Influence of Theta Burst Stimulation and Carbidopa-Levodopa on Motor Performance in Stroke Patients
Condition: Stroke
MeSH terms: Stroke
Study type: Observational

Summary: 
      This study will examine whether transcranial magnetic stimulation (TMS) of the brain used in
      combination with carbidopa-levodopa is more effective in temporarily improving the speed of
      hand movement in stoke patients than TMS alone. In TMS, a wire coil is held on the patient's
      scalp. A brief electrical current is passed through the coil, creating a magnetic pulse that
      stimulates the brain. The effect of TMS on the muscles is detected with small metal disk
      electrodes taped to the skin of the arms or legs. Carbidopa-levodopa is a medication usually
      used to treat Parkinson's disease, but it may improve the effect of theta burst stimulation.

      Two kinds of TMS are used in this study. In single-pulse TMS one or two pulses are delivered
      at a time in order to measure brain activity at that moment. In repetitive TMS (rTMS), a
      series of pulses are given in short bursts, temporarily altering brain activity. The type of
      rTMS used in this study is called theta burst stimulation.

      Healthy normal volunteers and people who had a stroke 6 months or more before entering the
      study may be eligible to participate. All candidates must be between 18 and 90 years of age.
      Stroke patients must have had significant hand weakness and made a moderate or good recovery
      and must be able to move either the thumb or the wrist on the affected hand reasonably well.
      Normal volunteers must be right-handed.

      Participants complete the testing for this study in four main sessions scheduled at least a
      week apart and five short follow-up sessions. At each main session, participants take either
      a carbidopa-levodopa tablet or a placebo (a look-alike inactive substance). Stroke patients
      have their arm and hand function assessed using two tests. One requires them to insert pegs
      into holes; the other includes writing, lifting various objects, and performing activities
      like turning pages, feeding or stacking checkers.

      All subjects complete a questionnaire regarding their mood and alertness and then perform
      tests of thumb or wrist movement. For this test, a small electrical stimulus is applied to
      the side of the hand and the subject must respond to the stimulus as quickly as possible by
      making a thumb or wrist movement. This is repeated several times over about 3 minutes. A
      second test follows in which the subject moves the thumb or wrist in response to a beep from
      a speaker. This test is repeated several times over about 8 minutes. Some measurements are
      taken using single-pulse TMS during the beginning, middle and end of this test. In two of the
      four sessions, theta burst stimulation is applied after the single-pulse TMS and in the other
      two sessions, sham theta burst stimulation is applied.

      Five follow-up sessions are scheduled one day after each main session and one week following
      the final one. In these sessions, subjects perform an abbreviated form of the thumb movement
      tests.
    

Detailed description: 
      OBJECTIVE:

      Theta Burst Stimulation (TBS) is a type of sub-threshold repetitive Transcranial Magnetic
      Stimulation (rTMS) which has effects on the excitability of human motor cortex that outlast
      stimulation by up to an hour. TBS also affects performance of a motor task for up to 30
      minutes after stimulation in healthy subjects, and improves reaction times (and increases
      corticospinal excitability) in patients with chronic stroke (Talelli 2005). The advantages of
      TBS over other non-invasive brain stimulation strategies are its low intensity, short
      duration of application and long lasting effects.

      The spectrum of behavioral effects investigated is so far modest. Evidence is accumulating
      that dopaminergic agents enhance synaptic plasticity (Otani 1998) and improve motor training
      in healthy humans (Meintzchel 2005). After stroke, Carbidopa-Levodopa has also enhanced the
      response to physiotherapy and motor learning (Scheidtmann 2001, Floel 2005). This protocol
      aims to test the hypothesis that Carbidopa-Levodopa may enhance the beneficial effect of TBS
      on reaction times in patients with chronic stroke.

      STUDY POPULATION:

      We plan to investigate 18 patients with motor impairment more than 6 months after ischemic
      stroke, and 10 healthy volunteers. Approval is sought for a total of 28 patients and 30
      healthy volunteers to account for possible dropouts and pilot experiments (described below).

      DESIGN:

      Each subject will be asked to participate in 4 sessions, at least a week apart. The
      experiment will test simple reaction times in the thumb or wrist of the paretic hand before
      and 7 minutes after either genuine or sham TBS. This will be followed by a measure of motor
      learning, using a well-characterized paradigm (Muellbacher 2001), which involves optimizing
      an externally paced ballistic thumb (or wrist) movement, and TMS measurement of corticospinal
      excitability. Performance of the learned task will be further assessed (and TMS measures
      made) at 2 hours, 1 day and 1 week following the training session. The experimental design
      for the four sessions will be 2x2 with TBS/sham and Carbidopa-Levodopa/placebo. For TBS, the
      patient will be given 3 minutes of either genuine or sham TBS to the hand representation of
      the motor cortex (Huang 2005). For Carbidopa-Levodopa/placebo, identical preparations from
      the NIH pharmacy will be given 1 hour beforehand. TBS has previously been used in 72 healthy
      subjects (7 studies) in Europe and in 10 patients with chronic stroke (2 studies) in the Lead
      Associate Investigator's lab in London. No side effects or seizures have been reported. Ten
      normal volunteers will be studied first to optimize experimental settings.

      OUTCOME MEASURES:

      The primary outcome measure will be reaction times. Improvement in peak acceleration in the
      learning task will constitute a secondary measure. We expect to see improved reaction times
      with genuine TBS (vs. sham) and will look for an interaction whereby Carbidopa-Levodopa may
      enhance this effect (vs. placebo). This would suggest that synergy between dopaminergic
      modulation and TBS may show promise to produce clinical gains after stroke.
    

Keywords: Neuromodulation; Stroke; Motor Cortex; Motor Learning; L-Dopa; Transcranial Magnetic Stimulation; Levodopa; Healthy Volunteer; HV