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Will There Be A Cure For Chronic Spinal Cord Injury

Image A question and answer session with Dr. Wise Young, Ph.D at W. M Keck Center for Collaborative Neuroscience

Will a cure work for chronic spinal cord injury?

Many people are anxious that all the treatments that they hear about seem to be aimed at acute spinal cord injury. When they look at their bodies, they ask how any therapy can restore a body that has been paralyzed and senseless for years, in some cases decades. How will therapy restore muscle and bone? Not surprisingly, many people with chronic spinal cord injury think that the cure is for the newly injured and not for those with chronic spinal cord injury.

I believe there will be effective restorative therapies for chronic spinal cord injury for the following reasons.

First, much animal and human data indicate that regeneration of relatively few axons can restore function such as walking, bladder function, and sexual function. This is because the spinal cord contains much of the circuitry necessary to execute and control these functions. Only 10% of the axons in the spinal cord are necessary and sufficient to restore locomotor and other functions.

Second, axons continue to try to regrow for many years after injury. Treatments that provide a path for growth, that negate factors that inhibit growth, and that provide long-term stimulation of axonal growth can restore function.

Third, many people recover function years after injury. These observations give me hope that there will be therapies that will restore function in chronic spinal cord injury.

Most of my reasons for hope do not stem from animal studies of spinal cord injury but from many years of observing people with spinal cord injury. People can and do recover after injury, often years afterwards. I have seen people recover when their spinal cords have been decompressed or an arteriovenous malformation has been obliterated, often after years of paralysis and sensory loss. Sometimes the recovery is rapid, suggesting that connections were present but suppressed. Other times, the recovery occurs over weeks, suggestive of remyelination. The recovery may take years, suggestive of regeneration.

Before discussing these reasons for hope, I want to first deal with several misapprehensions that many people seem have about their spinal cord injury.

Over the years, many people have expressed surprise when I have told them that the spinal cord below the injury site is alive and kicking. They think that the spinal cord below the injury site is “dead”. Another common belief is that it is not possible to restore atrophic muscle and bone that have become flaccid and osteoporotic. Finally, there is a general notion that the spinal cord is far too complex for it to be reparable with a dash of cells, a squirt of growth factors, and a sprinkle of growth inhibitor blockers. These concerns are understandable.

Common Misapprehensions about Spinal Cord Injury

Many people are anxious that the therapies will not work for chronic spinal cord injury. Some believe that the spinal cord below the injury site is “dead” and cannot be revived. Others think that chronic spinal cord injury is associated with many changes of the body that cannot be reversed, including atrophy of muscle and bone. Finally, most people are concerned that the spinal cord is too complex to be repaired by transplanting some cells, splashing on some growth factors, blocking a few axonal growth inhibitors, and exercising. Let me address these concerns first.

Isn’t the spinal cord dead below the injury site?

Christopher Reeve asked me once why his legs move whenever his respirator filled his lungs with air. Aren’t they supposed to be paralyzed? I answered that Penelope is there waiting for Odysseus to come home, referring of course to the Greek myth where Penelope is Odysseus’ wife waiting for him to come home from a long journey. Many suitors are knocking on her door. Like the neurons in the spinal cord below the injury site, she is impatient for her husband’s return. Spasticity and spasms are proof that the spinal cord is alive and kicking. People who have flaccid paralysis below the injury site may have had some damage to the spinal cord below the injury site. However, this does not necessarily mean that the spinal cord is “dead”. It does mean that there is insufficient excitability to cause spasticity and spasms.

Can we reverse nerve, muscle and bone atrophy?

It takes time and a lot of work but activity can and will reverse the bone and muscle loss. For example, recent studies suggest that even completely denervated muscles can be restored with intense electrical stimulation. Astronauts who stay for prolonged periods of time in microgravity lose bone just like people in spinal cord injury but bone will return as the person spends time weight bearing in normal gravity. Finally, the central nervous system is like muscle and bone in that it also undergoes atrophy when it is not active. Called “learned non-use”, the central nervous system “forgets” its function. Much evidence suggests that learned “non-use” could be reversed by intensive repetitive exercise.

Dr John McDonald at the Working to Walk Conference in DC 2008 Isn’t the spinal cord is too complex to repair and restore?

How can we hope to restore millions of connections between the brain and spinal cord? It turns out that the spinal cord is not only much simpler but is much capable and plastic than we had ever imagined. Your brain doesn’t control muscles directly when you walk. The brain simply turns on the walking program that resides in the spinal cord and then modulates it to go faster slower, to turn, to slow down, to turn, etc. The central pattern generator (CPG) resides in the L2 spinal cord and controls walking. One does not need many axons to initiate and control walking. That is why both humans and animals can walk with only 10% of the nerve fibers in their spinal cord.

In summary, the spinal cord below the injury site is alive and often kicking. Flaccidity simply means insufficient excitability. Although it takes time and a lot of work, atrophy of nerves, muscles, and bone can be reversed. The spinal cord can learn and possess programs for movements, including walking. It doesn’t take a lot to turn the programs on and control them. That is why people with 10% of their spinal cord can walk.

The Ten Percent Rule

Less than ten percent of the spinal cord is necessary and sufficient to support complex functions such as walking. We know from animal studies that rats and cats can walk with less than 10% of the spinal tracts crossing an injury site [1]. This is true for humans as well.

In the 1980’s, I used to do evoked potential monitoring [2, 3] for Fred Epstein, a neurosurgeon who operated on spinal cord tumors of kids. He would often cut open the spinal cord and remove the tumor, leaving behind spinal cord that is thin that it is almost transparent. On the Upper East Side of New York, there used to be bagel store where some Chinese guy would cut lox that is so thin that you could almost see through it. That was what the spinal cord of these kids looked like and yet they would walk out of the hospital.

How do people walk with so little spinal cord?

The brain doesn’t directly control the muscles used for walking. The spinal cord does [4]. All the movements for walking a programmed into the spinal cord [5]. To start walking, the brain sends a message to the spinal cord to tell it to walk [6]. A center in the L2 spinal cord called the central pattern generator (CPG) initiates and coordinates the muscles responsible for walking [7, 8]. The CPG is of course why chickens can continue to run around after their heads have been cut off [9]. It is also the reason why we can sleepwalk at nights. You don’t need much of your brain to walk. In fact, it is possible to stimulate the lower spinal cord at L2 and activate walking and the CPG is under sensory control [10].

Herman, et al. [11-13] reported in 1999 that subthreshold stimulus (not strong enough to activate walking by itself) made it easier for people with spinal cord injury to initiate and control walking. This is of interest for locomotor training. Herman describes a person who is just a household walker after years of overground locomotor training, normally taking over 160 seconds to walk ten meters. However, when the L2 stimulator was turned out, at a level that does not activate walking, the person is able to walk 10 meters in less than half the time. The walking recruited more muscles and the gait was more efficient. After several months of training with the stimulator, the person is now able to walk more than a km at normal speeds. Energy studies indicate that the walking pattern is much more efficient when the stimulator has been turned on.

Humans evolved tremendous redundancy of the spinal cord because of spinal cord injury because regeneration takes too long. At one mm a day, regeneration may take a year or more to restore function. No animal can survive his long without being able to escape, hunt, and procreate. Therefore, animals (and humans) have evolved redundant spinal cords. Such redundancy provides a major survival advantage because spinal cord injury is relatively common. For example, although there are over a million cases of cervical whiplash every year in the United States, less than 10,000 result in spinal cord injury requiring hospitalization. By having a redundant spinal cord, humans could survive even after 90% of their spinal cord has been damaged. This is why a football player can keep playing after having gotten a “stinger” and people with incomplete spinal cord injury, ever severe ones destroying 90% of the spinal cord, will recover walking.

Axons Keep Trying to Grow

The first thing that I was taught in neuroscience as a graduate student was that the central nervous system cannot regenerate. But, if you look at the injured spinal cord, this is not true. Axons in the spinal cord not only can and do grow but continue to try growing throughout adult life. This may sound like heresy but science is really about overturning dogmas and the dogma that the spinal cord cannot regenerate has been toppled many times over the past 20 years. The spinal cord not only can grow and does so routinely but it continues to try to grow many years after spinal cord injury. Let me explain.

After an injury, the spinal axons that have been damaged “die-back” a short distance and then start regrowing towards the injury site. In most cases, they stop at the edge of the injury site, although some axons apparently will invade into the injury site itself. In the first detailed and systematic study of axon regrowth in contused spinal cords [14], we found axonal growth into the injury site of over 70% of contused rat spinal cords at 6 weeks after injury. Most of the axons did not grow out of the injury site but they have clearly grown up to and into the spinal cord. Many axons, however, stop at the injury and appear to be waiting.

Ramon y Cajal [15] first described these waiting axons. They have enlarged bulbous endings that he called “sterile terminal bulbs”. He thought that these were just axons that had been damaged and could not grow. The problem is that you can find these at 2 week, 2 years, and even 20 years after injury. My friend Richard Bunge [16] once showed me a slide of a human spinal cord 20 years after injury. The spinal cord was from a woman who had died 20 years after injury. At the injury edge, thousands of axons with their bulbous endings were present, as if they were waiting. This amazed me. Were these axons just sitting there for 20 years? That seemed highly unlikely.

The answer to this question did not come to me until I saw a talk once by Jerry Silver. He was trying to get axons to grow in culture dishes. To mimic the inhibitory growth environment of the spinal cord, he and his students had coated a cell culture with laminin (which supports axonal growth) and put a drop of solution containing chondroitin-6-sulfate-proteogylan or CSPG (which stops axonal growth). As the drop of CSPG solution dried, it left a concentration gradient of CSPG that was lowest at the center of the drop zone and highest at the drop edge. Jerry then placed a dorsal root ganglion in the center of the drop zone and took videos of the dorsal root ganglion axons growing.

When an axon grows, it forms a growth cone at the tip. In its fast growth mode, the growth cone is like a spearhead. However, as axons grow in a progressively growth inhibitory environment, the growth cones tend to spread out. They eventually stop and become bulbous terminals. In his useful insight way, Jerry called these “frustrated” growth cones. When viewed in on video, one can see that axons start growing, becoming frustrated, and then falling back, repeatedly trying over and over again. The fact that these terminal bulbs are present in spinal cord 20 years after injury tells me that there is continued regrowth in the spinal cord, probably for the entire life of the individual. Even if it did not, there are probably ways to kickstart the growth again.

Give Them a Path and They will Take it All the Way

In the 1980’s, Sam David and Alberto Aguayo [17, 18] literally stood the non-regeneration dogma on its head when they hypothesized that spinal axons can grow but that there are growth inhibitors in the spinal cord that stops growth. To test the hypothesis, they excised a peripheral nerve, one end into the cervical spinal cord and the other end into the lumbar spinal cord of a rat. Spinal axons grew into the nerve inserted into the spinal cord (on both sides) and all the way to the other end. However, they would not re-enter the spinal cord on the other side.

In 1999, I heard Thomas Carlstedt [19] of the Royal National Orthopedic Hospital at Stanmore speak about his work inserting avulsed brachial plexus nerves back into the spinal cord. Brachial plexus injuries cause avulsion of the spinal root from the cord. He would expose the spinal cord and insert the avulsed nerve back into the spinal cord. Several months later, all the patients recovered some movement in their paralyzed arm. In fact, some of these patients had “breathing arms” because their arms would move as they breathed, suggesting that the axons that normally activate breathing have entered into the peripheral nerve to the arms. To me, this is proof that if you give spinal axons a path to grow, they will take it and go all the way.

Giorgio Brunelli, et al. [20] used peripheral nerves to bridge from the spinal cord above the injury site to muscles below the injury site. He started by using a branch of the ulnar nerve that innervates the little finger side of the hand and moving the nerve to the sciatic nerve of the leg, to innervate the leg muscles. He has done this to a number of people but moved from this procedure to doing a nerve bridge from above the spinal cord to muscles below the injury site [21]. Brunelli et al. [22, 23] have shown that glutamatergic spinal axons from the spinal cord innervate muscle.

Shaochen Zhang [24] has done thousands of peripheral nerve grafts above the injury site to muscles below the injury site, not only from arms to the legs but from neck to arms, from upper arm and shoulder nerves to the hand, and from intercostal nerves to the bladder and legs. Xiao, et al. [25-30] has been diverting the L2 or L3 ventral root to reinnervate the pudendal nerve (S2), which innervates the bladder. This procedure restores bladder function in close to 80% of patients. Scratching the dermatome for L2 can initiate micturition (bladder voiding). Many patients were able to produce a 3-foot stream of urine. The procedure seems to work in spinal cord injury and spina bifida.

To me, the finding that spinal axons will grow into peripheral nerves and connect cells at the end is proof that they can regenerate and that all you have to do is give them a path and they will take it all the way. They will make synapses with the cells that they find at the end, including muscles. But, even more amazing was the finding somatic motor nerves from the lumbar cord will reinnervate and make the bladder function again. This is amazing because micturition (the act of urination) is a complex act that involves bladder contraction and relaxation of the bladder sphincter and ability to stop when the bladder is empty. For a somatic nerve to mediate this complex response is amazing.

Recovery is Possible in Chronic Spinal Cord Injury

Recovery is the rule and not the exception after spinal cord injury. Since most people have incomplete spinal cord injury, a majority of people recover substantial function. Even those with so-called “complete” spinal cord injuries usually recover 1 or more segments. This may come as a surprise to most people who are used to being told that people do not recover after spinal cord injury. Spontaneous recovery from spinal cord injury provide several insights into the mechanisms [31]. First, recovery is often slow and may take years. Second, repetitive training facilitates and accelerates the recovery. Third, absence of function does not necessarily mean that the structures are absent. These will be discussed in turn below.

Most people continue to recover some function years after the original injury. For example, Christopher Reeve, who was certified by many doctors to have a so-called “complete” spinal cord injury and did not receive any experimental regenerative therapy, begin recovering sensory about 2 years after injury, to the point that he had light touch sensation over 75% of his body [32-35]. His anal area was so sensitive that they had to use lidocaine cream during bowel procedures. At 6 years, his wife Dana noticed that Christopher could move his left index finger. It turns out that he has quite good control on his left index finger. Christopher also found that he could move his legs slightly. The time frame and nature of this recovery is consistent with the possibility of spontaneous regeneration after spinal cord injury [36].

Repetitive training can restore function even in people who have not functioned for years after injury. When a particular function has not been used for a long period of time, atrophy is not limited to bone and muscle. It appears also to occur in the central nervous system. Called “learned non-use”, this remarkable phenomena can be mimicked by denervating an animal’s arm by cutting the dorsal root, and then allowing the subject to stop using the arm. After several months, the arm become effectively paralyzed. However, intensive and repetitive exercise can restore function, even many years after injury [37]. Constraint-induced movement therapy [38] is now used to treat multiple sclerosis [39], stroke [40], and many other conditions [41]. Locomotor training is a formed of forced-use exercise [42-45] that can and has been used to restore locomotor function in people, often many years after their spinal cord injury.

Finally, neurologists have long assumed that absence of function means loss of the structure mediating the function. However, central nervous system function can be suppressed for years without loss of structure. For example, treating an arteriovenous malformation (AVM) or decompressing the spinal cord can result in rapid recovery of function. I use to monitor evoked potentials of patients undergoing surgical or radiological procedures [3, 46-48]. One of the patients was a paraplegic athlete with thoracic spinal cord AVM. Although paralyzed for nearly 7 years, he recovered rapidly after the embolization and walked out of the hospital after embolization. Such rapid functional recovery could not have been due to regeneration or remyelination. It was due to removing a cause that had suppressed function for many years.

Summary and Conclusions

Many people are concerned that the cure for spinal cord injury will apply to newly injured people and not to people with chronic spinal cord injury. While these concerns are legitimate, it is important to dispose several common misapprehensions. First, the spinal cord is not “dead” below the injury site. Injury disconnects the lower spinal cord from the brain and upper spinal cord. Spasticity and spasms is proof that the lower spinal cord is alive and kicking. Second, neural, muscle, and bone atrophy can be reversed even after years of loss. Finally, the spinal cord contains programs for complex functions such as walking. Those should be preserved and the goal is to reconnect enough axons to initiate and modulate these programs.

About 10% of spinal cord tracts is necessary and sufficient to support complex functions, including walking. Humans, for example, can walk even after damage to 90% of the spinal cord because the brain does not directly control walking. All the movements for walking, for example, are programmed in the spinal cord. The brain sends a message to the central pattern generator (CPG) in the spinal cord, telling it to walk. The CPG is located in the L2 lumbar cord and can be stimulated to initiate or facilitate walking of people after spinal cord injury. Humans evolved redundancy of the spinal cord because regeneration is too slow to help an animal to survive after spinal cord injury.

Axons continue to try to grow after injury. At the injury site, they die back a short distance and grow back to the lesion edge. In contusion injuries, some axons grow into the injury site but many stop at the lesion edge. Ramon y Cajal described axons at the injury site with terminal bulbs. These axons with bulbous endings were present in human spinal cords even 20 years after injury. These terminal bulbs are “frustrated” axons that are still trying to grow at the injury site, due to growth inhibitors that collect in the extracellular matrix surrounding the injury site.

If you give axons a path to grow, they will take it and grow all the way. David & Aguayo first showed this in the 1980’s by inserting peripheral nerves into the spinal cord and showing that many axons from the spinal cord would grow into the nerve and continue all the way to the other end. Thomas Carlstedt used this method to treat patients with avulsed brachial plexus, showing that axons from the spinal cord not only grew in the nerve by innervated muscle. Giorgio Brunelli likewise showed that the axons that grew into the peripheral nerves were spinal axons rather than motoneurons and that they form glutamatergic synapses. Finally, Zhang and Xiao in China diverted nerves from various parts of the spinal cord to innervate and control organs that they normally do not.

Recovery is possible in chronic spinal cord injury. A majority of people recover substantially after spinal cord injury, particularly those with incomplete spinal cord injuries. Even people with so-called “complete” spinal cord injuries continue to recover some function, often years after injury. Christopher Reeve is an example. Likewise, intensive repetitive training can reverse learned non-use, including restoration of locomotion in people who have not walked for many years after spinal cord injury. Finally, certain conditions in the spinal cord can suppress function for years and removal of the causes can result in rapid restoration of function, within days.

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