Modulating brain activity to preserve gait in older adults.

描述(由申请人提供)：我的职业目标是缓解经常伴随年龄增长的行走和行动障碍。我将通过在人类衰老、运动和康复医学领域领导一个跨学科的转化研究项目来实现这一目标。我的长期计划是通过1)确定中枢神经系统对与年龄和疾病相关的感觉运动损伤的适应机制，以及2)将这些对适应能力的机械性理解转化为改进的康复方法，来加强这些领域。我将通过将最先进的功能神经成像和非侵入性脑刺激范例与传统的基于生物力学的行为评估相结合来做到这一点。通过这个奖项，我将利用贝丝以色列女执事医学中心和哈佛医学院提供的出色培训和研究机会，继续我的职业发展。通过完成拟议的研究、课程、科学服务，以及与老年学研究、神经生理学、神经心理学、神经成像和脑刺激方面的领先专家合作，我将：1)成为与运动控制相关的衰老神经生理学方面的专家；2)学习脑成像和刺激的新技术及其在运动控制中的应用；3)在老龄化领域获得国家认可并发展领导技能。这项拟议的研究将识别和调节大脑网络，这些网络有助于健康老年人复杂地控制行走。来自行为研究的证据表明，在这一人群中，走路时执行认知任务会降低速度，增加运动可变性。然而，认知任务干扰行走的机制尚不清楚。重要的是，神经成像证据表明，初级躯体感觉皮质(SI)对触觉刺激的反应依赖于传入反馈，以及来自大脑高级区域的“自上而下”的神经调节。为了能够研究与行走相关的触觉刺激对大脑皮层的反应，我开发了一种与fMRI兼容的系统，可以在躺在扫描仪中一动不动的情况下，模拟行走时对脚施加压力。我们对年轻人的初步研究表明，当受试者同时执行认知任务时，这种刺激诱导的SI激活强度会降低。然而，目前尚不清楚在健康的老年人中，执行认知任务是否会降低大脑对与步行相关的脚底刺激的体感皮质反应。经颅直流电刺激(TDC)是控制皮层对躯体感觉刺激反应性的一种很有前途的方法，它利用低幅度的直流电瞬间改变皮层的兴奋性。我们的初步研究表明，将tDCs应用于前额叶脑区a)不会影响休息时SI的大脑活动，b)增加年轻人对脚底刺激的SI反应，c)可能改善健康老年人的步行结果。基于这些观察，我们建议使用我的fMRI足部刺激范式、tDC和行为评估来测试以下假设：我们假设，在健康的老年人中，执行认知任务会减少皮质对与行走相关的脚底刺激的体感反应(H1)，向认知大脑区域提供兴奋性tDC会增加皮质对这种刺激的体感反应(H2)，并改善这一人群的步行结果(H3)。我们将通过三个目标来检验这些假说：目标1：确定在健康的老年人中，执行认知任务对脚底刺激的皮质体感反应的影响。目的：探讨以认知脑区为靶点的TDCs对健康老年人足底刺激皮层体感反应的影响。目的：探讨以认知脑区为靶点的TDCs对健康老年人步行的影响。我们将招募30名认知完好、健康的65岁至80岁的老年男性和女性。每个科目将完成六次考察访问。《探访1》将上映。访问2将评估机动性、认知力和 外周感觉运动功能。在第三次和第四次访问中，受试者将使用足部刺激系统完成区块设计的大胆功能磁共振成像方案。我们将在“N-back”工作记忆任务(目标1)的两个不同难度的同时进行和不同时进行的情况下，确定大脑皮层对足部刺激的反应。然后，受试者将在扫描室外的椅子上休息20分钟，接受针对左侧前额叶大脑区域的真实或虚假的tdcs。然后将立即重复功能磁共振成像方案，以确定tdcs对足部刺激的皮质反应性的影响(目标2)。在第5次和第6次，受试者将完成行走和认知的评估，在相同的真实或虚假的TDC之前和之后，以左侧dlPFC为目标(目标3)。该项目将提供新的证据，证明在健康的老年人中，皮质对与行走相关的体感刺激的反应依赖于大脑高级区域的神经调节。我们的发现还可能引入一种新的治疗方案(即tdcs)，以改善这一脆弱人群的行走。

DESCRIPTION (provided by applicant): My career goal is to alleviate the walking and mobility impairments that often accompany aging. I will achieve this goal by leading an interdisciplinary, translational research program in the fields of human aging, locomotion and rehabilitative medicine. My long-term plan is to enhance these fields by 1) identifying mechanisms of central nervous system adaptation to age- and disease-related sensorimotor impairments, and 2) translating these mechanistic understandings of adaptive capacity into improved rehabilitation methods. I will do so by combining state-of-the-art functional neuroimaging and noninvasive brain stimulation paradigms with traditional biomechanics-based behavioral assessments. Through this award, I will continue my career development by leveraging outstanding training and research opportunities available at the Beth Israel Deaconess Medical Center and Harvard Medical School. By completing the proposed research, coursework, scientific service, and collaboration with leading experts in gerontological research, neurophysiology, neuropsychology, neural imaging and brain stimulation, I will: 1) Become an expert in the neurophysiology of aging in relation to locomotor control; 2) Learn new techniques in brain imaging and stimulation and their application to motor control; 3) Achieve national recognition and develop leadership skills in the field of aging. The proposed research will identify and modulate brain networks that contribute to the complex control of walking in healthy older adults. Evidence from behavioral studies indicates that performing a cognitive task while walking decreases speed and increases movement variability in this population. Mechanisms through which cognitive tasks disturb walking, however, are unknown. Importantly, neuroimaging evidence indicates that the primary somatosensory cortex (SI) response to a tactile stimulus is dependent upon afferent feedback, as well as "top-down" neuromodulation from higher brain regions. To enable study of the cortical response to walking-related tactile stimuli, I developed an fMRI-compatible system to apply pressure to the feet that mimics those of walking, yet while lying motionless in the scanner. Our preliminary studies in younger adults indicate that the intensity of SI activation induced by this stimulation was reduced when subjects simultaneously performed a cognitive task. However, it remains unknown whether performing a cognitive task decreases the brain's somatosensory cortical response to walking-related foot sole stimulation in healthy older adults. One promising approach to manipulate the cortical responsiveness to somatosensory stimuli is transcranial direct current stimulation (tDCS), which utilizes low-amplitude direct current to transiently alter cortical excitability. Our pilot studies indicate tha tDCS applied to the prefrontal brain regions a) does not affect SI brain activity during rest, b) increases the SI response to foot sole stimulation in younger adults, and c) may improve walking outcomes in healthy older adults. Grounded in these observations, we propose to use my fMRI foot stimulation paradigm, tDCS and behavioral assessments to test the following hypotheses: We hypothesize that in healthy older adults, performing cognitive tasks diminishes the cortical somatosensory response to walking-related foot sole stimulation (H1), and that providing excitatory tDCS to cognitive brain regions increases the cortical somatosensory response to this stimulation (H2) and improves walking outcomes (H3) in this population. We will test these hypotheses via three Aims: Aim 1: To determine the effect of performing cognitive tasks on the cortical somatosensory response to foot sole stimulation in healthy older adults. Aim 2: To determine the effect of tDCS targeting cognitive brain regions on the cortical somatosensory response to foot sole stimulation in healthy older adults. Aim 3: To determine the effect of tDCS targeting cognitive brain regions on walking in healthy older adults. We will recruit 30 cognitively-intact, healthy older men and women aged 65-80 years. Each subject will complete six study visits. Visit 1 will be screening. Visit 2 will evaluate mobility, cognition and peripheral sensorimotor function. On Visits 3 and 4, subjects will complete a block-design BOLD fMRI protocol using the foot stimulation system. We will determine the cortical response to foot stimulation with and without concurrent performance of two different difficulties of the "N-Back" working memory task (Aim 1). Subjects will then receive 20min of real or sham tDCS targeting the left prefrontal brain region while resting in a chair outside of the scanner room. The fMRI protocol will then be immediately repeated to determine the effects of tDCS on the cortical responsiveness to foot stimulation (Aim 2). On Visits 5 and 6, subjects will complete assessments of walking and cognition, before and after the same real or sham tDCS targeting the left dlPFC (Aim 3). This project will provide novel evidence that in healthy older adults, the cortical response to walking-related somatosensory stimuli is dependent upon neuromodulation from higher brain regions. Our discoveries may also introduce a novel therapeutic option (i.e., tDCS) to improve walking in this vulnerable population.