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Study Suggests a Different Target for Spinal Cord Recovery

ARTICLE IN BRIEF

  • ✓ A new study of mice with a partial cord injury reported that the animals' propriospinal cells grew axons around the lesion. This restored some cellular communication that helped them regain the ability to walk in eight to 10 weeks.

When it comes to helping paralyzed people regain function, the conventional wisdom is that therapies should stimulate growth of the long fibers that link the brain to the base of the spinal cord. But a new study suggests a different route to recovery — the short fibers within the spinal cord known as propriospinal connections.

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Dr. Michael E. Selzer: “We dont know what the nature of this plastic change is and where precisely it is occurring.”

The report, published online on Jan. 6 by Nature Medicine, states that when mice had a partial cord injury, the propriospinal cells grew axons around the lesion, restoring some cellular communication. In eight to 10 weeks most of the mice regained the ability to walk, although recovery was incomplete and they could not walk as well as they did before the injury.

Researchers at the University of California-Los Angeles (UCLA) experimented with combinations of spinal cord lesions to evaluate reorganization. With bilateral lesions — paralyzing both hind limbs simultaneously — there was no recovery. But if only one side of the long, corticospinal tracts was cut, the nervous system could reroute messages to the propriospinal nerve pathways.

To determine which of the anatomical pathways retained or regained connection with the locomotor circuits, the researchers injected the mice with a tract-tracer dye. Mice injected 10 weeks after the injury showed an increase in propriospinal neuronal labeling (p<0.01) compared to mice injected immediately after the injury. Neuronal labeling was about 40 percent of the amount seen in uninjured mice.

The researchers also wanted to see what would happen if the propriospinal nerve pathways in the center of the cord were severed; when they did this the paralysis returned.

HUMAN IMPLICATIONS

“The implications for this are that people who do have some preservation of these pathways but who aren't initially able to use them might, through training, get at least some function out of them,” said lead study author Michael Sofroniew, MD, PhD, professor of neurobiology at the David Geffen School of Medicine at UCLA.

In some people, the propriospinal pathways may relay information about walking when corticospinal fibers that directly link the brain to lumbar motor segments have been damaged, he said.

“In our studies this reorganization did take time and went through phases of initial paralysis, discoordinated movement, and finally coordinated movement,” Dr. Sofroniew said. “We think this recovery occurred in part because we always only had one of the limbs being completely paralyzed. The other hind limb was always functioning and trying to walk. If our interpretation is correct, this other limb was, in a way, training the injured one.”

Susan Harkema, PhD, rehabilitation research director at the Kentucky Spinal Cord Injury Research Center and Frazier Rehab Institute in Louisville, said the study has “shown for the first time that there can be plasticity in the absence of regeneration or interventional repair.” It also provides evidence for the effectiveness of activity-based therapies for people with spinal cord injury. One example is locomotor training, in which a person is suspended over a treadmill with a harness and rehabilitation technicians or therapists assist the legs and hips in standing movements. That activity is thought to activate networks in the spinal cord, she said.

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Dr. Susan Harkema said the study provides evidence for the effectiveness of activity-based therapies for people with spinal cord injury.

“If we can remodel the relay connections and drive plasticity across the lesion, it can really enhance recovery,” said Dr. Harkema, who was not involved in the study. “I think that this may be the mechanism responsible for dramatic improvement we now see in people with incomplete injury.”

Dr. Sofroniew agreed but said animals are probably more likely to show spontaneous recovery than humans: “A human who depends on two legs to stand and walk is going to have a hard time getting around if one of those legs doesn't work. An animal can move on three legs and while it is moving on three legs it is continually trying to move the fourth. That in a sense is a form of training. You need to substitute this in humans by getting them up and moving with support on a regular basis.”

THE CAUSE OF PLASTICITY

Michael E. Selzer, MD, PhD, director of Rehabilitation Research and Development in the Department of Veterans Affairs, and professor of neurology at the University of Pennsylvania where he is also director of the Center for Experimental Neurorehabilitation Training, said the study is a valuable contribution to our understanding of why partial recovery often occurs after spinal cord injury. However, the findings do not completely answer what caused the mice to regain the ability to walk. He said the recovery could have been triggered by sprouting of axon branches from uninjured elements or by gradual strengthening of synapses that existed prior to the injury. “We don't know what the nature of this plastic change is and where precisely it is occurring,” he said.

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Dr. Michael Sofroniew said that in some people, the propriospinal pathways may relay information about walking when corticospinal fibers that directly link the brain to lumbar motor segments have been damaged.

Dr. Sofroniew said his team next plans to study the biology of the propriospinal cells and how to stimulate them to respond better after injury.

“A full recovery is going to take lots of different approaches and strategies,” said Dr. Harkema. “But people are suffering now and if we could focus the research on some of these incremental functional recoveries, although not the silver bullet for a cure, they will improve function and quality of life for people today.”

REFERENCE

• Courtine G, Song B, Sofroniew MV, et al. Recovery of supraspinal control of stepping via indirect propriospinal relay connections after spinal cord injury. Nat Med 2008;14:69–74; E-pub 2008 Jan. 6.