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）是神经调节的新方式，具有独特的功能 定性上与常规静电刺激。 NSPEF的潜在好处包括但 不限于长时间刺激，几乎没有电化学副作用；较低阈值的兴奋； 基于细胞充电时间常数的选择性；在刺激，抑制和 消融;并无创地实现这些影响，要么用于门诊大脑刺激或肿瘤 消融。 NSPEF的主要作用是快速积累细胞膜电位（MP）。实时测量 MP动力学是预测NSPEF刺激结果的关键。他们也是理解的关键 双极取消，这是一种独特的功能，可以使NSPEF的干扰靶向非侵入性 神经调节。但是，NSPEF的膜充电发生在纳秒时间尺度上，速度更快 与现有的电生理和成像方法可以解决。 我们已经通过实施频闪激光显微镜来解决这一挑战，以进行MP成像 大于50 ns准确。在这种独一无二的设置中，装有快速电压敏感的荧光的电池 染料暴露于高功率瞬时激光闪光（5 kW，6 ns）。闪光灯动态 与靶细胞的NSPEF刺激同步。在和 在NSPEF显示MP的实时动力学之后，这些变化如何变化在下游 效果，例如打开电压封闭离子通道，动作电位的主动性和纳米电化。 我们将采用这种全新设置来理解神经元如何反应的精细机制和原则 到纳秒电压。我们将表征唤起所需的NSPEF参数 神经调节效应并调整干扰靶向方案，以在距离 刺激电子。我们将对电场阈值进行有限元建模，并使用我们 体外结果定义了非侵入性深脑刺激的可行性和NSPEF要求。 该项目将对神经元功能产生新的基础知识，包括纳秒尺度 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 影响并将其链接到神经元的营养和物理特性以及NSPEF刺激 参数。这个体外项目将利用R21“高风险，高奖励”概念来收集机械和 NSPEF神经调节的动物和人类研究所需的定量数据。