Stroke is a leading cause of human death and disability but the development of effective pharmacologic neuroprotective agents have largely failed in clinical trials. Available evidence supports that repetitive TMS (rTMS) is safe and has a great potential to be developed as a clinically feasible treatment to reduce ischemic brain damage and stimulate neural plasticity/regeneration after stroke. RTMS is an emerging technique to non-invasively stimulate the cerebral cortex via the focal application of brief magnetic fields. When applied at low frequency and intensity the pulsed magnetic field evokes electrical currents in the underlying cortical neuropil, which results in a net effect of inhibitio. Reducing the cortical excitability in the acute stroke setting by means of rTMS may affect a wide range of cell death mechanisms, including energy depletion, free radical formation, and excitotoxicity. The efficacy and the underlying mechanism of low frequency rTMS treatment of acute ischemic stroke have not been examined before. Our own preliminary data derived from an awake acute rodent stroke model suggests that low frequency rTMS applied acutely after focal ischemic stroke results in significant reductions of the infarct volume and motor impairment.
In Specific Aim 1, we will determine the most effective rTMS protocol and time window for the neuroprotective effect of low frequency rTMS applied to the brain in the acute rodent stroke model. This will be done for bihemispheric and affected hemisphere stimulation.
In Specific Aim 2 we will explore the effects of repeated application of low frequency rTMS during the acute post- stroke phase on neuroregeneration and functional recovery. At the completion of this project, it is our expectation that we will have determined for the first time a safe and effective rTMS protocol for neuroprotection and neuroregeneration in the acute rodent stroke model. This knowledge has significant translational value, as it will inform the design of a phase 1 clinical trial for neuroprotection and regeneration in patients with acute stroke.
The research proposed in this pre- clinical trial of repetitive transcranial magnetic stimulation (rTMS) in the acute rodent stroke model links basic science to treatment of acute stroke patients by identifying an effective rTMS protocol and time window for neuroprotection and neuroregeneration. Such data has significant translational value, as it will inform the design of a phase 1 clinical trial for neuroprotection in patients after acute stroke. Successful reduction of infracted brain tissue and improvement in regeneration of neuronal tissue will reduce stroke morbidity and disability and, thus, dramatically reducing the costs for long-term ambulatory and nursing home care.
