What is this new research about?
Three years ago a team of life scientists reported that control of movement in a man with motor complete paralysis was restored after seven months of intense Locomotor Training (LT) using epidural stimulation.
These results were quite unexpected, leading the research team to speculate that some sensory nerve pathways were intact, and were somehow able to facilitate voluntary movement.
Now, three more participants have been tested -- all motor complete, and two who are sensory and motor complete. After being implanted with a spinal cord stimulator, each was able to execute intentional movements of the legs in response to a command.
What are the results?
The research team reports that three individuals were able to make voluntary movements when epidural stimulation was turned on; results were seen immediately after implant -- even in two who were diagnosed with a motor and sensory complete lesion.
The results are that four of four individuals who had no ability to move their legs were able to process conceptual, auditory and visual input to regain relatively fine voluntary control of paralyzed muscles.
Here's how the scientists put it: "We have uncovered a fundamentally new intervention strategy that can dramatically affect recovery of voluntary movement in individuals with complete paralysis even years after injury."
What's different about the three newest patients and the first one?
A main difference is that the second, third and fourth participants all began stimulation procedures soon after implantation of the device. They did not get locomotor training following implantation, as the first participant did. (All participants, however, did get a minimum of 80 locomotor training sessions before surgery).
The newest participants were not stimulated to stand or to take steps. They were tested while lying down. When the simulator was powered, all three could modulate their movements according to visual and auditory cues. For example, they were asked to synchronize flexing a leg or ankle or extending the toe to the rise and fall of a sine wave displayed on a computer screen. They also modified their motor task to correspond in intensity to the frequency of tones heard in headphones.
The results demonstrate that auditory and visual cues were processed by the brain, in the sensorimotor cortex, thus activating appropriate spinal nerve networks below the level of injury, and therefore enabling each individual to self-adjust intended movements.
After repeating stimulation patterns, the four men improved their ability to voluntarily move and were able to activate movements with less stimulation. This demonstrates the ability of the spinal networks to learn and improve function of nerves that control force generation and accuracy.
The study includes four male patients. Why are there no women?
Participants recruited for the study fit certain criteria (age, level of injury, length of time since injury, etc.). Gender was not a consideration. The four men were selected from the available pool of candidates -- spinal cord injury happens to men about four times as often as it does to women. There is no reason not to include women in future studies and no reason to expect women would respond differently to epidural stimulation.
So the stimulation switched on spinal nerves and made new connections?
The scientists are not sure exactly what's happening at the molecular level. The newly established functional connectivity probably involves multiple nerve pathways and connections. Spinal networks are activated and respond to sensory input. But it is possible that repetitive epidural stimulation and training leads to plasticity, or remodeling, of nerve pathways disrupted by injury. In animal models, exercise training after spinal cord injury enhanced sprouting or growth in the corticospinal tract, a set of nerves important for walking function. It is also possible that sprouting or growth of axons across the spinal cord lesion occurred in response to repetitive epidural stimulation and/or stand training. Axonal sprouting is a slow process and unlikely as the reason for early execution of the voluntary movement in the latest three individuals studied.
What is the significance of voluntary activity without Locomotor Training?
The results in the three individuals who were tested after implantation, but before repetitive training, suggests that nerve connections to the spinal cord circuitry may have existed since the time of injury. The first participant, who was implanted three years ago, did not show voluntary ability until after seven months of epidural stimulation and training. He was not tested soon after implant but may have been able to make movements similar to the more recent three participant, who were able to voluntarily execute movements after eleven, four and seven days of epidural stimulation, respectively. It is also possible that anatomical connections may have persisted after the injury but were "silent" because of lack of conduction as a result of myelin loss.
What exactly is epidural spinal cord stimulation?
In this case, epidural stimulation is the application of a continuous electrical current, at varying frequencies and intensities, to specific locations on the lower part (lumbosacral) of the spinal cord. A 16-electrode epidural spinal cord stimulator, commonly used in medicine today to treat pain, was implanted over the spinal cord at T11-L1. This location corresponds to dense neural networks that control movement of the hips, knees, ankles and feet.
But electrical stimulation has been used for many years to help people move paralyzed muscles. True, functional electrical stimulation has been used to activate paralyzed muscles in people with spinal cord injuries. But these neuromodulation studies are not about stimulating muscle. In this case, epidural stimulation activates nerve circuits in the spinal cord, substituting for nerve signals that would normally have come from the brain to modulate these spinal networks. Stimulation of the spinal circuitry itself activates what scientists call a central pattern generator -- a network of nerves that are able to initiate stepping function without input from the brain.
What is a central pattern generator?
The spinal cord used to be thought of as a passive nerve cable connecting the brain to the muscles in the body. It turns out the spinal cord is quite sophisticated and, to some degree, "smart." If certain sensory information is provided, the spinal cord can recognize this information and respond by generating a pattern of muscle activity. This activity can be enhanced with repetition and training. These recent human experiments confirm that the sensory system can actually control the movement, on command.
Motor function can be improved if networks of nerves in the lumbar spinal cord are made more receptive to sensory information. This is what epidural stimulation appears to do: it sensitizes the cord.
What is the implication of this research for paralysis patients?
The researchers envision a day when some individuals with complete spinal cord injuries will be able to use a portable stimulation unit and, perhaps with the assistance of a walker, stand independently, maintain balance bearing their own weight, and execute some effective stepping.
Moreover, secondary complications associated with spinal cord injury -- including impairment or loss of bladder control, sphincter control and sexual response -- may also be alleviated. Therefore, epidural stimulation could help improve the quality of life of individuals with spinal cord injury.
What's next? When will this treatment be available to the general public?
Although this research has been going on for many years, investigators are just beginning to develop an effective treatment for human spinal cord injury. Before this intervention can move into the public area its safety and efficacy must be established in many patients. Approval by the Food and Drug Administration is also required.
In addition, more sophisticated stimulation equipment needs to be developed. Scientists are also hoping to find the right pharmacological agents to boost the treatment's effectiveness.
Is this intervention effective in patients with complete or incomplete spinal cord injury? What about acute (new) versus chronic (old) injuries?
The current studies suggest that epidural stimulation included patients with chronic injuries from two to five years since injury; scientists believe it will be effective for those with very long-term injuries but have not tested this yet. Epidural simulation has not yet been tested on an acutely injured patient. The treatment is thought to have potential for patients with both complete and incomplete spinal cord injuries; again, further testing is required.
Is it possible for me to qualify as a subject for this research?
It's too soon to consider enrolling in a clinical trial. Once experiments expand to include more people, researchers will set forth the qualifying criteria. When trials do occur, information will be made public. For more information about epidural stimulation studies and other spinal cord injury research, please visit ReeveBigIdea.org and ChristopherReeve.org/epi.
What is the Reeve Foundation?
The Christopher & Dana Reeve Foundation is a national, non profit organization dedicated to curing spinal cord injury by funding innovative research, and improving the quality of life for people living with paralysis through grants, information and advocacy. ChristopherReeve.org to learn more.