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

通过经颅直流电刺激治疗失语性 AD，针对语言特异性和执行控制网络

• 批准号: 10522359
• 负责人: Kyrana Tsapkini
• 金额: $ 82.83万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10522359
• 关键词: Address; Adjuvant; Affect; Aftercare; Alzheimer' s Disease; Alzheimer' s disease pathology; American; Anodes; Anomia; Aphasia; Area; Atrophic; Behavior Therapy; Behavioral; Biological Markers; Blood; Brain; COVID-19 pandemic; Caregiver Burden; Cessation of life; Characteristics; Clinical; Clinical Research; Cognitive; Cognitive deficits; Coin; Complement; Controlled Clinical Trials; Coupled; Development; Diffusion Magnetic Resonance Imaging; Disease; Dorsal; Double-Blind Method; Etiology; Functional Magnetic Resonance Imaging; Glutathione; Impairment; Individual; Inferior frontal gyrus; Intervention; Investigation; Language; Language Disorders; Language Therapy; Left; Magnetic Resonance Spectroscopy; Measures; Membrane Potentials; Memory impairment; Modeling; Monitor; Names; Nerve Degeneration; Neurodegenerative Disorders; Neuronal Plasticity; Neurons; Neurophysiology - biologic function; Neurosciences; Neurotransmitters; Oral; Outcome; Oxidative Stress; Pathology; Pattern; Performance; Perfusion; Pharmacological Treatment; Phenotype; Physiological; Prefrontal Cortex; Primary Progressive Aphasia; Randomized Clinical Trials; Research; Rest; Short-Term Memory; Sleep; Speech; Structure of supramarginal gyrus; Symptoms; Synaptic Transmission; Techniques; Testing; Therapeutic; Time; Training; Translating; Update; Variant; Verbal Learning; base; brain pathway; brain volume; clinically significant; cognitive function; cognitive performance; comparative efficacy; cost; cost effective treatment; disability burden; effective therapy; executive function; gamma-Aminobutyric Acid; improved; language impairment; language outcome; neuroimaging; neurological rehabilitation; neuroregulation; novel; outcome prediction; perfusion imaging; phonology; post intervention; post stroke; predict responsiveness; relating to nervous system; sex; spelling; stroke-induced aphasia; targeted treatment; treatment effect; treatment research; white matter

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.

该项目旨在开发针对非典型阿尔茨海默病 (AD) 变异的治疗方法，该变异通常影响 左半球，包括语言减少变异型原发性进行性失语症 (lvPPA)，即 PPA-AD。 PPA 没有可用的药物治疗方法，并且是唯一可以缓解语言障碍的治疗方法 缺陷是言语语言治疗。 AD 的治疗研究强调针对神经元突触 传播。我们是世界上第一批展示神经调节技术功效的团队之一 以突触传递（经颅直流电刺激，tDCS）为目标，提供显着的 PPA 中语言障碍的症状缓解。在迄今为止最大的双盲、假对照临床试验中 试验中，我们证明了经颅直流电刺激 (tDCS) 作为言语治疗的辅助疗法的功效 PPA 中的命名和拼写缺陷。然而，减缓语言退化的努力受到以下因素的阻碍： 事实上，这些人还患有额外的认知缺陷。对于患有以下疾病的人来说尤其如此 AD 病因（病理学和萎缩分布）。在疾病早期，患有 PPA-AD 的个体会出现 其他认知缺陷，例如言语短期记忆障碍，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 中进行过研究。 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 问题：我们如何实施基于神经刺激的治疗来最大限度地推广他们的治疗方法 对重要的语言/认知功能有好处吗？我们将通过采用以下方法来做到这一点：（a）行为疗法 直接针对言语短期记忆和工作记忆 (vSTM/WM) 缺陷，并且已被证明可以 甚至可以有效地推广到中风后失语症中未经训练的语言功能，并且（b）有针对性的神经功能 基于最新网络神经科学和神经康复模型的刺激（高清 tDCS）。在 目标 1，我们将比较左侧边缘上回 (LSMG) 与左侧边缘上回 (LSMG) 的 tDCS 效果 背外侧前额皮质 (LDLPFC)，均与 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定和执行认知的概括 PPA-AD 中的功能。在目标 2 中，我们将采用神经影像技术来了解 tDCS 在以下方面引起的变化：(a) 网络功能连接，(b) 以前的和新的代谢物，例如 如 GABA 和谷胱甘肽（与神经变性中的氧化应激有关），以及 (c) 血液氧合，使用 灌注成像。最后，在目标 3 中，我们将评估 tDCS 反应性的新预测因子，例如 灌注、性和睡眠，从而补充了我们之前确定的临床、神经和行为预测因素 （变异、脑容量和初始语言/认知表现）。根据最近的情况，有更好的理解 网络神经科学的进展，以及 tDCS 的益处如何推广到未经训练的语言和执行能力 认知功能有可能彻底改变 PPA-AD 有效治疗方法的开发。