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: 10701784
• 负责人: Kyrana Tsapkini
• 金额: $ 80.15万
• 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/10701784
• 关键词: Address; Adjuvant; Affect; Aftercare; Alzheimer' s Disease; Alzheimer' s disease pathology; American; Anodes; Anomia; Aphasia; Area; Atrophic; Behavior Therapy; Biological Markers; Blood; Brain; COVID-19 pandemic; Caregiver Burden; Cessation of life; Characteristics; Clinical; Clinical Research; Cognitive; Cognitive deficits; Coin; Combined Modality Therapy; 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; Neurosciences; Neurotransmitters; Oral; Outcome; Oxidative Stress; Pathology; Pattern; Performance; Perfusion; Pharmacological Treatment; Phenotype; Physiological; Prefrontal Cortex; Primary Progressive Aphasia; Probability; Randomized Controlled 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; Writing; behavior prediction; biomarker identification; brain pathway; brain volume; clinically significant; cognitive function; cognitive performance; comparative efficacy; cost; cost effective treatment; disability; effective therapy; executive function; gamma-Aminobutyric Acid; improved; language impairment; language outcome; neural; neuroimaging; neurological rehabilitation; neuroregulation; novel; outcome prediction; perfusion imaging; phonology; post intervention; predict responsiveness; sex; spelling; stroke-induced aphasia; targeted treatment; transcranial direct current stimulation; treatment effect; treatment research; verbal; 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.

该项目旨在开发非典型阿尔茨海默病（AD）变体的治疗方法，通常影响