ARTICLE IN BRIEF
Using a combination of therapies, including electrostimulation; agents to increase spinal excitability; and gait training, investigators were able to restore voluntary control of movement in an animal model of spinal cord injury.
Rats who sustained paralyzing lesions at critical sites on the spinal cord were able to walk, avoid obstacles, and even climb stairs after undergoing a combination of interventions, including a robotic postural interface, a gait training program, and a systemically administered, tailored “electrochemical neuroprosthesis”— a cocktail of serotonin receptor agonists and dopamine receptor agonists designed to increase the general level of spinal excitability, paired with epidural electrical stimulation.
This finding, published by Swiss researchers in the June 1 edition of Science, is the first to combine a pharmacological intervention with other modalities, such as gait training and postural support, to restore movement after spinal cord injury.
“This is the kind of protocol that will probably be used in humans in the future,” said Jonathan Wolpaw, MD, chief of the Laboratory of Neural Injury and Repair at New York State's Wadsworth Center, who called the findings quite significant.
“It's put together a number of methods that have been developed individually over the years for inducing plasticity in the nervous system, and it's gotten quite impressive results. It's clear that there will be no single magic method to restore function after spinal cord injury; the treatments we use will be combinations of various interventions, such as this.” Dr. Wolpaw was not involved with the study.
In the study, researchers led by Gregoire Courtine, PhD, professor of neurology at the University of Zurich and the Center for Neuroprosthetics and Brain Mind Institute at the Swiss Federal Institute of Technology, induced two spinal cord lesions in adult rats: a left lateral over-hemisection at thoracic (T) vertebra T7 and a right lateral hemisection at T10. This injury interrupts all direct supraspinal pathways, but leaves an intervening gap of intact tissue. The rats lost all hind-limb function, showing no recovery over the course of two months.
The researchers then administered the electrochemical “neuroprosthetic” cocktail and applied epidural electrical stimulation over the L2 and S1 spinal segments, an intervention designed to transform lumbosacral circuits from dormant to highly excitable states.
Within seven days, the rats demonstrated coordinated (although involuntary) treadmill stepping. Thus prepared, the rats next underwent 30 minutes of daily gait training, both on a treadmill and using the robotic postural interface to force the rats to actively use their paralyzed hind limbs to move towards a target.
The first directed, voluntary steps emerged within three weeks of training. Gradually, training time was increased. By five to six weeks post-injury, all the rats were able to sustain full weight-bearing locomotion for an extended period of time, and could cover a distance of 21 meters in three minutes. Within a few more weeks, they could “sprint” up stairs and avoid obstacles. They required assistance from the neuroprosthesis and the robotic interface to sustain these gains, however.
Anatomical examinations demonstrated a similarly remarkable level of regeneration, with what the authors characterized as “an extensive remodeling of superspinal and interspinal projections.” For example, they wrote, “We found a nearly complete, lamina-specific restoration of T8/T9 serotonergic innervation in overground-trained rats, which contrasted with the depletion of 5HT fibers in non-trained and treadmill-trained animals (p < 0.05).”
WHAT THE FINDINGS MEAN
These findings are one of the most exciting aspects of the study, said Peter Gorman, MD, associate professor of neurology and chief of the division of rehabilitation medicine at the University of Maryland. “The trained rats were found to have a significantly greater number of new neurons at the spinal segments between the two surgical spinal hemisection lesions than the rats that were untrained. This implies that training, or practice, combined with some form of potentiation can cause true neuronal regeneration.”
These findings come almost exactly a year after the groundbreaking Lancet study, the first of its kind in humans, in which a former College World Series winner paralyzed after being hit by a drunk driver in 2006 was able to walk on a treadmill with support after two years of training with electrodes implanted in his spine, designed to mimic the signals that the brain normally sends to initiate movement. [See References for a link to the Neurology Today story about it last June.]
The young man, Robert Summers, along with Susan Harkema, PhD, the neural plasticity expert and Owsley Brown Frazier Chair in Clinical Rehabilitation Research at the University of Louisville who led the research that restored his movement, appeared at the National Institute of Biomedical Imaging and Bioengineering's (NIBIB) 10th anniversary celebration in June.
“This new study is essentially validating the human study and illustrating how it might be working using animal imaging, with the additional pharmacological component further sensitizing the spinal cord to do these tasks,” said Grace Peng, PhD, program director for NIBIB's Division of Discovery Science and Technology.
Summers, however, was not treated with the pharmacological cocktail used by the Swiss researchers; this particular combination of interventions has not yet been studied in humans. Is it ready to move to human trials yet?
Dr. Peng thinks so. “I think it has high potential to move to human trials soon. All of the individual components are currently being tested in humans: pharmacological agents, electrical stimulation, and motor training. They just haven't tried this particular combination in humans yet.”
But Dr. Gorman noted that some specific individual components of the Swiss approach have not yet been tried in humans. “The use of the serotonin the level of the lesion has to my knowledge not been done in humans,” he said.
Dr. Peng agreed that researchers have yet to overcome the technical challenge of administering pharmacological agents directly on the spinal cord in humans.
Another technical hurdle may be device approval from the FDA for human trials. The electrical stimulation device used in Summers' case was an over-the-counter tool marketed for pain control. “Because they used that device, the University of Kentucky and UCLA researchers who did that study were able to bypass some of the regulatory hoops,” said Dr. Peng. “But with a device that's more customized toward this type of application, we'll have to see what kind of regulatory requirements are needed to go to human trials.”
The study also has some design limitations. The knife-cut lesions are unlike any “real” traumatic spinal injury that would occur in human beings, Dr. Gorman noted. “A much more common experimental model of spinal injury in rats is the contusion model. This approach, developed at New York University many years ago, involves the dropping of a weight at variable heights above the exposed rat spinal cord. This injury's characteristics are much more like that seen in human spinal cord injury after trauma from a motor vehicle injury or fall.”
But Dr. Wolpaw pointed out that contusion model injuries are much more variable. “The reason they induced the injury this way was to know exactly what they did,” he said. “The contusion model does more closely mimic human injuries, but the injuries produced will be a lot less consistent. Ideally, the methodology they put together will now also be tried in animals with contusion injuries, and I expect that with injuries of similar severity, the results will be similar.”
“Spinal cord injury is a complex condition, so it is likely that the most effective treatment approaches will also be complex and feature a combination of approaches,” Dr. Gorman said. “While it is premature to say that this can be directly applied to people, it is certainly getting closer.”
• van den Brand R, Heutschi J, Courtine G, et al. Restoring voluntary control of locomotion after paralyzing spinal cord injury. Science 2012;336(6085):1182–1185.
• Harkema S, Gerasimenko Y, Edgerton VR, et al. Effect of epidural stimulation of the lumbosacral spinal cord on voluntary movement, standing, and assisted stepping after motor complete paraplegia: a case study. Lancet 2011;377(9781):1938–47. E-pub 2011 May 19.
• Moran M. After epidural stimulation, spinal cord injury patient stands and treadmill steps. Neurology Today
. June 16, 2011: http://bit.ly/mDaOx7