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Research to Improve Breathing After Spinal Cord Injury

Overview
Voluntary muscle movement occurs when certain nerve cells in the brain send impulses down into the spinal cord to activate the spinal cord nerve cells that control muscle movement. When the spinal cord is injured, it is not damage to the nerve cells, but rather damage to the "pathway of communication" between the cells that causes the major problem. Since the impulses triggering movement no longer reach the correct spinal cord nerve cells, muscles below the spinal cord injury level often become paralyzed.

A Simple Analogy
Suppose you wanted to drive to Kmart, but found that the freeway to the store was severely damaged by a storm. What would you do in that situation? Get out of your car and try to repair the road or simply take an alternate route? Obviously the first choice is an extremely difficult, labor-intensive task. How many of us know how to repair roads or own the tools necessary to accomplish this chore?

The first choice parallels in difficulty attempts to regenerate or repair the injured regions of the spinal cord to reestablish the damaged pathways of communication (roads) between nerve cells. Progress is being made in this area but because of the difficulty of the problem, progress is painstakingly slow.

However, if you were familiar with the area around Kmart, maybe because you lived or worked in the area for years, the obvious solution would be to select an alternate route to get there. But this is a good solution only if the alternate route is not damaged by the same storm.

In this regard, it is important to understand that in the majority of spinal cord injury cases, the spinal cord is usually not physically severed into two pieces; it is more often crushed or simply bruised. While the main pathways are often damaged, there are often areas at the injury site where the spinal cord is not damaged.

Thus, even in cases in which the spinal cord injury appears to be quite severe, there often remains some connection between the brain cells and spinal cord cells below the injury level.

With this in mind, the analogy of taking an alternate route to Kmart closely parallels the research strategy the. Goshgarian lab has taken to achieve recovery of respiratory muscle function following cervical spinal cord injury.

Activating Alternative Pathways
One of the most serious, life-threatening consequences of a cervical spinal cord injury is paralysis of the respiratory muscles, particularly the diaphragm. Patients with this injury often require mechanical ventilators to breathe.

After more than 20 years of animal research, we discovered that there are "alternate pathways" connecting the breathing cells in the brain with the spinal cord cells that control the breathing muscles. Moreover, we found that the alternate pathways are not located in the same area of the spinal cord as the main breathing pathways and thus, may be spared even if the main pathways are damaged by the spinal cord injury.

The research showed that the alternate pathways are normally not active. That is, in spite of the fact that the appropriate connections between the brain cells and spinal cord cells controlling breathing are present, there are normally no impulses traveling along the alternate pathways. After years of research, we discovered three different ways to activate the alternate pathways after a spinal cord injury damages the main breathing pathways. The result of this work is that significant amounts of functional recovery can be achieved in regions of the diaphragm that had been paralyzed by high cervical spinal cord injury in rats.

Current research in our lab uses all three techniques to further study the effectiveness of each in achieving functional recovery of paralyzed breathing muscles.  However, only one of the techniques is refined enough to be tried in humans.

Research in Humans
We are now trying one of the techniques utilizing a drug called "theophylline" to improve respiratory muscle function after cervical spinal cord injury in humans. A significant factor is that theophylline has been used clinically for years to treat respiratory diseases such as asthma and bronchitis. Therefore it has already gone through lengthy clinical trials and is already in the hands of clinicians. Although the drug has been used for decades to treat respiratory diseases, it has never been used to improve respiratory muscle function after spinal cord injury in any published clinical study to date.

In early 1998, we first tried theophylline on a C5-C6 spinal cord injured patient who was injured in 1979. In two separate studies on this same patient, the drug was administered either by an intravenous injection (acute study) or the patient took the drug as a pill at home for several weeks (chronic study).

In both the acute and chronic study, there was significant improvement of respiratory muscle function in this patient by as much as 172 percent. The patient's total inspiratory muscle force (PiMax which is assessed by inhaling through a tube which is blocked) increased by 25 percent in the chronic study.

Furthermore, in another test indirectly measuring the extent of breathing impulses that flow from the brain to the spinal cord (descending respiratory drive), the patient improved in both the acute and chronic study during both quiet and maximal breathing by 20-171 percent after the drug was administered. These results, coupled with the results of the animal studies, strongly suggest that alternate breathing pathways are present in humans and can be activated by theophylline to improve respiratory muscle function after spinal cord injury. Furthermore, the recovery can be induced by simply taking a pill. The research has been published in the November, 1999 issue of Neurorehabilitation and Neural Repair.

It should be stressed that theophylline does not induce the regeneration of damaged pathways. Rather, it works on activating alternative pathways found in the non-damaged regions of the spinal cord, which initially are not active. Therefore, the amount of recovery achieved depends on the extent and level of injury in each patient.

As of September, 1999, we have tried theophylline on seven spinal cord injury patients and have achieved positive results in four. One thing we found that is extremely encouraging is that the time between the spinal cord injury and administration of theophylline does not seem to be a critical factor in its success. One of the patients who achieved positive results was injured 20 years ago. Thus, this therapy may be useful not only to patients who sustain spinal cord injuries in the future, but also the many others currently suffering from breathing dysfunction as a result of a spinal cord injury in the past.