Pediatric Hemiplegia: Synergistic Treatment Using rTMS and CIT

1. 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.