Treating primary progressive aphasia and elucidating neurodegeneration in the language network using transcranial direct current stimulation

使用经颅直流电刺激治疗原发性进行性失语症并阐明语言网络中的神经退行性变

• 批准号: 10201511
• 负责人: Roy H Hamilton
• 金额: $ 75.5万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10201511
• 关键词: Address; Advanced Development; Affect; Age-associated memory impairment; Alzheimer' s Disease; Alzheimer' s disease patient; Anodes; Anterior; Area; Behavioral; Brain; Brain region; Clinical; Clinical Trials; Cross-Over Studies; Data; Degenerative Disorder; Disease; Disease Progression; Double-Blind Method; Frontotemporal Dementia; Functional Magnetic Resonance Imaging; Functional disorder; Future; Goals; Graph; Image; Individual; Injury; Intervention; Intervention Trial; Investigation; Knowledge; Language; Language Therapy; Left; Location; Measures; Methods; Modeling; Nature; Nerve Degeneration; Neurodegenerative Disorders; Neuronal Plasticity; Participant; Pathway Analysis; Patients; Pattern; Performance; Persons; Primary Progressive Aphasia; Production; Property; Quality of life; Randomized; Research; Role; Semantics; Site; Speech; Statistical Data Interpretation; Statistical Models; Structure; Syndrome; System; Techniques; Testing; Therapeutic; Variant; Work; behavioral response; cerebral atrophy; clinical phenotype; density; effective therapy; frontal lobe; frontotemporal degeneration; improved; indexing; insight; language impairment; meetings; multimodal data; neurodegenerative dementia; neuroimaging; neuroregulation; noninvasive brain stimulation; novel; predicting response; relating to nervous system; response; statistics; stroke-induced aphasia; treatment effect; treatment trial

PROJECT SUMMARY/ABSTRACT This revised application responds to PAR-18-175: “Pilot Clinical Trials for the Spectrum of Alzheimer's Disease and Age-related Cognitive Decline.” Primary progressive aphasia (PPA), a debilitating condition of language loss affecting many patients with frontotemporal dementia (FTD) and Alzheimer's disease (AD), currently lacks effective treatments. Recent studies suggest that transcranial direct current stimulation (tDCS), a form of noninvasive neuromodulation, may show promise as an intervention for PPA. However, these research efforts are hampered because they do not address important questions about plasticity in the language system, and because they do not fully utilize knowledge regarding the properties of the language network in PPA to guide treatment. This proposal aims to further advance investigation into tDCS as a potential intervention in PPA and to establish which components of the language network in PPA are most capable of tDCS-induced behaviorally relevant plasticity. Our proposal seeks to determine whether neuromodulation therapies in persons with PPA should aim to strengthen connections in the most degenerated regions of the language network or bolster compensatory changes in more intact areas. We will address this knowledge gap by pursuing a randomized, sham-controlled crossover study of high-density tDCS (HD-tDCS) focused over the anterior regions of the left hemisphere language network in participants with two PPA variants that are characterized by decreased word production but which feature different sites of maximal degeneration. This will allow for comparison of stimulation in a region that is degenerated in some subjects but relatively spared in others. Stimulation will be paired with a behavioral language therapy aimed at augmenting tDCS effects in the language system. Our first aim will be to determine how this intervention differentially impacts language performance in subjects with the two PPA variants. We will then use network graph statistical analyses of neuroimaging data to characterize language networks. We will focus on hubs as centers of critical connectivity in networks, and we propose that measuring changes in the ability of regions in the language network to function as hubs (indexed by hub scores) may be a way to describe how neurodegeneration impacts language network functions in PPA. Thus, the second aim of the proposal will explore differences in hub scores across the language network at baseline in our two PPA subtype groups. The third aim of the proposal will extend this approach by examining behaviorally relevant changes in hub scores induced by tDCS. The final aim of the project will integrate and extend prior findings by developing a model that employs clinical phenotypes, patterns of brain atrophy, and hub score data to predict which individuals are most likely to benefit from our stimulation approach. Taken together, this project will advance a potential intervention for a devastating condition associated with neurodegenerative diseases, elucidate network mechanisms of plasticity in these disorders, and develop a potentially generalizable, network-informed approach for predicting response to therapeutic neuromodulation.

项目总结/摘要 本修订申请响应PAR-18-175：“阿尔茨海默病谱系的试点临床试验 以及与抑郁症相关的认知能力下降。”原发性进行性失语症（PPA），一种使语言衰弱的疾病 影响许多额颞叶痴呆（FTD）和阿尔茨海默病（AD）患者的损失，目前缺乏 有效的治疗。最近的研究表明，经颅直流电刺激（tDCS），一种形式的 非侵入性神经调节可能显示出作为PPA干预的前景。然而，这些研究成果 因为它们没有解决语言系统中有关可塑性的重要问题， 因为他们没有充分利用PPA中关于语言网络属性的知识来指导 治疗该提案旨在进一步推进对tDCS作为PPA潜在干预措施的调查， 以确定PPA中语言网络的哪些组成部分最有能力在行为上引起tDCS 相关的可塑性我们的建议旨在确定PPA患者的神经调节治疗是否 应该致力于加强语言网络中最退化区域的联系， 更完整区域的代偿性变化。我们将通过一个随机的， 高密度tDCS（HD-tDCS）的假手术对照交叉研究，聚焦于左前区 具有两种PPA变体的参与者的半球语言网络，其特征是单词减少 生产，但具有不同的最大变性部位。这将允许比较 在某些受试者中退化但在其他受试者中相对较少的区域中的刺激。刺激会被 与旨在增强语言系统中tDCS效应的行为语言疗法相结合。我们的第一 目的将是确定这种干预如何不同地影响语言表现的主题与 两种PPA变体。然后，我们将使用神经成像数据的网络图统计分析来表征 语言网络。我们将把重点放在枢纽作为网络中关键连接的中心，我们建议， 测量语言网络中的区域作为中心（由中心索引）的能力的变化 分数）可能是描述神经变性如何影响PPA中语言网络功能的一种方式。因此，在本发明中， 该提案的第二个目标是探索各语言网络在基线时中心分数的差异 在我们的两个PPA亚型组中。建议的第三个目的是扩大这一做法， 由tDCS诱导的中枢评分的行为相关变化。该项目的最终目标是整合和 通过开发一种采用临床表型、脑萎缩模式和 中心评分数据来预测哪些个体最有可能从我们的刺激方法中受益。采取 总之，该项目将推进一种潜在的干预措施，用于与以下疾病相关的破坏性疾病： 神经退行性疾病，阐明这些疾病中可塑性的网络机制，并开发出一种新的神经退行性疾病模型。 潜在的可推广的，网络通知的方法，用于预测对治疗性神经调节的反应。