ARTICLE IN BRIEF
Four people with paraplegia were able to voluntarily move previously paralyzed muscles as the result of epidural stimulation combined with physical therapy. Experts discuss the implications for future therapy for spinal cord injury.
Neuromodulation of the spinal circuitry with epidural stimulation coupled with rigorous pre-intervention training enabled four completely paralyzed individuals to process conceptual, auditory, and visual input to regain relatively fine voluntary control of paralyzed muscles.
The report, appearing in the April 8 online edition of Brain, showed that neuromodulation of the lumbosacral spinal networks at sub-threshold motor levels with epidural stimulation appeared to be the key to recovery of intentional movement in the four individuals diagnosed as having complete paralysis of the legs.
In an earlier paper published in The Lancet in 2011, the same team of investigators — including Susan Harkema, PhD, director of rehabilitation research at the Kentucky Spinal Cord Injury Research Center at the University of Kentucky — reported that spinal stimulation, in conjunction with daily training on a treadmill, helped a patient who was paralyzed below his chest regain some ability for movement and the ability to stand unassisted for up to four minutes. The investigators reported that other impairments also began to improve over time, in the absence of stimulation, such as blood pressure control, body temperature regulation, bladder control, and sexual function. [Read Neurology Today's article, “After Epidural Stimulation, Spinal Cord Injury Patient Stands and Treadmill Steps,” http://bit.ly/1m1SC1k.]
In this follow-up study, Claudia Angeli, PhD, assistant professor at the University of Louisville Kentucky Spinal Cord Injury Research Center, Dr. Harkema, and colleagues reported that three additional patients with paralysis had recovered voluntary muscle control following stimulation of the spinal cord.
“The big message from this NIH funded study is that spinal cord injury may no longer mean a lifelong sentence of complete paralysis,” said Roderic Pettigrew, MD, PhD, director of the National Institute of Biomedical Imaging and Bioengineering, which sponsored the study, in an interview. “The results seen in four patients that have been treated with this new experimental approach to spinal cord injury have been quite significant. All of them had complete motor function loss from the chest down and all have gained some partial voluntary control of the lower extremities.
“Specifically that means that on command they can move their lower limbs, can flex knees, legs ankles and toes, and they can, with the electrical stimulator on, voluntarily stand unaided for about 45 to 60 minutes,” Dr. Pettigrew told Neurology Today.
The study also was funded in part by the Christopher & Dana Reeve Foundation.
In the study, an epidural spinal cord stimulation unit and a 16-electrode array (manufactured by Medtronics and RestoreADVANCED) were implanted at vertebrae T11–T12 over spinal cord segments L1–S1 in four men, age 26 on average, who had been injured at least two years earlier and ranged in neurological level from C7–T5. The three patients in the new study included two with complete motor and sensory paralysis, and one, similar to the original case report, who had complete motor paralysis but some ability to experience sensation below his injury. All four were unable to stand or walk independently or voluntarily move their lower extremities despite standard-of-care rehabilitation and additional intensive locomotor training.
Before electrode implantation, participants received a minimum of 80 locomotor training sessions using body weight support on a treadmill with manual facilitation.
After the implantation, all four were able to execute intentional movements of the legs in response to a verbal command. When the stimulation was turned off, there was no motor activity evident on electromyography (EMG) when the four attempted to move following a verbal comment or a visual cue. But all four individuals were able to generate EMG activity and movement during ankle dorsiflexion in the presence of epidural stimulation during their first experimental session, according to the report.
The investigators noted that the first person they implanted — in the pilot trial in 2011 — was unable to move or experience any sensation below his injury. “What was astounding about him was that not only was there voluntary movement, but we saw it in the first week of stimulation. We then saw it in the next two patients as well,” said Dr. Harkema, in a statement about the new study.
The effects of repetitive training in combination with the epidural stimulation were marked. Daily training using epidural stimulation with stand training and home-based voluntary training with epidural stimulation resulted in the generation of voluntary efforts with higher forces and lower stimulation voltages to reach the thresholds that enabled voluntary motor responses in two individuals. After 28 weeks of home-based stand and voluntary training with epidural stimulation in one patient, the stimulation threshold for force generation was lower. The threshold intensity was further reduced after an additional 12 weeks of training.
Dr. Pettigrew said the working theory is that the electrical stimulation effectively reprograms damaged nerve cells that enable them to respond again to stimulation using physical exercise, pressure, and stretching. “The thinking is that part of the injury process results in loss of nerve cells' ability to respond as they once did to stimulation at a typical level,” he said. “What the researchers did not do is to directly excite the nerve cells to the point of triggering a response, or electrically stimulate muscles to contract. Rather, what they were trying to do was re-program cells so that they respond to input.”
Experts who reviewed the study for Neurology Today agreed it is a promising report — but as a beginning, rather than an end to the story.
“The results are promising and well-documented,” said Michael Fehlings, MD, PhD, a professor of neurosurgery at the University of Toronto and Halbert chair in neural repair and regeneration of the Krembil Neuroscience Center at Toronto Western Hospital. “The strengths of this study are that it was a very rigorous evaluation supplemented with neurophysiological results that add to the growing literature related to activation of the central pattern generator in the lumbar cord.”
But he added that it's a small sample of patients and said one direction for future research is to determine which patients with paralysis will most likely benefit from this form of intervention. “We need to be cautious about extrapolating the results to everyone with spinal cord injury,” Dr. Fehlings told Neurology Today. “All of these young men had extensive rehabilitative training prior to implantation. And while there was some partial recovery of movement, it's not clear that it was to an extent sufficient to have any impact on quality of life.”
He added: “There will need to be considerably more research to determine how generalizable this intervention will be to the population with spinal cord injury and whether it can actually result in recovery of function.”
Peter Gorman, MD, FAAN, an associate professor in the department of neurology at the University of Maryland School of Medicine and chief of the division of rehabilitation at the university's Rehabilitation and Orthopaedic Institute, agreed. “This is novel in that it shows that electrical stimulation can modulate the circuitry of the lumbar spinal cord in such a way that the patients could cognitively move their limbs where they couldn't do it otherwise,” he told Neurology Today. “Physiologically, the 25 to 30 Hz stimulation essentially lowered the activation threshold so that voluntary signals from the brain allowed the patients to move their legs through what was probably preserved circuitry that was not previously clinically identifiable.”
Dr. Gorman said the results are an “impressive” proof of concept. “It shows that there is potentially a way to modulate the spinal cord to produce voluntary movement where it didn't exist before,” he said. “The questions are what type of patients would consistently exhibit this phenomenon and whether this technique can make a difference in their lives.”
Dr. Pettigrew said that future neuromodulation studies could focus on efforts to help patients realize finer motor control. “Additionally, there is ongoing research to replace the invasive electrode set which requires surgical implantation with a non-electrical, non-invasive transdermal stimulator. Another area of research is to apply the concept of neuromodulation to upper limb paralysis.”
Dr. Pettigrew continued: “This is not an endpoint but a milestone in a continuing process that starts with basic research to understand the fundamental mechanisms of paralysis, then developing technologies to address these, and later figuring out for whom it works. This experimental intervention is not available for clinical use yet, but its early success is very exciting and certainly offers hope to the many people living with paralysis due to spinal cord injury.”
WHAT EXPERTS THINK ABOUT EPIDURAL STIMULATION FOR SPINAL CORD INJURY
VIDEO ON DEMAND: KENT STEPHENSON, the second person to undergo epidural stimulation of the spinal cord at the University of Louisville in Kentucky, is shown here as he voluntarily raises his leg. Watch the video here at http://youtu.be/SBAB2_x3Owo.
•. Angeli CA, Edgerton VR, Gerasimenko YP, et al. Altering spinal cord excitability enables voluntary movement after chronic paralysis in humans. Brain. 2014; E-pub 2014 Apr 8.
•. Harkema S, Gerasimenko Y, Edgerton VT, 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):1938–1947. E-pub 2011 May 19.