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) 是治疗帕金森病、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，对于神经刺激（尤其是神经元尺度的刺激）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，特别是在皮层，为了实现 DLES 的精确、包容和有效的治疗承诺，需要对皮层刺激的生物物理学项目有更机械的理解。人类和小鼠皮层的单细胞电生理学，包括离体和体内药理学、物理光学科学和复杂的计算模型，以识别电刺激的机制，以真正的转化方法，这些多个研究角度将使我们能够。为了在小鼠中测试深入的机制假设以及这些结果在人类中是否成立，我们将测试 DLES 诱导随后的抑制性 (I) 神经元对抗的动态序列的兴奋性 (E) 神经元输出。刺激强度、频率、相位、距离和物种作为调节 E-I 动态序列的时间和强度的关键参数，这些有关神经动力学的数据将通过我们基于集成和激发的循环神经网络模型转化为可操作的知识。将用于预测皮层对新刺激的反应并开发特定的刺激模式以激发所需的神经输出，具体来说，我们将使用全细胞电生理学和识别 DLES 在人类和小鼠皮层急性脑切片中招募不同神经群的生物物理机制。然后，我们将使用清醒的人类和小鼠皮层中的 Neuropixels 探针，并辅以清醒小鼠的光学记录来表征体内对 DLES 的神经和群体反应（目标 2）。用于完善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）。该模型将成为根据所需输出（例如针对 E 细胞）开发特定刺激模式的试验场。或者该模型还将用于测试新的输入刺激，包括幅度和频率斜坡、线性调频脉冲和阶跃函数，以预测这些模型预测的输出或响应，然后将通过进一步的测试来进行。我们不仅将主要模型系统的动力学与人脑的活动联系起来，而且还将为单个神经元和局部回路的活动的可预测调节提供独特的途径，以设计定制的神经调节疗法。多尺度分析电刺激的神经机制将催生新颖的、有针对性的、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记忆障碍、抑郁症、中风恢复和许多其他神经精神疾病的治疗方法。