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）是年轻人和中年人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发展。管理MS的临床研究集中在开发和测试疾病修饰药理学药物。虽然这些药物降低了复发的频率，但它们不会改变潜在的残疾。相比之下，物理治疗可以改善MS实验室检查的运动能力，但很少对治疗益处转移到真实的世界进行评估。此外，MS涉及CNS的进行性变性，这与残疾显著相关。剧烈运动训练可显著重塑健康个体的大脑灰质和白色质结构。然而，目前尚不清楚这种训练效果是否会发生在MS中。MS中CNS的CNS依赖性结构重塑原则上可以缓和这种疾病的进行性变性。为了解决这些问题，该探索性研究计划将使用临床研究的几项最新发现，通过增加（1）长期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，确定进展性MS是否对特定形式的受控物理治疗有显著反应。拟议的研究依赖于以下观察结果：（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著改善其他慢性疾病（中风和脑瘫）的真实运动障碍的对照疗效的治疗方法。(2)CI治疗显著增加脑卒中患者大脑皮质灰质和白色物质结构的完整性，这两者反过来又与现实世界的功能改善相关。(3)来自小治疗样本的初步结果表明，CI治疗显著改善了进展型MS的实际功能能力，延长了时间，而没有不良事件或疲劳加重。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中真实世界功能和结构MRI的影响。33名轻中度进展性MS患者将首先在患者护理下接受多次基线评估，然后接受2周CI治疗。临床评价和结构性脑MRI测量（基于体素的形态测定、扩散张量成像）将评估CI治疗是否显著增加功能能力和CNS结构测量超过基线。6个月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MS的后期扩展III期随机临床试验，以提高对CI治疗在这种进行性衰弱性疾病中可使运动残疾和中度CNS结构变性受益的程度的理解。公共卫生相关性：这项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，CI疗法是一种物理疗法，具有改善许多其他神经系统疾病运动缺陷的有效性证据。此外，CI治疗已被证明在MRI上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。拟议的研究将进行第二阶段临床试验，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上大脑的显著结构变化有关。

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.