therapy or sham. Primary subjective (Canadian Occupational Performance Measure [COPM]), objective (Assisting Hand Assessment [AHA]), safety, and secondary outcomes were measured at 1 week and 2 months after intervention. Analysis was by intention to treat. Results: Twenty-four participants were randomized (median age 11.8 ± 2.7 years, range 6.7–17.8). COPM performance and satisfaction scores doubled at 1 week with sustained gains at 2 months (p < 0.001). COPM scores increased more with tDCS compared to sham control (p = 0.004). AHA scores demonstrated only mild increases at both time points with no tDCS effects. Procedures were safe and well tolerated with no decrease in either arm function or serious adverse events. Conclusion: tDCS trials appear feasible and safe in hemiparetic children. Lack of change in objective motor function may reflect underdosing of therapy. Marked gains in subjective function with tDCS warrant further study. ClinicalTrials.gov identifier: NCT02170285. Classification of evidence: This study provides Class II evidence that for children with perinatal stroke and hemiparetic cerebral palsy, the addition of tDCS to moderate-dose motor learning therapy does not significantly improve motor function as measured by the AHA.

Facilitation of descending excitatory and spinal inhibitory networks from training of endurance and precision walking in participants with incomplete spinal cord injury.

After incomplete spinal cord injury (iSCI), training of walking function that emphasizes both endurance and speed may produce different changes in spared neural pathways compared to precision training that emphasizes walking over obstacles and precise placement of the foot. To examine this, 16 participants with iSCI received 2 months of endurance or precision training, in random order, with 2 months of rest before crossing-over to the other type of training. Both forms of training increased the maximum motor-evoked potential (MEPmax) elicited by transcranial magnetic stimulation over the motor cortex, but only in tibialis anterior (TA) muscles that had small (<0.5 mV) MEPmax values before training, no matter when the specific type of training was performed. A similar pattern of training-induced increases in maximum voluntary contractions was also observed. Although walking function was improved by both forms of training, a positive correlation between MEPmax and clinical measures of walking function only occurred after endurance training. Endurance and precision training also increased the excitability of inhibitory spinal networks, as demonstrated by an increase in the suppression of TA MEPs by a prior, low-threshold stimulation to the common peroneal nerve and by increases in the inhibitory component of the cutaneomuscular reflex. The increase in the descending excitation of the spinal cord and the increase in excitability of inhibitory spinal networks may mediate the improved volitional control of walking and reduction of involuntary muscle spasticity, respectively, that are observed in response to intensive motor training in participants with incomplete spinal cord injury.

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.

Interhemispheric motor interactions in hemiparetic children with perinatal stroke: Clinical correlates and effects of neuromodulation therapy

OBJECTIVE Brain stimulation and constraint therapy may enhance function after perinatal stroke but mechanisms are unknown. We characterized interhemispheric interactions (IHI) in hemiparetic children and explored their relationship to motor function and neuromodulation. METHODS Forty-five hemiparetic perinatal stroke subjects aged 6-19 years completed a clinical trial of repetitive-transcranial magnetic stimulation (rTMS) and constraint therapy. Paired-pulse TMS measured IHI in cases and normal controls. Suprathreshold conditioning stimuli preceded contralateral test stimuli bidirectionally: stroke to non-stroke (SNS) and non-stroke to stroke (NSS). Primary outcome was the interhemispheric ratio (IHR) between conditioned and test only MEP amplitudes X100 (<100 implied inhibition). Motor outcomes at baseline and post-intervention were compared to IHR. RESULTS Procedures were well tolerated. IHI occurred bidirectionally in controls. Eighteen stroke participants had complete data. IHR were increased in stroke participants in both directions. SNS IHR was >100 (facilitation) in 39% of measurements and correlated with better motor function. NSS IHR correlated with poorer motor function. Intervention-induced clinical change was not associated with IHR. CONCLUSIONS Interhemispheric interactions are altered and related to clinical function, but not necessarily neuromodulation, in children with perinatal stroke. SIGNIFICANCE Adding interhemispheric interactions to evolving models of developmental plasticity following early injury may advance neuromodulation strategies.

Robotic TMS mapping of motor cortex in the developing brain

BACKGROUND The human motor cortex can be mapped safely and painlessly with transcranial magnetic stimulation (TMS) to explore neurophysiology in health and disease. Human error likely contributes to heterogeneity of such TMS measures. Here, we aimed to use recently pioneered robotic TMS technology to develop an efficient, reproducible protocol to characterize cortical motor maps in a pediatric population. NEW METHOD Magnetic resonance imaging was performed on 12 typically developing children and brain reconstructions were paired with the robotic TMS system. The system automatically aligned the TMS coil to target sites in 3 dimensions with near-perfect coil orientation and real-time head motion correction. Motor maps of 4 forelimb muscles were derived bilaterally by delivering single-pulse TMS at predefined, uniformly spaced trajectories across a 10 × 10 grid (7 mm spacing) customized to the participants MRI. RESULTS Procedures were well tolerated with no adverse events. Two male, eight-year-old participants had high resting motor thresholds that precluded mapping. The mean hotspot coordinate and centre of gravity coordinate were determined in each hemisphere for four forelimb muscles bilaterally. Average mapping time was 14.25 min per hemisphere. COMPARISON WITH EXISTING METHODS Traditional manual TMS methods of motor mapping are time intensive, technically challenging, prone to human error, and arduous for use in pediatrics. This novel TMS robot approach facilitates improved efficiency, tolerability, and precision in derived, high-fidelity motor maps. CONCLUSIONS Robotic TMS opens new avenues to explore motor map neurophysiology and its influence on developmental plasticity and therapeutic neuromodulation. Our findings provide evidence that TMS robotic motor mapping is feasible in young participants.

F140. Effects of tDCS and HD-tDCS on motor learning and motor maps in children

Introduction Perinatal stroke is the leading cause of hemiparetic cerebral palsy (CP). We have shown non-invasive brain stimulation enhances motor learning in healthy and hemiparetic children using transcranial-direct-current-stimulation (tDCS). High-definition (HD-tDCS) may offer additional potential but is unstudied in pediatrics. Motor maps are individualized representations of primary motor cortex (M1) topography measurable with single pulse TMS. Advances in MRI-guided imaging and robotic TMS may facilitate rapid and accurate motor mapping. How motor maps are altered by motor learning and tDCS are unknown. We aimed to determine the effects of tDCS/HD-tDCS enhanced motor learning on motor maps in children, hypothesizing tDCS-enhanced learning is associated with motor map enlargement. Methods AMPED (Accelerated Motor learning in PEDiatrics) is a randomized, sham-controlled trial (NCT03193580). Participants are healthy, right handed children aged 12–18 years. TMS motor mapping is performed using neuronavigated (Brainisght2), robotic (Axilum) TMS. A 10 × 10, 7 mm grid is placed over M1 with 4 stimulations per point generating motor evoked potentials (MEP) of individual hand muscles. Primary outcome is motor map area (volume, center of gravity, cortical excitability are secondary). Motor function is assessed with Purdue Pegboard (primary), Jebsen-Taylor Test, and Serial Reaction Time Task. Participants are randomized into three groups: right M1 1 mA tDCS, HD-tDCS, or sham. All practiced the PPT daily (8 trails) during stimulation with the left hand for 5 consecutive days. Safety and tolerability is assessed daily. All outcomes are repeated on day 5 and at 6 weeks. Two-way repeated measure ANOVA examined changes in performance and motor maps across groups and sessions. Results Fifteen of 24 participants have completed the study (median age 16.4, 67% female). Blinded interim analysis grouped interventions as A, B, or C. PPT scores improved across all groups (p  Conclusion Trials combining tDCS or HD-tDCS enhanced motor learning with robotic TMS motor mapping are feasible in children. Completion of the sample will determine how HD-tDCS enhancement of motor learning compares to tDCS, with potential to advance therapeutic applications in children with CP.

T126. Mapping contralesional motor cortex using robotic transcranial magnetic stimulation in children with perinatal stroke

Introduction Children with perinatal stroke have motor deficits lateralized to one side of the body (hemiparetic cerebral palsy, HCP). Motor control of the affected limb often resides in the contralesional hemisphere with preservation of ipsilateral corticospinal connections. Intensive therapies can improve hand function but mechanisms and predictors of response are unknown. Individualized maps of the motor cortex may provide insight but only two studies have examined this where manual motor mapping was tedious and potentially insensitive. This study aimed to determine the feasibility of using robotic transcranial magnetic stimulation (TMS) motor mapping to better characterize integrated motor maps of the contralesional hemisphere and their association with clinical function. Methods Ten children with unilateral perinatal stroke and HCP (aged 8–19 years) participated in a randomized controlled, double-blinded clinical trial. Children were engaged in a 2-week, goal-directed, child-friendly intensive intervention (constraint and bimanual therapies). Children were randomized to receive 20 min/day of contralesional motor cortex (M1) transcranial direct current stimulation (tDCS) or sham (1:1). Robotic TMS (Axilum Robotics) applied 4 single-pulses to each target on a custom map (12 × 12, 7 mm spacing) over the motor cortex at baseline and within one-week after intervention. Surface electromyography was recorded in bilateral first dorsal interosseous (FDI). Primary neurophysiological measures included the percentage overlap (sites inducing a motor evoked potential (MEP) in both FDI/sites inducing an MEP in the affected FDI), and area of bilateral FDI maps. Clinical outcome was assessed with the Jebsen-Taylor Test of Hand Function (JTTHF). Paired t-tests were performed to examine therapy-associated changes in all measures. Results All children completed the intervention. Two children with incomplete clinical assessments were excluded. Contralesional motor maps were successfully probed by using TMS robot. Motor map parameters did not correlate with clinical scores at baseline (p > 0.1). Percentage overlap of bilateral FDI in the contralesional M1 did not change (n = 7, baseline = 74.5 ± 29.5%, post = 71.7 ± 27.1%, p = 0.86). Averaged motor map areas of unaffected FDI may have increased from 1245 ± 854 mm2 at baseline to 1583 ± 981 mm2 after intervention (n = 10, p = 0.21). Motor map areas of the affected FDI did not change after intervention (n = 7, baseline = 1365 ± 951 mm2, post = 1358 ± 844 mm2,p = 0.98). On average, children moved 23.5 ± 20.8 s faster (12.6 ± 9.6%) with the more-affected hand in JTTHF after intervention (p = 0.02). Change in performance was not associated with change in motor map parameters. Conclusion Our preliminary findings demonstrated that it is feasible to study motor map characteristics using a TMS robot in children with HCP. The utility of using such motor maps as biomarkers to understand and predict treatment outcome will become clearer with completion of larger samples within this and other trials.

Early Intensive Leg Training to Enhance Walking in Children With Perinatal Stroke: Protocol for a Randomized Controlled Trial

Background. Development of motor pathways is modulated by activity in these pathways, when they are maturing (ie, critical period). Perinatal stroke injures motor pathways, including the corticospinal tracts, reducing their activity and impairing motor function. Current intervention for the lower limb emphasizes passive approaches (stretching, braces, botulinum toxin injections). The study hypothesis was that intensive, early, child‐initiated activity during the critical period will enhance connectivity of motor pathways to the legs and improve motor function. Objective. The study objective was to determine whether early intervention with intensive activity is better than standard care, intervention delivered during the proposed critical period is better than after, and the outcomes are different when the intervention is delivered by a physical therapist in an institution vs. a parent at home. Design. A prospective, delay‐group, single‐blind, randomized controlled trial (RCT) and a parallel, cohort study of children living beyond commuting distance and receiving an intervention delivered by their parent. Setting. The RCT intervention was provided in university laboratories, and parent training was provided in the childs home. Participants. Children 8 months to 3 years old with MRI‐confirmed perinatal ischemic stroke and early signs of hemiparesis. Intervention. Intensive, play‐based leg activity with weights for the affected leg and foot, 1 hour/day, 4 days/week for 12 weeks. Measurements. The primary outcome was the Gross Motor Function Measure‐66 score. Secondary outcomes were motion analysis of walking, full‐day step counts, motor evoked potentials from transcranial magnetic stimulation, and patellar tendon reflexes. Limitations. Inter‐individual heterogeneity in the severity of the stroke and behavioral differences are substantial but measurable. Differences in intervention delivery and assessment scoring are minimized by standardization and training. Conclusions. The intervention, contrary to current practice, could change physical therapy interventions for children with perinatal stroke.