Treating mild cognitive impairment with transcranial direct current stimulation

摘要 随着阿尔茨海默病（AD）和名义药物作用的增长率，需要 新的治疗方法。经颅直流电刺激（Transcranial direct current stimulation，tDCS）是一种无创性的脑电刺激方法。 用微弱的电流改变大脑兴奋性的刺激。初步证据显示， tDCS可以改善轻度认知障碍（MCI）和阿尔茨海默病患者的认知功能 痴呆因此，tDCS有望最大限度地提高认知和功能能力， 划分向痴呆症过渡的衰退;对个人和经济产生重大影响的影响 后果由于对最有效的治疗条件知之甚少，因此主要目标是 本研究旨在确定tDCS治疗参数，以便更有效地进行未来的研究， 成功的机会更大高清晰度（HD）tDCS将用于增强刺激聚焦性， 避免传统的基于PAD的方法的潜在混淆效应。在这项研究中，MCI患者将 随机接受5次连续的每日HD-tDCS治疗，剂量为假手术、1 mA、2 mA或3 mA。 刺激将靶向外侧颞叶皮质; AD病程早期受影响的神经解剖学靶点 这也是功能失调的默认模式网络的一部分。将测量HD-tDCS的认知效果 每天以及5次会议后。将使用静息状态功能评估网络连接 磁共振成像（fMRI）（治疗前与治疗后）。具体目标1： HD-tDCS耐受性良好，假手术是有效的对照条件。这将是第一项研究， 使用HD-tDCS和MCI患者系统地评估这些因素。具体目标2是确定 HD-tDCS电流强度对网络连接和认知的多会话影响 措施将采用人体连接体fMRI采集和图论分析方法建立 剂量-反应曲线，并在局部和网络层面上更深入地了解这些影响。 探索性特定目标3将评价AD生物标志物对HD-tDCS缓解的影响。这将是 第一个tDCS研究整合淀粉样蛋白，tau，神经变性（A/T/N）框架，特别是通过使用 正电子发射断层扫描（PET）配体测量β-淀粉样蛋白和神经元tau蛋白以及MRI， 量化脑容量。这种方法建立在数十年的努力，以加强早期发现AD病理 通过将这些知识转化为有针对性的治疗方法。这项研究立即解决了 关于剂量反应的现场相关问题（例如，线性与非线性效应）和作用机制。 这些结果将简化后续试验中参与者的选择，从而提高治疗效果， 通过精准医疗方法降低研究成本。综合来看，结果将引导理性 处方的刺激，并作为基础的一类新的非药物治疗。

Abstract With the growing rate of Alzheimer's disease (AD) and nominal medication effects comes the need for novel treatment approaches. Transcranial direct current stimulation (tDCS) is a method of non-invasive brain stimulation that uses weak electric currents to alter the excitability of the brain. Initial evidence suggests that tDCS may improve cognitive functioning in patients with mild cognitive impairment (MCI) and Alzheimer's dementia. As a result, tDCS holds promise for maximizing cognitive and functional abilities as well as delaying decline that demarcates transition to dementia; an impact that has significant personal and financial ramifications. Because very little is known about the most effective treatment conditions, the primary goal of this study is to define tDCS treatment parameters so that future studies can be performed more efficiently and with greater chances of success. High Definition (HD) tDCS will be used to enhance stimulation focality and avoid potential confounding effects of the traditional pad-based approach. In this study, patients with MCI will be randomized to receive five consecutive daily sessions of HD-tDCS at either sham, 1mA, 2mA, or 3mA. Stimulation will target the lateral temporal cortex; a neuroanatomical target affected early in the course of AD that is also part of the dysfunctional default mode network. The cognitive effects of HD-tDCS will be measured daily as well as after the 5 sessions. Network connectivity will be evaluated using resting-state functional magnetic resonance imaging (fMRI) (pre-treatment versus post-treatment). Specific Aim 1 is to establish that HD-tDCS is well tolerated and that sham is an effective control condition. This will be the first study to systematically evaluate these factors using HD-tDCS and in patients with MCI. Specific Aim 2 is to determine the multi-session impact of HD-tDCS electrical current intensity on network connectivity and cognitive measures. Human Connectome fMRI acquisition and graph theory analytic methods will be used to establish dose-response curves and obtain a deeper understanding of these effects at both local and network levels. Exploratory Specific Aim 3 will evaluate the impact of AD biomarkers on HD-tDCS response. This will be the first tDCS study to integrate the amyloid, tau, neurodegeneration (A/T/N) framework, specifically by using positron emission tomography (PET) ligands to measure beta-amyloid and neurofibrillary tau as well as MRI to quantify brain volume. This approach builds on decades of efforts to enhance early detection of AD pathology in vivo by translating this knowledge into a targeted treatment approach. This study immediately addresses field-relevant questions about dose-response (e.g., linear vs. non-linear effects) and mechanisms of action. The results will streamline participant selection in subsequent trials, thereby enhancing treatment outcome and reducing study costs through a precision medicine approach. Taken together, the results will guide the rational prescription of stimulation and serve as the foundation for a novel class of non-pharmacologic treatment.