The gospel of paralyzed patients, can it make you a normal person? !

Electrical stimulation therapy is expected to bring huge benefits to paralyzed patients. Since 2018, a large number of similar case studies have made headlines in laboratories in Kentucky, Minnesota, and Switzerland.

A previous news report in “Nature” magazine focused on a series of progressive research in this field. The stimulator originally designed to treat chronic pain has now helped a group of paralyzed patients twist their toes and bend their legs. Or walk under support.

Rob Summers was lying on his back in a rehabilitation facility in Kentucky, USA, and suddenly realized that he could twist his big toe.

Since a hit-and-run driver caused Summers to become paralyzed from below his chest, he has been unable to do this again. The doctor told him that the nerve connecting his leg had been severed and he could no longer move his lower body. The doctor classified it as a complete injury, and Summers was paralyzed. Now, he is participating in a pioneering trial to test the effects of electrical stimulation treatment in patients with spinal cord injury.

Susan Harkema, a neurophysiologist at the University of Louisville in Kentucky, couldn’t believe that Summers could move his toes. In 2009, when Harkema and her colleagues implanted a tiny electrode strip on Summers’ spine, they did not intend to restore his own ability to move, but just wanted to prove that the spine contains all the nerves that the human body needs to stand and walk.

The gospel of paralyzed patients, can it make you a normal person?  !

Figure | Rob Summers’s spine was completely injured, and the doctor said it would make him unable to walk (Source: Nature)

According to a report by Nature, it has long been widely believed that spinal cord injury means that the connection between the brain and the limbs is severed. For decades, researchers have been working to repair these connections, such as stem cell therapy. But results from Harkema’s research team and other laboratories show that some of the nerve connections in patients with spinal cord injuries are still intact, even for those who have suffered the most severe spinal cord injuries. Electrical stimulation therapy seems to help amplify the information transmitted at the injured site and restore these connections.

The gospel of paralyzed patients, can it make you a normal person?  !

Figure | After two years of recovery training, Rob Summers implanted an epidural stimulator on his back (Source: Nature)

Summers’ sudden awakening of neural connections is part of a series of research advances that have injected vitality into research on spinal cord injury.

In 2018, a large number of similar case studies made headlines in laboratories in Kentucky, Minnesota, and Switzerland. Stimulators originally designed to treat chronic pain have now helped about 12 paralyzed patients twist their toes, bend their legs, or walk under support. Some patients can even walk 1 kilometer.

These electrical stimulation devices also seem to provide a wider range of therapeutic benefits. Some study participants have also seen improvements in blood pressure, bowel and bladder control, and sexual function. For patients with spinal cord injury, these physiological functions are often more important than the exercise ability of the lower limbs. In some cases, these benefits persist even after turning off the stimulus.

The results of these studies have increased people’s hopes for improving the quality of life, even for people who were paralyzed years or decades ago. The findings overturned traditional views about spinal cord injury. “This is a new field,” said Reggie Edgerton, a physiologist at the University of California, Los Angeles (UCLA).

Today, there are thousands of names waiting to receive electrical stimulation treatment trials, and at least one hospital has begun to provide this trial treatment at a cost of tens of thousands of dollars. However, the risks and risks involved have not been formally approved. The benefits have yet to be fully assessed.

For some people, electrical stimulation therapy may be a familiar-sounding over-propaganda. After all, efforts to cure the paralysis have cost hundreds of millions of dollars, and so far, apart from bold predictions and dashed hopes, little effect has been achieved.

Starting with the cat on the treadmill

In the 1970s, Edgerton began to pay attention to a model that has been studied for a long time. Cats with severed spinal cords can be hung on a treadmill. With simple guidance, their legs move like steps to train them to walk again. After practice, these cats can adjust their gait to adapt to the speed of the treadmill, and even change direction. These actions do not require signal input from the brain.

The spinal circuit that pushes them forward, called the “central pattern generator,” controls their movement, and Edgerton tries to understand how it works.

When Harkema joined Edgerton’s laboratory in 1993, she was not so interested in the spine. But when Harkema started to study cats, she was fascinated by how cats regained so many functions. Edgerton commissioned Harkema to conduct a similar experiment on people with spinal injuries. They believe that perhaps the rigorous training of the awakening central pattern generator can also allow these patients to walk.

Stepping training with weight support on a treadmill can help people with spinal cord injuries, especially those with minor injuries, to improve their athletic ability. But Harkema and Edgerton hope to see greater impact. An epidural stimulator seems to be a good choice, as it can transmit electrical current to the lower part of the spinal cord.

Since the 1960s, this device has been used to treat chronic pain. But researchers discovered early on that they could do more. For example, in patients with spinal cord injury, stimulators seem to reduce the incidence of involuntary spasms.

In one study, researchers tested some patients with spinal cord injury who had implanted stimulators. When the stimulation was increased, participants began to move their legs rhythmically and automatically.

Karen Minassian, a medical physicist at the Medical University of Vienna, said: “This may be, and is still the most direct evidence of the so-called central pattern generator of human motion.”

There are even case studies showing that electrical stimulation can restore the ability to move autonomously, at least for those who retain some sense and movement in the lower body.

The gospel of paralyzed patients, can it make you a normal person?  !

Figure | Researchers use a tablet to control the electrode array on Rob Summers’s spine (Source: Nature)

In 2002, researchers in Arizona reported that a 43-year-old man with a spinal injury was trained and treated with electrical stimulation to walk in a “nearly effortless, coordinated mode of movement.”

Harkema and Edgerton began to discuss the possibility of using the same method. They just need a patient test to prove this principle. And Summers is determined to be the patient they want to test.

The desire to stand and walk

Ever since Summers was paralyzed by a speeding car on a summer night in 2006, he has refused to believe this.

In the first year, after intense rehabilitation, Summers recovered some sensation in his limbs, but he still couldn’t move his lower body. However, he was sure that he just needed the right treatment. Therefore, he and his parents sent more than 200 e-mails to research institutions around the world.

It was these efforts that led Summers to a rehabilitation training studio in Texas in September 2007, where he met Harkema. When Harkema mentioned that her team planned to study epidural stimulation, Summers was excited.

In Louisville, Summers underwent intensive rehabilitation for more than two years to assess his ability to recover without stimulation.

In December 2009, Harkema’s team installed him with an epidural stimulator. They placed 16 electrode arrays between the spine and spinal cord of Summers. A wire connects the array to the stimulator, which is a rechargeable device, about half the size of a deck of playing cards, just above his hip. Then the doctor remotely controlled the stimulator.

When the researchers turned on the stimulator, Summers immediately felt a sting. Three days later, the researchers tried to get him to stand. At first, all his weight was supported by a wire harness. The research team gradually began to reduce this assistance until Summers was able to stand on its own.

He watched the leg muscles contract in the mirror. “This can’t be true,” he thought. Then he looked around the room and saw his mother burst into tears.

However, this is nothing compared to the electrical stimulation that allowed Summers to twist the toes after 6 months.

Harkema’s team hopes to stimulate the neural circuits needed for the spine and legs when standing and walking, but they don’t expect any help from the brain. Harkema called Edgerton in the Los Angeles laboratory and told him about Summers’ toes.

“Oh my God, this couldn’t be true,” Edgerton recalled. “Everyone would think we were liars.”

Real breakthrough

When Harkema and her colleagues announced the details of the Summers case in 2011, many scientists were skeptical.

“I don’t believe it,” said Kendall Lee, a neurosurgeon at the Mayo Clinic in Rochester, Minnesota. Professor Lee believes that once they lose contact with the brain, they will never come back.

But gradually, the evidence began to increase. Harkema and her team published another study in 2014 involving Summers and three other people, including two people with no motor function or sensation in the lower body. The final results showed that all patients resumed some autonomous activities.

Soon, others began to try this method on humans, hoping to see if participants could take a step off the treadmill.

Gregoire Courtine, a neurologist at the Swiss Federal Institute of Technology Lausanne (EPFL), also worked with Edgerton. In 2008, he came to Europe to study the effects of epidural stimulation on rodents, and finally conducted experiments on rhesus monkeys.

In 2015, Courtine felt that she was ready to test this technology on humans.

His team used the same epidural stimulator that Harkema had used, but fine-tuned the software so that the device can provide stimulation patterns that are synchronized with walking.

“We try to activate the spinal cord, just like the brain is trained.” Courtine said. There is another major difference from Harkema’s research. Courtine’s team recruited some people who were not completely paralyzed, hoping that this group of people would recover more easily than those who were completely paralyzed.

The gospel of paralyzed patients, can it make you a normal person?  !

Figure | Sebastian Tobler (middle) took this step with the help of researcher Grégoire Courtine (right) and neurosurgeon Jocelyne Bloch (KEYSTONE/Valentin Flauraud)

At the same time, Edgerton helped a third group at the Mayo Clinic conduct another experiment.

In 2016, Lee, rehabilitation scientist Kristin Zhao, and their colleagues began to replicate Harkema’s results. They recruited two participants, received physical therapy for nearly six months before implanting the stimulator, and then underwent electrical stimulation for 10 months. The purpose of the research is to prove that stimulation and training can improve their standing ability and the ability to move the lower body autonomously. But the first participant achieved these goals so quickly that the researchers decided to add walking to the experimental protocol.

In the fall of 2018, the three teams announced the results of the first eight trial participants. A total of six people completed some form of ground walking with the help of slings, crutches or parallel bars. The other two groups also experienced the benefits. They were able to sit and stand independently under the stimulation treatment, and one group could walk a few steps with support on the treadmill.

Chet Moritz, a researcher in rehabilitation medicine at the University of Washington in Seattle, said, “This is where I really feel like a breakthrough.”

Exaggeration or close at hand?

However, there have been exciting “breakthroughs” in this field before, such as the hope of repairing nerve damage shown by the Stem Cell Research Institute. Studies have shown that when the spines of paralyzed mice were injected with stem cells, they miraculously restored the ability to walk or use their paws.

A cure seems to be within reach.

However, it is difficult to replicate these results in people. Keith Tansey, a neurologist at the Jackson Methodist Rehabilitation Center in Mississippi, said that although human trials of stem cells are still going on, and some of them have shown promising results, the excitement from funders, patients, and researchers about this method has been decreased.

Other high-tech treatments for paralysis, such as brain-computer interfaces, are still being developed, and powered exoskeleton systems have also been on the market, but they are expensive. However, these high-tech methods have not solved the potential problem of restoring neural connections.

Peter Grahn, a neurologist at the Mayo Clinic, said, “We’ve all heard things like’There will be a magic pill in five years’ time. You always hear things like this because five years is too long. Everyone will forget.”

But to many interested bystanders, the prospects of electrical stimulation therapy far exceed the hype. In particular, it is worth mentioning that it has a long history of treating chronic pain. Matthe Wrodreick, executive director of Unite 2 Fight Paralysis, a spinal cord injury advocacy organization based in Hood River, Oregon, said that this device has been implanted in thousands of people. In the human body. This does not mean that the strategy will be successful, but at least the road to approval is clear.

It is currently unknown how electrical stimulation therapy works and why some of the benefits still exist after turning off the stimulator. It is increasingly clear that for many people who are considered to be completely paralyzed, some nerve pathways in the brain that control movement do exist. They are just in a dormant state and cannot cause a response from the neurons below the injury site. Epidural stimulation seems to make neurons more prone to excitement-neurons are more prone to excitement when faced with signals from the brain to move a toe or start walking.

The gospel of paralyzed patients, can it make you a normal person?  !

Figure | Rob Summers and others need assistance and close monitoring to re-stand and walk, and this is just one of the benefits they reported experiencing (Source: Nature)

As for why some participants will continue to benefit, there are two possible explanations. Electrical stimulation can allow individuals to participate more fully in rehabilitation through exercise and strengthen muscle and nerve connections; or it can promote nerve plasticity, which helps to reconnect nerve circuits surrounding the damage. This is a particularly tempting possibility, because over time it may mean that there is potential for improvement.

Despite this, researchers have not yet determined who will benefit the most from this process. Harkema said that the 20 people implanted in Louisville all regained some voluntary movement. But in Tansey’s view, not everyone with a spinal cord injury can be improved. He wants to find a way to screen individuals, because implanting medical devices in the spine is not a trivial matter and is risky.

Although such stimulators have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of chronic pain, they occasionally produce dangerous side effects. Recipients reported that they were shocked, burned, or suffered nerve damage, resulting in muscle weakness and even paralysis. An Associated Press survey in 2018 found that since 2008, electrical stimulators have received nearly 80,000 injury reports, more than any other medical device except insulin pumps and metal hip replacement surgery.

This may also be a unique risk for patients with spinal cord injury, who are more susceptible to infection and usually have lower bone density. In the latest study by Harkema’s team, a participant had a hip fracture.

There are also some problems that are difficult to explain in the report.

In 2015, Xander Mozejewski with spinal cord injury joined an Edgerton trial to test the effects of non-invasive “transcutaneous” stimulation. Later, he began to feel cramps and pain in his lower body, which gradually worsened. In 2016, doctors implanted an epidural stimulator to try to control the spasm, but the device seemed to make the situation worse, and Mozejewski eventually removed it. In 2018, he filed medical malpractice lawsuits against UCLA, Edgerton, NeuroRecovery Technologies, and other companies.

Edgerton co-founded this company in San Juan Capistrano, California. The case is still under trial, but in a statement provided to Nature, the CEO of Nerve Regenerative Technologies, Nick Terrafranca, said: “The stimulator has been used in more than 60 research participants and has not been directly related to the use of the stimulator. Reports of adverse events related to the equipment developed and provided by the company.” TerraFranca added that the side effects recorded by the company, including muscle cramps, were “transient in nature.”

Harkema’s research has also received some criticism. In 2015, a colleague of her gave the University of Louisville Institutional Review Board, Human Subjects Protection Program (Human Subjects Protection Program) and National Institute on Disability, Independent Living and Rehabilitation (National Institute on Disability, Independent Living and Rehabilitation). Research, NIDILRR) wrote a letter expressing concerns about Harkema’s four studies.

An internal investigation revealed that these scientists failed to track and monitor adverse events, deviated from the research protocol, and recorded incorrectly. As a result, NIDILRR cancelled funding for one of the studies. The study cost US$914,000 to study the effects of muscle relaxants and treadmill training on patients with spinal cord injuries. The US Office for Human Research Protections also conducted an investigation, but did not impose sanctions on Harkema. The agency stated that the corrective actions taken by the Harkema team have adequately resolved the non-compliance issue.

Harkema admitted that her team did not keep records well, but she denied all allegations of serious wrongdoing.

Harkema’s research has been proceeding rapidly. The Christopher & Dana Reeve Foundation of New Jersey is supporting an extradural stimulation trial on 36 additional patients in its laboratory in Louisville. As of July, 11 people have been implanted with stimulators.

Blindness and optimism

The demand for new treatments has also spawned the spinal cord injury medical tourism industry. In Bangkok, the World Medical Center Hospital provides epidural anesthesia to anyone who meets hospital standards and can afford a price of more than $70,000.

The hospital is affiliated to a company called Unique Access Medical (UAM). The head of patient services Henning Kalwa said that as of July this year, the hospital had performed 70 implants. Kalwa wrote in a public post on LinkedIn, “While other colleagues in the neurology field are still busy researching and testing, UAM has successfully treated patients in the process of seeking treatment for paraplegia and quadriplegia. .”

Courtine warns patients with spinal cord injury not to undergo epidural stimulation treatment outside of clinical trials. He once saw the stimulator being implanted in the wrong position, and he pointed out that even the top scientists did not agree on how to configure stimulation and training. “It’s too early,” he said.

Tansey worries that in various clinics that suddenly appear, blindly receiving unsupervised epidural stimulation or stem cell treatments that may not work, may put serious research halfway.

For scientists, the focus is still on research. Each group seems to have its own ideas on how to promote scientific progress.

Harkema’s team continued to recruit participants for research funded by Reeve, and she also started a project to study the effects of stimulation and training on bowel and bladder function.

At the same time, Courting co-founded a company called GTX medical in Eindhoven, the Netherlands, to develop a customized stimulator for patients with spinal cord injury. He hopes that this technology will come out within a few years.

His team also conducted a study to conduct an epidural stimulation test on 20 patients who had recovered less than a month. He said that in these people, “it is indeed possible to see the recovery of the nervous system” and may even grow new nerve fibers.

Figure | During the treatment, Rob Summers was supported by his service dog Bear (Source: Nature)

After the initial study, Summers left Kentucky and traveled around the United States. In 2018, he moved back to Louisville to participate in another study on standing, stepping, and autonomous movement. He is now using his second machine. Stimulator.

Summers said that these stimulus pulses are “brittler and cleaner,” and every day he feels that he has reached a new milestone. On a Tuesday morning in April, he turned on the stimulator and attached it to the sling on the metal frame of the casters. Then he began to waddle on the promenade on the 12th floor of the Frazier Rehabilitation Institute in Louisville. Row.

Summers has made amazing improvements in his way of walking, and he is still improving. But this is still an ongoing experiment. He can’t walk in the park yet, or even hang out in the apartment.

As a perpetual optimist, Summers sees electrical stimulation as a treatment. For him, the biggest benefit is the least conspicuous improvement in blood pressure, bladder and bowel control, sexual function and thermoregulation. There are some more trivial feelings, such as the feeling brought by a pair of new socks. “I can feel its softness,” he said, “I can find fun in these little things, it’s crazy.”

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