Pediatric Hemiplegia: Synergistic Treatment Using rTMS and CIT
Condition: Stroke
MeSH terms: Hemiplegia
Study type: Interventional
Phase: Phase 1

Summary: 
      The strategy in rehabilitating pediatric hemiplegia is to overcome "developmental disuse".
      Disruption of the excitability in the non-stroke hemisphere, with resultant increased
      excitability (disinhibition) in the stroke hemisphere, can be achieved with low-frequency
      repetitive transcranial magnetic stimulation (rTMS), a noninvasive method of stimulating
      targeted areas of the brain. Furthermore, the disruptive effects of low-frequency rTMS can be
      increased and prolonged by preceding it with 6-Hz priming stimulation. We have recently
      demonstrated the safety of this priming/low-frequency rTMS in adults with stroke and we are
      currently engaged in an NIH-funded study exploring the effectiveness, mechanism and safety of
      serial treatments of rTMS combined with motor learning training. Very little research,
      however, has been attempted on interventions to promote brain reorganization and recovery in
      hemiplegia in children. Thus, this study will determine the effectiveness, mechanism, and
      safety of 5 treatments of 6-Hz primed low-frequency rTMS applied to the non-stroke hemisphere
      and combined with constraint induced therapy (CIT) to promote recovery of the paretic hand.
      Fifteen children with pediatric hemiplegia, age 8 -16 years, at each of two pediatric medical
      facilities (total N = 30), will be randomly assigned to one of two treatment groups that will
      receive treatment for 2 weeks. The rTMSreal/CIT group will receive alternating days of the
      real rTMS and CIT for 5 treatments of each. The rTMSsham/CIT group will receive alternating
      days of sham rTMS with real CIT for 5 treatments of each. Subjects will be tested at pretest
      and posttest. The hypotheses are: 1) the rTMS treatment will show no serious side effects, 2)
      both groups will show improvement in hand function but the rTMSsham/CIT group will show
      significantly greater improvement, 3) the rTMSreal/CIT group will also show significantly
      greater improvements in brain reorganization measured by paired-pulse TMS testing, cortical
      silent period testing, and fMRI. The proposed research is important because very little
      research on rehabilitation-induced brain reorganization has been done in pediatric
      hemiplegia. It is innovative because it applies a technique never used before, i.e. 6-Hz
      primed low-frequency rTMS combined with CIT. The potential impact of this research is a
      radical change to pediatric rehabilitation that accomplishes a higher functional recovery.
    

Detailed description: 
      A. Specific Aims The proposed research will explore a new method of promoting brain
      reorganization and recovery of function in children with hemiplegia. Evidence shows that
      although the brain has remarkable reorganization after neural insult, some changes are
      maladaptive and leave the individual with additional loss of function. In the adult, motor
      neurons in the ipsilesional (stroke) hemisphere that have survived the stroke can undergo a
      loss of excitability. Interhemispheric (transcallosal) inhibition is imposed on these neurons
      from the contralesional (non-stroke) hemisphere. In both the adult and the child, evidence
      suggests that increased ipsilateral projections from the contralesional hemisphere to the
      paretic hand, likely due to compensatory behaviors, actually compound the disability. We
      postulate that the effectiveness of paretic limb activity training can be enhanced when
      combined with electrophysiologic intervention that suppresses activity in the contralesional
      motor neurons. Repetitive transcranial magnetic stimulation (rTMS) is a potent and
      noninvasive way to influence the excitability of the brain. rTMS, at low frequencies,
      depresses neural function. By stimulating the contralesional motor cortex at low frequency,
      thereby depressing its interhemispheric inhibition of the ipsilesional motor cortex, a net
      excitatory effect (disinhibition) is induced upon the ipsilesional motor cortex. Preceding
      the low-frequency rTMS with priming rTMS (see below) has been shown to increase the magnitude
      of the after-effect. We have recently demonstrated the safety of single treatments of 6-Hz
      primed low-frequency rTMS in adults with stroke and we are currently engaged in an adult NIH
      R01-funded study exploring the effectiveness, mechanism and safety of serial treatments of
      rTMS combined with motor learning training. Failure to address the large gap in pediatric
      brain reorganization only perpetuates the use of conservative but likely suboptimal treatment
      strategies. Our long-term goal is to restore excitability to surviving but dormant motor
      neurons in the lesioned hemisphere of children with hemiplegia and thereby promote higher
      motor recovery. To achieve this goal, our objective is to combine the effects of 6-Hz primed
      low-frequency rTMS with a current form of motor learning training, constraint induced therapy
      (CIT), to achieve a synergism that may yield unprecedented brain reorganization and recovery
      of function.

      Specific Aim #1: Examine the safety of five treatments of 6-Hz primed low-frequency rTMS
      alternating with five treatments of CIT in children with hemiplegia.

      Adverse effects will be measured through observation for seizures, continual physician
      screening, evaluation of cognitive function and motor function in the nonparetic hand. The
      working hypothesis is:

      1. Five 6-Hz primed low-frequency rTMS treatments combined with CIT will not produce any
      seizure activity nor any other serious adverse effect.

      Specific Aim #2. Determine the synergistic effect of rTMS combined with CIT on functional
      outcomes in children with hemiplegia.

      Fifteen children with hemiplegia at each of two pediatric medical centers (total N=30) will
      be randomly assigned in equal numbers to one of two groups: rTMSreal/CIT, rTMSsham/CIT. The
      working hypotheses are:

        1. Both groups will show significant improvement in functional outcomes in the paretic hand
           at posttest compared to their pretest.

        2. The rTMSreal/CIT group will show significantly greater improvement in function in the
           paretic hand compared to the rTMSsham/CIT group.

      Specific Aim #3: Explore the brain reorganization associated with 6-Hz primed low-frequency
      rTMS combined with CIT.

      Treatment-induced brain reorganization in the ipsilesional hemisphere will be explored with
      evoked cortical excitability, using TMS for paired-pulse testing and cortical silent period
      testing, as well as with voluntary cortical recruitment using functional magnetic resonance
      imaging (fMRI). The working hypotheses are:

        1. Both groups will show significantly greater responses with TMS testing and fMRI testing
           at posttest compared to their pretest.

        2. The rTMSreal/CIT group will show significantly greater changes compared to the
           rTMSsham/CIT group.

      This research is innovative in that it combines a unique form of noninvasive brain
      stimulation (primed low-frequency rTMS) with behavioral training (CIT) to promote a synergism
      that could achieve higher recovery in pediatric hemiplegia than through either treatment
      alone. The expected outcomes are improved hand function with no adverse effects leading to
      improved quality of life and reduced burden of care across the lifespan of children with
      hemiplegia.
    

Intervention name(s): real rTMS combined with constraint induced therapy; sham rTMS combined with constraint induced therapy
Intervention type(s): Device; Device
Intervention description(s): 10 minutes of priming followed by 10 minutes of low-frequency is followed on the next day with constraint induced therapy. A total of 5 treatment days for each therapy is given.; 10 minutes of sham priming followed by 10 minutes of sham low-frequency is followed on the next day with constraint induced therapy. A total of 5 treatment days for each therapy is given.
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Participant)
Primary purpose: Treatment
Keywords: Stroke