University of Pittsburgh School of Medicine researchers carrying out a small pilot clinical trial demonstrating that a drug-free, minimally invasive intervention targets the root cause of progressive loss of neural function in patients with spinal muscular atrophy (SMA), an inherited neuromuscular disease.

匹兹堡大学医学院的研究人员进行了一项小型试点临床试验，证明无药物、微创干预的目标是脊髓性肌萎缩症（SMA）患者神经功能逐渐丧失的根本原因，SMA是一种遗传性神经肌肉疾病。

The pilot trial in three adults with SMA showed that epidural spinal cord stimulation (SCS), which involves electrical stimulation of the sensory spinal nerves, can gradually reawaken functionally silent motor neurons in the spinal cord and improve leg muscle strength and walking..

对三名患有SMA的成年人进行的初步试验表明，硬膜外脊髓刺激（SCS）涉及感觉脊髓神经的电刺激，可以逐渐唤醒脊髓中功能沉默的运动神经元，并改善腿部肌肉力量和行走。。

Early results from the trial found that one month of regular neurostimulation sessions improved motoneuron function, reduced fatigue, and improved strength and walking in all participants, regardless of the severity of their symptoms. The study is the first to show that a neurotechnology can be engineered to reverse the degeneration of neural circuits and rescue cell function in a human neurodegenerative disease.

该试验的早期结果发现，一个月的定期神经刺激治疗可以改善所有参与者的运动神经元功能，减少疲劳，提高力量和行走能力，无论其症状的严重程度如何。这项研究首次表明，可以设计一种神经技术来逆转人类神经退行性疾病中神经回路的退化并挽救细胞功能。

The researchers also suggest that the same neurostimulation approach could be used to treat other neurodegenerative diseases such as amyotrophic lateral sclerosis, or Huntington’s disease, if appropriate cellular targets can be identified..

研究人员还建议，如果可以确定适当的细胞靶点，同样的神经刺激方法也可以用于治疗其他神经退行性疾病，如肌萎缩侧索硬化症或亨廷顿舞蹈病。。

“To counteract neurodegeneration, we need two things—stop neuron death and restore function of surviving neurons,” said Marco Capogrosso, PhD, assistant professor of neurosurgery at Pitt. “In this study we proposed an approach to treat the root cause of neural dysfunction, complementing existing neuroprotective treatments with a new approach that reverses nerve cell dysfunction.”.

皮特大学神经外科助理教授马可·卡波格罗索博士说：“为了对抗神经退行性疾病，我们需要两样东西来阻止神经元死亡和恢复存活神经元的功能。”。“在这项研究中，我们提出了一种治疗神经功能障碍根本原因的方法，用一种逆转神经细胞功能障碍的新方法补充了现有的神经保护治疗。”。

Capogrosso is co-corresponding author of the team’s published study report in

Capogrosso是该团队在年发表的研究报告的联合通讯作者

Nature Medicine

自然医学

, titled “

First-in-human study of epidural spinal cord stimulation in individuals with spinal muscular atrophy

脊髓性肌萎缩症患者硬膜外脊髓刺激的首次人体研究

.” In their paper, the team noted, “In summary, our results provide insights into the disease mechanisms of SMA that lead to circuit and motoneuron dysfunction in humans. Notably, we leveraged the identification of these mechanisms to design a clinically relevant intervention that manipulated the maladaptive processes induced by SMA, improving function at a cellular, circuit, and behavioral level.”.

“在他们的论文中，该团队指出，“总之，我们的研究结果提供了对SMA导致人类回路和运动神经元功能障碍的疾病机制的见解。值得注意的是，我们利用这些机制的鉴定来设计临床相关的干预措施，操纵SMA诱导的适应不良过程，改善细胞，回路和行为水平的功能。”。

SMA is a genetic neurodegenerative disease that leads to progressive functional decline and death of motor neurons, the nerve cells that control movement by transmitting signals from the brain and the spinal cord to the muscles. “SMA is an inherited spinal motor circuit disorder caused by the homozygous loss of the SMN1 gene, which results in ubiquitous deficits of SMN protein expression,” the authors further explained.

SMA是一种遗传性神经退行性疾病，可导致运动神经元进行性功能衰退和死亡，运动神经元是通过将信号从大脑和脊髓传递到肌肉来控制运动的神经细胞。作者进一步解释说：“SMA是一种遗传性脊髓运动回路疾病，由SMN1基因的纯合缺失引起，导致SMN蛋白表达普遍存在缺陷。”。

Over time, the loss of motor neurons causes gradual muscle weakness and leads to a variety of motor deficits, which may include difficulty in walking, climbing stairs, and standing up from chairs. “Lack of SMN leads to selective death of spinal motoneurons and progressive muscle atrophy,” the team continued..

随着时间的推移，运动神经元的丧失会导致肌肉逐渐无力，并导致各种运动缺陷，其中可能包括行走，爬楼梯和从椅子上站起来的困难。“缺乏SMN会导致脊髓运动神经元选择性死亡和进行性肌肉萎缩，”研究小组继续说道。。

While there is no cure for SMA, several promising neuroprotective treatments have become available in the last decade. These include gene replacement therapies and medications, both of which stimulate the production of motoneuron-supporting proteins that prevent neuronal death and that slow down—though do not reverse—disease progression..

虽然SMA无法治愈，但在过去的十年中，已经有几种有前途的神经保护治疗方法可用。这些包括基因替代疗法和药物，这两种疗法都能刺激运动神经元支持蛋白的产生，从而防止神经元死亡，并减缓疾病的进展，但不能逆转疾病的进展。。

Studies show that movement deficits in SMA emerge before widespread motoneuron death, suggesting that underlying dysfunction in spinal nerve circuitry may contribute to disease onset and symptom development. “Animal models of SMA show that motor deficits appear before widespread motoneuron death, suggesting that spinal circuit dysfunction may play a role in disease onset and progression,” the investigators pointed out..

研究表明，SMA的运动缺陷在广泛的运动神经元死亡之前出现，这表明脊髓神经回路的潜在功能障碍可能导致疾病发作和症状发展。研究人员指出：“SMA的动物模型显示，运动缺陷出现在广泛的运动神经元死亡之前，这表明脊髓回路功能障碍可能在疾病的发生和发展中起作用。”。。

Earlier research in animal SMA models by study co-author George Mentis, PhD, at Columbia University indicated that surviving motor neurons receive fewer stimulation inputs from sensory nerves—fibers that return the information from skin and muscles back to the central nervous system. “Importantly, excitatory synaptic input to spinal motoneurons coming from proprioceptive afferents is lower in SMA,” the authors stated.

哥伦比亚大学（Columbia University）研究合著者乔治·门蒂斯（George Mentis）博士早期对动物SMA模型的研究表明，存活的运动神经元从感觉神经纤维接收的刺激输入较少，感觉神经纤维将皮肤和肌肉的信息返回中枢神经系统。作者指出：“重要的是，SMA中来自本体感受传入的脊髓运动神经元的兴奋性突触输入较低。”。

Compensating for this deficit in neural feedback might improve communication between the nervous system and the muscles, aid muscle movement, and combat muscle wasting. “Upregulating the activity of primary sensory afferents could compensate for the loss of excitatory input to motoneurons, potentially triggering circuit dysfunction reversal,” they suggested..

弥补神经反馈的这种缺陷可能会改善神经系统和肌肉之间的沟通，帮助肌肉运动，并对抗肌肉萎缩。他们建议：“上调初级感觉传入神经的活动可以弥补运动神经元兴奋性输入的损失，可能引发电路功能障碍逆转。”。。

Marco Capogrosso, Ph.D. [UPMC and Pitt Health Sciences]

Marco Capogrosso博士[UPMC和皮特健康科学]

The Pitt researchers hypothesized that a targeted epidural electrical stimulation therapy could be used to rescue lost nerve cell function by amplifying sensory inputs to the motor neurons and engaging the degenerated neural circuits. These cellular changes could, in turn, translate into functional improvements in movement capacity..

皮特的研究人员假设，有针对性的硬膜外电刺激疗法可以通过放大运动神经元的感觉输入并参与退化的神经回路来挽救神经细胞功能的丧失。这些细胞变化反过来可以转化为运动能力的功能改善。。

Their reported study was conducted as a pilot clinical trial that enrolled three adults with milder forms of SMA (Type 3 or 4 SMA). During a study period of 29 days, participants were implanted with two SCS electrodes that were placed in the lower back region on each side of the spinal cord, directing the stimulation exclusively to sensory nerve roots.

。在29天的研究期间，参与者植入了两个SCS电极，这些电极放置在脊髓两侧的下背部区域，将刺激仅引导至感觉神经根。

Testing sessions lasted four hours each and were conducted five times a week for a total of 19 sessions, until the stimulation device was explanted..

测试会议每次持续四个小时，每周进行五次，共19次，直到刺激装置被移植。。

After confirming that the stimulation worked as intended and engaged spinal motor neurons, the researchers performed a battery of tests to measure muscle strength and fatigue, changes in gait, range of motion, and walking distance, as well as motoneuron function. The results showed that all participants increased their 6-minute walk test score—a measure of muscle endurance and fatigue—by at least 20 meters, compared to a mean improvement of 1.4 meters over three months of comparable exercise regimen unaided by SCS, and a median increase of 20 meters after 15 months of SMA-specific neuroprotective pharmacologic therapy..

在确认刺激按预期工作并参与脊髓运动神经元后，研究人员进行了一系列测试，以测量肌肉力量和疲劳，步态，运动范围和步行距离的变化以及运动神经元功能。。。

These functional gains were mirrored by improved neural function, including a boost in motoneurons’ capacity to generate electrical impulses and transmit them to the muscles. “Our intervention led to improvements in strength (up to +180%), gait quality (mean step length: +40%), and endurance (mean change in 6-minute walk test: +26 m), paralleled by increased motoneuron firing rates,” the team further reported..

这些功能的提高反映在神经功能的改善上，包括运动神经元产生电脉冲并将其传递给肌肉的能力的提高。。。

Commenting on the findings, co-corresponding author Elvira Pirondini, PhD, assistant professor of physical medicine and rehabilitation at Pitt, said, “Because SMA is a progressive disease, patients do not expect to get better as time goes on. But that is not what we saw in our study. Over the four weeks of treatment, our study participants improved in several clinical outcomes with improvements in activities of daily living.

联合通讯作者、皮特大学物理医学与康复助理教授Elvira Pirondini博士在评论这一发现时说：“由于SMA是一种进行性疾病，患者预计不会随着时间的推移而好转。但这不是我们在研究中看到的。在治疗的四周里，我们的研究参与者在一些临床结果方面有所改善，日常生活活动有所改善。

For instance, toward the end of the study, one patient reported being able to walk from their home to the lab without becoming tired.”.

例如，在研究即将结束时，一名患者报告说能够从家里步行到实验室而不会感到疲倦。”。

In their report, the team stated, “In this study, we demonstrated that electrical stimulation of the sensory afferents alleviated motor deficits in three humans with SMA through a combination of immediate assistive effects and therapeutic effects that appeared over time with SCS OFF. Importantly, we found evidence of improved spinal motoneuron function in an otherwise progressive neurodegenerative disease.”.

在他们的报告中，该团队表示：“在这项研究中，我们证明了感觉传入的电刺激通过即时辅助作用和随着SCS关闭而出现的治疗效果的组合，减轻了三名SMA患者的运动缺陷。重要的是，我们发现了在其他进行性神经退行性疾病中脊髓运动神经元功能改善的证据。”。

Added co-corresponding author Robert Friedlander, MD, chair of neurosurgery at Pitt and co-director of the UPMC Neurological Institute, “Our results suggest that this neurostimulation approach could be broadly applied to treat other neurodegenerative diseases beyond SMA, such as ALS or Huntington’s disease, as long as appropriate cell targets are identified in the course of future research.

联合通讯作者、皮特神经外科主席兼UPMC神经学研究所联合主任Robert Friedlander博士补充道：“我们的研究结果表明，这种神经刺激方法可以广泛应用于治疗SMA以外的其他神经退行性疾病，如ALS或亨廷顿舞蹈病，只要在未来的研究过程中确定适当的细胞靶点。

We are hoping to continue working with SMA patients and launch another clinical trial to test the long-term efficacy and safety of electrical spinal cord stimulation.”.

我们希望继续与SMA患者合作，并启动另一项临床试验，以测试脊髓电刺激的长期疗效和安全性。”。

The authors further noted that while SCS is being studied as an assistive neuroprosthetic tool to improve movement after spinal cord injury, stroke, and other neurodegenerative diseases, “… this is the first time, to our knowledge, that a neurostimulation therapy was not engineered to assist movement but, rather, to reverse degenerative circuit processes and effectively rescue motoneuron function in a human motoneuron disease.”.

作者进一步指出，虽然SCS正在作为一种辅助神经假体工具进行研究，以改善脊髓损伤，中风和其他神经退行性疾病后的运动，“……据我们所知，这是第一次神经刺激疗法不是为了辅助运动而设计的，而是为了逆转退行性回路过程，有效地挽救人类运动神经元疾病中的运动神经元功能。”。

News

新闻

Amyotrophic lateral sclerosis

肌萎缩侧索硬化症

Electric stimulation therapy

电刺激疗法

Neurons

神经元

Spinal muscular atrophy

脊髓性肌萎缩症