Modulation of Brain Plasticity After Perinatal Stroke

NCT ID: NCT01189058

Last Updated: 2013-10-23

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

UNKNOWN

Clinical Phase

PHASE2/PHASE3

Total Enrollment

64 participants

Study Classification

INTERVENTIONAL

Study Start Date

2010-08-31

Study Completion Date

2014-03-31

Brief Summary

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Newborn stroke is the leading cause of a common type of cerebral palsy (CP) that affects thousands of Canadian children and families. Treatments for CP are generally ineffective, and have traditionally focused on the weak body rather than the injured brain. Understanding how the newborn brain responds to injuries like stroke (plasticity) carries the greatest potential for better treatments. We propose to study the ability of two interventions to modulate brain plasticity toward better function in children with stroke-induced CP. One is a rehabilitation method called constraint-induced movement therapy (CIMT), the other is a type of non-invasive brain stimulation called transcranial magnetic stimulation (TMS). TMS is safe and comfortable for children and we recently showed it could improve motor function in children with stroke.

We will perform a special study to test both treatments simultaneously. Children 7-18 years with stroke-induced CP will be recruited into the study from across Alberta. Each child will randomly receive either TMS, CIMT, both, or neither each day for two weeks while attending our new HemiKids Power Camp for motor learning. Improvements will be measured by trained therapists over 1 year. TMS will also measure brain plasticity, both initially and following treatment. Our lead investigator is an expert in both newborn stroke and TMS and has assembled an experienced team of accomplished collaborators to ensure the completion of this important work. This will be the largest study of children with CP examined in this manner. This will be the first clinical trial of non-invasive brain stimulation (TMS) in CP, the largest trial of CIMT (and the first exclusive to newborn stroke), and the first study allowing the direct comparison of two different therapies. In establishing the first dedicated pediatric TMS laboratory in Canada, we will be the first to measure plasticity changes in newborn stroke, advancing new treatments of this previously untreatable and disabling disease.

Patient recruitment is currently underway at Alberta Children's Hospital. Application is currently underway to expand recruitment to Northern Alberta through the Glenrose Rehabilitation Hospital and Stollery Children's Hospital, to enable patients from Northern Alberta greater opportunity to participate as subjects in this study.

Detailed Description

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Perinatal stroke is the leading cause of the most common term-born cerebral palsy: hemiplegic CP (HCP). With morbidity spanning all aspects of a child's life and lasting for decades, global impact is large. Mechanisms are poorly understood and prevention strategies remain elusive. Treatments are limited, leading to loss of hope in children and families that merits exploration of new interventions. Constraint-induced movement therapy (CIMT) may benefit but proper clinical trials are required. The investigators clinical-radiographic classifications have established perinatal stroke syndromes correlating with neurological outcome. Most common are: (1) arterial ischemic stroke of the middle cerebral artery (AIS-MCA) featuring cortical and subcortical damage acquired at birth and (2) periventricular venous infarction (PVI), a novel subcortical injury acquired in utero. These syndromes differ in the essential variables for plastic organization after perinatal injury: location and timing. In addition, recent animal and human studies suggest they may share a similar maladaptive plasticity whereby motor control of the weak side is "installed" in the non-lesioned hemisphere during development. Despite the ideal plasticity model such focal injury in a young brain provides, studies have been limited and suffer from small numbers of older patients with heterogeneous lesions. The value of studying plastic organization will be realized upon translation into meaningful patient benefits.

Transcranial magnetic stimulation (TMS) offers non-invasive measurement of the neurophysiological brain properties underlying neuroplasticity. Repetitive TMS (rTMS) may modulate such systems with therapeutic effect. the investigators recently demonstrated the ability of rTMS to improve motor function in children with chronic stroke. Advances in perinatal brain injury and neurodevelopment are, for the first time, affording novel windows of opportunity for interventions to direct plastic organization toward better outcomes. Via the Alberta Perinatal Stroke Project (APSP), the investigators propose a clinical trial of two interventions to improve function in HCP while measuring the fundamental neurophysiological properties at play.

Aim 1. Determine if rTMS and CIMT can improve motor function in HCP. Hypothesis: Two weeks of daily rTMS improves motor function at 30 days.

Aim 2. Define the neurophysiology of motor organization in stroke-induced HCP at baseline and following rTMS and CIMT.

Hypothesis: rTMS and CIMT reduce excitability of the non-lesioned motor cortex.

Population-based studies through the Alberta Perinatal Stroke Project (APSP) are establishing the largest perinatal stroke cohort to date. The investigators will complete a factorial 2 x 2 randomized clinical trial to determine the ability of daily rTMS and CIMT to improve motor function in children with HCP. Families will attend a child-centered, custom-designed intensive motor learning rehabilitation program (KidsCan Power Camp) for 2 weeks. Outcomes include validated measures of motor function and CP quality of life. The investigators will simultaneously measure the neurophysiology of plastic organization using TMS including cortical excitability, interhemispheric inhibition, and short interval intracortical inhibition. Baseline measures will define organization patterns while post-interventional measurement will evaluate the neurophysiological effects of rTMS and CIMT. Four groups of 16 children each (n=64) will be studied over 24 months with interim safety analysis after 10 and 32 patients.

Successful completion is assured by principle investigator experience in perinatal stroke and TMS and the collaborative support of world leaders in pediatric and adult stroke, TMS, basic neuroscience, and physiatry/rehabilitation. Understanding perinatal stroke plasticity and discovering methods to modulate it toward better outcomes carries a large impact, greatest for children with CP and their families.

Conditions

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Stroke Cerebral Palsy

Keywords

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Perinatal stroke Periventricular venous infarction Presumed perinatal stroke Neonatal stroke Arterial ischemic stroke Fetal stroke Transcranial magnetic stimulation Constraint-induced movement therapy CIMT Cerebral palsy Congenital hemiplegia Hemiplegic cerebral palsy Neuroplasticity Developmental plasticity

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

FACTORIAL

Primary Study Purpose

TREATMENT

Blinding Strategy

TRIPLE

Participants Caregivers Outcome Assessors

Study Groups

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rTMS and CIMT

This group will receive both rTMS and CIMT.

Group Type EXPERIMENTAL

Repetitive Transcranial Magnetic Stimulation (rTMS)

Intervention Type PROCEDURE

TMS can affect discrete functional ares of motor cortex offering non-invasive, painless mapping and modulation of motor systems. Inhibitory rTMS (1Hz)has been shown to safely lower motor cortex excitability in normal patients as well as adult and pediatric stroke patients. Dose is 20 minutes per day (1200 stimulations) x 10 days administered over the non-lesioned M1.

Constraint-induced movement therapy (CIMT)

Intervention Type PROCEDURE

CIMT uses gentle restraint of the fully functional upper extremity to promote functional gains in the affected upper extremity. CIMT is well established to be safe and is likely effective in children with hemiplegic cerebral palsy, many of whom have perinatal stroke as studied here. A custom-fitted, bivalved cast is applied and worn for \>90% of waking hours for the 2 weeks of active treatment according to protocol with daily assessments for comfort.

rTMS and no CIMT

This group will receive rTMS only.

Group Type EXPERIMENTAL

Repetitive Transcranial Magnetic Stimulation (rTMS)

Intervention Type PROCEDURE

TMS can affect discrete functional ares of motor cortex offering non-invasive, painless mapping and modulation of motor systems. Inhibitory rTMS (1Hz)has been shown to safely lower motor cortex excitability in normal patients as well as adult and pediatric stroke patients. Dose is 20 minutes per day (1200 stimulations) x 10 days administered over the non-lesioned M1.

Sham and CIMT

This group will receive CIMT and sham rTMS.

Group Type EXPERIMENTAL

Constraint-induced movement therapy (CIMT)

Intervention Type PROCEDURE

CIMT uses gentle restraint of the fully functional upper extremity to promote functional gains in the affected upper extremity. CIMT is well established to be safe and is likely effective in children with hemiplegic cerebral palsy, many of whom have perinatal stroke as studied here. A custom-fitted, bivalved cast is applied and worn for \>90% of waking hours for the 2 weeks of active treatment according to protocol with daily assessments for comfort.

Sham and no CIMT

This group will receive sham rTMS and no CIMT.

Group Type NO_INTERVENTION

No interventions assigned to this group

Interventions

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Repetitive Transcranial Magnetic Stimulation (rTMS)

TMS can affect discrete functional ares of motor cortex offering non-invasive, painless mapping and modulation of motor systems. Inhibitory rTMS (1Hz)has been shown to safely lower motor cortex excitability in normal patients as well as adult and pediatric stroke patients. Dose is 20 minutes per day (1200 stimulations) x 10 days administered over the non-lesioned M1.

Intervention Type PROCEDURE

Constraint-induced movement therapy (CIMT)

CIMT uses gentle restraint of the fully functional upper extremity to promote functional gains in the affected upper extremity. CIMT is well established to be safe and is likely effective in children with hemiplegic cerebral palsy, many of whom have perinatal stroke as studied here. A custom-fitted, bivalved cast is applied and worn for \>90% of waking hours for the 2 weeks of active treatment according to protocol with daily assessments for comfort.

Intervention Type PROCEDURE

Eligibility Criteria

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Inclusion Criteria

1. Symptomatic hemiplegic CP with impairment(s) of the upper extremity including the hand (Pediatric Stroke Outcome Measure motor \>0.5; AND Manual Ability Classification System I, II,III, or IV; AND both child and parent perceive functional limitations (able to identify personally meaningful deficits in function).
2. MRI confirmed AIS-MCA or PVI (neuroradiological syndrome classified by two blinded, experienced investigators according to previously validated methods)
3. Age at enrollment: 6-18 years
4. Resident in province of Alberta for period of study
5. Informed consent/assent

Exclusion Criteria

1. Multifocal perinatal stroke or other brain injury/abnormality
2. Severe hemiparesis (no voluntary contraction in paretic hand, MACS level V)
3. Intellectual disability causing an inability to comply with study protocol
4. Unstable epilepsy (\>1 seizure/month or \>2 medication changes (dose or agent) in the last 6 months or history of recurrent status epilepticus)
5. Any TMS contraindication including implanted electronic devices
6. Botulinum toxin A injection in the affected upper extremity within the preceding 6 months
7. Orthopedic surgery in the affected upper extremity in the previous 12 months
8. Unwilling to delay any new therapeutic rehabilitational intervention directed towards upper limb function (aside from study home program) for the 6 month duration of the study
Minimum Eligible Age

6 Years

Maximum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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Heart and Stroke Foundation of Canada

OTHER

Sponsor Role collaborator

University of Alberta

OTHER

Sponsor Role collaborator

University of Calgary

OTHER

Sponsor Role lead

Responsible Party

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Adam Kirton

Pediatric Neurologist

Responsibility Role PRINCIPAL_INVESTIGATOR

Principal Investigators

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Adam Kirton, MD MSc FRCPC

Role: PRINCIPAL_INVESTIGATOR

University of Calgary

Locations

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Alberta Childrens Hospital

Calgary, Alberta, Canada

Site Status

Countries

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Canada

References

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Kirton A, Shroff M, Pontigon AM, deVeber G. Risk factors and presentations of periventricular venous infarction vs arterial presumed perinatal ischemic stroke. Arch Neurol. 2010 Jul;67(7):842-8. doi: 10.1001/archneurol.2010.140.

Reference Type BACKGROUND
PMID: 20625091 (View on PubMed)

Kirton A, Deveber G, Gunraj C, Chen R. Cortical excitability and interhemispheric inhibition after subcortical pediatric stroke: plastic organization and effects of rTMS. Clin Neurophysiol. 2010 Nov;121(11):1922-9. doi: 10.1016/j.clinph.2010.04.021.

Reference Type BACKGROUND
PMID: 20537584 (View on PubMed)

Kirton A, Wei X. Teaching neuroimages: confirmation of prenatal periventricular venous infarction with susceptibility-weighted MRI. Neurology. 2010 Mar 23;74(12):e48. doi: 10.1212/WNL.0b013e3181d5a47a. No abstract available.

Reference Type BACKGROUND
PMID: 20308675 (View on PubMed)

Kirton A, deVeber G. Advances in perinatal ischemic stroke. Pediatr Neurol. 2009 Mar;40(3):205-14. doi: 10.1016/j.pediatrneurol.2008.09.018.

Reference Type BACKGROUND
PMID: 19218034 (View on PubMed)

Kirton A, Chen R, Friefeld S, Gunraj C, Pontigon AM, Deveber G. Contralesional repetitive transcranial magnetic stimulation for chronic hemiparesis in subcortical paediatric stroke: a randomised trial. Lancet Neurol. 2008 Jun;7(6):507-13. doi: 10.1016/S1474-4422(08)70096-6. Epub 2008 May 1.

Reference Type BACKGROUND
PMID: 18455961 (View on PubMed)

Kirton A, Deveber G, Pontigon AM, Macgregor D, Shroff M. Presumed perinatal ischemic stroke: vascular classification predicts outcomes. Ann Neurol. 2008 Apr;63(4):436-43. doi: 10.1002/ana.21334.

Reference Type BACKGROUND
PMID: 18306227 (View on PubMed)

Kirton A, Westmacott R, deVeber G. Pediatric stroke: rehabilitation of focal injury in the developing brain. NeuroRehabilitation. 2007;22(5):371-82.

Reference Type BACKGROUND
PMID: 18162700 (View on PubMed)

Raju TN, Nelson KB, Ferriero D, Lynch JK; NICHD-NINDS Perinatal Stroke Workshop Participants. Ischemic perinatal stroke: summary of a workshop sponsored by the National Institute of Child Health and Human Development and the National Institute of Neurological Disorders and Stroke. Pediatrics. 2007 Sep;120(3):609-16. doi: 10.1542/peds.2007-0336.

Reference Type BACKGROUND
PMID: 17766535 (View on PubMed)

Kirton A, Andersen J, Herrero M, Nettel-Aguirre A, Carsolio L, Damji O, Keess J, Mineyko A, Hodge J, Hill MD. Brain stimulation and constraint for perinatal stroke hemiparesis: The PLASTIC CHAMPS Trial. Neurology. 2016 May 3;86(18):1659-67. doi: 10.1212/WNL.0000000000002646. Epub 2016 Mar 30.

Reference Type DERIVED
PMID: 27029628 (View on PubMed)

Related Links

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Other Identifiers

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22163

Identifier Type: -

Identifier Source: org_study_id