Mechanisms of Deep Brain Stimulation: Joule Heating and Electroporation

描述（由申请人提供）：使用慢性脑深部电刺激（DBS）治疗医学难治性运动障碍和其他神经和精神疾病的兴趣越来越大。DBS的生理效应仍然是一个基本问题。目前还不清楚什么刺激参数对于DBS的当前或未来使用是最佳的。以前的基础研究主要集中在电刺激引起的神经元膜的直接极化。该提案旨在确定DBS是否可以通过以下方式间接影响脑功能（神经元极化）：1）组织的焦耳加热;或2）血脑屏障的电渗透。已经确定电流可以诱导组织加热和膜电穿孔;但是，尚不清楚临床DBS期间诱导的电场是否足以诱导这些效应。该提案的总体目标是通过分别使用生物热传递模型和体外内皮屏障模型来确定DBS诱导的温度和渗透性变化的潜在规模。即使脑温度或血脑屏障通透性的微小和短暂变化也会对神经元功能产生深远影响，从而影响DBS的疗效或安全性。本研究将首次深入了解这些新型“间接”DBS机制的作用，从而推进临床DBS方案/技术的改进。与公共卫生的相关性：脑深部电刺激（DBS）是一种非常有前途的技术，用于治疗帕金森病和震颤等神经系统疾病。这项提案将确定脑深部电刺激是否通过提高局部温度或改变血脑屏障的通透性来影响大脑功能。这些结果将提高DBS的成功率和安全性。

DESCRIPTION (provided by applicant): There is a growing interest in the use of chronic deep brain stimulation (DBS) for the treatment of medically refractory movement disorders and other neurological and psychiatric conditions. Fundamental questions remain about the physiologic effects of DBS. It is also unclear what stimulation parameters are optimal for the present or future uses of DBS. Previous basic research studies have focused on the direct polarization of neuronal membranes by electrical stimulation. The proposal aims to determine if DBS can indirectly affect brain function (neuronal polarization) through: 1) joule heating of tissue; or 2) electro-permeation of the blood-brain barrier. It is well established that electric current can induce tissue heating and membrane electroporation; however, it remains unclear if the electric fields induced during clinical DBS are sufficient to induce these effects. The overall goal of the proposal is to determine the potential scale of DBS induced temperature and permeability changes by using a bio-heat transfer model and an in vitro endothelial barrier model, respectively. Even small and transient changes in brain temperature or blood-brain barrier permeability can have profound effects on neuronal function and hence on DBS efficacy or safety. This study will provide the-first insight into the role of these novel 'indirect' DBS mechanisms and thus advance improvements in clinical DBS protocols/technology. Relevance to Public Health: Deep Brain Stimulation (DBS) is a highly promising technology for the treatment of neurological disorders such as Parkinson's disease and tremor. This proposal will determine if Deep Brain Stimulation is affecting brain function by raising local temperature or changing the permeability of the blood- brain barrier. These results will improve the success and safety of DBS.