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。我将通过领导人类衰老、运动和康复医学领域的跨学科、转化研究项目来实现这一目标。我的长期计划是通过1)识别中枢神经系统对年龄和疾病相关的感觉运动障碍的适应机制，以及2)将这些对适应能力的机制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神经成像和无创脑刺激范式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，我将利用贝斯以色列女执事医疗中心和哈佛医学院提供的优秀培训和研究机会，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、神经成像和脑刺激领域的权威专家合作，我将：1)成为与运动控制相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)在老龄领域获得国家认可，培养领导能力。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行走的复杂控制。行为学研究的证据表明，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，初级体感皮层（SI）对触觉刺激的反应依赖于传入反馈，以及来自高级脑区的“自上而下”神经调节。为了研究大脑皮层对与行走相关的触觉刺激的反应，我开发了一种功能磁共振成像兼容的系统，可以在扫描仪中一动不动地躺着的情况下，对脚施加模仿行走的压力。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，这种刺激引起的SI激活强度会降低。然而，在健康的老年人中，执行认知任务是否会降低大脑的体感皮层对步行相关的足底刺激的反应，目前尚不清楚。经颅直流电刺激（tDCS）是一种很有前景的控制皮层对体感刺激反应的方法，它利用低振幅直流电来短暂改变皮层的兴奋性。我们的初步研究表明，将tDCS应用于前额叶脑区a)不影响休息时的SI脑活动，b)增加年轻人对足底刺激的SI反应，c)可能改善健康老年人的步行结果。基于这些观察结果，我们建议使用我的fMRI足部刺激范式，tDCS和行为评估来验证以下假设：我们假设，在健康的老年人中，执行认知任务减少了皮质体感对步行相关的足底刺激的反应（H1），而在该人群中，向认知脑区提供兴奋性tDCS增加了皮质体感对这种刺激的反应（H2）并改善了步行结果（H3）。我们将通过三个目的来验证这些假设：目的1：确定执行认知任务对健康老年人足底刺激皮质体感觉反应的影响。目的2：确定针对认知脑区的tDCS对健康老年人足底刺激皮质体感觉反应的影响。目的3：确定针对认知脑区的tDCS对健康老年人行走的影响。我们将招募30名认知功能完好、年龄在65-80岁之间的健康老年男女。每位受试者将完成六次研究访问。第一次访问将进行筛查。第二次检查将评估活动能力，认知能力和

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.