Ultrasonic Neural Stimulation for Neuromodulation Therapeutics

总结/摘要 神经组织的电刺激，例如深部脑刺激（DBS）和皮层刺激，被广泛应用于神经系统。 应用治疗性神经调节技术治疗神经疾病。穿透电极（例如， 微导线和硅探针）用于DBS提供高空间分辨率，但具有侵入性， 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。由于这些限制，目标 该提议的一个重要方面是开发使用超声波的微创且高度局部化的神经元刺激。 具有高能量的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）可以将2 - 20 MHz声波聚焦在亚毫米大小的区域， 电可调焦距和力方向。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， 超声波刺激本计画的主要目的为：（1）确定最佳的SFAT设计与制作 具有新特性的SFAT，用于拟议的细胞内和细胞外实验;（2）表征 在正常脑片上观察基于SFAT的超声刺激诱发的神经调节功能，并检测其 癫痫脑切片中的神经调节作用。利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电位，同时改变声刺激频率， 强度、脉冲宽度、脉冲形状和脉冲重复频率以及焦斑、焦点尺寸和 力的方向。将通过组织学评估声刺激的安全性。本项目将提供 深入了解超声波神经刺激的生物学机制，如果成功的话， 朝着开发一种微创替代神经调制的电刺激， 治疗神经系统疾病，如癫痫。

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.