Non-Surgical Recovery of Function: Not a Fantasy

Kate Willette

Kate Willette

“Improved voluntary hand function occurred within a single session in every subject tested.”

That’s the killer sentence from a new study soon to be published in the Journal of Neurotrauma. The principal investigator is our old friend, Professor Reggie Edgerton, who has been looking for ways to help people with chronic spinal cord injury since the late 1960s. I’ve met him a number of times in my own efforts to get my head around the difficulty of restoring function. In the small, intense universe of SCI research, he’s a sort of godfather — having mentored and trained a great many of the students currently on the hunt for therapies.

Until the first epidural stimulators were implanted in volunteers back in 2009 and 2010, no substantial functional recovery was happening with chronic injuries. You got back what you got back in the first year or two post-injury, and then you lived with it. Even the breakthrough moments of trials involving different kinds of cells were questionable, because they were invariably aimed at people with very new injuries.

The epidural stimulation work that I covered in my last column originated in Edgerton’s lab, but his new study is about what his team has christened tEMC, short for transcutaneous enabled motor control, also called transcutaneous stimulation.

There is no surgery, nothing implanted, no wires snaking through the body to a device embedded under the flesh. Instead, there are a couple of electrodes taped right onto the skin, not unlike the functional electrical stimulation units a lot of people use to ride stim bikes. The difference is that FES units are designed to push current directly into targeted muscle groups, while tEMC units push current toward the spinal cord itself. In that way, tEMC is just like epistim, and like epistim, it seems to work — in the sense that people do regain volitional movement.

In the fall of 2016, Edgerton published a report based on this question: If putting a stimulator into the lower back epidural space results in voluntary movement of feet and legs, would putting one into the cervical area result in the same for hands and fingers? The report included this line: “Herein we show that epidural stimulation can be applied to the chronic injured human cervical spinal cord to promote volitional hand function.”

Volitional hand function means successfully willing the hand to move. We went from reports of epistim working on the lower limbs to studies showing epistim worked on the hands, and now we have tEMC working on the hands. I got to see this for myself in May. One of Edgerton’s collaborators, Chet Moritz, Ph.D., runs a lab for SCI research at the University of Washington. He invited me to visit during one person’s tEMC session.

What a tEMC Session Looks Like

The session participant, Joe, a 60-something C3-4 quad, was undergoing follow-up work from an earlier tEMC study he’d done with Moritz. It’s the first documentation of tEMC helping a person with limited hand function regain a measure of independence.

Joe was a genial person working with a small team of grad students engaged in setting him up, monitoring his blood pressure, helping him move from place to place, giving him specific tasks to perform and measuring every scrap of data associated with the process. The electrodes were placed in the center of the back of his neck a few inches apart, one above the other.

Transcutaneous stimulation in the Moritz Lab at the University of Washington. Photo by Matt HagenTranscutaneous stimulation in the Moritz Lab at the University of Washington. Photo by Matt Hagen.

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One of the grad students operated a tablet that controlled the amount and nature of the current being sent to his cervical cord. Joe said it did not hurt at all. Did it feel like those FES units from the stim bikes? He said it was nothing like that. “It doesn’t tingle on your skin. It’s like you can feel the current moving through your spine and all the way down your legs.”

The session lasted for about an hour and a half, with plenty of rests and adjustments. Joe seemed to enjoy it, though I could see that he was getting tired by the end. In a video of Moritz discussing the initial study with Joe, you can see that while he’s not in any sense “cured,” Joe is able to do things independently that were impossible before the study. And as it turned out, Joe wasn’t an anomaly.

Edgerton’s team recruited a total of eight people with SCIs ranging from C3-4 to C7 who were 13 months to 21 years post-injury. None were vent users. Their hand function covered the range from barely a trace to measurable, but weak. The study began with three sessions of testing designed to locate a baseline function for each person. That was followed by four weeks of intervention with the tEMC, twice a week for an hour or two at a time. By the end, two of the subjects had to drop out, both for reasons unrelated to the study.

During each session, with their wrists in neutral positions and arms stabilized to prevent compensating, the subjects worked on maximizing grip strength and rhythmically opening and closing their hands. Electrodes were attached to the appropriate forearm and bicep muscles to measure the exact amount of energy their efforts were generating. All of them got stronger immediately under the influence of the tEMC — and those gains stayed with them. With each new session, their baseline grip strength improved from the previous time. Because the strength was retained, the improvements from week to week were also cumulative.

Finger dexterity also improved. Some could pinch a debit card and get it into an ATM, use a cell phone or turn a key in a lock. One of them was able to twist the cap off a water bottle. Their average maximum grip strength had more than tripled by the end of the study, but also — just as in the epistim trials — they enjoyed improvements in other quality of life measures. Sensation was better. Trunk control was more reliable. They even made gains in bowel and bladder control.

Understanding How It Works

It turns out the spinal cord is not just a collection of individual neurons all wired to other individual neurons; it’s more like a collection of wired-together collections. In my imagination, these collections of neurons that function all together — called neural networks — are sort of like the clumps of jigsaw puzzle pieces you put together off to the side when you’re building a big puzzle. They lock on to one another, and they form part of the picture, but until you find at least one place where your small clump connects to the larger puzzle, they’re just floating, useless.

The neural networks are intact in the undamaged parts of the cord below the injury, but they’re useless without a sufficient connection to the brain. The tEMC and the epistim units light them up in such a way that whatever slender link exists becomes enough.

But what if there’s no link at all? Isn’t that exactly what we mean by “complete injury?” When I was writing Don’t Call It a Miracle in 2014, I asked Lyn Jakeman, Ph.D., about this. As program director, Repair and Plasticity, at the National Institute of Neurological Disorders and Stroke, her job is to oversee research funded by the National Institutes of Health that’s aimed at finding therapies for us. She told me that it’s possible the conventional wisdom is wrong — that there’s no such thing as a complete injury. There seems to exist in every cord, no matter how badly damaged, a way to restore some connection.

I call that good news. As Edgerton’s paper puts it: “The increasing number of examples of regained/improved supraspinal control after ‘complete’ paralysis suggest that the basic biology of a spinal lesion that is presently clinically defined to be motor complete must, at least, be challenged.”

What’s even better is these gains were not only quick, they were lasting. Combined with a few months of therapy, stimulator-enabled changes didn’t go away once the study was over. We’re entering a time, at long last, when there is reason to think that even years after injury, some recovery is possible. As Edgerton said, “We have no evidence that the intervention here has been developed to its optimal potential.”

The next task is to work out what that optimal potential might be. It is too early to know for certain. It will take time and a lot of dedicated effort, but we are definitely going to be hearing a lot more about transcutaneous stimulation.

Watch our interview with Dr. Edgerton here.

Resources
• Edgerton Neuromuscular Research Laboratory, edgertonlab.ibp.ucla.edu
• Moritz Lab, depts.washington.edu/moritlab/
• Don’t Call It a Miraclewww.christopherreeve.org/living-with-paralysis/free-resources-and-downloads/research-101-on-spinal-cord-injury

Paving the Way for a Cure campaign receives $25,000 donation from Wawanesa Insurance

This week, the Canadian Spinal Research Organization (CSRO) received a $25,000 donation from Wawanesa insurance. This generous donation will support the ‘Paving a Way for a Cure’ campaign and Wawanesa will sponsor one subject in an upcoming study on epidural stimulation.

Our Paving the Way for a Cure campaign was kicked off last fall with an initial $25,000 donation by the Insurance Bureau of Canada (IBC) and the insurance industry has continued its support with Wawanesa’s sponsoring of 1 candidate for an epidural stimulation study.

Each candidate in the study requires $25,000 to be funded and to be part of the study – and that is the focus of our Paving the Way for a Cure campaign, with the funding of our first candidate we have achieved our first success!  Thanks so much to Wawanesa Insurance for being one of the first to help us kick off this important campaign that will ultimately fund 40 candidates for this study.

Research shows that 43% of spinal cord injuries are caused by motor vehicle crashes, and through our ‘Paving the Way for a Cure’ campaign, we are uniting the aid and the interests of the Road Building, Auto Parts Manufacturers, Personal Injury Law, and Auto Insurance industries. The CSRO is aiming to fund a Canadian Epidural Stimulation study through this campaign. The potential outcome of this study could be a cure for paralysis caused by spinal cord injury. The cost to fund 40 candidates for an Epidural Stimulation Study is $1,000,000. With 40 candidates at $25,000 each, the CSRO is hoping to secure $250,000 from each associated industry.

 

Epidural Stimulation

Epidural Stimulation is the application of a continuous electrical current to the lower part of the spinal cord. The stimulation is carried out via a chip implanted over the dura (protective coating) of the spinal cord, or secured transcutaneously (above the skin). Studies that have been conducted in the United States have not only shown improvements of the motor system but also better function of the autonomic nerve system including:

 

  • Overall improvement in quality of life
  • Temperature regulation
  • Enhanced sexual function
  • Increased bladder control

Thanks to Wawanesa for their generous donation, 1 down 39 more to go!

 

About Wawanesa:

Wawanesa Insurance is a Canadian mutual company owned by its policyholders. It is one of the largest property and casualty insurers in Canada. Wawanesa has a rich history dating back to September 25, 1896, when it was founded in the Village of Wawanesa, Manitoba. Today executive offices are located in Winnipeg, Manitoba, Canada.

Wawanesa delivers funding support to over 400 charitable organizations each year. In 2015 their annual corporate giving totaled $3 million – well above internationally recognized benchmarks for excellence in corporate philanthropy.

MTO Reconnection Golf Tournament 2018

The 11th Annual MTO Reconnection Tournament was held at Cardinal Golf Club on June 11th, and it was a tremendous success. MTO employees, retirees, and other notable members of the road-building community all came out to show their support for Carl Hennum & the CSRO/ASRO. Carl, who was an Assistant Deputy Minister at the time of his retirement, worked for 40 years at the MTO. It was shortly after his retirement that he had an accident on his property, and suffered a spinal cord injury leaving him a paraplegic.

What began as fundraiser for Carl has now become an annual event, and 11 years since retiring Carl’s presence is still felt in the industry today. There were numerous accounts from people who had never met Carl but admired his work and attended to support him. In 2016, the CSRO/ASRO created the Carl Hennum Fellowship for spinal cord research and thanks to over 90 golfers and corporate sponsors, we ended up raising over $27,000 for the fellowship this year.

Since its inception, this tournament has now raised over $300,000 towards crucial research to restore function to those living with spinal cord injuries. In order to continue to grow the tournament we implemented some fantastic changes. Instead of the traditional putting contest, golfers participated in a golf dartboard competition; the winner of the contest achieved an amazing score of 121, hitting two triple twenties in the process. There was also more of an emphasis on networking and making new connections this year. Rather than a dinner, everyone gathered for a reception where industry members got together to network and celebrate the event.

We would like to thank all the golfers, corporate sponsors and especially the organizing committee for all their hard work, dedication and efforts that were put into making this a successful annual tournament!

If you want to see more pictures of the tournament head to our Facebook Page @CSROASRO

 

UCLA researchers find a way to repair nerve damage with stem cells

 

UCLA researchers have developed a way to use stem cells to help potentially rebuild damaged spinal cords.

In a study published in January, researchers in the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research established a way to derive sensory

 

interneurons, which are cells involved in reflexes and relaying sensory information to the brain, from stem cells. The researchers identified a specific signaling molecule that caused the stem cells to mature into sensory interneurons.

Stem cells are young cells that can differentiate, or mature, into specific cell types, such as blood cells or neurons, according to the National Institutes of Health. Learning how to differentiate stem cells into specific neuron types is important for some therapies for spinal cord injuries that replace old or damaged tissues with young and healthy cells, according to the study.

Spinal cord injuries cost $40 billion in health care annually in the United States, according to the study. Current therapies focus on protecting the spinal cord from further damage, while stem cell therapies have the potential to reverse and repair damage by replacing damaged cells with new ones.

Samantha Butler, a professor of neurobiology and senior author of the study, said sensory interneurons are involved in fast reflexes, like moving your hand away from heat. They process information and either react immediately or pass the information to the brain for further analysis, she added.

Butler said other researchers have already found ways to differentiate stem cells into other kinds of neurons, but had not yet found a way to differentiate stem cells into interneurons.

“Directing stem cells into spinal motor neurons was developed a while ago,” Butler said. “But how to differentiate stem cells into sensory interneurons was really an open question – a protocol needed to be developed.”

READ THE FULL STORY AT DAILY BRUIN

Stem Cell Reports Full Article:

Deriving Dorsal Spinal Sensory Interneurons from Human Pluripotent Stem Cells

Gene jumpstarts regeneration of damaged nerve cells

 

Searching the entire genome, a Yale research team has identified a gene that when eliminated can spur regeneration of axons in nerve cells severed by spinal cord injury.

For the first time, the limits on nerve fiber regeneration were studied in an unbiased way across nearly all genes,” said Stephen Strittmatter, the Vincent Coates Professor of Neurology and senior author of the study appearing April 10 in the journal Cell Reports. “We had no idea whether we knew a lot or a little about the mechanics of nerve cell regeneration.”

The Yale team found more than 580 different genes that may play a role in regeneration of axons in nerve cells, something that rarely occurs in adult mammals but is of vital interest to scientists hoping to repair injuries to the central nervous system. Intriguingly, said the researchers, about one in 10 of those came from a family of genes involved in transport of information within cells. The researchers also reported that eliminating one of those genes, Rab27, led to regeneration of axons in the optic nerve or spinal cord of mice.

We only looked at this one gene, and we have hundreds more to investigate,” Strittmatter said. “It is not hard to envision an approach where you can knock down two or three of these pathways and help spur regeneration further than achieved previously.”

The work was primarily funded by the National Institutes of Health.

Yale’s Yuichi Sekine is lead author of the paper.

Technology Networks Article

Reference: Sekine, Y., Lin-Moore, A., Chenette, D. M., Wang, X., Jiang, Z., Cafferty, W. B., … Strittmatter, S. M. (2018). Functional Genome-wide Screen Identifies Pathways Restricting Central Nervous System Axonal Regeneration. Cell Reports, 23(2), 415–428. https://doi.org/10.1016/j.celrep.2018.03.058

 

Restorative effects of human neural stem cell grafts on the primate spinal cord

We grafted human spinal cord–derived neural progenitor cells (NPCs) into sites of cervical spinal cord injury in rhesus monkeys (Macaca mulatta). Under three-drug immunosuppression, grafts survived at least 9 months postinjury and expressed both neuronal and glial markers. Monkey axons regenerated into grafts and formed synapses. Hundreds of thousands of human axons extended out from grafts through monkey white matter and synapsed in distal gray matter. Grafts gradually matured over 9 months and improved forelimb function beginning several months after grafting. These findings in a ‘preclinical trial’ support translation of NPC graft therapy to humans with the objective of reconstituting both a neuronal and glial milieu in the site of spinal cord injury.

Ephron S Rosenzweig, John H Brock, Paul Lu, Hiromi Kumamaru, Ernesto A Salegio, Ken Kadoya, Janet L Weber, Justine J Liang, Rod Moseanko, Stephanie Hawbecker, J Russell Huie, Leif A Havton, Yvette S Nout-Lomas, Adam R Ferguson, Michael S Beattie, Jacqueline C Bresnahan, Mark H Tuszynski.

Restorative effects of human neural stem cell grafts on the primate spinal cord. Nature Medicine, 2018; DOI: 10.1038/nm.4502

Science Daily:
AAAS Article at Eureka Alert:
Medical Express Article
The Scientist Article:
Gen News Article:
Nature.com

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