Effects of direct-current stimulation on synaptic plasticity

直流电刺激对突触可塑性的影响

• 批准号: 9913593
• 负责人: LUCAS C PARRA
• 金额: $ 30.91万
• 依托单位: CITY COLLEGE OF NEW YORK
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-15 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9913593
• 关键词: AMPA Receptors; Affect; Anodes; Apical; Area; Behavior Therapy; Behavioral; Binding; Biophysics; Brain; Calcium; Calcium Channel; Charge; Clinical; Clinical Trials; Cognitive; Computer Models; Dendrites; Dependence; Development; Disease; Dose; Electrodes; Fostering; Goals; Head; Hippocampus (Brain); Human; Image; In Vitro; Intervention; Investigational Therapies; Learning; Link; Long-Term Depression; Long-Term Potentiation; Measures; Membrane; Mental Depression; Methods; Modeling; N-Methylaspartate; NMDA receptor antagonist; Nature; Neurologic; Neurons; Outcome; Pain; Pathway interactions; Pharmacology; Phosphorylation; Protocols documentation; Pyramidal Cells; Reporting; Research Personnel; Role; Science; Series; Slice; Sodium Channel; Specificity; Stroke; Synapses; Synaptic plasticity; Techniques; Testing; Tetanus; Time; Treatment Protocols; United States National Institutes of Health; Validation; clinically relevant; cognitive function; experience; experimental study; extracellular; improved; innovation; learned behavior; neuronal cell body; neurophysiology; neuroregulation; neurotropic; patch clamp; polarized cell; predict clinical outcome; public health relevance; response; side effect; two-photon; voltage

 DESCRIPTION (provided by applicant): Transcranial direct current stimulation (tDCS) is a neuromodulatory technique that applies weak electric currents to the head. tDCS is proposed to modulate cognitive function with few known side effects and is under investigation for the treatment of diverse neurological or psychiatric conditions such as pain, depression, and stroke. The conventional assumption for the mechanism of action of tDCS is that a positively charged electrode increases cortical 'excitability' and this 'enhances' function attributed to the targeted cortical area. However, this simplistic excitability assumption does not explain the diversity across studies and specificity within studies of reported cognitive effects, and has not been reliable at predicting outcomes of clinical trials. To guide and accelerate the development of new treatment protocols, it is important to clarify the cellular mechanisms of direct current stimulatin (DCS). We propose that DCS acts via a modulation of endogenous synaptic plasticity mechanisms. Support for this comes from pharmacological experiments in humans as well as direct evidence that DCS can boost synaptic plasticity in brain slices. The goal of this proposal is to determine the cellular mechanisms by which DCS modulates long-term synaptic plasticity. We have recently demonstrated robust effects of DCS on long-term potentiation (LTP) and long-term depression (LTD) using standard plasticity induction protocols such as tetanus and theta burst stimulation. We will probe well-established cellular mechanisms of these induction protocols in hippocampal slices, which provide unique control of the effects of stimulation on different cellular compartments. In Aim 1 we explore the specific hypothesis that DCS modulates LTP/LTD by polarizing dendrites directly affecting calcium dynamics through voltage dependent calcium channels. In Aim 2 we test the specific hypothesis that DCS modulates LTP by polarizing cell somata, thus modulating post-synaptic firing rate. A series of predictions that result from these specific hypotheses will be tested using two-photon calcium imaging, stimulation and recordings from multiple pathways, patch-clamp recordings, and pharmacological interventions to determine involvement of calcium and sodium channels as well as neuro-modulators such as brain-derived neurotropic factor (BDNF). Finally, all experimental results will be synthesized in biophysically realistic computational models. Our basic proposal provides a mechanistic explanation for observed functional specificity, because only networks undergoing plasticity are boosted by DCS. Importantly, if confirmed, our specific hypotheses link the mechanisms of DCS with well-established mechanisms of LTD/LTP, which are in turn linked to learning and disease. This has important clinical implications. For instance, it suggests that tDCS will be most effective as an adjunct to behavioral interventions that foster plasticity and it provides answers for clinically relevant questions such as how long the effects of tDCS persist. The results of this project will provide a precise and quantitative framework to understand the cellular mechanistic of DCS, which is required in order to advance the science and treatment of tDCS.

 描述（由申请人提供）：经颅直流电刺激 (tDCS) 是一种向头部施加微弱电流的神经调节技术，旨在调节认知功能，且几乎没有已知的副作用，并且正在研究用于治疗各种神经或疾病。经颅直流电刺激（tDCS）作用机制的传统假设是，带正电的电极会增加皮质的“兴奋性”，而这种“增强”的功能归因于目标。 然而，这种简单化的兴奋性假设并不能解释研究中报告的认知效应的多样性和特异性，并且在预测临床试验结果方面并不可靠。对于阐明直流刺激 (DCS) 的细胞机制很重要，我们认为 DCS 通过调节内源性突触可塑性机制发挥作用，这一点来自人体药理学实验以及 DCS 可以增强刺激的直接证据。该提案的目标是确定 DCS 调节长期突触可塑性的细胞机制。我们最近证明了 DCS 对长时程增强 (LTP) 和长期抑制 (LTD) 的强大作用。 ）使用标准的可塑性诱导方案，例如破伤风和 theta 爆发刺激，我们将在海马切片中探索这些诱导方案的成熟细胞机制，这些机制提供了对不同细胞的刺激效果的独特控制。在目标 1 中，我们探讨了 DCS 通过极化树突通过电压依赖性钙通道直接影响钙动态来调节 LTP/LTD 的具体假设。在目标 2 中，我们测试了 DCS 通过极化细胞体来调节 LTP 的具体假设，从而调节后。由这些特定假设产生的一系列预测将使用双光子钙成像、来自多个通路的刺激和记录、膜片钳记录和最后，所有实验结果都将在生物物理现实的计算模型中进行综合，我们的基本建议为观察到的现象提供了机制解释。功能特异性，因为只有经历可塑性的网络才会受到 DCS 的增强，重要的是，如果得到证实，我们的具体假设会将 DCS 机制与完善的 LTD/LTP 机制联系起来，而后者又与学习和疾病相关。例如，它表明经颅直流电刺激 (tDCS) 作为促进可塑性及其行为干预的辅助手段最为有效。 为临床相关问题提供答案，例如 tDCS 的影响持续多久。该项目的结果将为了解 DCS 的细胞机制提供精确和定量的框架，这是推进 tDCS 科学和治疗所必需的。

项目成果

Optimization of interferential stimulation of the human brain with electrode arrays.

用电极阵列优化人脑干扰刺激。

• 发表时间: 2020
• 作者: Huang, Yu;Datta, Abhishek;Parra, Lucas C
• 通讯作者: Parra, Lucas C

Weak DCS causes a relatively strong cumulative boost of synaptic plasticity with spaced learning.

较弱的 DCS 会导致突触可塑性与间隔学习相对较强的累积提升。

• 发表时间: 2022-01
• 影响因子: 7.7
• 作者: Sharma, Mahima;Farahani, Forouzan;Bikson, Marom;Parra, Lucas C
• 通讯作者: Parra, Lucas C

Effects of direct current stimulation on synaptic plasticity in a single neuron.

直流电刺激对单个神经元突触可塑性的影响。

• 发表时间: 2021-05
• 影响因子: 7.7
• 作者: Farahani, Forouzan;Kronberg, Greg;FallahRad, Mohamad;Oviedo, Hysell V;Parra, Lucas C
• 通讯作者: Parra, Lucas C

Robust enhancement of motor sequence learning with 4 mA transcranial electric stimulation.

通过 4 mA 经颅电刺激强力增强运动序列学习。

• 发表时间: 2023
• 影响因子: 7.7
• 作者: Hsu, Gavin;Shereen, A Duke;Cohen, Leonardo G;Parra, Lucas C
• 通讯作者: Parra, Lucas C

Tolerability of Repeated Application of Transcranial Electrical Stimulation with Limited Outputs to Healthy Subjects.

对健康受试者重复应用输出有限的经颅电刺激的耐受性。

• 发表时间: 2016
• 影响因子: 7.7
• 作者: Paneri, Bhaskar;Adair, Devin;Thomas, Chris;Khadka, Niranjan;Patel, Vaishali;Tyler, William J;Parra, Lucas;Bikson, Marom
• 通讯作者: Bikson, Marom