Will there ever be neuroplastic surgeons

Paraplegia: The dream of being able to walk again

It sounds a bit like a miracle: With the power of his thoughts, a paralyzed 28-year-old can move his arms and legs again, and even take a few steps. More precisely, it is not running, but a robotic device hanging from the ceiling. The man was strapped into it. Before that, doctors had implanted two devices with electrodes on his hard meninges that read his brain waves and convert them into computer signals. The man controls the exoskeleton via this brain-machine interface.

Would that be what researchers from the University of Grenoble are presenting (Lancet Neurology: Benabid et al., 2019), one day safe, suitable for everyday use, affordable and paid for by health insurances as an aid, that would certainly be a step forward. But such sensations currently have nothing to do with the life of paraplegics. You have completely different questions: Am I in need of care forever? How can I live barrier-free? Who should pay for all of this? Can I continue to do my job? Have children?

A severed or damaged spinal cord is one of the most serious injuries a person can suffer. All the nerves from the brain to the body run through here. Depending on the level at which the spinal cord is injured, the person is paralyzed from there downwards. Rehabilitation and therapies can improve the situation. A cure is - it sounds bitter - not realistic.

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It is above all medical professionals who dream of helping the paralyzed to walk again. It is about patients who can no longer feel anything from the shoulders down. Your arms and legs cannot move and you may no longer be able to control your bladder. Up to 120,000 women and men in Germany are currently living with this diagnosis. About 2,300 are added every year. The cause is an accident or illness. These people are dependent on a wheelchair and need help with simple everyday activities.

Because even the best exoskeleton cannot cure a paraplegic, working groups around the world have been researching for decades how such a paralysis could one day be actively alleviated or even cured. The successes are manageable. It is not uncommon for individual cases in which someone was able to move parts of the body again within the scope of a study are reported too positively and with little differentiation: Because what may have worked in a laboratory is far from functioning in everyday life. And yet there are individual cases in which the astonishing becomes possible again.

In the future, nerves may really be regenerated, spinal cords grown in the laboratory, or signals from the brain may be redirected to the limbs within the body. Four approaches in which medical professionals are placing their hopes:

Redirecting nerves to feel again

Thirteen young patients from Australia made headlines recently. They were able to move their arms and hands again after an operation, although they were paralyzed by an injury to the cervical spine (The Lancet: van Zyl et al., 2019). While the spinal cord is naturally almost incapable of making new connections between nerve cells after an injury, peripheral nerves that supply arms and legs, for example, are able to do so. The prerequisite for this method is that there are still intact nerve connections from the brain via the spinal cord to a muscle, for example in the upper arm.

Paraplegia

What is spinal cord injury?

If the spinal cord is cut or damaged, there is one Paraplegia the consequence. How strong it is depends on the Amount of injury from. The spinal cord is divided into different segments, each segment for the Control of certain muscle groups and organ functions responsible for. In the case of an injury to the cervical spine, the affected person typically cannot move their arms or legs.

What is plegia, what is paresis?

Depending on how severe the damage is, a distinction is made between complete paralysis (Plegia) from incomplete paralysis (Paresis). Are below the injury no motor or sensory Functions more there, one speaks of one complete paraplegia. Are they still partially preserved, from an incomplete. In many cases, being paraplegic also means being with Pain and spasticity - a pathologically increased muscle tension - to live or your own Bladder and bowel functionn no longer being able to control arbitrarily.

How many are affected?

Currently living in Germany 100,000 to 120,000 people with paraplegia. Come every year at least 2,300 due to illnesses and accidents added, as reported by the paraplegia working group of the German Social Accident Insurance. Infections, TumorsSo, radiation damage or vascular diseases can lead to it as well as a car accident.

Is there hope for a cure?

To this day, paraplegia as such not curable. Depending on the severity are through rehabilitation measures Improvements in motor skills and sensory skills possible and the level of paralysis after an accident can still shift.

A team of surgeons had redirected such functional nerves so that they could grow into paralyzed muscles for months. In some cases, the doctors also transplanted muscle tendons to enable more vigorous movements. With the help of intensive physiotherapy, the patients learned over two years to carry out everyday activities again, such as brushing their teeth, holding a glass or typing.

"This method can have a future," says Norbert Weidner, Medical Director of the Clinic for Paraplegiology at Heidelberg University Hospital. So far, the few centers that have been offering the method for some time have only reported independently of individual cases. The great merit of the Australian team: It has systematically and successfully examined the technology for the first time. "When people can grip again, that's great," says Weidner. That might not sound like a lot, but it does mean independence and less dependence on carers and relatives.

The disadvantage of the method: "Overall, there are probably only a few patients who are eligible," says Weidner. It's not a solution for everyone. For example, a prerequisite for the study was that the spinal cord injury had not been more than 18 months ago. In addition, the shoulder and elbow function had to be at least partially still present.

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Wake up the spinal cord with electricity

Another approach is to wake up the spinal cord below the injury site with an electric current. Epidural electrical stimulation (EES) is the name of the procedure that research teams around the world have been refining for years. The stimulation is supposed to get the brain to reactivate unused lines in the lower half of the body. Paralyzed rodents, for example, were able to stand or walk again with the help of this technique, but this did not work for humans for a long time (The Neuroscientist: Shah & Lavrov, 2017). Until last autumn.

After an operation in which electrodes were placed in the spinal cord, followed by electrical stimulation and intensive training, the three patients were able to stand and walk independently again, as reported by Swiss researchers in November 2018 (Nature: Wagner et al.). Two of them not only in a clinical setting, but also in everyday life with the help of a walker.

Using electrodes below the injury site is not a new approach. But probably to do without a permanent stimulus. The Swiss research team stimulated nerve cells that control the movements of the hip and leg muscles in a spatially and temporally offset manner, as is the case with natural movement. Because some movements were even possible without the stimulator after months of training, the scientists suspect that nerve connections may have re-established across the injury site. Fresh nerves that function independently. Even if this has not yet been proven, some see the future in targeted electrical stimulation.

The doctor Norbert Weidner is more reserved. The process is scientifically very exciting, he says. However, the results were achieved in a highly controlled environment with intensive months of care from physiotherapists. "To what extent this can be transferred to everyday situations remains to be seen," says Weidner. In everyday life, after all, people don't walk across the smooth hospital floor in company, but switch independently from carpeting to parquet, sometimes having to overcome a threshold or two steps.

Another point of criticism: According to current knowledge, incompletely paralyzed people who still have a significant proportion of functional nerve tracts could benefit from the method. In the case of completely paraplegic people, it cannot be assumed that the stimulation will make them walk again in everyday life, says Weidner.

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Growing neurons from stem cells

About twenty years ago, the idea of ‚Äč‚Äčtreating paraplegics with stem cells was considered extremely promising. The first euphoria has since subsided because the quickly expected successes have not materialized. But there are new developments that researchers are now relying on.

The original plan was to first transplant stem cells - immature cells that can develop into different cell types - into the patient's spinal cord. These should then become nerve cells and form new connections across the injury site. Injury bridged, problem solved! In experiments with rats, this even worked surprisingly well: the stem cells became neurons that connected themselves to the animals' nervous system (Stem Cell Reports: Adler et al., 2017). But the rodents could not walk. The reason: There are hundreds, if not thousands, of different types of nerve cells in the spinal cord. Not every guy gets along with the others.

Stem cells

Stem cells: what are they?

In the first days of its development, an embryo is not yet fully differentiated - that is, all possible organs can develop from its cells. Research wants to make use of this fact and from such embryonic stem cells Grow replacement tissues. Embryonic stem cells were isolated from mice for the first time in 1981. In 1998, the American researcher James Thomson from the University of Wisconsin succeeded in growing the first cell lines from human embryos.

But even adults can still form stem cells, for example in the bone marrow, where new blood cells are produced from them. These adult stem cellsthat opponents of embryonic cell research are hoping for can also recreate tissue. However, they are not so versatile and capable of multiplying. In the case of paraplegics who want to voluntarily undergo stem cell therapy in the USA, it is hoped to be able to regenerate destroyed nerve tissue.

For the treatment of brain damage - for example from Parkinson's disease or after a stroke - researchers set out fetal (or fetal) stem cells. These are taken from five to twelve week old fetuses whose bodies have been released for research after an abortion.

What can you?

Whether Alzheimer's, Parkinson's, diabetes, paraplegia or heart attack - in these diseases tissue dies or is damaged, so that the organs no longer function properly. Researchers hope from embryonic stem cells Replacement fabric to breed. In addition, drugs could be tested on tissue produced in this way.

Controversial research

In Germany the production of embryos for stem cell production is prohibited. This is to protect the unborn life. Although the embryos are at an early stage of development when the cells are removed and only consist of a few cells, a person could theoretically grow out of them if they were implanted in a woman's uterus.

In other countries, for example in the USA, embryos that are "left over" from artificial insemination are used for research. Until April 2008, only research on embryonic stem cells from abroad and obtained before January 1, 2002 was allowed in Germany. Since these old cell lines are contaminated and genetically modified by the frequent replication, this cut-off date in April 2008 was moved to May 1, 2007.

Many scientists are calling for the legislation in Germany to be relaxed further in order to be internationally competitive. Some opponents want a general ban on research on embryonic stem cells.

iPS

The abbreviation stands for induced pluripotent stem cell. They arise when the mature body cells of an adult are programmed back to a very early, quasi-embryonic state with the help of biochemistry. Skin cells, for example, then develop characteristics of embryo cells: practically any cell type in the body can develop from them.

The iPS are genetically identical to the original skin cells. A decisive advantage: tissue grown from it would not be rejected by the cell donor's immune system after a transplant. The iPS could also solve an ethical problem in the future: an embryo does not have to die to obtain them.

The reprogramming was first achieved in 2006 by the team of the Japanese stem cell researcher Shinya Yamanaka with mouse cells. In 2008, Kevin Eggan from Harvard University transformed human skin cells first into stem cells and then into nerve cells.

The iPS was made possible because research on real embryonic stem cells had previously identified four genetic factors that are crucial for the virgin status of the cell.

Think of it as if 5,000 people were sitting in a room and each one wanted to deliver a message to a friend on the opposite side, says Jennifer Dulin, a neuroscientist at Texas A&M University. The others could theoretically forward the message, but each speaks only two of 50 possible languages. So, to get the message across, you have to first find someone around you who speaks your language, as well as the next person, and so on. "Nerve cells only communicate with very specific partners," says Dulin. So that a nerve impulse can pass the injured area, there must be enough correct neurons. That is still left to chance. But with the help of new techniques, it is possible to track which connections the transplanted cells form. By observing and understanding the processes, Dulin and other researchers will, at best, learn in the future how the stem cells can be used in a more targeted manner.

At the same time, the first phase I studies are currently being carried out on humans. A research group at the University of California, San Diego, transplanted stem cells to three men and a woman with spinal cord injury for the first time (Cell Stem Cell: Curtis et al., 2018). The doctors injected 1.2 million nerve stem cells directly into the patient's spinal canal six times. All test subjects tolerated the treatment well; no serious side effects had occurred for two years afterwards - the prerequisite for further studies. Three of the participants showed slight neurological improvements, but none of them improved their quality of life. Further studies must now show whether the method can actually help people.

The problem, however, is the question of where the stem cells come from. In the San Diego study, they came from a fetus that had been aborted at eight weeks of age. That would also be legally permitted in Germany, but it is ethically controversial. Another possible source: induced pluripotent stem cells (iPS cells), which, for example, can be reprogrammed from the patient's adult skin or fat cells. Japanese researchers announced in the spring that they would be testing such iPS cells for the first time in the treatment of paraplegics. Admittedly, this technology is not free of risk either. Jennifer Dulin sees one advantage, however, in the fact that paralyzed patients can receive transplants from the body's own cells.Not only would that be more ethical, it could also reduce the risk of the immune system rejecting them.

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Inhibit proteins so that nerves can recover

Another reason why the nerves in the spinal cord do not recover on their own is the protein Nogo-A. It is found in the membrane that surrounds nerve fibers and prevents them from sprouting again in the event of an injury. The protein was discovered by the neurobiologist Martin Schwab from ETH Zurich at the end of the 1980s.

Schwab and his team have now developed an antibody that inhibits the protein. Because animal experiments have shown that nerves can regenerate in this way, and initial tests on humans did not show any serious side effects, a phase II study started this summer (Neurorehabilitation and Neural Repair: Kucher et al., 2018). Doctors at 15 European centers want to test the effectiveness of the drug in 132 patients with recently developed spinal cord injuries; nerves are most likely to grow again within the first few months after an injury.

However, it also depends on how severely the spinal cord is injured in the specific case. The chances are particularly good for patients who still have some mobility, says the doctor Norbert Weidner, because the antibody promotes the growth of intact nerve tracts.