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利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 脊髓损伤(SCI)在美国仍然是一个主要的医疗问题。每年有超过11,000名新患者遭受新的SCI并存活下来(1)，美国的患病率接近25万。许多继发性的医学问题使脊髓损伤更加严重。以美元计算的终生成本在SCI患者的年龄不同，但对于大多数四肢瘫痪患者来说，成本超过100-200万美元。 在大约一半的脊髓损伤患者中，损伤被认为是完全的，这意味着脊髓损伤水平以下的任何运动或感觉功能都不受大脑控制，而仅仅是由反射或局部脊髓事件引起的。在另一半患者中，损伤是不完整的，这意味着只有一小部分正常的大脑对亚损伤脊髓事件的控制。 有几条证据表明，脊髓损伤后，行为缺陷往往比通过测量解剖损伤所预测的更严重。如果是真的，这表明在固定病变的情况下，即使在缺陷严重的情况下，也有可能改善运动状态。证据包括 (1)解剖学证据：在大多数确诊为完全性脊髓损伤的患者中，神经病理学观察显示大脑和脊髓运动区之间存在解剖联系(2)。这类患者被称为不完全患者(3)。自主运动功能正常的脊髓损伤患者皮质脊髓外侧束内纤维数量最少为3,173条(正常41,472条)，完全性脊髓损伤患者皮质脊髓外侧束内纤维数量平均为2,113条，而不是零。 (2)生理学证据：神经生理学研究可以证明完全性脊髓损伤患者的部分或少数患者存在皮质脊髓束功能残存。这些患者的运动皮质经颅磁刺激(TMS)显示，电信号可以传递到损伤以下的脊髓区域(4-6)。 (3)皮质中风患者的类似发现：我们最近证明，在影响手部初级运动皮质区域的中风患者中，当大约37%--而不是100%--正常的手运动皮质地图被疾病破坏时，自主手运动功能就会丧失[7]。 (4)使用极端物理疗法的运动增加的报道：在脊髓损伤(例如C.Reve)(8)或中风(强迫诱导治疗的报道，例如Schaechter等人在我的实验室进行的一项研究(9))之后，固定损伤和很少或没有运动的患者的运动状况可以得到改善。如果最初的瘫痪是由于所有关键的运动底物被消融所致，则不太可能恢复。 本研究的总体思路是评估强化理疗对脊髓损伤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一个治疗中心(“步行计划”)进行测量。 除了仔细评估极限运动疗法对脊髓损伤的影响外，这项拟议的研究还代表着迈向以家庭为基础的患者评估的第一步。 具体目标 经颅磁刺激的定义。TMS线圈轻轻地放置在头皮上，安全地产生一个磁场，激活下面大约1平方厘米的大脑皮层区域。运动皮质上方的TMS产生沿皮质脊髓束向下的电击射。用目前的方法，典型的反应是一块肌肉或肌群的短暂抽搐。目前的研究将只使用单脉冲TMS，这在当前的方案中应用是完全安全的。 MEP-运动诱发电位的定义。从TMS应用到运动皮质的信号沿着脊柱下行并激活脊髓灰质神经元，之后身体相应部位的肌肉随后改变其电位-这就是MEP。有时这是一种可见的肌肉痉挛，但有时这是一种看不见的肌肉收缩，可以用普通表面肌电(EMG)方法测量。 在这项拟议的研究中，所有受试者都将是脊髓损伤患者。所有患者都将接受两次临床评估、TMS评估和MRI检查，包括功能磁共振成像(FMRI)：一次在基线时，一次在6个月后。对于一些患者，中间的6个月将被项目行走的参与所填满。在其他脊髓损伤患者中，他们将作为对照组，时间将花在常规活动上，不包括Project Walk的极端运动干预。脊髓损伤患者不会被随机分配到这两组，因为参加Project Walk的费用很高，而且目前的资金无法支付这些费用。相反，参加步行计划的脊髓损伤患者将被提供参与研究；从广告中确定的脊髓损伤患者也将被提供作为对照对象参与。 这项拟议研究的具体目的是检验这样一个假设，即剧烈运动比对照(即不运动)干预更能改善运动系统评估，这是脊髓损伤领域一个基本但鲜有研究的问题。主要终点将是ASIA运动评分，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、运动系统激活的功能磁共振测量以及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.