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的潜在益处包括但不限于 不限于具有很少或没有电化学副作用的延长刺激; 基于电池充电时间常数的选择性;在刺激、抑制和 消融;以及非侵入性地实现这些效果，无论是门诊深部脑刺激还是肿瘤 消融术 nsPEF的主要作用是快速建立细胞膜电位（MP）。实时测量 MP动力学是预测nsPEF刺激结果的关键。它们也是理解 双极消除，这是一项独特的功能，可实现nsPEF的干扰靶向， 神经调节然而，通过nsPEF的膜充电发生在纳秒时间尺度上，快得多， 比现有的电生理学和成像方法所能解决的要多。 我们已经解决了这一挑战，通过实施频闪脉冲激光显微镜的MP成像， 精度优于50 ns。在这个独一无二的装置中，细胞装载了快速电压敏感荧光， 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。在不同时间拍摄的荧光照片， nsPEF后显示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，如电压门控离子通道的开放、动作电位的引发和纳米电穿孔。 我们将采用这种全新的设置来理解神经元如何响应的精细机制和原理 纳秒级的电应力我们将描述唤起所需的nsPEF参数， 神经调节作用，并调整干扰靶向协议，以实现这种效果的距离， 刺激电极。我们将执行电场阈值的有限元建模，并使用我们的 体外结果，以确定无创脑深部电刺激的可行性和nsPEF要求。 该项目将产生新的神经元功能的基础知识，包括纳秒级 细胞膜和离子通道的生物物理学。我们将系统地描述nsPEF神经调节 影响，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”的概念收集机械和 nsPEF神经调节的动物和人类研究所需的定量数据。