Ultrasonic Neural Stimulation for Neuromodulation Therapeutics

摘要/摘要 神经组织的电刺激，如脑深部刺激(DBS)和皮质刺激，被广泛使用 应用神经调节技术治疗神经性疾病。穿透电极(例如， 微丝和硅探针)为DBS提供了高空间分辨率，但具有侵入性，取代了神经 组织，产生急性插入创伤，并可能引起异物反应。表面电极， 虽然侵入性较小，但不能产生高度局部化的电场。在这些限制的激励下，目标是 这项提议的目的是开发使用超声波的微创但高度局部化的神经元刺激。 高能聚焦声束传统上用于细胞消融。在这里，我们建议使用 低声能避免任何消融或损伤，利用前所未有的自聚焦功能 声学换能器(SFAT)，可将2-20 MHz声波聚焦在亚毫米大小的区域 电子可调焦距和作用力方向。我们将进行细胞内和细胞外实验 确定基于SFAT的神经调节效应的价值和潜在机制 超声波刺激。该项目的目标是(1)确定最优的SFAT设计和制造 具有新性质的SFAT用于拟议的细胞内和细胞外实验和(2)表征 基于SFAT的超声刺激对正常脑片神经调节功能的影响及其检测 癫痫大脑片的神经调节作用。使用膜片钳和细胞外记录方法，我们将 分别监测离子通量和局部场势，同时改变声刺激频率， 强度、脉冲宽度、脉冲形状、脉冲重复频率以及焦斑(S)、焦点大小和 力量方向。声刺激的安全性将通过组织学进行评估。该项目将提供 对超声波神经刺激的生物学机制的洞察，如果成功，可能是关键的一步 开发一种通过电刺激来替代神经调节的微创方法 治疗癫痫等神经系统疾病。

Summary/Abstract Electrical stimulation of neural tissue, such as deep brain stimulation (DBS) and cortical stimulation, is widely applied therapeutic neuromodulation techniques for neurologic disorders. Penetrating electrodes (e.g., microwires and silicon probes) for DBS provide high spatial resolution, but are invasive, displacing neural tissue, producing acute insertion trauma, and potentially eliciting a foreign-body response. Surface electrodes, while less invasive, cannot generate a highly-localized electrical field. Motivated by these limitations, the goal of this proposal is to develop minimally-invasive and yet highly-localized neuronal stimulation using ultrasound. Focused acoustic beams with high energy are traditionally used for cellular ablation. Here, we propose to use low acoustic energy to avoid any ablation or lesion, exploiting the unprecedented features of Self-Focusing Acoustic Transducers (SFATs) that can focus 2 - 20 MHz sound waves at a sub-mm-sized area with electrically tunable focal length and force direction. We will conduct intracellular and extracellular experiments to determine the value and underlying mechanisms of neuromodulation effects induced by SFAT-based ultrasonic stimulation. The aims of this project are (1) to determine the optimal SFAT designs and fabricate SFATs with novel properties for the proposed intracellular and extracellular experiments and (2) to characterize the neuromodulatory function evoked by SFAT-based ultrasound stimulation in normal brain slices and test its neuromodulatory effect in epileptic brain slices. Using patch clamp and extracellular recording methods, we will monitor ionic flux and local field potentials, respectively, while varying the acoustic stimulation frequency, intensity, pulse width, pulse shape and pulse repetition frequency as well as the focal spot(s), focal size and force direction. The safety of acoustic stimulation will be assessed by histology. This project will provide insights into biologic mechanisms of ultrasonic neural stimulation, and if successful, could be a critical step toward the development of a minimally invasive alternative to neuromodulation by electrical stimulation in the treatment of neurologic disorders such as epilepsy.