Enhancing Motor Plasticity After Perinatal Stroke Using tDCS
Condition: Perinatal Stroke; Cerebral Palsy
MeSH terms: Stroke; Cerebral Palsy
Study type: Interventional
Phase: Phase 2

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Interventional TDCS; Sham TDCS
Intervention type(s): Device; Device
Intervention description(s): 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.; 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.
Other intervention name(s): DC stimulator (neuroConn GmbH, GE)
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: Triple (Participant, Care Provider, Outcomes Assessor)
Primary purpose: Treatment
Keywords: perinatal stroke; hemiparetic cerebral palsy; brain stimulation; tDCS; constraint-induced movement therapy; hand arm bimanual intensive therapy