Treating mild cognitive impairment with transcranial direct current stimulation

摘要 随着阿尔茨海默病(AD)发病率的增长和名义上的药物效应，需要 新的治疗方法。经颅直流电刺激(Tdcs)是一种无创的脑电刺激方法。 利用微弱电流改变大脑兴奋性的刺激。初步证据表明 TDCs可改善轻度认知障碍(MCI)和阿尔茨海默病患者的认知功能 痴呆症。因此，tdcs有望最大限度地提高认知和功能能力，并延迟 衰退是向痴呆症过渡的分界线；对个人和经济都有重大影响 后果。由于人们对最有效的治疗条件知之甚少，因此 这项研究是为了确定tdcs处理参数，以便未来的研究可以更有效地进行和 有更大的成功机会。将使用高清晰度(HD)TDC来增强刺激焦点和 避免传统的基于PAD的方法的潜在混淆效果。在这项研究中，MCI患者将 随机接受连续五次的HD-tDCs治疗，治疗时间分别为假手术、1 mA、2 mA或3 mA。 刺激将以外侧颞叶皮质为目标；这是AD病程早期受影响的神经解剖学目标 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。 每天以及在5次会议之后。将使用休眠状态功能评估网络连通性 磁共振成像(FMRI)(治疗前和治疗后)。具体目标1是确定 HD-TDCS的耐受性很好，SHAM是一种有效的控制条件。这将是第一项研究 使用HD-tDCS和MCI患者对这些因素进行系统评估。具体目标2是确定 HD-tDCS电流强度对网络连通性和认知功能的多时段影响 措施。将使用人类Connectome功能磁共振成像获取和图论分析方法来建立 并在地方和网络两级对这些影响有更深入的了解。 探索性特异性目标3将评估AD生物标志物对HD-tDCs反应的影响。这将是 第一项整合淀粉样蛋白，tau，神经变性(A/T/N)框架的tdcs研究，特别是通过使用 正电子发射断层扫描(PET)配体测量β-淀粉样蛋白和神经原纤维tau以及MRI以 量化大脑体积。这一方法建立在几十年来加强AD病理早期检测的努力基础上 通过将这一知识转化为有针对性的治疗方法，在体内进行治疗。这项研究立即解决了 关于剂量反应(例如，线性效应与非线性效应)和作用机制的领域相关问题。 结果将简化后续试验中参与者的选择，从而提高治疗结果和 通过精准医学方法降低研究成本。综上所述，这些结果将指导理性 刺激的处方，并作为一类新的非药物治疗的基础。

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.