Targeted Neuromodulation by Nanosecond Pulsed Electric Fields

纳秒脉冲电场的靶向神经调节

• 批准号: 10515459
• 负责人: Andrei G Pakhomov
• 金额: $ 24万
• 依托单位: OLD DOMINION UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10515459
• 关键词: Ablation; Action Potentials; Address; Affect; Animals; Apoptotic; Biophysics; Bypass; Cations; Cell Size; Cell membrane; Cell physiology; Cells; Charge; Chronic; Complex; Cytoskeleton; Data; Deep Brain Stimulation; Disease; Distant; Dyes; Electric Stimulation; Electric Stimulation Therapy; Electrodes; Electrophysiology (science); Elements; Ensure; Event; Exposure to; Fluorescence; Future; Goals; Health; Human; Image; In Vitro; Interdisciplinary Study; Ion Channel; Ion Channel Gating; Ions; Kinetics; Knowledge; Laser Microscopy; Lasers; Link; Maps; Medical; Membrane; Membrane Potentials; Membrane Proteins; Methods; Modality; Modeling; Monitor; Necrosis; Neural Inhibition; Neurons; Neurophysiology - biologic function; Neurosciences; Outpatients; Phosphatidylinositol 4,5-Diphosphate; Photography; Physiologic pulse; Physiological; Property; Protocols documentation; Research; Resolution; Rest; Scientist; Second Messenger Systems; Signal Transduction; Stimulus; Stress; Swelling; Testing; Time; Tissues; Work; base; bioelectricity; design; dielectric property; electric field; fluorescence imaging; high reward; high risk; imaging modality; in vivo; innovation; nano; nanopore; nanosecond; neural network; neuroregulation; novel; outcome prediction; receptor; response; side effect; temporal measurement; tool; tumor ablation; voltage

Nanosecond pulsed electric field (nsPEF) is a new modality for neuromodulation, with unique capabilities qualitatively different from the conventional electrostimulation. The potential benefits of nsPEF include but are not limited to prolonged stimulation with little or no electrochemical side effects; excitation at lower thresholds; selectivity based on cell charging time constant; the capability of choosing between stimulation, inhibition, and ablation; and achieving these effects non-invasively, either for outpatient deep brain stimulation or for tumor ablation. The primary effect of nsPEF is a rapid build-up of cell membrane potential (MP). Real-time measurements of MP kinetics are a key to predicting the outcomes of nsPEF stimulation. They are also a key to understanding bipolar cancellation, a unique feature that enables interference targeting of nsPEF for non-invasive neuromodulation. However, membrane charging by nsPEF occurs on a nanosecond time scale, much faster than could be resolved by the existing electrophysiological and imaging methods. We have addressed this challenge by implementing strobe pulsed laser microscopy for MP imaging with better than 50 ns accuracy. In this one-of-a-kind set-up, cells loaded with a fast voltage-sensitive fluorescence dye are exposed to high-power momentary laser flashes (5 kW, 6 ns). The flashes are dynamically synchronized with nsPEF stimulation of target cells. Photos of fluorescence taken at different times during and after nsPEF show the real-time dynamics of MP changes and how these changes culminate in downstream effects, such as opening of voltage gated ion channels, initiation of action potentials, and nanoelectroporation. We will employ this all-new set-up for understanding fine mechanisms and principles how neurons respond to the nanosecond electric stress. We will characterize nsPEF parameters needed to evoke the desired neuromodulation effect and tune the interference targeting protocols to achieve this effect at a distance from stimulating electrodes. We will perform finite element modeling of the electric field thresholds and use our in vitro results to define the feasibility and nsPEF requirements for non-invasive deep brain stimulation. This project will generate new basic knowledge of neuronal function, including nanosecond-scale biophysics of the cell membrane and ion channels. We will systematically characterize nsPEF neuromodulation effects and link them to dielectric and physiological properties of neurons and to nsPEF stimulation parameters. This in vitro project will utilize R21 “high risk, high reward” concept to collect mechanistic and quantitative data necessary for animal and human studies of nsPEF neuromodulation.

纳秒脉冲电场 (nsPEF) 是一种新的神经调节方式，具有独特的功能 与传统的电刺激有质的不同。 nsPEF 的潜在好处包括但不限于 不限于具有很少或没有电化学副作用的长时间刺激；较低阈值的激发； 基于电池充电时间常数的选择性；在刺激、抑制和刺激之间进行选择的能力 消融；并以非侵入性方式实现这些效果，无论是对于门诊深部脑刺激还是肿瘤 消融。 nsPEF 的主要作用是细胞膜电位 (MP) 的快速增加。实时测量 MP 动力学的研究是预测 nsPEF 刺激结果的关键。它们也是理解的关键 双极消除，这是一种独特的功能，可以实现 nsPEF 的干扰定位，实现非侵入性 神经调节。然而，nsPEF 的膜充电发生在纳秒级时间范围内，速度要快得多 现有的电生理学和成像方法可以解决这个问题。 我们通过采用频闪脉冲激光显微镜进行 MP 成像来应对这一挑战 精度优于 50 ns。在这种独一无二的设置中，细胞装载有快速电压敏感荧光 染料暴露于高功率瞬时激光闪光（5 kW，6 ns）。闪光是动态的 与靶细胞的 nsPEF 刺激同步。期间和期间不同时间拍摄的荧光照片 nsPEF 显示 MP 变化的实时动态以及这些变化如何在下游达到顶峰 效应，例如电压门控离子通道的开放、动作电位的启动和纳米电穿孔。 我们将采用这种全新的设置来理解神经元如何反应的精细机制和原理 到纳秒电应力。我们将描述激发所需的 nsPEF 参数 神经调节效应并调整干扰目标协议以在一定距离内实现这种效果 刺激电极。我们将对电场阈值进行有限元建模，并使用我们的 体外结果以确定非侵入性深部脑刺激的可行性和 nsPEF 要求。 该项目将产生神经元功能的新基础知识，包括纳秒级 细胞膜和离子通道的生物物理学。我们将系统地表征 nsPEF 神经调节 效应并将其与神经元的介电和生理特性以及 nsPEF 刺激联系起来 参数。该体外项目将利用R21“高风险、高回报”的理念，收集机械和 nsPEF 神经调节的动物和人类研究所需的定量数据。