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

经颅直流电刺激 (tDCS) 的耦合血管假说

• 批准号: 9891113
• 负责人: MAROM BIKSON
• 金额: $ 34.34万
• 依托单位: CITY COLLEGE OF NEW YORK
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9891113
• 关键词: Acute; Address; Affect; Anatomy; Biological Models; Blood; Blood - brain barrier anatomy; Blood Vessels; Brain; Brain Diseases; Brain imaging; Brain-Derived Neurotrophic Factor; Chemicals; Clinical; Cognition; Collaborations; Collection; Computer Models; Coupled; Coupling; Data; Dependence; Diffusion; Dose; Electric Stimulation; Elements; Endothelial Cells; Environment; Erythema; Etiology; Filtration; Foundations; Functional Magnetic Resonance Imaging; Gene Expression; Genes; Goals; Grant; Head; Homeostasis; Human; Image; In Vitro; Individual; Ion Transport; Ions; Learning; Link; Liquid substance; Metabolic; Modeling; NOS3 gene; Neuroglia; Neurons; Neurosciences; Nitric Oxide; Osmosis; Permeability; Physics; Play; Process; Production; Rattus; Research; Role; Science; Shunt Device; Skin; Synaptic plasticity; System; Testing; Thinking; Time; Training; Vascular System; Water; Work; blood filtration; blood-brain barrier function; blood-brain barrier permeabilization; brain cell; capillary bed; cellular targeting; density; design; electric field; flexibility; foot; in silico; in vivo; innovation; multi-photon; multidisciplinary; neurotrophic factor; novel; quantitative imaging; relating to nervous system; response; solute; theories; tool

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.

项目摘要 研究了经颅直流刺激（TDC），以治疗广泛的脑部疾病和至 改变健康个体的认知。 TDCS人体试验的规模和广度已经超过 了解细胞机制。 TDCS的灵活性与培训结合使用。 任务，以提高特定任务可塑性（学习）的“神经元能力”。因此，TDC是 在任务期间或之前使用，以产生神经能力的急性或持续变化。理性 TDC作为临床/神经科学工具的发展需要了解刺激的细胞靶标，并且 将它们的激活与TDC期间和之后的神经元能力的变化联系起来。神经元，较小 胶质神经胶质已被研究为TDCS细胞靶标。血脑屏障（BBB）的内皮细胞具有 直到最近我们的团队都没有解决。然而，BBB功能众所周知对其他形式的敏感 电刺激以及BBB的变化将改变大脑功能。确实，BBB刺激是一致的 TDC的概念通常使大脑呈现（例如，改变兴奋性或代谢能力）。 该提案介绍了BBB调制如何增强的新型假设和科学信念 TDC期间或之后的神经容量。我们建议跨大脑分流的导电血管网络 电流和在此过程中产生的电场跨BBB高于神经元周围的电场。我们相信 TDCS的BBB极化改变了水和溶液在BBB上的运输（在刺激期间）和 激活导致神经活性化学物质产生的基因表达（包括NO） BBB的血管（刺激后），所有这些都调节神经元的微环境和 神经元能力。 鉴于自然而然地解释任何TDC的作用反映了直接神经元激活（因此BBB 作为次级/epiphenomena的响应）我们需要最先进的建模和实验工具来量化 TDC对BBB的直接刺激。我们介绍了来自硅，体外和IN中的大量初步数据 体内研究支持我们的总体前提。该数据反映了我们团队成功的R21合作； 该RO1显示出可行的新细胞靶标，建立了 TDCS直接激活BBB。 AIM 1：我们将开发一个多尺度（从头部解剖到微血管系统） 多物理（具有电扩散过滤传输的电场耦合电场）模型。目标2：我们将验证 使用特殊设计的体外BBB模型的急性（在DC期间）水和分子通透性的变化 缺乏神经元可以在BBB上建立电流的直接作用的系统，并测试 在没有神经元的情况下，DC激活一氧化氮（NO）和其他神经活性基因（神经营养）。 AIM 3：使用多光子脑成像来确定大鼠模型中的BBB渗透性，我们将分析 TDC诱导的持续（分钟）BBB渗透性变化及其对NO的依赖性。