Modulating brain activity to preserve gait in older adults.

描述（由申请人提供）：我的职业目标是减轻经常伴随衰老的行走和行动障碍。我将通过领导一个跨学科的，在人类衰老，运动和康复医学领域的转化研究计划来实现这一目标。我的长期计划是通过1）确定中枢神经系统适应年龄和疾病相关的感觉运动障碍的机制，以及2）将这些对适应能力的机械理解转化为改进的康复方法来加强这些领域。我将通过结合最先进的功能性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来做到这一点。通过这个奖项，我将继续我的职业发展，利用优秀的培训和研究机会，在贝丝以色列女执事医疗中心和哈佛医学院。通过完成拟议的研究，课程，科学服务，并与老年学研究，神经生理学，神经心理学，神经成像和脑刺激的领先专家合作，我将：1）成为与运动控制有关的衰老神经生理学专家; 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）获得国家认可，发展老龄领域的领导能力。这项拟议中的研究将识别和调节有助于健康老年人复杂控制行走的大脑网络。来自行为研究的证据表明，在行走时执行认知任务会降低速度并增加该人群的运动变异性。然而，认知任务干扰行走的机制尚不清楚。重要的是，神经影像学证据表明，初级躯体感觉皮层（SI）对触觉刺激的反应取决于传入反馈，以及来自更高大脑区域的“自上而下”的神经调节。为了研究皮层对行走相关触觉刺激的反应，我开发了一种fMRI兼容系统，可以对脚施加压力，模仿行走，但在扫描仪中静止不动。我们在年轻人中的初步研究表明，当受试者同时执行认知任务时，由这种刺激引起的SI激活的强度降低。然而，在健康的老年人中，执行认知任务是否会降低大脑对步行相关足底刺激的体感皮层反应仍然是未知的。一种有前途的方法来操纵皮层对体感刺激的反应性是经颅直流电刺激（tDCS），它利用低幅度直流电瞬时改变皮层兴奋性。我们的初步研究表明，tDCS应用于前额叶脑区a）不影响休息期间的SI脑活动，B）增加年轻人对足底刺激的SI反应，以及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足部刺激范例，tDCS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层对步行相关足底刺激的体感反应（H1），向认知脑区提供兴奋性tDCS增加了皮层对这种刺激的体感反应（H2），并改善了行走结果（H3）在这个人群中。我们将通过三个目的来测试这些假设：目的1：确定在健康老年人中执行认知任务对足底刺激的皮层体感反应的影响。目标二：确定针对认知脑区的tDCS对健康老年人对脚底刺激的皮质体感反应的影响。目的3：确定tDCS靶向认知脑区对健康老年人步行的影响。我们将招募30名年龄在65-80岁之间的认知功能完整、健康的老年男性和女性。每例受试者将完成6次研究访视。访视1为筛选。访视2将评估活动性、认知和 外周感觉运动功能在访视3和4时，受试者将使用足部刺激系统完成区块设计BOLD fMRI方案。我们将确定皮层对足部刺激的反应，同时执行和不执行两个不同难度的“N-Back”工作记忆任务（目标1）。然后，受试者将在扫描室外的椅子上休息时接受靶向左前额叶脑区的20分钟真实的或假tDCS。然后立即重复fMRI方案，以确定tDCS对足部刺激皮质反应性的影响（目的2）。在访视5和6时，受试者将在靶向左侧dlPFC（目标3）的相同真实的或假tDCS之前和之后完成行走和认知评估。该项目将提供新的证据表明，在健康的老年人中，皮层对步行相关的体感刺激的反应取决于来自更高大脑区域的神经调节。我们的发现还可能引入一种新的治疗选择（即，tDCS），以改善这一弱势群体的行走。

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.