Biophysical Mechanisms of Cortical MicroStimulation

直接局部电刺激（les）在治疗帕金森病、癫痫和强迫症等脑部疾病方面越来越重要。然而，关于神经刺激，尤其是神经元刺激，如何影响人脑功能，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。为了提供精确、包容和有效的治疗承诺，需要对皮层刺激的生物物理学有更机械的理解。该项目结合了人类和小鼠皮层的单细胞电生理学，体外和体内，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。在真正的转化方法中，这些多个研究角度将使我们能够在小鼠中测试深入的机制假设，以及这些结果是否适用于人类。我们将验证这一假设，即les诱导兴奋性(E)神经元输出的动态序列被随后的抑制性(I)神经元抵消。我们将评估刺激强度、频率、相位、距离和物种作为调节这一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活的循环神经元网络模型转化为可操作的知识，我们将使用该模型来预测皮层对新刺激的反应，并开发特定的刺激模式来唤起期望的神经输出。具体来说，我们将利用全细胞电生理学和药理学来确定脉冲脉冲在人类和小鼠皮层急性脑切片中募集不同神经元群的生物物理机制（目的1）。然后，我们将在清醒的人和小鼠皮层中使用神经像素探针，辅以清醒小鼠的光学记录，在体内表征神经元和群体对脉冲脉冲的反应（目的2）。这个广泛而详细的数据集将用于完善和验证我们开发的可训练神经网络模型，以评估刺激对E和I细胞类型的影响（目的3）。该模型将作为试验场，开发基于期望输出的特定刺激模式，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，包括振幅和频率斜坡、啁啾和阶跃函数，以预测神经反应。测试这些模型预测的输出或反应，然后将通过进一步的体外和体内生理学进行。我们不仅将主要模型系统的动力学与人类大脑的活动联系起来，而且这项工作还将为个体神经元和局部回路的活动的可预测调节提供一条独特的途径，以设计量身定制的神经调节疗法。我们对电刺激的神经机制的多尺度分析将催化新的、有针对性的、机制驱动的治疗方法，这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。

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.