Exploring the Effects of Rehabilitation on Brain Remodeling in Progressive MS

探索康复对进行性多发性硬化症患者大脑重塑的影响

• 批准号: 7706697
• 负责人: Victor William Mark
• 金额: $ 21.97万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7706697
• 关键词: Activities of Daily Living; Address; Adult; Adverse event; Aftercare; Attenuated; Brain; CNS degeneration; Cerebral Palsy; Cerebrum; Chronic Disease; Clinical; Clinical Research; Clinical Trials; Development; Diffusion Magnetic Resonance Imaging; Disease; Evaluation; Fatigue; Forms Controls; Frequencies; Histologic; Individual; Investigation; Laboratories; Lesion; Life; Magnetic Resonance Imaging; Manuscripts; Measures; Methods; Motor; Movement; Multiple Sclerosis; Neuronal Plasticity; Outcome; Patients; Persons; Phase; Phase II Clinical Trials; Physical therapy; Preparation; Process; Public Health; Publishing; Randomized Clinical Trials; Reducing Agents; Rehabilitation therapy; Relapse; Research; Rest; Sampling; Stroke; Structure; Testing; Therapeutic; Training; Traumatic Brain Injury; Upper Extremity; base; brain remodeling; chronic stroke; clinical effect; constraint induced movement therapy; design; disability; follow-up; functional gain; functional improvement; gray matter; hemiparesis; improved; middle age; morphometry; motor deficit; motor impairment; nervous system disorder; programs; public health relevance; research clinical testing; response; success; treatment as usual; treatment effect; white matter; young adult

DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is the leading cause of non-traumatic physical disability for young and middle-aged adults. Worse, the disability progresses for the remainder of the individual's lifetime. Clinical research for managing MS has focused on developing and testing disease-modifying pharmacological agents. Although such agents reduce the frequency of relapses, they do not change the underlying disability. In contrast, physical therapy improves movement ability on laboratory tests in MS, but transfer of treatment benefits to the real world has only rarely been evaluated. In addition, MS involves progressive degeneration of the CNS, which is significantly related to disability. Intense motor training can significantly remodel cerebral grey matter and white matter structure in healthy individuals. However, it is unknown whether such training effects can occur in MS. Use-dependent structural remodeling of the CNS in MS could, in principle, moderate the progressive degeneration of this disorder. To address these concerns, this exploratory research program will use several recent findings from clinical research to determine whether progressive MS significantly responds to a specific form of controlled physical therapy by increasing (1) real-world functional abilities for extended periods and (2) structural neuroplasticity of the CNS as determined by quantitative MRI. The proposed research relies on the following observations: (1) Constraint-Induced Movement therapy (CI therapy) is the only treatment that has demonstrated controlled efficacy for significantly improving real-world motor disability in other chronic disorders (stroke and cerebral palsy) in randomized clinical trials. (2) CI therapy significantly increases cerebral cortical grey matter and white matter structural integrity in stroke, both of which in turn are correlated with real-world functional improvement. (3) Preliminary results from a small treatment sample indicate that CI therapy significantly improves real-world functional ability in progressive MS for extended periods without adverse events or exacerbation of fatigue. Accordingly, this 2-year Phase II exploratory clinical trial will use a within-subjects design to evaluate CI therapy effects on real-world function and structural MRI in MS. 33 persons with mild-moderate progressive MS will first undergo multiple baseline evaluations under Usual Care, followed by 2 weeks of CI therapy. Clinical evaluations and structural brain MRI measures (Voxel-Based Morphometry, Diffusion Tensor Imaging) will assess whether CI therapy significantly increases functional ability and CNS structural measures over baseline. Follow-up at 6 months will assess the retention of clinical improvements. Positive findings from this study would support later, extended Phase III randomized clinical trials in MS to improve understanding the extent to which CI therapy may benefit motor disability and moderate CNS structural degeneration in this progressively debilitating disorder. PUBLIC HEALTH RELEVANCE: The relevance of this research to public health is that it will assess the response of progressive multiple sclerosis (MS) to Constraint-Induced Movement therapy (CI therapy), a form of physical therapy that has controlled evidence of efficacy for improving motor deficit in many other neurological disorders. In addition, CI therapy has been demonstrated to produce significant remodeling of brain structure on MRI, which in turn has been correlated with improvement in daily living function. The proposed research will conduct a Phase II clinical trial to determine to what extent persons with progressive MS improve in their daily living activities after CI therapy, and whether such improvement is associated with significant structural changes in the brain on MRI.

描述（由申请人提供）：多发性硬化症（MS）是青壮年非创伤性身体残疾的主要原因。更糟糕的是，残疾在个人的余生中不断恶化。治疗多发性硬化症的临床研究重点是开发和测试缓解疾病的药物。尽管此类药物可以降低复发频率，但它们不会改变潜在的残疾。相比之下，物理治疗可以改善多发性硬化症实验室测试的运动能力，但将治疗益处转移到现实世界的情况很少得到评估。此外，多发性硬化症还涉及中枢神经系统的进行性退化，这与残疾密切相关。高强度运动训练可以显着重塑健康个体的大脑灰质和白质结构。然而，尚不清楚这种训练效果是否会在多发性硬化症中发生。原则上，多发性硬化症中枢神经系统的使用依赖性结构重塑可以减缓这种疾病的进行性退化。为了解决这些问题，该探索性研究计划将利用临床研究的几项最新发现，通过增加（1）长时间的现实世界功能能力和（2）定量 MRI 确定的中枢神经系统的结构神经可塑性，来确定进行性多发性硬化症是否对特定形式的受控物理治疗有显着反应。拟议的研究基于以下观察结果：（1）约束诱导运动疗法（CI 疗法）是唯一一种在随机临床试验中证明可显着改善其他慢性疾病（中风和脑瘫）现实世界运动障碍的控制疗效的治疗方法。 (2) CI 治疗显着增加中风患者大脑皮质灰质和白质结构的完整性，而这两者又与现实世界的功能改善相关。 (3) 小治疗样本的初步结果表明，CI 治疗可在较长时间内显着改善进展性多发性硬化症的现实功能能力，而不会出现不良事件或疲劳加剧。因此，这项为期 2 年的 II 期探索性临床试验将使用受试者内设计来评估 CI 治疗对 MS 真实功能和结构 MRI 的影响。 33 名患有轻度至中度进展性多发性硬化症的患者将首先在常规护理下接受多项基线评估，然后进行 2 周的 CI 治疗。临床评估和结构性脑 MRI 测量（基于体素的形态测量、扩散张量成像）将评估 CI 治疗是否显着提高功能能力和 CNS 结构测量超过基线。 6 个月的随访将评估临床改善的保留情况。这项研究的积极结果将支持随后针对多发性硬化症进行扩展的 III 期随机临床试验，以提高对 CI 治疗在多大程度上有益于这种进行性衰弱性疾病的运动障碍和中度中枢神经系统结构退化的了解。公共健康相关性：这项研究与公共健康的相关性在于，它将评估进行性多发性硬化症（MS）对约束诱导运动疗法（CI 疗法）的反应，CI 疗法是一种物理疗法，已控制了改善许多其他神经系统疾病运动缺陷的疗效证据。此外，MRI 已证明 CI 疗法可显着重塑大脑结构，进而与日常生活功能的改善相关。拟议的研究将进行一项 II 期临床试验，以确定进行性多发性硬化症患者在接受 CI 治疗后日常生活活动的改善程度，以及这种改善是否与 MRI 上大脑的显着结构变化有关。