Reggie Edgerton, Ph.D.
For the first time, rats with completely severed spinal cords were able to walk bipedally on a treadmill with a near normal gait while bearing their full weight. This research, funded in part by the Reeve Foundation, showed that the walking was facilitated not by restoring brain control but by tapping into circuitry in the spinal cord itself.
The work, published in the journal Nature Neuroscience, comes from a collaboration of scientists in Switzerland, Russia and the United States. The project was led by Reggie Edgerton, Ph.D., professor of physiological sciences and neurobiology at the University of California, Los Angeles, and a member of the Reeve International Research Consortium on Spinal Cord Injury.
To achieve what is being hailed a breakthrough in research to treat spinal cord injury, completely paralyzed rats received a combination of a drug to induce a serotonin-like effect and thus facilitate synaptic transmission, epidural electrical stimulation of the spinal cord, and aggressive rehabilitation (treadmill) training.
The animals began to walk within a week after treatment; after two months each could walk for half an hour on the treadmill bearing full weight. The rats could step sideways, backwards and could vary their speed. The researchers suggest that the drug and electrical stimuli prepare the neural circuits for activation, and that active training completes the process.
"What this demonstrates," said Edgerton, "is that in the rat, there are neural circuits within the lumbar-sacral spinal cord that can control full weight-bearing and coordinated stepping without any input from the brain. But the more novel result is that these experiments show that the sensory system can actually control the stepping."
While the experiment is based on a tri-part treatment, it's the ability to tap into sensory circuits that is of primary importance, said Edgerton. "We're seeing these results because we have figured out a way to get to this circuitry – the spinal cord already knows what to do, it just needs to be reminded what to do. And it needs to be prepared, physiologically; the way we prepare it is pharmacologically and with epidural stimulation. That's our way of saying, OK cord circuitry, get ready for this information. This sensory information is going to come through and you'll know what to do with it."
"Another thing that's unique about this paper – and people have not grasped the importance of this – is that the sensory information coming from the lower legs when one steps is going back to the spinal cord and is being interpreted almost as well as you would expect the brain to interpret it."
Said Edgerton, "We usually think of sensory information as being a mechanism for correcting an action, for adjusting movement when we make a mistake – when we trip, for example. This research tells us that spinal circuitry is really a much more sophisticated system, it's not just a reflex system, it's predictive of what should be happening. Based on the information that it has just received, it's already predicting what should happen next. It's generally been thought of as a feedback system. But it's really what engineers refer to as a feed-forward system."
Edgerton said that for example, we don't usually think about the act of walking. It's more or less automatic. "We're not always thinking, well, what did my leg just do and what's it going to do next to walk. I think these results demonstrate that automaticity is basically located within the spinal coråd."
Edgerton accepts that this study is indeed a "breakthrough," although for a scientist who's been on the locomotion path since the early 1980s, he keeps it in perspective. "These ideas have been evolving for a long time. They started in the late 70s, early 80s. And so where our thinking is now is the result of cumulative studies over years. Many people have helped contribute to the idea – as many scientists say, we're constantly building on everybody else's ideas. Of course many of the ideas have come from our lab; we've been going in this direction a long time." Said Edgerton, "One of the reasons we've been able to make progress is the key contribution [on epidural stimulation] from our Russian colleagues at the Pavlov Institute in St. Petersburg."
"So I'm thinking, why is this being considered a big breakthrough? I'm seeing it as incremental. But I'm OK considering it a breakthrough because it really demonstrates that full weight-bearing walking can be achieved with a combination of specific interventions, all of which scientifically make sense, so it's by putting all these pieces together we've reached a significant point."
When the media get hold of the word ‘breakthrough' it usually implies a direct link to human treatment. To be sure, the abstract from the published paper (from first author Gregoire Courtine, who was a post-doc in the UCLA lab for five years before heading last year to the University of Zurich) states: "These findings provide a strategy by which individuals with spinal cord injuries could regain substantial levels of motor control."
But Edgerton, who prefers to let the facts speak, again urges perspective. "Certainly we scientists are obligated to do whatever we can to explain the results of our experiments. Sometimes even if you explain the results as they are, though, they're going to be interpreted in a number of ways and some are going to say ‘well that's expressing false hope.'"
Others will expect human therapies right away. "These experiments have been freely interpreted as being the same as what one should do in humans... forgetting about the difference between rats and humans," said Edgerton.
But the scientist can't control the headlines in newspapers. "We need to tell everybody what these results are, very straightforward; we don't have to make them more than they are or less than they are. But if we didn't think these experiments were related or had any significance to our progression toward human treatments, we wouldn't be doing them. So, to imply that is has something to do with humans is OK with me. How much one wants to extend and generalize that and convert it to hope isn't something that's under my control."
G Courtine, Y P Gerasimenko, R van den Brand, A Yew, P Musienko, H Zhong, B Song, Y Ao, R Ichyama, I Lavrov, R R Roy, M V Sofroniew & V R Edgerton, Transformation of nonfunctional spinal circuits into functional states after the loss of brain input, Nature Neurosci (2009) September 20; doi:10.1038/nn.2401
What's Next for Edgerton lab?
Edgerton and his team continue to study the hidden potential of neural networks within in the spinal cord. They believe the cord is smart and that the same biochemical phenomena that accompany learning in the brain also occur in the cord.
"We're not doing anything in humans yet," said Edgerton, "but that's another obvious direction to go. It's a very important part of the puzzle." Edgerton speculates that a drug to stimulate nerve function could be applied intrathecally. "Conventional technology exists to have pumps implanted to apply the drug baclofen on the spinal cord to treat spasticity. That anesthetizes the spinal cord, and obviously that's not what we're interested in doing; we're interested in just the opposite. We can imagine our group finding, or someone finding, an optimal pharmacological cocktail that could be placed in a pump to facilitate the locomotion."
Said Gregoire Courtine, first author of the Nature Neuroscience study: "The idea is to develop a neuroprosthesis for the spinal cord, basically a set of electrodes that can be implanted below a lesion to stimulate and activate the circuits." This might enable a completely paralyzed person to stand, maintain balance and execute some effective stepping. "They're not going to be stepping normally, but small improvements can be made in an individual's life."
"We have plans to implant our first subject with conventional epidural electrodes very soon," said Edgerton. The type of stimulators used with the rats are similar to what is already used in people with spinal cord injuries. "The electrodes for humans appear to be safe. In fact, they are already being used conventionally – for spasticity and pain. No one has used them for locomotion before, although three or four years ago a group from Phoenix implanted epidural stimulators in an individual with an incomplete injury who had some ability to walk; when stimulated, that subject felt he could walk with more ease."
There is plenty to speculate about here. Said Edgerton, "We're doing these experiments assuming there is no axonal connection above and below the spinal cord lesion; we're seeing what activating spinal circuits can do without any connection. But assume that someday someone is going to figure out how to get axons across the lesion. Now when that happens, if that connection can tap into the smart spinal cord circuitry we're talking about, the results can be quite big."