The coupled vascular hypothesis for transcranial direct current stimulation (tDCS)

项目摘要 经颅直流电刺激（tDCS）被研究用于治疗广泛的脑部疾病， 改变健康个体的认知。tDCS人体试验的规模和广度已经超过了 了解细胞机制。tDCS的灵活性来自于与培训相结合的使用 任务，目标是增强特定任务的可塑性（学习）的“神经元能力”。因此，TDCS 在一项任务中或任务前使用，以产生神经能力的急性或持续变化。合理 tDCS作为临床/神经科学工具的进步需要了解刺激的细胞靶点， 将它们的激活与tDCS期间和之后神经元容量的变化联系起来。神经元，和一个较小的 神经胶质细胞，已经被研究为tDCS细胞靶点。血脑屏障（BBB）的内皮细胞具有 直到最近才被我们的团队发现。然而，众所周知，BBB功能对其他形式的干扰敏感。 电刺激，并且BBB的变化会改变脑功能。事实上，BBB刺激与 tDCS的概念通常用于启动大脑（例如，改变兴奋性或代谢能力）。 该提议提出了一个新的假设和科学前提，即BBB调制如何增强 在tDCS期间或之后的神经容量。我们认为大脑中的传导血管网络 电流，并在此过程中产生的电场跨越血脑屏障高于周围的神经元。我们认为 通过tDCS的BBB极化改变了水和溶质穿过BBB的运输（在刺激期间）， 激活基因的表达，导致神经活性化学物质（包括NO）的产生。 血脑屏障的血管（刺激后），所有这些都调节神经元的微环境， 神经元能力 考虑到将任何tDCS动作解释为反映直接神经元激活（以及因此BBB）的自然偏见， 作为次要/附带现象的反应），我们需要最先进的建模和实验工具来量化 tDCS直接刺激血脑屏障。我们提出了大量的初步数据，从计算机，在体外， 支持我们整体假设的体内研究。这些数据反映了我们团队成功的R21合作; 已经显示了一种新的细胞靶点的可行性，这种RO 1建立了以下机制和潜在影响： 通过tDCS直接激活BBB。目标1：我们将开发多尺度（从头部解剖结构到微血管） 多物理场（耦合电场与电扩散过滤传输）模型。目标2：我们将验证 使用专门设计的体外BBB模型，水和分子渗透性的急性（DCS期间）变化 系统，其中神经元的缺失建立了电流对BBB的直接作用，以及测试 一氧化氮（NO）和其他神经活性基因（神经营养因子）在神经元不存在的情况下被DCS激活。 目的3：使用多光子脑成像技术测定大鼠模型中BBB通透性，我们将分析 tDCS诱导的持续（分钟）BBB通透性变化及其对NO的依赖性。

PROJECT SUMMARY Transcranial Direct Current Stimulation (tDCS) is investigated to treat a broad range of brain disorders and to change cognition in healthy individuals. The scale and breadth of tDCS human trials has outpaced understanding of cellular mechanisms. The flexibility of tDCS derives from use in combination with a training task, with the goal to enhance “neuronal capacity” for plasticity (learning) on the specific task. tDCS is thus applied either during or before a task, to produce an acute or persistent change in neural capacity. The rational advancement of tDCS as a clinical/neuroscience tool requires knowing the cellular targets of stimulation, and linking their activation with changes in neuronal capacity during and after tDCS. Neurons, and to a lesser extent glia, have been studied as tDCS cellular targets. Endothelial cells of the blood-brain barrier (BBB) have been unaddressed until recently by our team. Yet BBB function is well known to be sensitive to other forms of electrical stimulation, and that changes in BBB will alter brain function. Indeed BBB stimulation is consistent with the concept of tDCS acting to generally prime the brain (e.g. changing excitability or metabolic capacity). This proposal addresses a novel hypothesis and scientific premise for how BBB modulation may enhance neural capacity during or after tDCS. We propose that the conductive vascular network across the brain shunts current and in the process generates electric fields across the BBB higher than around neurons. We believe that BBB polarization by tDCS alters the transport of water and solutes across the BBB (during stimulation) and activates the expression of genes leading to the production of neuroactive chemicals (including NO) by the blood vessels of the BBB (after stimulation), all of which modulate the microenvironment of neurons and neuronal capacity. Given a natural bias toward interpreting any tDCS actions as reflecting direct neuron activation (and thus BBB response as secondary/epiphenomena) we require state-of-the-art modeling and experimental tools to quantify the direct stimulation of BBB by tDCS. We present substantial preliminary data from in silico, in vitro, and in vivo studies that support our overall premise. This data reflects a successful R21 collaboration by our team; having shown feasibly of a novel cellular target, this RO1 establishes the mechanism and potential impact of direct BBB activation by tDCS. Aim 1: We will develop a multi-scale (from head anatomy to micro-vasculature) multi-physics (coupling electric fields with electro-diffusion filtration transport) model. Aim 2: We will validate acute (during DCS) changes in water and molecule permeability using a specially designed in vitro BBB model system where the absence of neurons establishes a direct action of current on the BBB, as well as test the activation of nitric oxide (NO) and other neuro-active genes (neurotrophins) by DCS in the absence of neurons. Aim 3: Using multi-photon brain imaging for determining BBB permeability in a rat model, we will analyze the persistent (minutes) BBB permeability changes induced by tDCS and their dependence on NO.