Interaction of Motor Learning with Transcranial Direct Current - Efficacy and Mechanisms

项目摘要 尽管对经颅直流电刺激的机制和应用进行了数十年的研究， （tDCS），将tDCS转化为广泛使用和有意义的治疗方法的过程停止了。我们建议这是一个 这是三个因素的结果，将在本建议中加以解决。一是刺激力度保持 其次，对于刺激是否应该与特定的行为配对，缺乏明确性。 第三，对基本的行动机制缺乏共识。我们在体外实验中 电场刺激可以使神经元与所施加的场成比例地收缩，所施加的场与 同时诱导突触可塑性，因此是功能特异性的。鉴于此，tDCS应该继承 同步行为训练的特异性和效果应与强度成比例。这一假设将是 在运动学习的背景下进行了平行的人类和大鼠实验。目标1是测试 预测刺激必须与行为运动学习同时进行，并且效果随强度而变化 并与极性相反。在人类身上，我们将用一种新开发的电极蒙太奇来测试这一点， 迄今为止运动皮层上的最高场强，导致运动序列的强效应量 学习对于大鼠，我们将使用一种新的刺激方案，对大鼠在到达颗粒的学习中具有强烈的影响。 任务目标2是在人类和大鼠中测试这种预测，即刺激运动皮层的效果是特定的 而在人类身上，这种效果是针对训练任务的。结果测量将是运动学习和 运动皮质兴奋性（运动诱发电位）。目的3是在大鼠中检验行为 tDCS的益处与运动皮层的空间特异性功能和结构变化相关 （用2D运动图和突触标记物测量），并且因果地取决于运动皮层的调制 活性（用化学发生失活控制）。这些实验的结果，无论是否 他们证实或反驳基本假设，将直接解决限制进步的因素。通过 强调严谨性，该项目将产生强大的实验，可以作为未来的标准工具， 探索通过专注于运动学习，这项工作立即适用于运动康复。

PROJECT SUMMARY Notwithstanding decades of work on the mechanisms and applications of transcranial direct current stimulation (tDCS), the translation of tDCS to a broadly-used and meaningful therapy is halted. We propose that this is a result of three factors that will be addressed in this proposal. First, the intensity of stimulation has remained limited; Second, there is a lack of clarity as to whether stimulation should be paired with a specific behavioral task; and third, there is a lack of consensus on the underlying mechanisms of action. We have shown in vitro that electric field stimulation can polarize neurons in proportion to the applied field, which interacts with concurrent induction of synaptic plasticity, and is thus functionally specific. In light of this, tDCS should inherit the specificity of concurrent behavioral training and effects should scale with intensity. This hypothesis will be tested here in parallel human and rat experiments in the context of motor learning. Aim 1 is to test the prediction that stimulation has to be concurrent to behavioral motor learning, and effects scale with intensity and reverse with polarity. In humans we will test this with a newly-developed electrode montage that achieves the highest field-intensities on the motor cortex to-date, resulting in strong effect sizes for motor sequence learning. For rats, we will use a new stimulation protocol with strong effects on learning in a pellet-reaching task. Aim 2 is to test the prediction, in humans and rats, that effects are specific to the stimulated motor cortex and, in humans, that effects are specific to the trained task. Outcome measures will be motor learning and motor cortex excitability (motor-evoked potentials). Aim 3 is to test the hypothesis in rats that behavioral benefits of tDCS are associated with spatially specific functional and structural changes in the motor cortex (measured with 2D motor map and synaptic markers), and causally depends on modulation of motor cortex activity (controlled with chemogenetic inactivation). The outcomes of these experiments, regardless of whether they confirm or refute the basic hypothesis, will directly address the factors that are limiting progress. By emphasizing rigor this project will yield robust go-to experiments that can serve as standard tools for future exploration. By focusing on motor learning, the work is immediately applicable to motor rehabilitation.