Omar Damji

Brain stimulation and constraint for perinatal stroke hemiparesis: The PLASTIC CHAMPS Trial

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

Glutamate alterations associated with transcranial magnetic stimulation in youth depression: a case series.

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

Evaluating developmental motor plasticity with paired afferent stimulation

Brain plasticity mechanisms are probably different in children but remain poorly understood. Paired afferent stimulation (PAS) combines peripheral sensory stimulation with transcranial magnetic stimulation (TMS) of primary motor cortex to induce rapid, reversible, topographically specific increases in primary motor cortex excitability suggestive of long‐term potentiation in adults. Our aim was to determine frequency, characteristics, age effects, and reproducibility of PAS in school‐age children.

Contralesional Corticomotor Neurophysiology in Hemiparetic Children With Perinatal Stroke: Developmental Plasticity and Clinical Function.

Background. Perinatal stroke causes most hemiparetic cerebral palsy. Ipsilateral connections from nonlesioned hemisphere to affected hand are common. The nonlesioned primary motor cortex (M1) determines function and is a potential therapeutic target but its neurophysiology is poorly understood. Objective. We aimed to characterize the neurophysiological properties of the nonlesioned M1 in children with perinatal stroke and their relationship to clinical function. Methods. Fifty-two participants with hemiparetic cerebral palsy and magnetic resonance imaging–confirmed perinatal stroke and 40 controls aged 8 to 18 years completed the same transcranial magnetic stimulation (TMS) protocol. Single-pulse TMS to nonlesioned M1 determined rest and active motor thresholds (RMT/AMT), motor-evoked potential (MEP) latencies, and stimulus recruitment curves (SRC: 100%-150% RMT). Paired-pulse TMS evaluated short-latency intracortical inhibition (SICI) and intracortical facilitation (ICF). Ipsilateral (IP) participants (ipsilateral MEP ≥0.05 mV in ≥5/20 trials) were compared with contralateral MEP only, nonipsilateral (NI) participants. Assisting Hand and Melbourne assessments quantified clinical function. Results. Twenty-five IP were compared with 13 NI (n = 38, median age 12 years, 66% male). IP had lower motor function. SRC to unaffected hand were comparable between IP and NI while IP had smaller ipsilateral SRC. Ipsilateral MEP latencies were prolonged (23.5 ± 1.8 vs 22.2 ± 1.5 ms contra, P < .001). Contralateral SICI was different between IP (−42%) and NI (−20%). Ipsilateral SICI was reduced (−20%). Contralateral ICF was comparable between groups (+43%) and ipsilaterally (+43%). Measures correlated between contralateral and ipsilateral sides. Conclusion. Neurophysiology of nonlesioned M1 and its relationship to motor function is measureable in children with perinatal stroke. Correlation of excitability and intracortical circuitry measures between contralateral and ipsilateral sides suggests common control mechanisms.

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.

OP29 – 2815: Brain stimulation and constraint for perinatal stroke hemiparesis: The PLASTIC CHAMPS trial

Objective Perinatal stroke causes hemiparetic cerebral palsy and lifelong disability. Constraint-induced movement therapy (CIMT) can improve motor function in congenital hemiparesis and adult stroke. Repetitive transcranial magnetic stimulation (rTMS) may improve motor function in adult stroke. The two have not been formally tested in perinatal stroke hemiparesis. Methods PLASTIC CHAMPS ( www.clinicaltrials.gov/NCT01189058 ) was a blinded, controlled, factorial trial of rTMS and CIMT in perinatal stroke hemiparesis. Children 6–18 years participated in a 2 week, goal-directed, peer-supported, motor learning camp. Subjects were randomized to daily inhibitory rTMS (1Hz, 1200 stimulations) over contralesional primary motor cortex, CIMT, both or neither. Primary outcomes were the Assisting Hand Assessment (AHA) and Canadian Occupational Performance Measure (COPM) at 1 week, 2 months, and 6 months. Additional outcomes included the Melbourne Assessment, quality-of-life, safety and tolerability. Corticospinal tract arrangement was defined using single-pulse TMS. Intent-to-treat analysis assessed change across treatment groups over time (ANOVA, linear mixed effects model). Results All forty-five children completed the trial (median 11.4 years). Across all subjects, COPM performance and satisfaction scores increased >100% with sustained, maximal gains at 6 months (p 5 logit units). Combined rTMS+CIMT resulted in larger AHA gains at all time points (6 months p=0.006). CIMT alone increased AHA at 2 months (p=0.007), rTMS alone increased AHA at 1 week (p=0.002). Neither treatment decreased unaffected hand function. Affected hand function did not decrease with rTMS in children with ipsilateral corticospinal tract arrangements. Procedures were well tolerated. Conclusion Children with hemiparesis participating in intensive, psychosocial rehabilitation programs perceive marked and sustained increases in goal-specific function. Non-invasive brain stimulation trials are feasible in children with CP. Contralesional inhibitory rTMS may enhance motor learning therapy in children with perinatal stroke.

Effects of transcranial direct-current stimulation on laparoscopic surgical skill acquisition

Changes in medical education may limit opportunities for trainees to gain proficiency in surgical skills. Transcranial direct‐current stimulation (tDCS) can augment motor skill learning and may enhance surgical procedural skill acquisition. The aim of this study was to determine the effects of tDCS on simulation‐based laparoscopic surgical skill acquisition.

P034 Lesioned motor cortex neurophysiology in children with perinatal stroke

Introduction Perinatal stroke (PS) causes most hemiparetic cerebral palsy. Motor recovery is highly dependent on developmental plasticity in bilateral motor cortex. The fundamental neurophysiology of the lesioned motor cortex (M1) is poorly understood. Objective To characterize lesioned corticomotor neurophysiological properties in hemiparetic children with perinatal stroke. Methods Children 6–18years with MRI-confirmed PS and hemiparesis were recruited (Alberta Perinatal Stroke Project). Transcranial magnetic stimulation (TMS) protocols applied to the lesioned M1 measured rest and active motor thresholds (RMT/AMT) and stimulus response curves (SRC:100-150RMT). Paired-pulse TMS explored short-latency intracortical inhibition and intracortical facilitation (SICI/ICF; 2/10ms ISI). Measures were compared to the non-lesioned hemisphere and healthy controls ( n =40, median 12.2years, range 8–18). Motor outcomes by blinded occupational therapists were Assisting Hand (AHA), Melbourne (MA) assessments and Box and Block (BB). Safety and tolerability were assessed. Results Of 45 children (median 11.3years, 25 male; 65% arterial, 35% PVI), TMS of lesioned M1 evoked contralateral MEPs in only 12 (27%). No ipsilateral MEPs were recorded. Thresholds for evoking a stroke-side MEP were higher than the non-lesioned side ( p =0.04).The s-shaped SRC indicated that the morphology and responsiveness to increases in TMS intensities was preserved but shifted down compared to non-lesioned side or controls contralateral SRC. Contralateral SICI (−39.2%, −42.1%) and ICF (42.5%, 43.6%) effects were comparable between lesioned and non-lesioned sides ( p =0.43, p =0.54, respectively), as well as controls SICI ( p =0.30) and ICF ( p =0.22). Latencies of MEPs from the lesion side (24.3ms) were longer than contralateral, non-lesioned MEP (24.3ms versus 21.6ms, p =0.003). The area under the SRC curve is correlated with all AHA ( r =0.9, p =0.01), MEL ( r =0.9, p =0.02) and BB ( r =0.8, p =0.05). Protocols were well tolerated with no adverse events. Conclusion Cortical physiology of contralateral projections from the lesion side can be measured in hemiparetic children with PS using TMS. Individualized neurophysiology will further inform recently demonstrated therapeutic neuromodulation interventions in this population.

EPA-0491 – Glutamate alterations associated with transcranial magnetic stimulation in youth depression: a case series ‘ptsd and the phantom of the opera’

Objective We hypothesized an increase in dorsolateral prefrontal cortex (DLPFC) glutamate levels would occur after three weeks of repetitve transcranial magnetic stimulation (rTMS) treatment and a decrease in major depressive disorder (MDD) symptoms. Method We report six cases (four females) 15–21 years of age with treatment-resistant MDD. Participants had a mean age of 18.7 years and a mean IQ of 102.3. Short echo proton magnetic resonance spectroscopy (H-MRS) was used to quantify glutamate levels in the left DLPFC (4.5cc) before and after rTMS treatment. rTMS was localized to the left DLPFC and applied for 15 consecutive weekdays. Treatment response was defined as a greater than 50% reduction in Hamilton Depression Rating Scale scores (Ham-D).1H-MRS data was analyzed with LCModel to determine glutamate concentration. Results Following rTMS, treatment responders (N=4) showed an increase (relative to baseline) in left DLPFC glutamate levels (11%), which corresponded to an improvement in depressive symptom severity (68% Ham-D score reduction). Treatment non-responders (N=2) had elevated baseline glutamate levels compared to responders in that same region, which decreased with rTMS (−10%). Procedures were generally well tolerated with no adverse events. Conclusions rTMS is feasible and possibly efficacious in adolescents with MDD. In responders, rTMS may act by Induced elevations in elevating DFPLC glutamate levels in the left DLPFC, thereby leading to symptom improvement. Transcranial Magnetic Stimulation for Adolescent Depression (TMSAD)