Hope grows for patients with spinal cord injuries

Severe spinal cord injuries (SCIs) — often called complete injuries by clinicians — are ones where no readable signal from the brain reaches the spinal cord beneath the trauma, resulting in total paralysis. The possibility that a patient with this type of severe injury might regain movement was once considered so remote that rehab has traditionally seemed a waste of time.

And yet, in a handful of patients spanning multiple levels of severity, movement is being regained. None of these patients have regained total motor function — but considering that any recovery has been previously considered impossible, it’s extraordinary. The movements, ranging from the purposeful (walking) to the autonomic (blood pressure, bladder control, and sexual function) are happening despite catastrophic collapse of the nervous system that controls them.

The breakthrough, scientists say, was recognizing that the spinal cord is not just a conduit — something the brain jacks into to send its messages to the body — but a complex driver of the nervous system in its own right.

While the specific approach varies by lab and research team, the basic mechanics are similar. Atop the patients’ spinal columns, scientists place a small, oblong paddle atop the patients’ spinal columns which then releases electricity into the body, exciting the various mechanisms of the spinal cord which now are firing across the gap created by the injury. With the stimulator running, a myriad of functions are regained as the system winks back to life: the body regulates its blood pressure, the bladder and bowels come back under control, and steps are possible once again.

After decades of animal research, a combination of new and old techniques — including spinal stimulation with surgically implanted devices, transcutaneous stimulation from electrodes on the skin, and locomotor training (weight-supported and assisted treadmill-based rehab) — is changing how science views spinal cord injury, paralysis, and the spinal cord itself. Lazarus-like lab footage shows clinically paralyzed people regaining their ability to stand and walk, spurring interest and investment as the number of labs doing the work blooms.

Even with all the cutting-edge science, recovery is not guaranteed, and the risks are real and potentially serious — but so are the rewards.

“We Are So Impressed with Our Cortex”

All the threads of this story converge in California, where Reggie Edgerton’s UCLA lab produced early work on spinal stimulation and where most of the leading figures in the field trace their academic roots. Two of the most prominent researchers, Susan Harkema of the Kentucky Spinal Cord Injury Research Center at the University of Louisville and Grégoire Courtine, Principal Investigator for the G-Lab team at Switzerland’s EPFL, came out of Edgerton’s lab.

Together, these researchers have challenged how science views the spinal cord, the brain, and the interplay between the two. For decades, the prevailing impression was that the spinal cord mostly just translated and delivered the messages from the brain, like a telephone wire running down our backs.
But biology has long held a different view, with studies on animal models suggesting that the brain and spinal cord often handle overlapping functions. Edgerton’s own work explored this phenomenon in cats, where much of the research was conducted that laid the groundwork for the human studies being done now.

“But there’s been such strong dogma among neurologists that everything is occurring in the brain,” Edgerton says. It’s possible a sort of human chauvinism led scientists to dismiss evidence from cats showing that the spinal cord was shouldering a lot of the load when it came to managing movement and bodily functions. “We are so impressed with our cortex.”

What has emerged in spinal stimulation labs is a picture of a much more complex — and poorly understood — system. The spinal cord and brain share similar cells and structures, and they carry out similar functions. Dr. Harkema argues the spinal cord, not the brain, is the primary controller for certain kinds of movement.

“It makes the final decisions,” Harkema says.

Which is not to say that it does not communicate with the brain. Rather than either one operating unilaterally, they work in tandem to exercise the complex movements and functions of the body. That connection is damaged in a spinal cord injury, and with it the ability for motor control. However, what the spinal stimulation labs have shown is that that gap may not be so insurmountable as we once believed.

Dr. Harkema argues the spinal cord, not the brain, is the primary controller for certain kinds of movement.

Spinal Study Breakthroughs

Perhaps the most famous work in the field is being conducted down in the bluegrass of the basketball belt. At the University of Louisville’s Kentucky Spinal Cord Injury Research Center, Dr. Harkema has used locomotor training and surgically implanted stimulators to restore autonomic and voluntary functions.

In a study published in September 2018 in the New England Journal of Medicine, Harkema’s lab demonstrated recovery of over-ground walking (as opposed to treadmill walking) in two of four patients with motor complete spinal cord injuries, meaning complete loss of voluntary movement below the level of injury.

“Being a participant in this study truly changed my life, as it has provided me with a hope that I didn’t think was possible after my car accident,” said Kelly Thomas, a 23-year-old participant in the study who achieved over-ground walking, according to the University of Louisville.

“One minute I was walking with the trainer’s assistance and, while they stopped, I continued walking on my own. It’s amazing what the human body can accomplish with help from research and technology.”

Jeff Marquis, the other participant to achieve over-ground walking, told the University that his “main priority is to be a participant in this research and further the findings, as what the University of Louisville team does each day is instrumental for the millions of individuals living with paralysis from a spinal cord injury.” Freethink was able to visit Jeff and Dr. Harkema at the lab and witnessed his fierce determination to help further spinal cord research.

All four participants in Harkema’s study had been injured for at least two years and were unable to stand, walk, or voluntarily move their legs. Two were classified as having a grade A injury — meaning a complete loss of both sensory and motor function below the level of injury — while the others were classified as grade B — meaning loss of motor function but with some sensory function below the level of injury.

Through weeks of rigorous training with weight assistance and treadmills, with stimulation of the spinal cord by epidural electrodes, the two grade B participants, Thomas and Marquis, regained the ability to walk over ground with assistive devices (such as a walker or poles for balance). The two grade A subjects “achieved some components of independent stepping on a treadmill with body-weight support,” according to the study. All four achieved independent standing. 

None of the subjects were able to achieve these actions after the stimulator was off, but the study indicates that technology may be able to improve the quality of life for the approximately 1.2 million people living with paralysis from a spinal cord injury in the U.S. alone.

“This research demonstrates that some brain-to-spine connectivity may be restored years after a spinal cord injury,” Harkema told the University of Louisville. 

Harkema’s lab is not without controversy. In March 2016, a federal agency took the highly unusual step of pulling funding from one of her studies, involving a muscle relaxer used in physical therapy, in response to concerns over inadequate reporting of adverse events, among other problems. In response, Harkema told the Kentucky Center for Investigative Reporting that the issues with record keeping were overblown and had been addressed, and that patients were not put at risk. (The university denied that any of the adverse events were related to the study, while the whistleblower disagreed.)

Further studies at the Mayo Clinic, in collaboration with UCLA, and EPFL reported similar gains as Harkema’s 2018 study, in one and three patients, respectively.

Courtine’s lab at EPFL achieved their results via a different form of stimulation. Whereas Harkema’s study used a continuous current to increase the “excitability” of neural functions (essentially inducing the environment necessary for the spinal cord to function), Courtine’s groups used “burst” stimulation, lighting up only the networks needed for walking.

“From the beginning, we target selectively specific spots of the spinal cord, specific nerve roots on the lumbosacral spinal cord, that would control a group of muscles that are synergistic,” Fabien Wagner, a lead scientist working with Courtine’s lab, says by Skype. With this method, patients gain walking ability that must then be honed by training, rather than training first, as in Harkema’s study.

Unique to the EPFL study was the retention of movement without the stimulator running. Their most recovered subject can take approximately 10 steps between parallel bars without the use of his hands (although his hips are in contact) before he needs to rest.

This research demonstrates that some brain-to-spine connectivity may be restored years after a spinal cord injury.

Importantly, however, EPFL used patients with spinal injuries graded a C and D, meaning some motor function was preserved below the level of injury or that most of the muscles below the injury were strong enough to move against gravity. Whether their burst method is more promising in patients with more severe injuries is not yet known, although the lab is getting ready to test this. Also unknown is whether, and how, the targeted stimulation impacts autonomic function.

Is Movement Possible Without the Risk of Surgery?

While epidural stimulation, like those used in Dr. Harkema’s and Dr. Courtine’s labs, has been promising in a small population, the cost of surgically implanting the device — and the inherent risk involved — make surface stimulators an appealing option. Researchers like Rebecca Martin at Kennedy Krieger Institute are studying transcutaneous methods — methods applied on the skin rather than implanted — because of their potential clinical, safety, and screening benefits.

Dr. Martin’s study uses transcutaneous stimulators placed on the surface of the skin. Thus far, hers is one of the larger studies, using 11 patients with injuries graded C and D. With a combination of continuous stimulation from the electrodes and locomotor therapy, patients have shown improvements in voluntary muscle movement and autonomic function (though the study is still ongoing).

The research carries important implications. The use of electrodes is already widespread in clinics across the country, and it is comparatively more affordable than epidural implants and often reimbursed by insurance. If the results are similar in more severe injuries, the electrodes could be a safer and cheaper alternative.

Surface stimulation could also be an effective screening tool, ensuring patients respond to stimulation at all before taking the bigger risk of surgery.

“We reduce the complications of surgery if we are better able to identify candidates,” Martin says by phone.

The Long Path from Lab to Clinic

All of the methods are currently far from widespread clinical application. “One of the main drivers of my work is to try and translate the therapy,” David Darrow, a researcher and clinician at the University of Minnesota, says by phone.

Dr. Darrow’s work is focusing on bringing these possible advancements to patients like the ones he sees every day, including those in remote areas or with limited time and finances.

He believes the field can do better on the translational front. “We have to do everything we can to make sure patients get the care they deserve.”

The nuance of various protocols highlights a current issue with the science, namely a lack of understanding about which patients are likely to benefit and which routines are necessary.

When Darrow asks his patients what they would miss the most should the stimulator be turned off, many say bowel function — an answer that may surprise those who assume walking, standing, and other dramatic movements would be the major goals. Martin also finds autonomic function and hand movement to be the main desires of patients, especially those further removed from their injury.

“A Lot to Learn”

That’s why it’s important for researchers to understand what potential patients care most about, say patient advocates. “One of those novelty exploitations is this notion of walking,” Matthew Rodreick says by phone. He is executive director of the patient advocacy group Unite 2 Fight Paralysis and father of an SCI patient.

Rodreick cautions people against getting caught up in the sensational this-has-people-walking, spinal-stimulation-is-the-cure narrative. If the media were to dig deeper for context, Rodreick says, they would hear different stories from the paralyzed community and learn their perspectives and desires.

Small study sizes (and the ever more porous classifications of different kinds of paralysis) make it hard to tease out what aspects of the spinal stimulation techniques are benefiting the patients and, crucially, what patients will respond best.

To that end, Roedrick is encouraging collaboration between scientists and patient groups by hosting conference calls with the key players, both for the sharing of knowledge and to eventually build larger study cohorts.

The lack of control groups present another challenge. Without a control to compare results to, it is impossible to determine definitively how much of a patient’s improvement is from stimulation, locomotion, or some combination of the two. The small patient population, however, makes finding a control group a daunting task; it took Martin two years to find her 11 subjects, and if it were to take two more to find a control, the field would already pass her by. 

While the population is small, the data that studies can be compared against is not. Decades of research has led to a strong understanding of the recovery rates of patients, and that data can serve as a comparison to patients undergoing stimulation.

The risk calculations involved — surgery inherently has risks, as does the physical therapy, which can break bones — require clinical science, Darrow says, and the risks will only grow as more high-risk patients receive treatment.

Working with SCI patients also requires a higher ethical bar be cleared.

“The injuries tend to be more severe,” Martin says. Patients are looking for answers and are more willing to try cutting-edge science. “So as researchers, not just as clinicians but as researchers, we have a real responsibility to not over-promise, to be very clear about what we understand and what we don’t understand, and what we hope to learn from their participation in the study.”

That participation requires great courage and selflessness. The work is grueling, and the outcome is not guaranteed to help the patient directly. Researchers show immense respect for what participants are doing and going through, and they understand the emotional turmoil that can come from having functions restored in a lab — if those gains happen at all — only to have them taken away in the end.
“You could move here, and sacrifice being with your family and friends, and get surgery and take all these risks and do all of that and be exactly the way you are right now,” Harkema says. “But what we guarantee you is that we will learn something. Something that will advance our knowledge about human beings and spinal cord injury.”

That knowledge is everything in a field that so desperately needs clay before making bricks. There is not enough research to determine which patients respond best to stimulation (let alone why), or to determine how much improvement stems from therapy with treadmills vs. electrodes, or even to fundamentally understand the spinal cord itself.

We’re at the Model T stage, Edgerton says, but we need to be whipping up Teslas.

“So anybody that feels cocky enough to feel like they really know how this works, I’ve got news for ‘em,” Edgerton chuckles. “We have a lot to learn.”

However, while data and clinical knowledge may be lacking, hope is not. Hope grows with every promising study that is published. There is now a distinct possibility that what were once thought of as complete injury cases with no hope of recovery might not be as permanent as they once seemed.