Targeting language-specific and executive-control networks with transcranial direct current stimulation in aphasic AD

该项目旨在开发一种非典型阿尔茨海默病（AD）变体的治疗方法， 左半球，包括逻辑缺失变异型原发性进行性失语症（lvPPA），因此，PPA-AD。 PPA没有可用的药物治疗，唯一的治疗显示，以减轻语言 就是语言治疗AD的治疗研究强调靶向神经元突触， 传输我们是世界上第一批展示神经调节技术有效性的团队之一 靶向突触传递（经颅直流电刺激，tDCS）， PPA语言障碍症状缓解。在迄今为止最大的，双盲，假对照临床试验中， 一项试验证明了tDCS作为辅助语言治疗的有效性， PPA中的命名和拼写缺陷。然而，减缓语言退化的努力受到了 事实上，这些人还患有额外的认知缺陷。这对于那些 AD病因学（病理学和萎缩分布）。在疾病早期，患有PPA-AD的个体表现为 额外的认知缺陷，如语言短期记忆障碍，甚至被认为是主要的 语言缺陷的根本原因。然而，这些缺陷的治疗尚未在PPA中进行研究- AD使用神经调节方法。为了解决这一差距，拟议的研究旨在回答以下问题 问：我们如何实施基于神经刺激的治疗，以最大限度地推广他们的 对重要的语言/认知功能有好处吗？我们将通过以下方式做到这一点：（a）行为疗法， 直接针对语言短期和工作记忆（vSTM/WM）缺陷，并已被证明 有效地推广到中风后失语症中甚至未经训练的语言功能，和，（B）靶向神经- 刺激（高清晰度tDCS）基于最近的网络神经科学和神经康复模型。在 目的1，我们将比较tDCS在左侧缘上回（LSMG）与左侧 背外侧前额叶皮层（LDLPFC），两者都与vSTM/WM行为治疗相结合，特别是 检查治疗效果对未经训练的重要语言特异性和执行认知的推广 PPA-AD中的功能。在目标2中，我们将实施神经影像学技术，以了解 tDCS诱导的变化：（a）网络功能连接，（B）先前和新的代谢产物，如 如GABA和谷胱甘肽（与神经变性中的氧化应激有关），和（c）血氧，使用 灌注成像最后，在目标3中，我们将评估对tDCS反应性的新预测因子，如 灌注，性和睡眠，从而补充了我们以前确定的临床，神经和行为预测因子 （变量，脑容量和初始语言/认知表现）。更好的理解，基于最近的 网络神经科学的进展，tDCS的好处如何推广到未经训练的语言和执行 认知功能具有革命性地开发PPA-AD的有效治疗的潜力。

This project aims in developing treatments for an atypical Alzheimer's disease (AD) variant, usually affecting the left hemisphere and comprising the logopenic variant primary progressive aphasia (lvPPA), thus, PPA-AD. There are no pharmacological treatments available for PPA, and the only treatment shown to alleviate language deficits is speech-language therapy. Treatment research in AD has emphasized targeting neuronal synaptic transmission. We were amongst the first groups in the world to show the efficacy of a neuromodulation technique that targets synaptic transmission (transcranial direct current stimulation, tDCS) in providing significant symptomatic relief of language impairments in PPA. In the largest-to-date, double-blind, sham-controlled clinical trial we demonstrated the efficacy of tDCS as an adjuvant for speech-language therapy for the treatment of naming and spelling deficits in PPA. However, the efforts to slow language degeneration are hindered by the fact that these individuals also suffer from additional cognitive deficits. This is especially true for individuals with AD etiology (pathology and atrophy distribution). Early in the disease, individuals with PPA-AD present with additional cognitive deficits such as verbal short-term memory impairment, even believed to be a primary underlying cause of language deficits. However, treatment of these deficits has not been investigated in PPA- AD using neuromodulation approaches. To address this gap, the proposed research aims to answer the following question: How can we implement neurostimulation-based treatments to maximally generalize their benefits to vital language/cognitive functions? We will do that by employing: (a) a behavioral therapy that directly targets verbal short-term and working memory (vSTM/WM) deficits and that has been shown to effectively generalize even to untrained language functions in post-stroke aphasia, and, (b) targeted neuro- stimulation (high-definition tDCS) based on recent network-neuroscience and neuro-rehabilitation models. In Aim 1, we will compare the efficacy of tDCS delivered over the left supramarginal gyrus (LSMG) vs. the left dorsolateral prefrontal cortex (LDLPFC), both coupled with vSTM/WM behavioral treatment, specifically examining the generalization of treatment effects to untrained vital language-specific and executive cognitive functions in PPA-AD. In Aim 2, we will implement neuroimaging techniques to understand the mechanisms of tDCS-induced changes in terms of: (a) network functional connectivity, (b) previous and novel metabolites such as GABA and glutathione (related to oxidative stress in neurodegeneration), and (c) blood oxygenation, using perfusion imaging. Finally, in Aim 3, we will evaluate novel predictors of responsiveness to tDCS such as perfusion, sex and sleep, thus complementing our previously identified clinical, neural and behavioral predictors (variant, brain volume and initial language/cognitive performance). A better understanding, based on recent advances in network neuroscience, of how tDCS benefits may generalize to untrained language and executive cognitive functions has the potential to revolutionize the development of effective treatments for PPA-AD.