Study pinpoints neurons that may help paralyzed people walk again | Science

It seems like something out of science fiction: People paralyzed from a motorcycle or other accident are suddenly able to walk again when doctors jolt their spinal cord with electricity. Now, scientists have pinpointed the nerve cell population that’s responsible—at least in injured mice—potentially opening the door to new treatments for paralysis.

This work “is finally getting at the important contributors to recovery,” says Sarah Mondello, a neuroscientist at the University of Washington, Seattle, who was not involved with the study.

A bad fall or car accident can sever nerve connections in the spinal cord, cutting off the circuitry that allows people to control various parts of their body. But some connections remain. Zapping these with electricity—by surgically implanting a bundle of electrodes into the lower spinal cord—in combination with physical therapy and rehab can restore limb movement, bowel and bladder function, and even sexual activity.

This so-called epidural electrical stimulation is “one of the few [advances] that has shown remarkable changes in performance,” says Arun Jayaraman, a clinician and scientist at the Shirley Ryan AbilityLab, a rehabilitation center for patients with traumatic injuries.

But neither doctors nor scientists are clear on why or how the approach works. So in the new study, neuroscientist Grégoire Courtine at the Swiss Federal Institute of Technology, Lausanne, and his colleagues tracked nine spinal paralysis patients through a 5-month program of electrical stimulation, exercise, and rehab. With electrical stimulation, all nine regained their ability to walk unassisted.

The team obtained images depicting nerve cell activity in the spinal cord of these people while walking, both before and after undergoing treatment. Surprisingly, after treatment, the spinal cords of these individuals showed less activity than before. This suggested that perhaps only a subset of neurons was being activated during stimulation to help patients recover.

To get a better sense of what was going on, the team repeated the study—but this time on mice whose spinal cords had been injured. At different points throughout the therapy, which included mice walking on a treadmill with support and electrical stimulation, the researchers determined which genes are activated in specific populations of nerve cells across the spinal cord, creating a diagram based on the cells’ locations. They then used a computer program to determine which nerve cell populations were most important during the recovery process. A specific subpopulation of neurons in the mouse spinal cord, which express two markers called Vsx2 and Hoxa10, was activated after electrical stimulation, the team reports today in Nature.

To verify that these neurons are essential to recovery, the researchers selectively manipulated their activity in mice. When the scientists activated this population of neurons, the mice recovered their ability to walk. When they blocked these cells during stimulation, the mice did not. Blocking the activity of the cells in healthy mice did not affect their ability to walk, the team found, suggesting these cells become crucial for recovery after spinal cord injury.

Courtine cautions that these neurons are probably not the only ones playing a role in recovery and that other neuron populations might also be important.

In addition to neurons that control walking recovery, the findings could also direct researchers to look for the types of neurons that help with recovery of other impacted functions, including limb function, Mondello says.

Jayaraman says the work should help doctors better target the right nerves during epidural electrical stimulation. That might not only improve the success of the therapy, but also reduce unwanted side effects like an inability of the bladder to fully empty, that may result from stimulating the entire spinal cord. Courtine himself is now conducting a clinical trial of this more targeted therapy as the chief scientific officer of ONWARD, a medical technology company he founded in 2014 to develop therapies for people with spinal cord injuries.

However, this study is just the first step and many questions need to be answered before epidural electrical stimulation becomes a go-to therapy for spinal cord patients, says Jayaraman, who was not involved with the research. It’s still unclear whether the approach causes side effects, he says, or how long it lasts, for example. “There are 15 more pieces to this puzzle.”

It seems like something out of science fiction: People paralyzed from a motorcycle or other accident are suddenly able to walk again when doctors jolt their spinal cord with electricity. Now, scientists have pinpointed the nerve cell population that’s responsible—at least in injured mice—potentially opening the door to new treatments for paralysis.

This work “is finally getting at the important contributors to recovery,” says Sarah Mondello, a neuroscientist at the University of Washington, Seattle, who was not involved with the study.

A bad fall or car accident can sever nerve connections in the spinal cord, cutting off the circuitry that allows people to control various parts of their body. But some connections remain. Zapping these with electricity—by surgically implanting a bundle of electrodes into the lower spinal cord—in combination with physical therapy and rehab can restore limb movement, bowel and bladder function, and even sexual activity.

This so-called epidural electrical stimulation is “one of the few [advances] that has shown remarkable changes in performance,” says Arun Jayaraman, a clinician and scientist at the Shirley Ryan AbilityLab, a rehabilitation center for patients with traumatic injuries.

But neither doctors nor scientists are clear on why or how the approach works. So in the new study, neuroscientist Grégoire Courtine at the Swiss Federal Institute of Technology, Lausanne, and his colleagues tracked nine spinal paralysis patients through a 5-month program of electrical stimulation, exercise, and rehab. With electrical stimulation, all nine regained their ability to walk unassisted.

The team obtained images depicting nerve cell activity in the spinal cord of these people while walking, both before and after undergoing treatment. Surprisingly, after treatment, the spinal cords of these individuals showed less activity than before. This suggested that perhaps only a subset of neurons was being activated during stimulation to help patients recover.

To get a better sense of what was going on, the team repeated the study—but this time on mice whose spinal cords had been injured. At different points throughout the therapy, which included mice walking on a treadmill with support and electrical stimulation, the researchers determined which genes are activated in specific populations of nerve cells across the spinal cord, creating a diagram based on the cells’ locations. They then used a computer program to determine which nerve cell populations were most important during the recovery process. A specific subpopulation of neurons in the mouse spinal cord, which express two markers called Vsx2 and Hoxa10, was activated after electrical stimulation, the team reports today in Nature.

To verify that these neurons are essential to recovery, the researchers selectively manipulated their activity in mice. When the scientists activated this population of neurons, the mice recovered their ability to walk. When they blocked these cells during stimulation, the mice did not. Blocking the activity of the cells in healthy mice did not affect their ability to walk, the team found, suggesting these cells become crucial for recovery after spinal cord injury.

Courtine cautions that these neurons are probably not the only ones playing a role in recovery and that other neuron populations might also be important.

In addition to neurons that control walking recovery, the findings could also direct researchers to look for the types of neurons that help with recovery of other impacted functions, including limb function, Mondello says.

Jayaraman says the work should help doctors better target the right nerves during epidural electrical stimulation. That might not only improve the success of the therapy, but also reduce unwanted side effects like an inability of the bladder to fully empty, that may result from stimulating the entire spinal cord. Courtine himself is now conducting a clinical trial of this more targeted therapy as the chief scientific officer of ONWARD, a medical technology company he founded in 2014 to develop therapies for people with spinal cord injuries.

However, this study is just the first step and many questions need to be answered before epidural electrical stimulation becomes a go-to therapy for spinal cord patients, says Jayaraman, who was not involved with the research. It’s still unclear whether the approach causes side effects, he says, or how long it lasts, for example. “There are 15 more pieces to this puzzle.”