It’s NeuroRecovery Network month at the Reeve Foundation. If you haven’t already, please go to this landing page
to learn more about the program, its community based centers and to hear some compelling stories of success.
Basically, the NRN
is a group of rehabilitation centers that have special expertise in intensive activity-based treatments. The program works with people with incomplete spinal cord injuries, suspending them in harnesses over treadmills as therapists move their legs to simulate walking. This process reawakens a part of the spinal cord called a central pattern generator, which as the name implies, regulates motor patterns, such as walking. It does this even when there is no input from the brain. Just about everybody who enters the NRN benefits – improved circulation and breathing, increased bone density, decreased spasticity, etc. Some are able to regain walking function; as the headline says, the program is changing people’s lives now.
The NRN is a direct clinical application of science discoveries that go back many years. The NRN is by no means the end product of research; there is much more to learn about spinal cord circuitry and recovery of function. But the sort of intensive activity the NRN promotes in its clinics and in the Community Fitness and Wellness Facilities
is indeed the basis for a new era in rehabilitation.
Let’s look back the basic science that underpins the NRN and treadmill, aka locomotor, training. To be sure, this work continues to be rigorously pursued today.
The story starts with cats. Let’s pick it up just over 100 years ago. At the University of Liverpool, Charles Sherrington (1857-1952) spend his illustrious neurobiology career trying to figure out why cats could still walk when they had complete spinal cord injuries, or even still when their brains were detached from their bodies – decerebrated is the term – perhaps sounds less gruesome. Sherrington, who discovered synapses, and who won the Nobel Prize for medicine, is sometimes cited in the literature pertaining to this movement without seeming connection to brain inputs. It was Sherrington’s colleague, Thomas Graham Brown (1882-1965) who did the experiments on the neural control of stepping that are most often cited, even today. Brown was first to reveal the intrinsic capability of the spinal cord in the guinea pig and cat to generate a stepping pattern that did not depend upon brain or sensory inputs. This idea was considered revolutionary; the prevailing viewpoint was that stepping rhythms were mainly just spinal reflexes.
Brown’s main stepping paper
, dating to 1911, is available online, in full. Interestingly, he continued to work on cats and stepping but didn’t publish much in his later years. He became more interested in mountaineering, less in disabled cats, although a photo exists from Brown’s lab of a cat walking on an inclined treadmill, unpublished, from mid-1930s – this is a clear foreshadow of what Reggie Edgerton was up to at UCLA in the 1980s and 90s with cats on treadmills.
Stepping research more or less disappeared until Swedish neuroscientist Anders Lundberg (1920-2009) from Göteborg University rescued Brown's concepts from obscurity. In the late 1950s he remade the case for Brown’s idea that connections between a pair of flexor and extensor "half-centers" on each side of the spinal cord were tied together and mutually inhibitory; the rhythmic output, Lundberg suggested, was modulated by sensory input. He spent his career trying to unravel the complex anatomy of the spinal cord, the apparent source of the input to the muscles.
Thus began the modern era of locomotor studies. Lundberg and his colleague Elzbieta Jankowska, who is 82 this year and still hard at work on spinal cord circuitry and publishing regularly, provided compelling evidence that this half-center circuitry was in control of stepping. This lead to the concept of a smart spinal cord and of a central pattern generator (CPG) to control stepping rhythms.
Sten Grillner, who was Lundberg’s student, also studied cats and also wanted to understand how they could step without any nerve signals from the brain. He took things to a much higher level. He found that there was something in the spinal cord circuitry itself that controlled the stepping, and that this newly discovered CPG could be manipulated. Grillner’s work in the late 1960s attracted French Canadian Serge Rossignol to come to Sweden. The two worked on CPG experiments and published widely. American Reggie Edgerton also came to Sweden and learned from the Griller’s group. To fast forward to the modern era, Grillner, now at the Nobel Institute for Neurophysiology at the Karolinska Institutet in Stockholm, is quite active in the field and was the winner of the inaugural Kavli Prize for Neuroscience in 2008 (splitting $1 million with two others). Rossignol, who has in the past been funded by the Reeve Foundation, also marches on; just two weeks ago he published a paper in the Journal of Neurophysiology
called “Incomplete Spinal Cord Injury Promotes Durable Functional Changes Within the Spinal Locomotor Circuitry
.” These findings, says the paper, offer “new insights into the organization of the spinal CPG for locomotion such that phases of the step cycle (swing, stance) can be independently regulated for adapting to speed and also that the CPGs controlling the left and right hindlimbs can up to a point be regulated independently.” Edgerton, is of course, quite prominent in the field. As a member of Reeve Foundation International Consortium on Spinal Cord Injury, he was the principal investigator for the first human application of spinal cord CPG manipulation -- last year’s big proof of concept
achievement with paraplegic Rob Summers and his motor recovery by way of epidural stimulation.
Edgerton published a paper two weeks ago called “A New Age for Rehabilitation” in the European Journal of Physical and Rehabilitation Medicine
. From the paper: “It appears that much can be done to improve motor function after a SCI. There is a clear biological basis for developing new rehabilitative strategies.” The full text is available here
, and it’s a good overview of the CPG clinical possibilities.
There are of course many other scientists and clinicians on the trail of the CPG, including Hughes Barbeau, a former student of Rossignol’s who helped move the idea of body-weight supported treadmill training to the clinic, first in Europe. Here is a 1991 paper
that sets the stage for clinical gait training to come.
Two of Edgerton’s former students, Susan Harkema and Gregoire Courtine, have also come in to their own. Harkema directs the Human Locomotion Research Center at Frazier Rehab Institute at the University of Louisville. She was the main author of the Rob Summers epidural stim paper
and directs the Reeve Foundation's NeuroRecovery Network.
Courtine is now in Switzerland, as Associate Professor of Life Sciences at the École Polytechnique Fédérale de Lausanne School of Life Sciences. His group recently published a paper, Journal of Neuroscience, “Controlling Specific Locomotor Behaviors Through Multidimensional Monoaminergic Modulation of Spinal Circuitries
With new tools and techniques coming into play, it’s safe to bet the spinal cord will one day yield the secrets of its circuitry. It is important, as the NRN takes a few bows, to appreciate the efforts of at least four generations of dogged investigators, and to support a young generation of scientists motivated to carry this work forward.