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氏病（AD）变体的治疗方法，通常会影响 左半球和包含徽标变体的主要进行性失语（LVPPA），因此，PPA-AD。 PPA没有药理治疗 缺陷是言语疗法。 AD的治疗研究强调针对神经元突触 传播。我们是世界上首批展示神经调节技术功效的团体之一 靶向突触传播（经颅直流电流刺激，TDCS），以提供显着的 PPA中语言障碍的有症状缓解。在最大，双盲，假手术的临床中 试验我们证明了TDC作为语音语言疗法的辅助治疗的功效 PPA中的命名和拼写缺陷。但是，慢慢语言变性的努力受到了 这些人也遭受了其他认知缺陷的痛苦。对于有 AD病因（病理学和萎缩分布）。在疾病的早期，患有PPA-AD的个体存在 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。但是，这些缺陷的治疗尚未在PPA- 使用神经调节方法的广告。为了解决这一差距，拟议的研究旨在回答以下 问题：我们如何实施基于神经刺激的治疗以最大程度地概括其 对重要语言/认知功能的好处？我们将通过采用以下操作来做到这一点：（a）行为疗法 直接针对言语短期和工作记忆（VSTM/WM）缺陷，这已被证明 有效地概括为中风后失语症的未经训练的语言功能，并且（b）有针对性的神经 基于最近的网络神经科学和神经护理模型的刺激（高清TDC）。在 AIM 1，我们将比较在左上角（LSMG）与左边的TDC的功效 背外侧前额叶皮层（LDLPFC）都与VSTM/WM行为治疗相结合 检查对未经训练的重要语言和执行认知的治疗效果的概括 PPA-AD的功能。在AIM 2中，我们将实施神经影像学技术来了解 TDCS诱导的变化在以下方面：（a）网络功能连接，（b）以前和新型代谢物此类 如GABA和谷胱甘肽（与神经退行性中的氧化应激有关），以及（c）使用血液氧合 灌注成像。最后，在AIM 3中，我们将评估对TDC的响应能力的新预测指标，例如 灌注，性和睡眠，因此补充了我们先前确定的临床，神经和行为预测因子 （变体，大脑体积和初始语言/认知表现）。基于最近的更好的理解 网络神经科学的进步，TDCS福利如何推广到未经培训的语言和执行 认知功能有可能彻底改变PPA-AD有效治疗的发展。