Cellular Mechanisms Underlying State-Dependent Neural Inhibition with Magnetic Stimulation

磁刺激状态依赖性神经抑制的细胞机制

• 批准号: 10574102
• 负责人: Hui Ye
• 金额: $ 14.55万
• 依托单位: LOYOLA UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10574102
• 关键词: Address; Advocate; Affect; Aplysia; Basic Science; Biological; Brain; Brain Injuries; Cell physiology; Cells; Clinical; Computer Models; Computer Simulation; Data; Data Reporting; Dependence; Development; Devices; Electrodes; Electrophysiology (science); Epilepsy; Frequencies; Grant; Guidelines; Impairment; In Vitro; Individual; Interneurons; Ion Channel; Magnetism; Membrane; Mental Depression; Methods; Modeling; Molecular; Monitor; Motor Neurons; Nervous system structure; Neural Inhibition; Neuraxis; Neurons; Neurophysiology - biologic function; Outcome; Output; Pathologic; Pharmacology; Physicians; Physiologic pulse; Physiological; Plant Roots; Play; Population; Post-Translational Protein Processing; Prostheses and Implants; Prosthesis Design; Protocols documentation; Reporting; Research Personnel; Resolution; Retinal Ganglion Cells; Role; Shapes; Sodium Channel; Specificity; Study of magnetics; Synapses; Synaptic Transmission; System; Techniques; Technology; Testing; Tissues; base; behavioral outcome; biophysical properties; brain machine interface; cell type; design; excitatory neuron; experimental study; hippocampal pyramidal neuron; improved; insight; magnetic field; migration; myelination; nervous system disorder; neuromechanism; neuroregulation; next generation; novel; prevent; relating to nervous system; repetitive transcranial magnetic stimulation; response; success; tool; voltage clamp

Neural modulation with repetitive transcranial magnetic stimulation (rTMS) is widely used for the treatment of many neurological diseases. Output of magnetic stimulation is largely dependent on the stimulation parameters, such as the duration, frequency, and intensity of the magnetic field, because they affect the excitation of individual neurons, synaptic transmission, and ion channel dynamics. Recent clinical evidence suggests that the excitation state of the nervous system plays a significant role in the outcome of magnetic stimulation (termed “state-dependent”). For example, magnetic stimulation produces different perceptual or behavioral outcomes that are dependent on the excitability levels of the brain. The instantaneous brain state has been used to promote efficacious induction of plasticity by TMS. In comparison to the clinical success, the neural mechanisms underlying state-dependent magnetic stimulation is largely unknown. Previously, this question has been difficult to address at the cellular and ion channel levels because the large sized TMS coil could not provide highly specific stimulation. Recent development of the micro-coil technology improved the cellular specificity of coil stimulation. These sub-millimeter sized coils allow the study of single cell responses to the magnetic stimulation, and the observation of its state-dependency. Preliminary data report an interesting “state-dependent” phenomena at the single cell level – neurons in a low active state are easier to be completely inhibited by the same magnetic stimulation than the neurons in a high active state. This advocates for monitoring the dynamics of the brain’s excitation states for the optimal design, practice, and analysis of magnetic stimulation on the brain. In this proposal, we will use combined tools of electrophysiology, pharmacology, and computer simulation to investigate the cellular and molecular mechanisms underlying state-dependent neural inhibition by magnetic stimulation with the novel micro-coil technology. Since the level of neural activity is essential in the neuronal response to magnetic inhibition, Aim 1.1 will investigate the state-dependent magnetic stimulation under a spectrum of in vitro physiological/pathological conditions. The biophysics properties of single neurons, such as the size, shape, and membrane conductivity of the neuron, play important roles in magnetic stimulation. Cells of different types have also been found to have different sensitivities in magnetic stimulation. Aim 1.2 will investigate the impact of biophysics properties and types of neurons on state-dependent stimulation. Computational modeling provides insights on the cellular and ion channel mechanisms underlying state-dependent inhibition. We will test the hypothesis that high frequency magnetic stimulation causes a significant reduction in sodium channel conductance, which leads to the state-dependent suppression of neuron activity. Aim 2.1 seeks to directly observe the reduced sodium channel conductance with voltage clamp experiments. Aim 2.2 will use pharmacological tools to directly activate the sodium channels and observe its impact on state-dependent magnetic stimulation. Individual neurons are the building units of the nervous system. The state-dependent inhibition by the magnetic field could have significant implications to the mechanistically-based design of TMS practice in clinical settings. Micro-coil technology is brand new, and only a few labs are able to combine fabrication of the next generation micro-coil devices with an understanding of the technique's effects at a molecular level. Understanding the cellular and molecular mechanisms of micro-coil stimulation will provide guidelines for the development of this cutting-edge technology.

具有重复经颅磁刺激（RTMS）的神经调制广泛用于 许多神经系统疾病的治疗。磁刺激的输出在很大程度上取决于 仿真参数，例如磁场的持续时间，频率和强度， 因为它们会影响单个神经元的兴奋，突触传播和离子通道的兴奋 动力学。最近的临床证据表明，神经系统的兴奋状态发挥了 在磁刺激的结果中起着重要作用（称为“状态依赖性”）。 例如，磁刺激会产生不同的感知或行为结果 取决于令人兴奋的大脑水平。瞬时大脑状态已用于 促进TMS有效诱导可塑性。与临床成功相比 基本依赖状态磁刺激的机制在很大程度上未知。 以前，这个问题在细胞和离子通道级别很难解决，因为 大尺寸的TMS线圈无法提供高度特异性的刺激。最近的发展 微芯技术改善了线圈刺激的细胞特异性。这些亚毫米大小 线圈允许研究单细胞对磁刺激的反应，并观察到它 国家依赖。初步数据报告了一个有趣的“国家依赖”现象 单细胞水平 - 低活性状态的神经元更容易被同一完全抑制 磁刺激比在高活性状态下的神经元。这是监视的倡导者 大脑兴奋的动力状态，以实现磁性的最佳设计，实践和分析 刺激大脑。 在此提案中，我们将使用电生理学，药理学和计算机的组合工具 仿真以研究状态依赖性中性基础的细胞和分子机制 通过新型微型机芯技术抑制磁刺激。由于神经元水平 活动在对磁抑制的神经元反应中至关重要，AIM 1.1将研究 在体外生理/病理学谱下，状态依赖的磁刺激 状况。单神经元的生物物理特性，例如大小，形状和膜 神经元的电导率，在磁刺激中起重要作用。不同类型的单元具有 还发现在磁刺激中具有不同的灵敏度。 AIM 1.2将调查 生物物理特性和神经元类型对状态依赖性刺激的影响。 计算建模提供了有关细胞和离子通道机制的见解 国家依赖性抑制。我们将测试高频磁刺激的假设 导致钠通道电导率显着降低，从而导致状态依赖性 抑制神经元活性。 AIM 2.1试图直接观察减少的钠通道 电压夹具实验的电导。 AIM 2.2将使用药品工具直接 激活钠通道并观察其对状态依赖性磁刺激的影响。 单个神经元是神经系统的建筑单位。国家依赖性抑制 磁场可能与基于机械的TMS设计具有重要意义 在临床环境中练习。微芯技术是全新的，只有少数实验室能够 结合下一代微型油线圈设备的制造与了解 技术在分子水平上的影响。了解 微型线圈刺激将为这项尖端技术的开发提供指南。