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: 10450141
• 负责人: Roy H Hamilton
• 金额: $ 75.16万
• 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 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10450141
• 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; 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.

项目摘要/摘要 这项修订了对PAR-18-175的申请反应：“阿尔茨海默氏病谱的试验临床试验 和与年龄有关的认知能力下降。 影响许多额颞痴呆（FTD）和阿尔茨海默氏病（AD）患者的损失，目前缺乏 有效的治疗方法。最近的研究表明，thrancranial直流电流刺激（TDCS），一种形式 无创神经调节可能显示出有望作为对PPA的干预。但是，这些研究工作 受到阻碍，因为它们没有解决语言系统中有关可塑性的重要问题，并且 因为他们没有完全利用有关PPA语言网络属性的知识来指导 治疗。该建议旨在进一步提高对TDC的调查，以作为对PPA的潜在干预措施 确定PPA中语言网络的哪些组成部分最能够在行为上诱导的TDC诱导 相关的可塑性。我们的建议旨在确定PPA患者的神经调节疗法是否 应该旨在加强语言网络最退化区域或加强的连接 完整区域的补偿性变化。我们将通过追求随机的， 高密度TDC（HD-TDC）的假控制跨界研究集中在左侧的前区域 参与者的半球语言网络具有两个PPA变体，这些变体以高级单词为特征 生产但最大变性的位置不同。这将允许比较 在某些受试者中退化但在另一些受试者中相对幸免的区域中的刺激。刺激将是 与旨在增强语言系统中TDCS效应的行为语言疗法配对。我们的第一个 目的是确定这种干预措施如何不同地影响与主体的语言表现 两个PPA变体。然后，我们将使用神经影像数据的网络图统计分析来表征 语言网络。我们将专注于集线器作为网络中关键连通性的中心，我们建议 测量语言网络中区域功能充当集线器的能力的变化（由集线器索引 分数）可能是描述神经变性如何影响PPA语言网络功能的一种方法。那， 该提案的第二个目的将探索基线上语言网络的集线器分数的差异 在我们的两个PPA亚型组中。该提案的第三个目标将通过检查该方法 TDC诱导的集线器分数的行为相关变化。该项目的最终目标将整合，并 通过开发采用临床表型，脑萎缩模式和 集线器分数数据以预测哪些人最有可能从我们的刺激方法中受益。拍摄 该项目将共同推动与与之相关的毁灭性状况的潜在干预措施 神经退行性疾病，阐明这些疾病中可塑性的网络机制，并发展 潜在的可推广，网络信息的方法，以预测对治疗性神经调节的反应。