Nature: From severe paralysis to resumption of walking, a miracle of recovery from 9 people with spinal cord injuries

▎WuXi AppTec content team editor 

For many years, spinal cord injuries were considered a "terminal illness.
"
Because the severed spinal nerve connection cannot be repaired, the patient is paralyzed, unable to move, and even lost sensation
in the limb.

However, in a recent clinical study, nine patients who were severely or completely paralyzed by a spinal cord injury not only got back on their feet after a treatment called epidural electrical stimulation (EES), but also miraculously regained the ability to
walk.

During the 5-month electrical stimulation treatment, combining physiotherapy and rehabilitation, these 9 patients were able to walk an average of 50 meters
in 6 minutes.
After the treatment period, 4 participants were able to walk without any electrical stimulation, indicating that motor function has been continuously improved and the neural connections used for walking have been successfully
reorganized.

▲ Nine paralyzed patients recovered their ability to walk to varying degrees (Image source: Reference [4]; Credit: NeuroRestore-Jimmy Ravier）

What's even more exciting is that behind the miracles of recovery from these spinal cord injury patients, researchers have identified specific neurons that play a key role in regaining the ability to walk — and in the future, manipulating these specific neurons may help more paralyzed patients regain motor function
.

The research paper, published in the top academic journal Nature and also on the radar of Science, noted that the discovery "may open the door to new ways to treat paralysis.
"

Epidural electrical stimulation has been around for more than 50 years, but was originally designed to relieve neuropathic pain
.
In this clinical trial, Professor Grégoire Courtine, a neuroscientist at the Ecole Polytechnique Fédérale de Lausanne in Switzerland, and Professor Jocelyne Bloch, a neurosurgeon at the University Hospital of Lausanne, surgically implanted an electrode they designed into the patient's lumbar spine, targeting the "dorsal root" area of the spinal cord to provide electrical current
to the nerve pathways that control the legs.
In the case of spinal cord injury, this approach can reactivate surviving neurons
below the injured site.

"We mimic the way the spinal cord is activated by electrical signals from the brain when a person walks, electrically stimulating the spinal cord at the right place at the right time to control the leg muscles
.
" Professor Bloch explained
.
To this end, the researchers also used artificial intelligence to individualize the patterns and locations of electrical stimulation to precisely match each patient's activity
.

▲ Epidural electrical stimulation (EES) is performed on patients through implanted wireless electrical pulse generators, and ground walking is achieved with the help of weight support systems (Image source: Reference [4]; Credit: NeuroRestore）

This electrical stimulation therapy has helped patients substantially improve motor function, and the researchers' work has just begun: revealing the neural mechanisms
behind rehabilitation.
Because only by figuring out how the neural circuits that restore the ability to walk are remodeled can more effective treatments be developed to help as many patients as possible improve their quality of life
.

To do this, the researchers built a model of a mouse spinal cord injury that paralyzed its hind legs, and then implanted electrodes in its spinal cord to improve the mice's ability
to walk through electrical stimulation.
In other words, this mouse model can reproduce the key characteristics
of the recovery of paralyzed patients after epidural stimulation.

Throughout the different stages of treatment, the researchers used mononuclear DNA sequencing, spatial transcriptomics and other methods to map in detail the damaged spinal cords of paralyzed mice, determine which genes are activated in specific nerve cell groups of the spinal cord, and algorithmically determine which nerve cell groups are most important
during electrical stimulation treatment.

▲ Mice with spinal cord injury simulate the rehabilitation process of patients receiving electrical stimulation therapy (Image source: Reference [1]).

So, the researchers found a specific group of neurons in the mouse spinal cord, which expressed two markers, Vsx2 and Hoxa10, which were activated
after electrical stimulation treatment.

By specifically blocking the activity of this group of neurons by optogenetic methods, paralyzed mice could not be improved
by electrical stimulation therapy.
At the same time, healthy mice blocked the activity of this group of neurons and did not affect their activity
.
These results further verify that the group of neurons identified this time is indispensable for restoring the ability to walk after paralysis, but not necessary for individuals without spinal cord injury
.

▲Neurons that promote the recovery of motor capacity were identified by mouse models (Image source: Reference [1]).

In this regard, the expert commentary published in Nature at the same time pointed out, "Understanding the rehabilitation principle of epidural electrical stimulation therapy and identifying the cell types of tissue rehabilitation is a huge advance
.
" ”

With this advance, doctors in the future can more precisely target the right nerves when treating patients with spinal cord injury with epidural electrical stimulation, which will not only improve the success rate of treatment, but also reduce the side effects of stimulating the entire spinal cord, such as affecting bladder emptying
.

However, Professor Courtine is also cautious to point out that the group of excitatory neurons identified this time should not be the only type of neuron
that helps patients regain the ability to walk.
For example, the researchers found an overall decline in spinal nerve activity during walking before and after electrical stimulation treatment, suggesting that neurosuppression is also part of
rehabilitation.

Researchers may still have many questions to answer before more people with spinal cord injuries can regain their ability to walk through treatment, but this study certainly offers hope: Spinal cord injury does not equal lifelong paralysis
.

Resources:

[1] Claudia Kathe et al.
, The neurons that restore walking after paralysis.
Nature (2022) DOI: 10.
1038/s41586-022-05385-7

[2] Neurons that promote recovery from paralysis identified.
Retrieved Nov.
10, 2022 from style="margin-bottom: 0px;line-height: normal;">[3] Study pinpoints neurons that may help paralyzed people walk again.
Retrieved from style="margin-bottom: 0px;line-height: normal;">[4] Scientists identify neurons that restore walking after paralysis.
Retrieved Nov.
11, 2022 from https://actu.
epfl.
ch/news/scientists-identify-neurons-that-restore-walking-a/