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Columbia researchers have designed a novel surgical technique that bypasses the site of a spinal injury. Their research was published in the March 3 issue of the Journal of Neuroscience and was accompanied by an editorial commentary. The study was subsequently highlighted in the April 2004 issue of Nature Reviews: Neuroscience. The lead author was Lucas Campos, an M.D./Ph.D. student with Dr. Jack Martin in the Center for Neurobiology and Behavior.

Spinal cord injuries are devastating because they produce severe motor and sensory deficits below the lesion and because they occur most often in young people who will have to live with this condition for the rest of their lives. The injury damages neurons and severs axons that communicate between the brain and spinal cord, creates a cavity within the cord, and after a short time, a scar is formed.

Molecules that inhibit axon growth are also exposed at the injury site and, with the scar, prevent regeneration of axons through the site of the lesion, both in the direction below the injury to restore motor function and in the direction above the injury to re-establish sensation. Although the spinal circuitry below the lesion is disconnected from the brain, this circuitry remains viable.

Great efforts are being made to promote growth of severed axons through the lesion. But, given the complexity of the processes capable of inhibiting this growth, treatments based on this approach are still decades in the future and, significantly, are likely to be applicable to newly injured patients. The United States has approximately 200,000 chronic spinal cord patients, and roughly 8,000 new cases occur each year, 50 percent of which will become chronic.

The researchers' approach was to detach a thoracic nerve from its muscle in the abdomen and to insert the cut end of the nerve into the spinal cord below the lesion (see figure). The operation was designed by Dr. David Chiu, adjunct professor in anatomy and cell biology and professor of plastic surgery at NYU and his postdoc, Dr. Guoli Hu. The hope was that axons in the inserted nerve would grow into the spinal cord. "The results greatly exceeded our expectations," say co-authors Drs. Martin and Richard Ambron, professor of anatomy and cell biology.

The researchers knew that axons in peripheral nerves readily regenerate, but the great extent of the growth into the spinal cord was surprising, as was the fact that the regenerating axons targeted neurons in the parts of the spinal cord that control muscle. Mr. Campos, using immunocytochemistry with specific neuronal markers, as well as tracer molecules, mapped the new connections made by regenerating axons in the inserted nerve with the spinal circuits below the injury. Electrophysiological studies in the Martin lab then showed that stimulation of the inserted nerve activated spinal circuits below the lesion to cause muscles to contract and the leg to move. The animals were far from being able to walk, however, but the inserted nerve was able to control muscles that had been paralyzed because they were disconnected from the brain.

There were additional surprises. They found that they could activate specific subsets of muscles by inserting the nerve at particular spinal cord levels. This targeting is very important, because it may be possible to tap into specific circuits, such as those that control the bladder. Kidney and bladder infections are a major problem in spinal cord patients because they cannot control micturition. Mr. Campos also showed that the inserted nerve reduced the spasticity and muscle wasting that accompanied control spinal cord lesions, further evidence that the regenerating axons were good surrogates for the axons that were severed by the injury.

Several challenges lie ahead. "First, we want to know whether the brain can learn to control the movements," says Dr. Martin. "A particular advantage to our procedure is that the regenerating axons retain their connection to the brain and should, in principle, be able to exert control over the muscles." This is the case in humans where the brain establishes control over redirected nerves.

Second, this system is well suited for studies of synaptogenesis. "Here we have axons that normally synapse on muscle, but are now in this new environment where they seek out and establish synapses on neurons in the CNS," Dr. Ambron says. "Since many of the molecules involved in the formation of the neuromuscular junction have been identified, it will be interesting to see how many of these are retained in the new synapses."

Most important, however, is to test the procedure in rats with chronic injuries. "We are very excited about our technique," said Dr. Martin, "especially its applicability to people who have lived with spinal cord injuries for years." Dr. Ambron suspects the new circuit will work even better in chronic cases, since many axons in the spinal cord below the lesion will have atrophied, leaving more room for new connections. If all goes well, the researchers hope that clinical trials can begin within the next few years.

"I'm sure a surgeon might like to do this on patients," Dr. Chiu says, "but I want to emphasize that the approach has to be refined before it is translated into an ethical surgical procedure for humans."

The research was funded by the New York State Department of Health Spinal Cord Injury Research Board, the Christopher Reeve Foundation, and the NIH Medical Scientist Training Program.



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