Influence of Theta Burst Stimulation and Carbidopa-Levodopa on Motor Performance in Stroke Patients

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.