Frontal Cortex and Gait Freezing in Parkinson's Disease: Rehabilitation Impact

说明： 我们的长期目标是开发有效的康复治疗，以改善帕金森病(PD)患者的平衡和步态。为了达到这一目标，这项建议的目的是开发一种有效的、客观的步态冻结测量方法，将其与大脑连接异常联系起来，并[确定使用这些冻结步态和脑生物标志物进行步态康复的可行性 帕金森病中的精神障碍。]步态冻结是间歇性无法行走的现象，也是帕金森病和其他退行性神经系统疾病患者跌倒的常见原因。[三] 这项研究的目的是：1)用身体佩戴的传感器客观地表征帕金森病患者的冰冻状态；2)利用静息状态功能成像(FMRI)来探索这些冰冻客观指标与大脑功能连接异常之间的关系；以及[3]确定ABC康复干预雾化治疗的未来随机对照试验所需的受试者数量。]我们假设，可以从临床试验和临床实践中实用的便携式无线惯性传感器开发出有效的、仪表化的冰冻严重程度测量方法。我们还假设，冰冻的严重程度将与内侧额叶皮质与基底节和脑干运动区的功能连接异常有关。[我们预测，使用客观的步态和脑连接生物标记物将有助于评估康复干预如何减少帕金森病患者的冻结，改善步态和平衡。]一项观察性研究将在三组匹配的30名受试者中，从最先进的静息状态fMRI对转身和行走期间的平衡和步态协调程度的定量测量与额叶-皮质下功能连接进行关联：帕金森病伴冰冻、帕金森病不伴冰冻，以及老年对照组受试者。为了评估步态冻结，特发性帕金森病患者在停止服用抗帕金森药物12小时后，将在关闭左旋多巴的状态下进行测试。为了形成“冻结指数”，所有受试者都要原地转身，穿过狭窄的门道，左耳或右耳都有听觉音调，以指示方向的变化。在两个小腿上的无线同步惯性传感器，下背部和胸骨将记录角速度和线加速。静息状态(无任务)的fMRI连接将在同一天获得，并基于涉及内侧额叶皮质、脑干运动区、纹状体和基底节的纹状体和丘脑底核以及小脑的功能网络中低频活动的同步进行分析。[此外，一项试验性的干预性研究将把20名步态冻结的帕金森病患者随机分为8周的ABC康复计划或常规护理。盲检人员将在两组8周的前后进行客观的雾化评估、rsfMRI和认知测试，作为竞争更新该提案的临床试验的试点数据。]这项研究的结果将为我们的长期目标--对患有帕金森病的退伍军人雾进行康复干预研究--确定最佳的活动能力和脑功能指标。弄清步态缺陷和额叶缺陷之间的关系将导致更有效的康复干预措施，不仅可以改善患有帕金森病的退伍军人的行动能力和认知功能，而且还可以改善许多由于影响大脑额叶的神经缺陷而有高跌倒风险的老年退伍军人。) 公共卫生相关性： 帕金森氏病(PD)给VHA医疗系统中超过3%的美国退伍军人带来了沉重的负担。帕金森病是主要的行动障碍和认知障碍的罪魁祸首，导致比大多数其他慢性病更差的生活质量。步态冻结是导致行动不便的主要原因，并与认知障碍有关，导致老年人跌倒和死亡，以及许多其他退行性神经疾病。超过80%的帕金森氏症患者出现这种间歇性行走障碍。结果是 这项研究将为我们的长期目标--对患有帕金森病的退伍军人雾进行康复干预研究--确定最佳的活动能力和脑结果指标。弄清步态缺陷和额叶缺陷之间的关系将导致更有效的康复干预措施，不仅可以改善患有帕金森病的退伍军人的行动能力和认知功能，而且还可以改善许多由于影响大脑额叶的神经缺陷而有高跌倒风险的老年退伍军人。

DESCRIPTION: Our long-term goal is to develop effective rehabilitation to improve balance and gait in patients with Parkinson's disease (PD). To reach this goal, the purpose of this proposal is to develop a valid, objective measure of 'freezing of gait', relate it to abnormal brain connectivity and [determine the feasibility of using these freezing and brain biomarkers for rehabilitation of gait disorders in PD.] Freezing of gait is the intermittent inability to step and is a common cause of falls in patients with PD and other degenerative neurological diseases in the elderly. The [three] aims of this study are: 1) To objectively characterize freezing in PD with body-worn sensors, 2) To explore how these objective measures of freezing are associated with abnormal functional connectivity in the brain using resting state functional imaging (fMRI), and [3) To determine the number of subjects needed for a future randomized, controlled trial of the ABC rehabilitation intervention on FoG.] We hypothesize that valid, instrumented measures of severity of freezing can be developed from portable, wireless inertial sensors practical for clinical trials and clinica practice. We also hypothesize that freezing severity will be related to abnormal functional connectivity of the medial frontal cortex with the basal ganglia and the brainstem locomotor region. [We predict that use of objective gait and brain connectivity biomarkers will be useful to evaluate how rehabilitation intervention reduces freezing and improves gait and balance in patients with PD.] An observational study will relate quantitative measures of coordination of balance and gait during turning and walking to frontal-subcortical functional connectivity from state-of-the art, resting state fMRI in three matched groups of 30 subjects: PD with freezing, PD without freezing, and elderly control subjects. To evaluate freezing of gait, subjects with idiopathic PD will be tested in the OFF levodopa state after withholding their antiparkinson medication for 12 hours. To develop a 'freezing index', all subjects will turn in place and walk through narrow doorways with auditory tones in their left or right ears to indicate change in direction. Wireless, synchronized inertial sensors on the two shanks, low back and sternum will record angular velocity and linear accelerations. Resting-state (task free) fMRI connectivity will be obtained on the same day and analyzed based on synchronization of low frequency activity in a functional network involving the medial frontal cortex, brainstem locomotor region, the striatum and subthalamic nucleus of the basal ganglia, and the cerebellum. [In addition, a pilot, interventional study will randomize 20 of these PD subjects with freezing of gait into either an 8- week ABC rehabilitation program or usual care. A blinded examiner will conduct objective FoG assessment, rsfMRI, and cognitive tests before and after the 8-week period in both groups as pilot data for a clinical trial in the competing renewal of this proposal.] The results of this stdy will identify the best mobility and brain outcome measures for our long- term goal of a rehabilitation intervention study for FoG in Veterans with PD. Clarifying the relationships between gait deficits and frontal lobe deficits will lead to more effective rehabilitation interventions that can improve both mobility and cognitive function not only in Veterans with PD, but also in many elderly Veterans at high risk of falling due to neurological deficits that affect the frontal lobe of the brain.) PUBLIC HEALTH RELEVANCE: Parkinson's disease (PD) imposes a heavy burden on over 3% of US veterans in the VHA health care system. PD is responsible for major mobility disability as well as cognitive disabilit, resulting in worse quality of life than most other chronic diseases. Freezing of gait is a major reason for mobility disability and associated with cognitive disability, leading to falls and mortality in PD and many other degenerative neurological disorders in the elderly. Over 80% of patients with PD develop this intermittent failure to initiate or maintain walking. The results of this study will identify the best mobility and brain outcome measures for our long-term goal of a rehabilitation intervention study for FoG in Veterans with PD. Clarifying the relationships between gait deficits and frontal lobe deficits will lead to more effective rehabilitation interventions that can improve both mobility and cognitive function not only in Veterans with PD, but also in many elderly Veterans at high risk of falling due to neurological deficits that affect the frontal lobe of the brain.