Electrical stimulation helps paralyzed people walk again - and now we know why

Electrical stimulation helps paralyzed people walk again – and now we know why

Spinal cord.  Light micrograph of a cross section of a mammalian cervical spinal cord.

Spinal cord injuries can be partially cured by remodeling certain neurons.Credit: Steve Gschmeissner/SPL

Neuroscientists have identified the nerve cells responsible for helping paralyzed people walk again, opening up the possibility of targeted therapies that could benefit a wider range of people with spinal cord injuries1.

Severe spinal cord injuries can disrupt the connection between the brain and the networks of nerve cells in the lower spine that control walking. In 2018, neuroscientist Grégoire Courtine of the Ecole polytechnique fédérale de Lausanne and his colleagues showed that sending electrical impulses to these lower nerves in the spine – a technique known as epidural electrical stimulation (EES) – could, when combined with intensive training, get people with this type of spinal cord injury to walk again2. All three participants in one trial went from severe or complete motor paralysis and minimal sensation in the legs to being able to walk alone, or with a walker or crutches. Two other teams showed similar results that year3,4.

Courtine’s team have now extended the work, showing that the system works in people who have lost feeling in their legs. The group reports in Nature today that nine participants in the same trial – three of whom had complete paralysis and no sensation in their legs – regained the ability to walk after training combined with EES delivered by devices implanted in their spine. Five months into the trial, all participants could support their own weight and take steps, using a walker for added stability.

Four no longer need the EES to be on to walk. This sustained recovery suggests that stimulation triggers remodeling of spinal neurons to restart the locomotion network.

“The amount of hope this gives people with spinal cord injury is incredible,” says Marc Ruitenberg, a neurologist at the University of Queensland in Brisbane, Australia, who studies spinal cord injury.

Depreciated activity

Courtine’s team also discovered the neurons responsible for improving rehabilitation. Counterintuitively, when EES was activated in people, nerve cell activity at the stimulation site decreased. The team used this clue to further investigate the process. First, the researchers emulated every aspect of the treatment in mice – from injury and electrical stimulation to training with a specially designed robotic support for stability. The results mimicked those of the people.

Next, the researchers measured gene activity in thousands of individual neurons in mouse spinal tissue samples. This produced an extremely detailed map of nerve cell types in the lower spinal cord. They then used a machine learning algorithm to search for mouse neurons that exhibited changes in gene activity at defined stages of EES-assisted rehabilitation that matched observed changes in walking ability in human participants.

The algorithm identified a subpopulation of excitatory interneurons – nerve cells that connect motor and sensory neurons – that seemed to match. When Courtine and her team silenced these cells in injured mice, they found that the EES no longer allowed the injured animals to walk.

The overall decrease in neural activity at the site during rehabilitation reflects a learning process, Courtine says. “When you think about it, that shouldn’t be a surprise,” he says, “because in the brain, when you learn a task, that’s exactly what you see — there are fewer and fewer neurons activated” as you improve. .

Next steps

The technology does not exist to collect this kind of direct evidence from people. But Eiman Azim, a neuroscientist at the Salk Institute for Biological Studies in La Jolla, California, says the same neurons are likely responsible for the effect because the architecture of the spine is very similar in vertebrates, including humans. and mice.

Eventually, Azim says, a detailed understanding of spinal circuitry could allow neuroscientists to manipulate the activity of specific neurons directly with other treatments, such as gene therapy. Stem cell therapies could one day replace crucial populations of damaged neurons in spinal cord injuries, Ruitenberg says.

Courtine and colleagues also used EES to restore arm movement and hand grip in monkeys5. And a group from the University of Washington in Seattle did the same for six people with spinal cord injuries, using noninvasive skin patches with electrodes placed on their necks.6.

As dramatic as it can be to see people with spinal cord injuries walk again, Ruitenberg says walking is often not a priority for people. Loss of bladder control, bowel control, and sexual function can have a greater impact on quality of life. “It would be really interesting to see if those kinds of functions can be improved with this technology as well,” he says.

Courtine says identifying the nerves responsible for these functions is on his list of next steps now that he has a detailed molecular map to work with. He also launched a start-up — ONWARD, based in the Netherlands — to commercialize the technology. The company will begin recruiting 70 to 80 participants in the United States for a new trial in 2024.

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