Biophysical Mechanisms of Cortical MicroStimulation

皮质微刺激的生物物理机制

• 批准号: 10711723
• 负责人: SYDNEY S CASH
• 金额: $ 336.02万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-06 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10711723
• 关键词: Acute; Adult; Affect; Animal Model; Biological Models; Biophysical Process; Biophysics; Brain; Brain Diseases; Calcium; Calibration; Cells; Clinical; Clinical Trials; Complement; Computer Models; Coupled; Critiques; Data; Data Set; Development; Disease; Electric Stimulation; Electrophysiology (science); Elements; Engineering; Epilepsy; Exhibits; Feedback; Fire - disasters; Frequencies; Future; Human; Image; Individual; Knowledge; Logic; Mediating; Memory Disorders; Mental Depression; Modeling; Mus; Neural Network Simulation; Neurons; Operative Surgical Procedures; Optics; Outcome; Output; Parkinson Disease; Patients; Pattern; Pharmacology; Phase; Physiological; Physiology; Population; Ramp; Recurrence; Research; Resolution; Resources; Rodent; Route; Slice; Stimulus; Techniques; Testing; Therapeutic; Time; Translating; Type I Epithelial Receptor Cell; Work; Writing; awake; biophysical properties; cell type; clinical application; density; design; experimental study; in vivo; insight; meetings; microstimulation; network models; neural; neural stimulation; neuromechanism; neuropsychiatry; neuroregulation; novel; novel therapeutics; patch clamp; predictive modeling; prevent; recruit; response; side effect; stroke recovery; therapeutically effective; tool; translational approach; two-photon

Direct local electrical stimulation (DLES) is an increasingly important therapeutic tool for treating brain disorders such as Parkinson’s, epilepsy, and OCD. There is considerable disagreement, however, as to how neural stimulation, especially at the scale of neurons, affects human brain function. This lack of understanding hampers the design and implementation of more effective stimulation approaches, particularly in the cortex. To deliver on the precise, inclusive, and effective therapeutic promise of DLES, a more mechanistic understanding of the biophysics of cortical stimulation is required. This project combines single-cell electrophysiology in both human and mouse cortex, both ex-vivo and in vivo with pharmacology, optical physiology, and sophisticated computational modeling to identify the mechanisms underlying electrical stimulation. In a truly translational approach, these multiple research angles will allow us to test in-depth mechanistic hypotheses in the mouse and whether these results hold true in the human. We will test the hypothesis that DLES induces a dynamic sequence of excitatory (E) neuron output countered by subsequent inhibitory (I) neuron. We will evaluate stimulation intensity, frequency, phase, distance, and species as key parameters in modulating the timing and strength of this E-I dynamic sequence. These data on neuronal dynamics will be leveraged into actionable knowledge through an integrate-and-fire based recurrent neuronal network model which we will use to predict cortical responses to novel stimuli and develop specific stimulation patterns to evoke desired neural outputs. Specifically, we will identify the biophysical mechanisms by which DLES recruits different neuronal populations in acute brain slices of human and mouse cortex using whole-cell electrophysiology and pharmacology (Aim 1). We will then characterize neuron and population responses to DLES in vivo, using Neuropixels probes in awake human and mouse cortex, complemented by optical recordings in the awake mouse (Aim 2). This extensive and detailed data set will be used to refine and validate a trainable neural network model we have developed to assess stimulation effects on E and I cell types (Aim 3). The model will be the testing ground to develop specific patterns of stimulation based on desired outputs such as targeting either E or I cells. The model will also be used to test novel input stimuli including amplitude and frequency ramps, chirps, and step functions to predict neural responses. Testing these model-predicted outputs, or responses, will then be carried out through further ex- and in-vivo physiology. Not only will we connect dynamics of a primary model system to activity in the human brain, but this work will also provide a unique route toward predictable modulation of activity in individual neurons and local circuits to design tailored neuromodulation therapies. Our multi-scale analyses of the neural mechanisms of electrical stimulation will catalyze novel, targeted, and mechanistically driven therapeutic approaches that could revolutionize stimulation-based treatment for memory disorders, depression, stroke recovery, and a host of other neuropsychiatric ailments.

直接局部电刺激(DLEs)是治疗帕金森氏症、癫痫和强迫症等脑部疾病的一种日益重要的治疗工具。然而，关于神经刺激，特别是神经元规模的刺激如何影响人类大脑功能，存在相当大的分歧。这种理解的缺乏阻碍了更有效的刺激方法的设计和实施，特别是在大脑皮层。为了实现DLES的精确、包容和有效的治疗承诺，需要对皮质刺激的生物物理学有更多的机械性理解。该项目结合了体外和体内人类和小鼠大脑皮质的单细胞电生理学，以及药理学、光学生理学和复杂的计算模型，以确定电刺激的机制。在一种真正的翻译方法中，这些多个研究角度将允许我们在老鼠身上测试深入的机械论假设，以及这些结果是否适用于人类。我们将检验这样一个假设，即DLES诱导兴奋性(E)神经元输出的动态序列被随后的抑制性(I)神经元对抗。我们将评估刺激强度、频率、相位、距离和种类作为调节这个E-I动态序列的时间和强度的关键参数。这些关于神经元动力学的数据将通过一个基于整合和激发的递归神经网络模型被利用到可操作的知识中，我们将使用该模型来预测皮质对新刺激的反应，并开发特定的刺激模式来唤起期望的神经输出。具体地说，我们将使用全细胞电生理学和药理学来确定DLES在人和小鼠皮质的急性脑片中招募不同神经元群体的生物物理机制(目标1)。然后，我们将使用清醒的人类和小鼠皮质中的神经像素探针，辅之以清醒的小鼠的光学记录，在活体中表征神经元和群体对DLEs的反应(目标2)。这一广泛而详细的数据集将用于改进和验证我们开发的可训练神经网络模型，以评估对E和I细胞类型的刺激效果(目标3)。该模型将作为试验场，根据期望的输出开发特定的刺激模式，例如针对E细胞或I细胞。该模型还将用于测试新的输入刺激，包括幅度和频率斜坡、线性调频和阶跃函数，以预测神经反应。然后，将通过进一步的体外和体内生理学来测试这些模型预测的输出或响应。我们不仅将初级模型系统的动力学与人脑中的活动联系起来，而且这项工作还将提供一条独特的途径，对单个神经元和局部电路的活动进行可预测的调制，以设计定制的神经调节疗法。我们对电刺激神经机制的多尺度分析将催化新的、有针对性的和机械驱动的治疗方法，这些方法可能会彻底改变基于刺激的治疗记忆障碍、抑郁症、中风康复和许多其他神经精神疾病。