Ted Teng Director of SCI Research at Veterans Administration Health

NEUROLOGY
Revived Technique Shows Promise for Spinal-cord Injury Repair

Spinal Cord’s Adaptation May Be Critical to Recovery
A spinal-cord injury splits the body into two opposing realms—the one above remains abuzz with activity; below, all goes silent. What is especially tragic is the way the lesion cuts off still healthy organs and muscles from life-giving electrical signals. In fact, nerve fibers extending from the spinal cord into these tissues remain viable for weeks and even months after the damage. In the 1950s, researchers had an idea. Why not rescue these at-risk peripheral nerves by attaching them to fibers emanating from the spinal cord above the site of injury. This rerouting technique, called neurotization, was revived in the 1980s and 1990s, but the results have been mixed.

“The outcomes have been very murky,” said Yang (Ted) Teng, director of spinal-cord injury research at the Veterans Administration Healthcare System. “Sometimes you see improvement, other times not.”
Part of the problem is that nobody really knows what happens during a successful neurotization. Common sense suggests that recovery of function is due largely to the fresh input of electrical signals, carried by the patched-together peripheral fiber, to the target organ. That is, in fact, the prevailing scientific take on the subject. Teng, working with Deniz Konya, Wei-Lee Liao, Howard Choi, Dou Yu, and colleagues, has recently replaced this common-sense view with a more complex scenario. In an exhaustive series of experiments, they neurotized the nerves of spine-injured rats and found that the innervation provided by the rerouted nerves is but an initial spark, setting in motion a series of cellular and molecular events that result in renewed activity, not just in the target organ but in the previously silenced and sequestered spinal cord. The findings appear in the May Regenerative Medicine.
Spinal-cord Rescue
In contrast to peripheral neurons, which remain viable long after injury, those residing within the spinal cord are more perishable. Though the newly injured spinal cord puts out a burst of stem cells, which produce neuron-nurturing substances, the rescue effort is short-lived, and most spinal-cord neurons begin dying off a week to 10 days after injury. If neurotization depends largely on the goings-on inside the spinal cord, rather than on innervation of the target organ by peripheral neurons, then the rerouting procedure should be most likely to produce a recovery of hindlimb function when performed no more than a week to 10 days after injury.
Target tissues play a key role in the whole neurotization process. They receive innervation, but are also the source of sensory signals that through the patchwork nerve and other intact fibers feed back into and stimulate the cells in the spinal cord.

To test this proposition, Konya, Liao, Choi, with Teng and colleagues, created hindlimb-paralyzing lesions in the spinal cords of rats and then divided them into two groups. The first underwent neurotization a week to ten days after injury. The second group received the repair process four weeks after injury. When tested several weeks later, the first group of animals exhibited much greater recovery of limb function. In fact, some of the animals moved almost normally.
Even more compelling, their spinal cords exhibited signs of renewed synaptic activity—higher levels of synaptophysin, an indicator of synapse formation, and of serotonin, which is associated with motor activity—and, remarkably, they did so below the site of the spinal-cord lesion. These lesion-topped regions also harbored a tiny but significant population of neurotrophic-factor–producing stem cells.
“My hypothesis is that this whole innervation is a trigger. The real mechanism lies within the spinal cord,” said Teng, also an HMS associate professor of surgery at Children’s Hospital Boston and of physical medicine and rehabilitation at Spaulding Rehabilitation Hospital.
Work-around
Teng first encountered the whole phenomenon of neurotization while in graduate school, but it was not until 2003, while talking to Choi, that he thought about studying it. Choi and Liao, both fellows in his lab at the time, had recently returned from a conference in Beijing, where they heard investigators talk about using neurotization to help spinal-cord injury patients recover bladder function. Choi was impressed.
“I challenged him,” Teng said. “I said, ‘Are you familiar with the dogma of neurotization?’”
Teng had doubted the received view, that neurotization was due simply to re-innervation of the target organ, and reeled off its problems. To begin, even in successful cases, the number of innervating fibers was typically very small relative to the size of the target organ. Also, repairs made on one side of the body often resulted in behavioral improvements to the other half. “I said, ‘I’ll give you a better hypothesis,’” Teng said.
Choi, currently at Mt. Sinai Hospital, and Liao, now an HMS clinical instructor in physical medicine and rehabilitation, set out to test this idea—that the lion’s share of recovery was accomplished by neuroplastic changes in the spinal cord—by looking for a therapeutic window. But it wasn’t until late 2004 that their efforts took off. By then, Konya—“a superb surgeon,” said Teng—had joined the lab as a clinical fellow. The trio spent several months mapping out the site of injury—the juncture between the thoracic and lumbar regions—and the nerves that would be cut and patched together—T12 and L3 (see figure).
Konya, assisted by Liao, and Choi spent the following year carrying out the surgeries. They made lesions to half of the spinal cord—they left the remaining half intact to see if it played a role in conducting nerve impulses—and then carried out neurotization at staggered intervals: the first group, a week to 10 days later; the second group, after four weeks.

Adapted from original by Yang Teng
Mix and match. The spinal cord is hemisected at the juncture of the thoracic and lumbar regions. The nerve fiber, L3, located below the injury is clipped and attached to a fiber, T12, emanating from the spinal cord above the lesion. The patched-together nerve fiber provides an initial spark that stimulates the target muscle and keeps it healthy. This muscular activity then feeds back through the stitched nerve and through remaining intact fibers to spinal-cord neurons located below the injury.

In addition, they created a series of controls: rats with hemisected spinal cords but no repair; rats with repair but no lesions; animals with completely transected spinal cords and repair. None of the controls exhibited the recovery or the cellular and molecular changes exhibited by the first group of hemisected early-repaired rats.
To prove that the adaptive changes in the spinal cord, observed primarily by Yu, HMS research fellow in surgery, were responsible for the early-treated animals’ recovery, the researchers tried enhancing plasticity by exposing some of these animals to a growth factor, FGF. Additionally, some of these animals were raised in enriched environments. “We built a cage that is really a luxury flat,” Teng said—complete with two levels, running space, tunnels, and opportunities for social interaction.
“We saw some improvement, but it was not statistically important because the number of animals tested was small,” Teng said.
What was striking—and critical—was the improvement in the tone of the hindlimb muscles of the early-repaired group. Indeed, Teng believes that these target tissues play a key role in the whole neurotization process. They receive innervation, but are also the source of sensory signals that through the rerouted nerve and other intact fibers feed back into and stimulate the cells in the spinal cord.
“This nerve opens a new highway for the sensory input initiating in that leg muscle to get back into the spinal cord. That is pivotal,” he said.
Rodents move on all fours, and many of their movements are initiated at the level of the spinal cord rather than the brain as in humans. Still, Teng believes the strides made by his neurotized rats could someday lead to new treatments for spinal-cord–injured patients.
“If we can understand to which degree the human spinal cord can offer a similar potential, then we could recover a lot of function for spinal-cord–injured patients without fully regenerating the spinal cord,” he said. “If we can combine peripheral-nerve rerouting with the paradigm developed to mechanically retrain completely dissociated spinal cords, perhaps together we can really lift the functional recovery to a new level.”

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