Exploring the Effects of Rehabilitation on Brain Remodeling in Progressive MS

描述（由申请人提供）：多发性硬化症（MS）是导致中青年非创伤性身体残疾的主要原因。更糟糕的是，残疾会在个人的余生中不断发展。治疗多发性硬化症的临床研究主要集中在开发和测试疾病修饰药物。虽然这些药物减少了复发的频率，但它们并不能改变潜在的残疾。相比之下，物理治疗在实验室测试中提高了MS患者的运动能力，但将治疗益处转移到现实世界中却很少得到评估。此外，MS涉及中枢神经系统进行性变性，这与残疾有显著关系。高强度运动训练可以显著重塑健康人的大脑灰质和白质结构。然而，尚不清楚这种训练效应是否会发生在多发性硬化症中。原则上，多发性硬化症中中枢神经系统的使用依赖性结构重塑可以缓解这种疾病的进行性变性。为了解决这些问题，本探索性研究项目将使用临床研究的几个最新发现来确定进行性MS是否对特定形式的受控物理治疗有显著反应，通过增加(1)长时间的真实世界功能能力和(2)定量MRI确定的CNS结构神经可塑性。本研究基于以下观察结果：(1)在随机临床试验中，约束诱导运动疗法（CI疗法）是唯一一种被证明对其他慢性疾病（中风和脑瘫）的实际运动障碍有显著改善的治疗方法。(2) CI治疗显著增加脑卒中患者大脑皮层灰质和白质结构完整性，两者又与现实世界功能改善相关。(3)来自小样本治疗的初步结果表明，CI治疗可显著改善进展性MS患者长时间的实际功能能力，且无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采用受试者内设计来评估CI治疗对MS真实世界功能和结构MRI的影响。33名轻度-中度进展性MS患者将首先在常规护理下进行多次基线评估，然后进行2周的CI治疗。临床评估和脑结构MRI测量（基于体素的形态测量，弥散张量成像）将评估CI治疗是否在基线基础上显著提高功能能力和中枢神经系统结构测量。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后来在MS中扩展的III期随机临床试验，以提高对CI治疗可能对这种进行性衰弱疾病的运动残疾和中度中枢神经系统结构变性的程度的了解。公共卫生相关性：该研究与公共卫生的相关性在于，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。约束诱导运动疗法是一种物理疗法，有证据表明它对改善许多其他神经系统疾病的运动缺陷有效。此外，MRI显示CI治疗可产生显著的脑结构重塑，这反过来又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MS患者在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显示的显著脑结构变化有关。

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.