EFFECT OF INTERNET-ENABLED INTENSE EXERCISE THERAPY ON MOTOR STATUS AFTER SPINAY

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 脊髓损伤（SCI）仍然是美国的一个主要医疗问题。每年有超过11，000名新患者遭受新的SCI并存活下来（1），美国患病率接近25万人。SCI还伴有许多次要医疗问题。 以美元为单位的终生成本随着SCI的年龄而变化，但对于大多数四肢瘫痪者来说超过1-2百万美元。 在大约一半的SCI患者中，损伤被认为是完全的，这意味着SCI水平以下的运动或感觉功能都不受大脑控制，而是完全由反射或局部脊髓事件引起。 在另一半患者中，损伤是不完全的，这意味着正常大脑对损伤后脊髓事件的控制仍然存在。 几条证据表明，SCI后，行为缺陷往往比从解剖损伤的措施预测更严重。 如果是真的，这表明在固定病变的情况下，即使缺陷严重，也有改善运动状态的潜力。 证据包括 (1)解剖学证据：在大多数诊断为完全性SCI的患者中，神经病理学观察表明大脑和脊髓运动区之间存在解剖学连接（2）。 这种患者被称为不完全性（3）。 保留自主运动功能的SCI患者的皮质脊髓侧束中的最小纤维数量为3，173（正常为41，472）;在完全SCI患者中，该束中的平均纤维数量不是零，而是平均2，113。 (2)生理学证据：神经生理学研究可以证实部分（少部分）完全性脊髓损伤患者的皮质脊髓束功能残留。 这些患者的运动皮层经颅磁刺激（TMS）显示，电信号可以传输到损伤下方的脊髓区域（4-6）。 (3)皮质卒中患者的类似发现：我们最近证明，在影响手部初级运动皮层区域的卒中患者中，当大约37%而不是100%的正常手部运动皮层地图被疾病破坏时，随意手部运动功能被废除（7）。 (4)极端物理疗法的运动增益报告：SCI后（如C。Reeve）（8）或中风（限制诱导治疗的报告，例如Schaechter等人（9）在我实验室的一项研究），对于固定病变且运动很少或没有运动的患者，运动状态可以得到改善。 如果初始麻痹是由于所有关键运动基质消融所致，则不太可能恢复。 这项研究的总体原理是评估强化物理治疗对SCI患者运动状态的影响。 结果评估将在实验室、家中和卡尔斯巴德的治疗中心进行（“步行项目”）。 除了仔细评估极端运动疗法对SCI的影响外，这项拟议中的研究还代表了家庭患者评估的第一步。 具体目标 TMS-经颅磁刺激的定义。 一个TMS线圈轻轻地放在头皮上，安全地产生一个磁场，激活大约1平方厘米的大脑皮层。 运动皮质上方的TMS产生一个沿皮质脊髓束向下的电子齐射。 当前方法的典型反应是一个肌肉或肌肉群的短暂抽搐。 当前研究将仅使用单脉冲TMS，其在当前方案中的应用完全安全。 MEP-运动诱发电位（Motor Evoked Potential） 从TMS应用到运动皮层的信号沿着脊柱下行并激活脊髓灰质神经元，之后相应身体部位的肌肉随后改变其潜力-这就是MEP。 有时这是一个可见的肌肉抽搐，但有时这是一个不可见的肌肉收缩，可以用常见的表面肌电图（EMG）方法测量。 在拟定研究中，所有受试者均为SCI患者。 所有患者将接受临床评估、TMS评价和MRI检查，包括两次功能性MRI（fMRI）：一次在基线，一次在6个月后。 在一些患者中，中间的6个月将充满参与Project Walk。 在其他SCI患者中，他们将作为对照，时间将用于日常活动，不包括Project Walk的极端运动干预。 SCI患者不会被随机分配到两组，因为参与Project Walk的费用很高，目前的资金无法支付这些费用。 相反，将为入组Project Walk的SCI患者提供参与研究的机会;从广告中识别的SCI患者也将作为对照受试者参与研究。 拟议研究的具体目的是检验这一假设，即剧烈运动比对照（即不运动）干预更能改善运动系统评估，这是SCI领域中一个基本但很少研究的问题。 主要终点将是ASIA运动量表，这是SCI临床试验中最常用的终点。 次要终点将包括运动系统功能的其他测量、运动功能的互联网评估、神经生理学的TMS测量、运动系统激活的fMRI测量和脊髓直径的解剖测量。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Spinal cord injury (SCI) remains a major medical problem in the U.S. Over 11,000 new patients suffer and survive a new SCI each year(1), with U.S. prevalence of nearly a quarter million persons. SCI is compounded by numerous secondary medical problems. The lifetime cost in dollars varies with the age at SCI but exceeds 1-2 million dollars for most quadriplegics. In approximately half of all patients with SCI, the injury is said to be complete, meaning that none of the motor or sensory function below the level of SCI is controlled by the brain, instead arising solely from reflex or localized spinal cord events. In the other half of patients, injury is incomplete, meaning a fraction of the normal brain control of sub-lesional spinal cord events remains. Several lines of evidence suggest that, after SCI, behavioral deficits are often more severe than would be predicted from measures of anatomical injury. If true, this suggests the potential to improve motor status in the setting of a fixed lesion, even when deficits are severe. Evidence includes (1) Anatomical evidence: In most patients diagnosed with complete SCI, neuropathological observations suggest surviving anatomical connections between brain and spinal cord motor areas (2). Such patients have been termed discomplete (3). The minimum number of fibers in the lateral corticospinal tract of SCI patients with preserved voluntary motor function was 3,173 (normal 41,472); the mean number of fibers in this tract among complete SCI patients was not zero, but instead averaged 2,113. (2) Physiological evidence: Neurophysiological studies can demonstrate residual corticospinal tract function in some, alebit a minority, of patients with complete SCI. Transcranial magnetic stimulation (TMS) of motor cortex in these patients shows that electrical signals can be transmitted to spinal cord areas below the injury(4-6). (3) Analogous findings in patients with cortical stroke: We recently demonstrated that, among patients with stroke affecting the hand's primary motor cortex area, voluntary hand motor function was abolished when approximately 37%--and not 100%--of the normal hand motor cortex map was destroyed by the disease (7). (4) Reports of motor gains with extreme physiotherapy: After SCI (eg C. Reeve) (8) or stroke (reports of constraint induced therapy, eg a study from my lab by Schaechter et al (9)), motor status can be improved in patients with a fixed lesion and little or no movement. No recovery would be likely if initial plegia were due to ablation of all key motor substrates. The overall rationale of the proposed study is to evaluate the effect of intensive physical therapy on motor status in patients with SCI. Outcome assessments will be measured in the lab, in the home, and at a center for therapy in Carlsbad ("Project Walk"). In addition to carefully evaluating the effects of extreme exercise therapy on SCI, the proposed study also represents a first step towards home-based patient assessments. SPECIFIC AIMS Definition of TMS-transcranial magnetic stimulation. A TMS coil gently set atop the scalp safely produces a magnetic field that activates an approximately 1 cm2 area of underlying cerebral cortex. TMS above motor cortex produces an electrical volley down the corticospinal tract. A typical response with current methods is a brief twitch in one muscle or muscle group. The current study will only use single pulse TMS, which is completely safe as applied in the current protocol. Definition of MEP-Motor evoked potential. The signal from TMS application to motor cortex goes down the spine and activates spinal gray matter neurons, after which muscles in the respective body part subsequently change their potential-this is the MEP. Sometimes this is a visible muscle twitch but sometimes this is a subvisible muscle contraction that can be measured with common surface electromyography (EMG) methods. In the proposed study, all subjects will be patients with SCI. All will undergo clinical assessment, TMS evaluation, and MRI exam including functional MRI (fMRI) twice: once at baseline and once 6 months later. In some patients, the intervening 6 months will be filled with participation at Project Walk. In other patients with SCI, who will serve as controls, the time will be spent in usual activities that will not include the extreme exercise intervention of Project Walk. Patients with SCI will not be randomly assigned to the two groups, as participation in Project Walk is expensive and current funding can not cover such costs. Instead, patient with SCI who enroll in Project Walk will be offered study participation; and patients with SCI who are identified from advertisements will be also offered participation as control subjects. THE SPECIFIC AIM OF THE PROPOSED STUDY is to test the hypothesis that intense exercise will improve motor system assessments more than the control (ie no exercise) intervention, an elementary yet little studied question in the field of SCI. The primary endpoint will be ASIA motor scale, the endpoint most often used in clinical trials of SCI. Secondary endpoints will include other measures of motor system function, internet-enabled assessments of motor function, TMS measures of neurophysiology, fMRI measures of motor system activation, and anatomical measures of spinal cord diameter.