Repetitive Transcranial Magnetic Stimulation (rTMS) to Promote Hand Recovery in Stroke
Condition: Stroke
MeSH terms: Stroke
Study type: Interventional
Phase: Phase 1

Summary: 
      Paralysis following stroke stems not only from the loss of neurons killed by the stroke but
      also from the loss of neurons lying dormant in the stroke hemisphere. One of the reasons
      viable neurons become dormant (down-regulated) is because of excessive interhemispheric
      inhibition imposed on them from the nonstroke hemisphere. The challenge in
      neurorehabilitation is to restore excitability and voluntary control of these down-regulated
      neurons in the stroke hemisphere. Suppression of the source of this excessive
      interhemispheric inhibition can be achieved with the noninvasive method called repetitive
      transcranial magnetic stimulation (rTMS). It has been shown in healthy subjects that the
      known depressant effects of low-frequency rTMS can be increased and prolonged by preceding it
      with 6-Hz priming stimulation. In a recent safety study, we showed that one treatment of 6-Hz
      primed low-frequency rTMS applied to the nonstroke hemisphere is safe. It is now important to
      evaluate a series of these treatments and whether their efficacy can be enhanced by combining
      the rTMS with motor learning training. The specific aims of this study are to determine the
      efficacy, mechanism, and safety of a series of 5 treatments of 6-Hz primed low-frequency rTMS
      applied to nonstroke hemisphere and combined with motor learning training to promote recovery
      of the paretic hand. Forty subjects with stroke will be randomly assigned to one of four
      treatment groups. The rTMS/only group will receive 20 min. of rTMS per day. The Track/only
      group will receive 20 min. of finger tracking training per day. The rTMS/combined group will
      receive alternating days of the rTMS and Track treatments. The rTMS/sham group will receive
      20 min. of rTMS using a sham electrode each day. The hypotheses are: 1) the rTMS/combined
      group will show the greatest improvements in hand function, 2) the rTMS/combined group will
      show the greatest improvements in cortical excitability using paired-pulse TMS testing and in
      brain reorganization using fMRI, and 3) the rTMS treatment will be safe. The proposed
      research is important because it addresses the greatest cause of long-term disability in
      society, hemiparesis following stroke, and it is innovative because it applies a technique
      never used before, 6-Hz primed low-frequency rTMS combined with motor learning training. The
      potential impact of this research is a radical change to rehabilitation that accomplishes a
      higher quality of life in stroke.
    

Detailed description: 
      The proposed research penetrates the problem of hemiparesis following stroke. This problem
      devastates quality of life in thousands of people each year. The brain shows remarkable
      ability to reorganize under certain conditions, including after stroke. Unfortunately, some
      changes are maladaptive and leave the individual with additional loss of function beyond that
      caused directly by the ischemic damage. Specifically, motor neurons in the ipsilesional
      (stroke) hemisphere that have survived the stroke can undergo a loss of excitability due to
      exaggerated interhemispheric inhibition imposed on them from neurons in the contralesional
      (non-stroke) hemisphere through transcallosal pathways. Fortunately, the maladaptive
      reorganization is reversible, even in chronic stroke, through forced-use and forced-learning
      paradigms with the paretic limb. But we postulate that the effectiveness of behavioral
      training can be richly enhanced when combined with electrophysiologic intervention that also
      affects neural excitability. Repetitive transcranial magnetic stimulation (rTMS) is a potent
      and noninvasive way to influence the excitability of the brain. rTMS, at low stimulation
      frequencies, depresses neural function. By stimulating the contralesional motor cortex at low
      frequency, thereby depressing interhemispheric inhibition, a net excitatory effect
      (disinhibition) is induced upon the ipsilesional motor cortex. Furthermore, it has been shown
      in animals and in healthy humans that the depressive effect on the stimulated hemisphere can
      be magnified by preceding the low-frequency rTMS with 6-hz "priming" rTMS. We will call this
      arrangement 6-Hz primed low-frequency rTMS. We contend that by combining 6-Hz primed
      low-frequency rTMS with behavioral motor learning training unprecedented improvements in
      recovery from hemiparesis can be achieved. We have recently demonstrated the safety of a
      single treatment of 6-Hz primed low-frequency rTMS in stroke but a large gap in knowledge
      still exists in not knowing the effect of serial treatments of 6-Hz primed low-frequency rTMS
      combined with motor learning training. Failure to address this gap only perpetuates the use
      of conservative strategies in stroke rehabilitation, which may rob individuals of their
      fullest possible recovery.

      Our long-term goal is to maximize motor recovery following stroke. The objective of this
      proposal is to integrate the excitability effects induced exogenously by rTMS with those
      produced endogenously by motor learning to produce a powerful yet safe interactive effect
      leading to improved recovery from hemiparesis. The central hypothesis is that serial
      treatments of 6-Hz primed low-frequency rTMS combined with motor learning training will be
      effective and safe. Our research team is uniquely qualified to execute this project because
      of 1) special training in rTMS undertaken by the PI in the laboratory of an international
      leader in rTMS, 2) participation of this leader as a consultant, 3) participation of a
      neuroscientist with expertise in stroke neuroplasticity as a consultant, 4) participation of
      a recognized expert in cerebrovascular disease as a co-investigator, 5) conducting the study
      in the University of Minnesota's General Clinical Research Center to maximize protection of
      patients, and 6) inclusion of the Center for Magnetic Resonance Research for studying brain
      reorganization.

      The specific aims of this project are to:

      Specific Aim #1. Determine the efficacy of using serial treatments of 6-Hz primed
      low-frequency rTMS, in isolation and in combination with motor learning training, to improve
      hand function in stroke.

      Forty subjects with stroke (with partial movement in weak hand, able to walk 100 feet, able
      to follow directions, no history of seizures, no medical devices or metal incompatible with
      mri) will be randomly assigned in equal numbers to one of four treatment groups: The rTMSonly
      group will receive 5 treatments of rTMS to the primary motor area (M1) of the contralesional
      hemisphere consisting of 10 min. of 6-Hz ("priming") rTMS at 90% of resting motor threshold
      interrupted into 20 trains of 5-s duration with 25-s intervals between trains then followed
      immediately by 10 additional min. of 1-Hz ("low-frequency") rTMS continuously at 90% of
      resting motor threshold. Treatments will be every other day over two weeks. The Trackonly
      group will receive 5 treatments of computerized finger tracking training every other day for
      two weeks. The rTMScombined group will receive the same rTMS as the rTMSonly group and it
      will be alternated with the same tracking training as the Trackonly group until 5 days of
      each have occurred over a two-week period. The rTMSsham group will receive the same rTMS
      procedures, including similar sound, but no magnetic stimulation will occur. The four
      treatments have a 2x2 factorial design, with rTMS and tracking as the factors, which allows
      estimation of any synergistic effects of rTMS combined with tracking. Behavioral gains in the
      paretic hand will be measured with finger prehension/dexterity tests, finger tracking
      accuracy, subject self ratings and examiner ratings. The working hypotheses are:

        1. the rTMScombined group will show greater improvements in paretic hand function than the
           rTMSonly and Trackonly groups at posttest and at one-month follow-up, and

        2. the rTMSonly and Trackonly groups will show greater improvements than the rTMSsham
           group.

      Specific Aim #2. Explore the neural mechanism associated with 6-Hz primed low-frequency rTMS
      combined with tracking training.

      Following the treatments described in Aim #1, M1 excitability will be measured with
      paired-pulse TMS testing in the ipsilesional hemisphere. This testing will allow for
      examination of both cortical inhibition and excitation. In addition, brain reorganization
      associated with voluntary activation will be measured with functional MRI yielding data on
      volume and signal intensity of active voxels during paretic finger tracking. The working
      hypotheses are:

        1. the rTMScombined group will show greater increases in cortical excitability and brain
           reorganization in the ipsilesional hemisphere than the rTMSonly and Trackonly groups at
           posttest and at one-month follow-up,

        2. the rTMSonly and Trackonly groups will show greater increases than the rTMSsham group.

      Specific Aim #3. Determine the safety of serial 6-Hz primed low-frequency rTMS treatments in
      stroke.

      Associated with the treatments described in Aim #1, adverse effects will be measured through
      observation for seizures at the time of treatment. Neurocognitive tests will measure mood,
      verbal comprehension, perceptual organization, working memory and processing speed. Also, a
      finger tracking test will measure motor control in the nonparetic hand. The working
      hypothesis is:

      1. five 6-Hz primed low-frequency rTMS treatments, given alone or in combination with motor
      learning training, will not produce any seizure activity or any other serious adverse effect.
    

Intervention name(s): rTMS; Motor learning training; rTMS and Tracking; Sham rTMS
Intervention type(s): Device; Procedure; Procedure; Device
Intervention description(s): 600 pulses of 6 hz priming rTMS at 90% of threshold followed by 600 pulses of low-frequency rTMS at 90% of threshold.; one hour of repeated finger tracking movements toward a changing target.; Combination of rTMS and finger tracking; Sham treatment of rTMS
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Participant)
Primary purpose: Treatment