Andrea Behrman, PhD, of the UofL Department of Neurological Surgery and the (KSCIRC), pioneered the use of locomotor training in children at UofL since 2012. Until now, however, Behrman’s team has used treadmills and harnesses designed for adults that have been adapted for children. The oversized equipment is cumbersome for children and working on cut-down adult-sized devices has resulted in unnecessary strain for the trainers and therapists who work with them.

So, Behrman enlisted Tommy Roussel, PhD, of the at UofL, to engineer a treadmill and harness system specifically for young children. Using engineering expertise, user feedback and a patent held by Susan Harkema, PhD, professor of neurosurgery and a pioneer in spinal cord injury research in adults at UofL, a new treadmill was designed from the ground up just for children.��

“It was kind of like putting a kid on an adult bicycle or watching kids play basketball with a 10-foot goal,” Roussel said. “So we have redesigned the system with the same operational capacity, but with kids in mind.”

The new pediatric treadmill has multiple advantages for both children and trainers:

• Suspension tower is located behind the child on the treadmill so therapists can more easily and directly engage with the child
• Narrower tread, focusing the child’s steps and bringing trainers closer to the child’s legs and feet
• Trainers’ seats are more appropriately positioned closer to the child and are adjustable to accommodate trainers of different heights
• Treadmill tower swivels to allow the child to be hoisted from a wheelchair and onto the treadmill
• Smaller, more adaptable harness that is more comfortable and easier to adjust to the child’s changing capability

“The treadmill is a tool for us, but we want it to be a smart tool. By making it better, we are going to do our jobs better and the child is going to participate better,” Behrman said. “We changed it to make the child more accessible to the trainer with good body posture and position for all this repetitive activity.”

Thanks to funding and support from the , the team was able to develop the initial prototype. Behrman and Roussel then collaborated with other specialized manufacturers, further refining the treadmill and harnesses. Once they had a customized treadmill, the team worked to commercialize the device and harness system to make it available to therapists in other centers.

“We starting thinking, ‘How can we make it better?’” Roussel said. “If we are going to move to manufacturing this, how can we make it more modular and with fewer parts that need to be assembled? That’s where the magic and the fun happened.”

The treadmill design was licensed to and units are in place or on their way to facilities in Pittsburgh, Houston and New York, as well as in Louisville at Frazier Rehab Institute.

“In the last several years, we have been able to achieve things that have not historically happened in terms of rehabilitation outcomes for these children,” Behrman said.��“Children once unable to sit on their own, for example, can now do so due to locomotor training. Such improvements open up other possibilities to play and engage, and help a child get back on the developmental track.��This new treadmill system gives physical therapists and trainers a device that is state-of-the-art in design and utility and revolutionizes the way we deliver locomotor training specifically for children.”

Check out video of the new treadmill system:

Donors and developers include: Christopher and Dana Reeve Foundation, Kosair Charitie, WHAS Crusade for Children, Independent Pilots Association Foundation, Ty Adams, Jena Allen, Laura Argetsinger, Andrea Behrman, Yangsheng Chen, Ran Cheng, Susan J. Harkema, Dena Howland, Winston Rauch, Tommy Roussel, Shelley Trimble, Winston Industries, Haffendorfer Machine Inc., Tuff Tread Treadmills, Rich and Norrie Oelkers and the Bonita Bay Tennis Club, Goose Kearse, Rachel Marsilia, MacKenzie Roberts and Misty Mountain Threadworks.

The research, conducted at the at the University of Louisville, was published online early and will appear in the Sept. 27 issue of the .��

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This groundbreaking progress is the newest development in a string of outcomes at UofL, all pointing to the potential of technology in improving quality of life – and even recovery – following spinal cord injury. This latest study builds on initial research published in The Lancet in 2011 that documented the success of the first epidural stimulation participant, Rob Summers, who recovered a number of motor functions as a result of the intervention. Three years later, a study published in the medical journal Brain discussed how epidural stimulation of the spinal cord allowed Summers and three other young men who had been paralyzed for years to move their legs. Later research from UofL demonstrated this technology improved .

“This research demonstrates that some brain-to-spine connectivity may be restored years after a spinal cord injury as these participants living with motor complete paralysis were able to walk, stand, regain trunk mobility and recover a number of motor functions without physical assistance when using the epidural stimulator and maintaining focus to take steps,” said Susan Harkema, PhD, the study’s author, professor and associate director of the . “We must expand this research – hopefully, with improved stimulator technology – to more participants to realize the full potential of the progress we’re seeing in the lab, as the potential this provides for the 1.2 million people living with paralysis from a spinal cord injury is tremendous.”

Progress for individuals living with paralysis

The American Spinal Injury Association Impairment Scale (AIS) was used to classify the spinal cord injuries of each of the four participants. When the four participants joined the study, they were at least 2.5 years post injury. They were unable to stand, walk or voluntarily move their legs.

Eight to nine weeks prior to the implantation of an epidural stimulator, they started daily locomotor training – manual facilitation of stepping on a treadmill – five days per week for two hours each day. Although there were no changes to their locomotor abilities prior to the implant, following the epidural stimulation participants were able to step when the stimulator was on and the individual intended to walk. Participants 3 and 4 were able to achieve walking over ground – in addition to on a treadmill – with assistive devices, such as a walker and horizontal poles for balance while the stimulator was on.

“Being a participant in this study truly changed my life, as it has provided me with a hope that I didn’t think was possible after my car accident,” said Kelly Thomas, a 23-year-old from Florida, also referred to as Participant 4. “The first day I took steps on my own was an emotional milestone in my recovery that I’ll never forget as one minute I was walking with the trainer’s assistance and, while they stopped, I continued walking on my own. It’s amazing what the human body can accomplish with help from research and technology.”

Jeff Marquis, a 35-year-old Wisconsin native who now lives in Louisville, was the first participant in this study to attain bilateral steps.

“The first steps after my mountain biking accident were such a surprise, and I am thrilled to have progressed by continuing to take more steps each day. In addition, my endurance has improved, as I’ve regained strength and the independence to do things I used to take for granted like cooking and cleaning,” said Marquis, who is participant 3 in New England Journal of Medicine study. “My main priority is to be a participant in this research and further the findings, as what the University of Louisville team does each day is instrumental for the millions of individuals living with paralysis from a spinal cord injury.”

“While more clinical research must be done with larger cohorts, these findings confirm that the spinal cord has the capacity to recover the ability to walk with the right combination of epidural stimulation, daily training and the intent to step independently with each footstep,” said Claudia Angeli, PhD, senior researcher, Human Locomotor Research Center at Frazier Rehab Institute, and assistant professor, University of Louisville’s Kentucky Spinal Cord Injury Research Center.

Advancements for spinal cord injury community

This research is based on two distinct treatments: epidural stimulation of the spinal cord and locomotor training.

• Epidural stimulation is the application of continuous electrical current at varying frequencies and intensities to specific locations on the lumbosacral spinal cord. This location corresponds to the dense neural networks that largely control movement of the hips, knees, ankles and toes.
• Locomotor training aims to ultimately retrain the spinal cord to “remember” the pattern of walking by repetitively practicing standing and stepping. In a locomotor training therapy session, the participant’s body weight is supported in a harness while specially trained staff move his or her legs to simulate walking while on a treadmill.

“We are seeing increasing interest in the use of neuromodulation procedures and technologies such as epidural stimulation in the treatment of spinal cord injury and restoration of locomotor, cardiovascular and urodynamic functions,” said Maxwell Boakye, MD, MPH, MBA, chief of spinal neurosurgery at UofL and clinical director of the Kentucky Spinal Cord Injury Research Center. “Epidural stimulation is likely to become a standard treatment with several improvements in design of the device to target more specific neurological circuits.”  

The study was funded by the Leona M. and Harry B. Helmsley Charitable Trust, University of Louisville Hospital and Medtronic plc.Fo

Left to right:  Kelly Thomas, Claudia Angeli, Ph.D., Jeff Marquis and Susan Harkema, Ph.D.

More about the research participants

Jeff Marquis, 35, Louisville

Jeff Marquis was living in Montana, working as a sous chef and enjoying an active life kayaking, mountain biking, skiing and snowboarding. However, in the fall of 2011 his life changed forever while biking on a mountain trail, as he missed a jump and landed on his head which left him unable to move.

He sustained a C 5-6, Asia B spinal cord injury and was a quadriplegic, paralyzed from the chest down. Marquis spent the next two years in rehab therapy, strengthening the muscles above his injury. He added his name to the research database at the University of Louisville’s Kentucky Spinal Cord Injury Research Center shortly after his injury and got the call to participate in 2014. As part of Marquis’s recovery process, he had an epidural stimulator surgically implanted in his spine and completed a rigorous schedule of daily activity-based step and stand therapy sessions at Frazier Rehab Institute. This technology and physical training, coupled with mental intention, allowed him to take voluntary steps on his own. In addition to being less fatigued, which was a significant problem prior to the implant, Jeff no longer needs daily in-home help and also now shops, cooks and bakes again— activities he was unable to do before the epidural stimulator.

Kelly Thomas, 23, Citrus County, Florida

Kelly Thomas grew up in Citrus County, Florida, riding horses, raising show cattle and helping her dad on the ranch. In 2014, a car accident left her a paraplegic with a C7, T1 incomplete spinal cord injury. She was paralyzed from the chest down, unable to use her legs.

Believing recovery was possible, Thomas learned about Harkema and applied to participate in research at the University of Louisville’s Kentucky Spinal Cord Injury Research Center. She was admitted to the research program in 2017 and had the epidural stimulator implanted that September. Thomas was committed to her training and achieved independent right leg stepping on the treadmill after just three therapy sessions. Among the many accomplishments in her journey towards recovery, she has achieved walking over ground with a walker, without contact assistance from trainers, when she has the mental intention to walk.

Thomas continues therapy training and has moved back to Florida to pursue a bachelor’s degree in criminal justice at the University of Central Florida. After graduating, she plans to attend law school.

A study published today in describes the recovery of motor function in a research participant who previously had received long-term activity-based training along with spinal cord epidural stimulation (scES). In the article, senior author Susan Harkema, PhD, professor and associate director of the  at the University of Louisville, and her colleagues report that over the course of 34.5 months following the original training, the participant recovered substantial voluntary lower-limb motor control and the ability to stand independently without the use of scES.

“Activity-dependent plasticity can re-establish voluntary control of movement and standing after complete paralysis in humans even years after injury,” Harkema said. “This should open up new opportunities for recovery-based rehabilitation as an agent for recovery, not just learning how to function with compensatory strategies, even for those with the most severe injuries.”

Previous research at KSCIRC involving four participants with chronic clinically motor-complete spinal cord injury found that activity-based training with the use of scES – electrical signals delivered to motor neurons in the spine by an implanted device – allowed the participants to stand and to perform relatively fine voluntary lower limb movements when the scES device was activated. Andrew Meas was one of the four participants in that study.

The original training protocol included daily, one-hour, activity-based training sessions with the aid of epidural stimulation. During these sessions, the participant trained on standing activity for several months, followed by several months of training on stepping.

After completing a nine-month training program in the lab, Meas continued activity-based stand training at home. After a year of independent training, he returned to the lab to train for three months in a revised activity-based training schedule. The revised training called for two, daily one-hour training sessions and included both stand and step training each day, all with the aid of epidural stimulation.

After that training, Meas was able to voluntarily extend his knees and his hip flexion was improved. In addition, using his upper body and minimal additional assistance to reach a standing position, he was able to remain in a standing position without assistance, and even stand on one leg, without the use of epidural stimulation.

“We observed that in participants we have worked with so far, eight months of activity-based training with stimulation did not lead to any improvement without stimulation,” said Enrico Rejc, PhD, assistant professor in the UofL Department of Neurological Surgery and the article’s first author. “This participant kept training at home and, after several months, he came back to the lab and we tried a different training protocol. After a couple of months of training with the new protocol, we surprisingly observed that he was able to stand without any stimulation – with two legs and with one leg – using only his hands for balance control.”

The authors suggest that several mechanisms may be responsible for Meas’ recovery of mobility, including the sprouting of axons from above the point of injury into areas below the lesion. Another possible explanation may be that the activity-based training with scES promoted remodeling of connections among neurons in the spinal cord.

In addition, they suggest that the participant’s own effort at voluntary movement may have been a factor in the recovery. During the revised training, Meas was attentive and focused on the trained motor task, actively attempting to contribute to the motor output.

“The voluntary component of him trying constantly with spinal stimulation on and while performing motor tasks can lead to unexpected recovery,” Rejc said.

“The human nervous system can recover from severe spinal cord injury even years after injury. In this case, he was implanted with the stimulator four years after his injury. We saw motor recovery two years later — so six years after injury,” Rejc said. “It is commonly believed that one year from injury, you are classified as chronic and it’s likely that you will not improve any more. This data is proof of principle that the human nervous system has much greater recovery capabilities than expected.”

Funding for the research in Harkema’s lab is supported by the Christopher & Dana Reeve Foundation, the Leona M. and Harry B. Helmsley Charitable Trust, Medtronic and the National Institutes of Health.

“We are enormously excited about this development in Dr. Harkema’s work, as it not only validates the promise of effective treatments for spinal cord injury, but further demonstrates the spinal cord’s ability to recover after severe trauma,” said Peter Wilderotter, president and CEO of the Christopher & Dana Reeve Foundation. “As we continue to support and fund Dr. Harkema’s research, it is awe-inspiring to see another breakthrough on the path to cures for paralysis, and how much this particular treatment has improved quality of life and health for Drew.”

Video files are available for download, including: 

.��The research participant with chronic motor complete spinal cord injury attempts to flex his right hip and subsequently his right knee voluntarily without epidural stimulation. He previously received long-term activity-based training with spinal cord epidural stimulation. Copyright, University of Louisville.

.��The first segment of the video shows the research participant prior to receiving the revised activity-based training, in which he is assisted to a standing position and was unable to stand independently. In the second segment of the video, taken after the intensified training, he is assisted to a standing position and is able to stand while holding the frame for balance without assistance and without epidural stimulation. He also is able to stand on one leg without epidural stimulation. The participant has chronic motor complete paraplegia and previously received long-term activity-based training with spinal cord epidural stimulation. Copyright, University of Louisville.

Check out footage from today’s press conference: 

“It turns out the spinal cord is really really smart. And it may be as smart as the brain,” Behrman said. “The brain gets information, listens to it, reads it, responds, integrates it and generates an outcome. When (the researchers) found that out, they said ‘I wonder if anybody can use this information in rehabilitating people with spinal cord injuries?’ And the answer is yes.” 

Watch more about UofL’s locomotor training, and Emmalie’s story: 

In the first research to be published on this protein’s role in the nervous system, Benjamin Harrison, PhD, a postdoctoral fellow in the Department of Anatomical Sciences and Neurobiology and lead author of the article, and his colleagues show that CD2AP, an adaptor protein, orchestrates a complex arrangement of other proteins that controls the branching of nerve axons, the tendrils reaching out from the nerve cell to connect to other nerve cells, skin and organs. This nerve growth occurs in uninjured nerve cells as they extend their reach and create new connections.

“CD2AP brings in all the correct players, forms a multi-protein complex and coordinates that multi-protein complex to achieve growth of the neurons,” Harrison said. “There are a whole bunch of proteins that it could bring together, but it only brings together the correct proteins to create the correct response. In this case, it changes the structure of the axons through sprouting and elongation.”

This axon sprouting may be helpful, but too much of it can be harmful. In normal adult cells, this growth creates new connections and can lead to improved functionality after an injury or stroke. However, if the axons sprout uncontrollably, the result can be exacerbated epilepsy, blood pressure spikes or neuropathic pain. The researchers hope this new understanding of the nerve growth process will lead to therapies that can improve healing and recovery of function following nerve damage while minimizing excessive growth.

“Through targeting this molecule, we could help the body’s natural healing process to coordinate the appropriate growth,” Harrison said.

The research team, based in the lab of Jeffrey Petruska, PhD, associate professor in the Department of Anatomical Sciences and Neurobiology and the Department of Neurological Surgery and the article’s corresponding author, identified CD2AP as a player in the neurological system via a to detect genes associated with neuron growth. Their research examined how CD2AP interacts with various molecules in controlling the neural sprouting process, particularly its relationship with nerve growth factor (NGF).

“People have been studying nerve growth factor and the responses it induces for a while, but this protein (CD2AP) forms a nice link between NGF and the response in the cell,” Harrison said.

Previous research also has associated CD2AP with genetic changes among individuals with Alzheimer’s disease and it may be helpful in understanding the mechanisms involved in Parkinson’s Disease, Huntington’s Disease and spinal cord injuries.

Petruska says this work relates closely to other research being conducted at UofL’s (KSCIRC). He says that understanding these molecular processes could one day be used to amplify the activity-based therapies such as locomotor training now being done with spinal cord injury patients by UofL faculty at Frazier Rehab Center, a part of KentuckyOne Health. Locomotor training helps spinal cord injury patients achieve functional recovery through standing and stepping activity.

“We are starting to discover that there are different modes of nerve growth and different sets of genes that control different kinds of growth,” Petruska said. “This is particularly important as it relates to locomotor training. When you train, you enhance the growth factor environment of the injured spinal cord, and those growth factors are involved in the axon plasticity. This mode that we study is dependent on the growth factors.”

Harrison, who also is part of the (KBRIN), plans to pursue research aimed at developing a drug to provide appropriate nerve growth for spinal cord injury patients.

“My dream,” Harrison said, “is to one day do a clinical trial with a drug that targets this protein and can enhance the ability of the patients to respond to the activity-based rehabilitation (locomotor training) that they are doing at Frazier Rehab Center.”

High school student Cassa Drury earned co-authorship on publication of original research

One member of the research team and a co-author on the publication that first described in the nervous system is Cassa Drury, a junior at Louisville’s duPont Manual High School. Drury has worked in the lab of Petruska, since he mentored her during middle school science fair competitions. As a middle schooler, Drury competed in science fairs at the national and international level with her research on the neurological systems of planaria worms under Petruska’s guidance.

In the team’s research into CD2AP, Drury recorded and analyzed changes in the nerve cells for the publication’s primary author, Harrison. Drury, a high school sophomore at the time, was working in the lab as part of a self-directed learning program offered by her high school.

Drury recorded the length and number of branches in images of neural cells that had been treated with different amounts of CD2AP and those that were not treated to determine the protein’s effect on nerve growth.

“Cassie was the one who did measurements in the cultured neurons to determine that the protein was a positive regulator of growth,” Harrison said.

That work earned Drury a listing as fifth author on the publication, released in the April 13 edition of . A total of 14 authors are credited on the article.

Drury is eager to follow the research to which she has contributed.

“I am really interested to see where this research goes,” Drury said. “This connection is a really strong one and I am excited to see what comes out of it and what Ben ends up doing. I hope he can hand them a drug. That would be wonderful.”

UofL announced that Kosair Charities is providing $7.3 million in support of the work of Andrea Behrman, PhD, PT, in exploring how to help children regain the use of limbs paralyzed as the result of spinal cord injuries and other causes.

The university also announced it is providing $2.7 million from proceeds of a previous gift from the late Owsley Frazier, former UofL board chair, bringing the total to $10 million in support of this burgeoning area of research and care.

“Today is a good day for children in Kentucky and beyond,” said UofL President James Ramsey. “A little more than a year ago, Dr. Behrman and two of her colleagues moved from Florida to join our prominent program researching how to overcome paralysis associated with spinal cord injury. Andrea brought with her a focus on children, enabling our efforts to explore how to treat people of all ages. Today’s gift will help Andrea, her team and UofL move the research forward more quickly.”

Behrman, a professor of neurological surgery, is a pioneer in the use of locomotor training in children. She and UofL faculty member Susan J. Harkema, PhD, professor of neurological surgery and the Owsley B. Frazier Chair in Neurological Rehabilitation and director of rehabilitation research at the UofL Kentucky Spinal Cord Injury Research Center, developed the intense physical therapy regime.

Locomotor training allows individuals with certain kinds of spinal cord injuries to repetitively practice standing and stepping using body weight support and a treadmill with manual facilitation from therapists and technicians. The ultimate goal is to re-train patients with spinal cord injuries to stand and walk again.

Behrman’s goal is to help children who not only have spinal cord injuries, but also conditions such as head trauma and tumors.

“Our mission at Kosair Charities is to protect the health and well-being of children in Kentucky and Southern Indiana by providing financial support for clinical services, research, pediatric health care education and child advocacy,” said Jerry Ward, chair of the Kosair board. “It is our honor and privilege to team with UofL, Dr. Behrman and all of her colleagues as she searches for ways to help children gain or regain the ability to walk.”

“One of the primary purposes for moving to Louisville is to lead and develop a unique and progressive, pediatric rehabilitation and research program aimed at maximizing recovery after neurologic injury using activity-based interventions,” Behrman said. “It has been a privilege to join the exceptional team that has been built at UofL.

“And the community support to help us accomplish our goals is outstanding. Our partnership with Kosair Charities is unmatched in terms of alignment of what we are trying to achieve and the people we are trying to help. The support Kosair Charities provides is critical to our advancing the science of rehabilitation in children.”

The funds from the gifts will help to create endowed chairs, one for Behrman and one to help recruit another leading scientist/clinician in the field. These resources also will help support the recruitment of pediatric rehabilitation personnel, purchase specialized pediatric rehabilitation equipment and help establish a truly cutting-edge research program in the field.