The purpose of this study is to test tDCS (transcranial direct current stimulation), a type of non-invasive brain stimulation, to determine whether it can improve motor function in children with perinatal stroke and hemiparesis. Children 6-18 years with imaging-confirmed perinatal stroke and functional motor impairment will be recruited. Children will be randomized (1:1) to receive sham or tDCS (20 minutes daily) during daily intensive, goal-directed motor learning therapy (90 minutes). Motor outcomes will be repeated at baseline, 1 week, and 2 months.
Aim 1: Establish the ability of tDCS to safely enhance motor learning in children with perinatal stroke.
Hypothesis 1: tDCS is safe and well tolerated in children.
Hypothesis 2: Contralesional, cathodal tDCS increases motor functional gains measured by AHA at 2 months in children with perinatal stroke.
Methods details not included elsewhere
Study: Randomized, sham-controlled, double blind, phase II clinical trial.
Patient Population. All children will be recruited through the Alberta Perinatal Stroke Project (APSP); a large population-based perinatal stroke research cohort based at Alberta Children's Hospital and directed by the PI. Prospective APSP ascertainment since 2007 is combined with retrospective enrolment (1992-2007) with comprehensive International Classification of Disease codes (ICD-9, ICD-10)237 and institutional databases. These are fully characterized patients with confirmed diagnosis by modern neuroimaging assessed in person in standardized APSP clinics. Recruitment will occur randomly from the population of all children meeting the criteria below.
Inclusion/exclusion criteria - see below
Data Collection and Management. Candidate APSP families will be contacted with review of consent/assent forms. Families residing outside Calgary will have equal opportunity to participate through existing APSP support systems. All complimentary data from existing studies is extractable from the APSP database (demographics, imaging, risk factors, outcomes).13 Neuroimaging data will be managed through the ACH Pediatric Neuroimaging Laboratory according to institutional protocols. Neurophysiology data will be collected at the ACH Pediatric TMS Laboratory and securely stored centrally.107 The institutional Clinical Research Unit is a database management unit designed for clinical research and currently houses all APSP studies and trials. The research database platform encompasses data capture utilities, management tools, and security measures (Health Canada-compliant). Methods will adhere to the CONSORT guidelines and the study will be registered prior to consent of the first patient (www.clinicaltrials.gov).
Intensive Motor Learning (all subjects). An evidence-based approach to upper extremity motor learning therapy in children with hemiparetic CP will be employed. Protocols have been designed by expert pediatric neurorehabilitation and occupational therapy co-investigators based on best available evidence. All children will participate in the same child-centered, age-appropriate, goal-directed, peer supported motor learning program. Designed as an "after school program" to optimize efficiency, children will attend our hospital for 10 consecutive weekdays over 2 weeks. Each session begins with a 30 minute social snack activity, providing the opportunity for peer social interactions and "recharging" from the school day while engaging their affected extremity in functional activity. Each subject then enters 90 minutes of goal-directed (see COPM in outcome measures) motor learning therapy with an individualized occupational therapist.
Week 1 will employ constraint induced movement therapy (CIMT) according to current practice guidelines. Each child will be custom fit with a removable, bivalved cast that will be worn throughout all therapy sessions. Week 2 will transition to intensive bimanual therapy to integrate gains into more practical bimanual functions. Intensive bimanual therapies are now evidence-based, safe, valid, and effective motor learning strategies in children with hemiparetic CP. Efficacy appears equal to CIMT but the absence of constraint facilitates functional bimanual motor learning and removes the complications of casting. Bimanual tasks will be graded and selected according to relative function with increasing complexity across the relevant spectrum (e.g. passive assist to active manipulator). Tasks will be both symmetrical and asymmetrical, geared to age-appropriate activities of daily living and individual interests, and include active patient participation. Following the acute 10 day intervention, all children receive a structured home program based on the same principles with ongoing therapist support, surveillance, and documentation for 2 months.
Randomization and blinding. Children will be randomized 1:1 to tDCS or sham. The study statistician will perform the randomization based on study number only, being blinded to all subject details. Allocation will then be communicated to the study PI and tDCS neurophysiologist only. The subject, parents, measuring and treating occupational therapists, and all other study members will be blinded to treatment allocation. The neurophysiologist will then program each subjects tDCS unit accordingly. All will experience identical ramp-up of current to 1mA over 30 seconds and maintained stimulation for 120 seconds. Those randomized to treatment will have the same current maintained for 20 minutes during therapy. The tDCS units of those randomized to sham will automatically ramp-down gradually to off over 60 seconds following the initial 120 seconds of stimulation. These sham procedures are well validated in adult tDCS trials. Blinding effectiveness will be evaluated.
Intervention: TDCS - see below.
Outcome measures - see below
Interim Safety Analysis. Any possible major side effects will be immediately reported to the IRB per policy. Minor side effects will be tracked by the safety outcomes specified. An interim safety analysis will be performed after the first 2 camps (12 subjects) to ensure no decrease in hand function has occurred in association with contralesional tDCS. This will be evaluated by comparing change in affected (AHA, MA) and unaffected (GS, PS, BB) hands at both 1 week and 2 months between tDCS and sham populations.
Sample Size. Variables were extrapolated from the most relevant literature, our previous studies in the same population, and personal communication with AHA creators. Smallest detectable difference for the AHA is estimated at 0.97 logit units or approximately 5 logit-based AHA units. Our previous trial in the same population found the proportion achieving this change was approximately 25% with CIMT alone compared to 65% receiving both CIMT and contralesional brain stimulation (rTMS). Therefore, for the primary hypothesis that tDCS improves AHA gains at 2 months, significance level alpha=0.05, power of 90%, and no drop-outs (100% completion in previous trials), 24 patients (12 per group) will be required. This is comparable or larger than most pediatric CP trials and positive tDCS and rTMS adult stroke trials.
Statistical Analysis. Co-investigator expertise in statistical methods (AN) and clinical trial methodology (MH) are established. Primary analysis will examine change in AHA and other outcome variables from baseline to final outcome at 2 months using simple ANOVA. Secondary analysis will explore effects of time and severity using repeated measures ANCOVA with deficit severity as a covariable to examine interactions across treatment groups (tDCS, sham). Safety outcomes will compare changes in unaffected hand function (as above), adverse event rates (tDCS vs sham) using Chi-square/Fisher exact and Mann-Whitney tests. Association between treatment group and subject's estimation of treatment received will be determined to evaluate sham effectiveness (Chi-square/Fisher exact). The sample is not large enough for multivariable modelling. Analysis will be intention-to treat.
- Sham tDCS Device
Intervention Desc: Sham subjects will undergo exactly the same tDCS protocol as outlined above. This includes the initial stimulation sequence, generating the initial transient scalp sensations identical to the treatment group. The stimulator will be programmed by the technologist to automatically ramp down to off over 30 seconds after 120 seconds of stimulation. ARM 1: Kind: Experimental Label: Sham tDCS Description: Sham subjects will undergo exactly the same tDCS protocol as outlined above. This includes the initial stimulation sequence, generating the initial transient scalp sensations identical to the treatment group. The stimulator will be programmed by the technologist to automatically ramp down to off over 30 seconds after 120 seconds of stimulation.
- Interventional TDCS Device
Other Names: DC stimulator (neuroConn GmbH, GE) Intervention Desc: The primary intervention will be cathodal (inhibitory) tDCS over non-lesioned M1. This will be targeted using TMS baseline mapping data and neuronavigation (Brainsight2, Rogue Research, Montreal) individualized to the subjects MRI. Soft, replaceable 25cm2 electrodes will be placed over clean, dry scalp with the cathode over marked M1 and the reference electrode over contralateral forehead/orbit consistent with standard protocols. The current-controlled DC stimulator (neuroConn GmbH, Ilmenau, GE) will be turned up slowly over 30 seconds to the treatment current of 1.0 mA. TDCS will be administered each day during the first 20 minutes of the 90 minute therapy session. Child, family, and both treating and measuring occupational therapists are blinded to treatment allocation. ARM 1: Kind: Experimental Label: Interventional tDCS Description: The primary intervention will be cathodal (inhibitory) tDCS (see below).
- Allocation: Randomized
- Masking: Double Blind (Subject, Caregiver, Outcomes Assessor)
- Purpose: Treatment
- Endpoint: Safety/Efficacy Study
- Intervention: Single Group Assignment
|Type||Measure||Time Frame||Safety Issue|
|Primary||Change from baseline in the Assisting Hand Assessment (AHA) at 1 week||Baseline, 1 week||Yes|
|Primary||Change from baseline in the Assisting Hand Assessment (AHA) at 8 weeks||8 weeks||Yes|
|Secondary||tDCS Safety and Tolerability evaluation (TST)||Each day following the tDCS treatment (10x)||Yes|
|Secondary||Change from baseline in the Canadian Occupational Performance Measure (COPM) at 1 week||Baseline, 1 week||Yes|
|Secondary||Change from baseline in the Canadian Occupational Performance Measure (COPM) at 8 weeks||8 weeks||Yes|