ELECTROMECHANICAL NONINVASIVE NEURAL STIMULATION: SAFETY AND EFFICACY

描述(申请人提供)：在过去的十年里，脑刺激设备在治疗各种运动障碍和其他神经病理方面的应用迅速增加。目前的非侵入性技术存在根本性的局限性，尚未达到侵入性方法的效果，如脑深部刺激。电机械刺激(EMS)是一种改进的非侵入性方式，它为非侵入性脑深部刺激提供了可能性。这项技术的初步实验表明，与其他形式的非侵入性刺激相比，该技术具有更好的聚焦和穿透能力。这项研究中提出的工作将探索与该技术相关的基本疗效和安全性标准。第一个研究部分将评估EMS的疗效，记录麻醉成年猫在电机械刺激后立即17区的联合局部视觉诱发电位(VEP)/脑电(EEG)，并与基线、假刺激、经颅磁刺激(TMS)、经颅直流电刺激(TDC)和机械刺激(MS)进行比较。将进行统计分析，以表征VEP/EEG数据的信号特性，并确定机电刺激对神经反应的影响(作为影响的幅度、深度和持续时间的函数)。假设与其他刺激方法相比，机电刺激将导致VEP反应和EEG信号中功率的显著放大，在其他刺激方法无效的脑深部区域产生可测量的影响，并且与这些其他技术相比反应持续时间显著更长。这项研究的第二部分，重点是该技术的安全性，将评估组织温度和组织学变化对机电刺激的影响。动物大脑皮层将暴露在EMS刺激的较长时间内，并通过植入微型热电偶测量和组织学变化，通过一系列组织学染色方法来寻找细胞丢失或胶质增生的模式，以及白质损伤和退化(髓鞘)的模式，以评估热力学变化。我们假设机电刺激的组织将与非刺激的组织难以区分，并且刺激引起的组织温度变化在生理上是微不足道的。这项研究的最后一部分将通过高分辨率14[C]2-脱氧葡萄糖成像(2DG)评估EMS在改变大脑活动功能模式方面的有效性。我们将把这些结果与以前为其他刺激方式(如TMS和TDC)开发的2-DG数据进行比较，以评估EMS的代谢和功能影响(在幅度、焦点和时间方面)。我们假设，与其他模拟方式相比，EMS将表现出更大的焦点、穿透深度和影响程度。这项技术的未来发展可以为创新和改进的神经治疗提供一个平台，同时提供一个巨大的市场机会。与公共健康相关的脑刺激设备被用于治疗各种神经和精神疾病。高地仪器的机电刺激(EMS)是一种非侵入性神经刺激方法，它改进了现有的非侵入性技术，具有优越的聚焦、靶向控制和穿透能力，首次提供了非侵入性脑深部刺激(即刺激大脑深层结构而不最大限度地刺激表面)的可能性。这项技术可以使患有运动障碍和其他神经病理疾病的患者受益，这些患者目前没有得到目前的非侵入性治疗。

DESCRIPTION (provided by applicant): The past decade has seen a rapid increase in the application of brain stimulation devices to treat a variety of movement disorders and other neuropathologies. Present noninvasive technologies suffer from fundamental limitations and have yet to reach the level of efficacy of invasive methods, such as deep brain stimulation. Electromechanical Stimulation (EMS) is an improved noninvasive modality, which offers the potential of noninvasive deep brain stimulation. Preliminary experiments with this technique have revealed improved focality and penetration compared to other forms of noninvasive stimulation. The work proposed in this study will explore fundamental efficacy and safety criteria related to the technique. The first study component will evaluate the efficacy of EMS, where recordings will be made of the combined local visual evoked potential (VEP)/ electroencephalogram (EEG) from area 17 of anaesthetized adult cats immediately following electromechanical stimulation and compared with baseline, SHAM stimulation, transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), and mechanical stimulation (MS). A statistical analysis will be performed to characterize the signal properties of the VEP/EEG data and determine the effect of electromechanical stimulation on neural response (as a function of magnitude, depth, and duration of effect). It is hypothesized that electromechanical stimulation will result in a significantly larger amplification of the VEP response and power in the EEG signal relative to the other methods of stimulation, a measurable effect in deep brain regions for which other stimulation methods are ineffective, and a significantly longer response duration in comparison to these other techniques. The second component of the study, focused on the safety of the technique, will assess tissue temperature and histology changes to electromechanical stimulation. Animal cortices will be exposed to extended durations of EMS stimulation and evaluated for thermodynamic changes, via implanted micro-thermocouple measurements, and histological changes, via an array of histological staining methods to look for patterns of cell loss or gliosis, and white matter damage and degeneration (myelin). We hypothesize that electromechanical stimulated tissue will be indistinguishable from the non-stimulated tissue and that tissue temperature changes from stimulation will be physiologically insignificant. The final component of this study will assess EMS's efficacy in modifying functional patterns of brain activity by means of high resolution 14[C]2-deoxyglucose imaging (2DG). We will compare these results to 2-DG data previously developed for other stimulation modalities (such as TMS and tDCS) to assess the metabolic and functional effects of EMS (in terms of magnitude, focality, and time). We hypothesize that EMS will demonstrate greater focality, depth of penetration, and magnitude of effect compared to other simulation modalities. Future developments with this technology could provide a platform for innovative and improved neurological treatments while simultaneously providing a tremendous market opportunity. PUBLIC HEALTH RELEVANCE Brain stimulation devices are used to treat a variety of neurologic and psychiatric disorders. Highland Instruments' Electromechanical Stimulation (EMS) is a noninvasive neurostimulation method which improves upon current noninvasive technologies with superior focality, targeting control, and penetration, and for the first time offers the possibility of noninvasive deep brain stimulation (i.e., stimulating deep brain structures without maximally stimulating the surface). The technology could benefit patients with movement disorders and other neuropathologies who are currently not served by present noninvasive options.