Non- invasive cortical stimulation as neuroprotective and regenerative treatment in stroke

 描述(申请人提供)：中风是人类死亡和残疾的主要原因，但有效的药理神经保护剂的开发在临床试验中基本上失败了。现有证据支持重复TMS(RTMS)是安全的，并有 作为一种临床可行的治疗方法，在减少缺血性脑损伤和刺激卒中后的神经可塑性/再生方面具有很大的潜力。RTMS是一种利用短时磁场聚焦无创刺激大脑皮层的新兴技术。当以低频率和低强度施加时，脉冲磁场在皮层神经束中激发电流，从而导致净抑制效应。通过rTMS降低急性卒中时皮质的兴奋性，可能会影响广泛的细胞死亡机制，包括能量耗竭、自由基形成和兴奋性毒性。低频rTMS治疗急性缺血性卒中的疗效和潜在机制尚未被研究过。我们自己的初步数据来自清醒的急性啮齿动物卒中模型，表明在局灶性缺血性卒中后急性应用低频rTMS可以显著减少梗塞体积和运动障碍。在具体目标1中，我们将确定最有效的rTMS方案和时间窗，以实现低频rTMS对急性啮齿动物中风模型的脑保护作用。这将用于双半球和受影响的半球刺激。在具体目标2中，我们将探讨卒中后急性期重复应用低频rTMS对神经再生和功能恢复的影响。在该项目完成后，我们期望首次确定一种安全有效的rTMS方案，用于急性啮齿动物卒中模型的神经保护和神经再生。这一知识具有重要的翻译价值，因为它将为急性中风患者神经保护和再生的1期临床试验的设计提供信息。

 DESCRIPTION (provided by applicant): 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.