“Optimism in Spinal Cord Research”

Maria Amador,  is a program coordinator for the information and referral at the Miami Project to Cure Paralysis. After receiving her Bachelor of Science in Nursing, she pursued the specialty of rehabilitation nursing and later specialized further in spinal injury care.

Prior to her involvement with the Miami Project, she was a staff- and then a clinical-educator for the Rehabilitation Center at the University of Miami Jackson Memorial Rehabilitation Center.

For the last nine years, Ms. Amador has represented the Miami Project to individuals with spinal cord injuries, their families and health care professionals, providing information about the Miami Project mission and research progress. In this role, she has fielded numerous clinical and research questions from thousands of people all over the world affected by spinal cord injury.

Today she will provide an overview of the scientific progress in finding a cure for paralysis resulting from spinal cord injury. Maria Amador.

I am excited to be here and really thank PRN for inviting a representative from the Miami Project here; and that I was chosen to do that. What I intend to do today is to talk about the mission of the Miami Project and overview some of the studies that we are currently doing or have done in the past at the Miami Project and, then also, how individuals get involved with the studies, people with spinal cord injury, how they get involved with some of these studies. Of course the title of the talk has to do with optimism in spinal cord injury research so we’ll discuss a little bit of the progress we’ve seen over the last 20 years and what we hope to be able to accomplish in the future.

I hope that meets your needs, and at the end feel free to ask any questions. I’ve heard many of them already from families and medical professionals in my years of work there so feel free to ask questions at the end.

The Miami Project is a multidisciplinary research center. We are located at the University of Miami School of Medicine. The Miami Project was an idea of Dr. Barth Greene, who is a neurosurgeon at the University. And in the late 70s and early 1980s, scientists were basically beginning to understand that the central nervous system had some potential for repair. Prior to 1980, what was believed is that nerves in the spinal cord cannot repair -- cannot regenerate.

But, by the early 1980s, scientists had discovered that, in fact, these nerves did have potential for repair but they were not in a good environment for repair. And with that information, Dr. Greene said, there is a little bit of hope. There is a little bit of information that we can begin to go on try to find a cure for spinal cord injury.

By 1985, basically with that information, he said, “Well, what we need to do is more research. We need to get scientists together. We need a collaborative team -- a collaborate effort.”

And by 1985, with the help of some patient friends of his, they were able to establish a research center at the University of Miami, and in 1985, we started with just five scientists.

Over the years, we have grown to a research staff, our faculty members, principle investigators at the Miami Project are now at a count of 26 principle investigators, and in our laboratories, working with them are the graduate students and the postdoctoral fellows. The technicians in the laboratory make our research staff of about 100 people. So at this point, it is believed that we are probably the largest group of scientists in one place dealing with spinal cord injury research.

What I’ll do today is give you an overview of some of the things that are going on in the laboratory.

If I only had five minutes to talk, I’d show you this slide, and we’d be done, but the Miami Project overview, and there is a lot there, so I’m not sure that you can see everything listed, but we do some clinical research and rehabilitation research as well as our basic science studies.

Surgical interventions -- I’ll talk about neuro-protection, understanding the pathology of human spinal cord injury as well as the physiology of human spinal cord injury. Try to understand how locomotion is controlled by the nervous system and the very basic science of cell transplantations. So we will touch on many of these things here today.

One of the studies that is conducted at the Miami Project is a study to try to understand what really happens in human spinal cord injury. Without really understanding the microscopic problems of spinal cord injury, the scientists aren’t able to be directed very well, but understanding the cellular problems. The cellular damage in the spinal cord helps to direct our scientists to look at possibilities in terms of cell transplantations.

We have a collection of human spinal cords, and this is a human spinal cord. The brain stem here, cervical portion, and this basically was cut so that it could fit on the slide, and we could get a picture of it. But what is also done is this is the cervical portion, down to thoracic, thoracic and into the lumbar and cauda equina.

What’s done with these spinal cords is, we’ll take these and take sections of the cord and prepare it for microscopic examination. At the present time, we have a collection of about 100 spinal cords that came from people that might have lived a couple of hours and others who lived a couple of decades. So this tissue is able to be taken into the laboratory and examined histologically. The cord is prepared for microscopic examination; various types of staining are used. In this case this is a stain for axons, and this is a stain for nerve cell bodies.

Down here what we have is the MRI. When this cord is brought to the laboratory, an MRI scan is done of it, and those records are then compared to the records of when the person was alive. But these records are also compared to the histology.

When we look at these under the microscope, we get an idea of what’s happening to the nerve fibers, to the axons, to the neurons.

In this case here, we can see a correlation between the loss of axons and myelin here and higher intensity here on the MRI. So this is a correlative study, which hopefully will help, our investigators have a better understanding of the microscopic level, the cellular level of the damage, and therefore, guide them in terms of cell transplantation techniques.

This is a cross section of the human spinal cord. You can see the cord is compressed. When a cord is compressed, what we are typically finding is the center of the cord becomes more damaged than the outer rims of the cord, and there is cavitation of the spinal cord in the center, but also possibly preservation of axons and myelin on the outside.

So this presents a challenge to our scientists of what can be done to fill the gap in the center, and since we still have axons and perhaps even myelin out here on the rims, are those nerve fibers functional? Can they be utilized? Can we reactivate these after an injury?

What we’ve learned from these types of pathology studies is in the area of cavitation. There can be cell death, so one of the problems that researchers are trying to understand, in terms of developing a new treatment, is if the cell has been lost to the injury; can we learn how to replace these cells?

This area of cavitation may have contained the cell bodies, and the cell body is dying. The immune system comes in to clean those cells out. You are left with the cavity. Can we learn how to replace these cells?

The other problems that can occur is that nerve cell bodies survive, their axon survives, but there is a loss of myelin. And then the third thing that possibly could occur is the nerve cell body survives, but the axon becomes damaged and you lose the connection.

So researchers are now having better understanding of, anatomically, what is happening in human spinal cord injury. And, with further pathology studies, we hope to have a better understanding of how much of these occur in the various types of injury.

There are several approaches -- possible therapies -- that we could be looking at, in terms of solving some of these problems. We are looking at neuro-protection. Can we protect the spinal tissue at the time of the injury or shortly after, so that we don’t have the kind of damage that we are seeing? Can we re-myelinate these axons? Can we repair the damaged nerve fibers? And can we replace the lost nerve cells?

What I’ll do is talk a little bit about each of these and give you an idea of the progress that we’re seeing so far.

Neuro-protection is an area that is important in the early stages of the injury. I imagine you are familiar with the primary injury being the trauma and the interruption of the blood flow, then, causing cell death. That occurs initially, but then, subsequently, this cell death can cause a secondary injury -- toxic changes occurring and inflammatory changes occurring because of the initial injury.

Then that leads to further cell death. And there is a therapeutic window, perhaps, for some treatments if can we prevent this secondary injury and the effects of this type of secondary injury.

Some of therapeutic strategies that have been looked at, or are under investigation at this point, are the use of steroids, using hypothermia and using growth factors and receptor blockers. And this is a list of some of the things that have been looked at -- possibly are already being used -- as well as things that are still under investigation.

Methylprednisolone is a standard drug for spinal cord injury treatment -- acute injury.  It is given within eight hours of the injury and may help to reduce the secondary injury that is occurring -- preserving some of the nerve fibers, preserving some of the myelin. We’ve seen that it has some benefit and is now a standard treatment for most contusive spinal cord injuries.

GM 1 was a drug that was given in a multi-center study, where it was given within 72 hours of the injury.

The preliminary result of that study is that the drug, when it was given at that timeframe and over a period of time in the protocol, when they looked at the individuals that received GM 1, or it’s also known as Sygen -- the individuals at three months out, post-injury, compared to the control group did have better outcomes.

But then when they looked at the two groups at six months post injury, the two groups were basically the same, so there is still more work to be done with GM 1 to try to determine if it should be given for longer periods of time, and if it’s effective for acute spinal cord injury.

There have been no studies of GM 1 in chronic injury that we are aware of. The other things are other possibilities -- Interleukin-10. In your packet, there is an article about Interleukin-10.

Our investigators use this in acute spinal cord injury in rats where they did a contusive injury of the spinal cord -- gave this drug within 30 minutes of the injury. In the animals that received the drug, there was less nerve damage. The size of the lesion was smaller than those animals that didn’t receive the drug.

Hypothermia is another consideration that is being looked at. Investigators are looking at cooling the body temperature slightly, and we may be taking that to clinical trial in the next couple of years. Interleukin-10 as well, we might start taking that to the clinic testing of those two things -- hypothermia and Interleukin-10 in the trauma centers and, perhaps, starting a multi-center study for the use of those drugs.

The problem with cell death, when we learn that the nerves have been lost to the injury, investigators want to know, is it possible to now find a source of cells that could replace those cells? Our molecular neurobiologists are interested in finding the source of cells --finding a source of cells that can be manipulated, controlled and prepared for transplantation.

Now the stem cell is a potential cell that could be used. Stem cells are precursor cells to all of our nerves and cells in the body, and the neuronal stem cells, when they develop, they will develop into any of the cells in the nervous system. It can be the neurons. It could be the oligodenrocytes, the astrocytes and any of the other glial supportive cells in the nervous system.

Investigators hoped to understand how this neural epithelial stem cell takes the neuronal course here and becomes a neuron, rather than becoming the oligodenrocytes or any of the other glial cells.

If investigators can understand, and I like to call it the traffic signals, if they can understand what signals the stem cell requires in order for it to develop into a neuron, then we may be able to duplicate that development in a culture dish and then have populations of these stem cells or neuronal stem cells that turn into neurons, and then use those cells for transplantation to replace the nerve cell body.

The other possible source of cells is through fetal tissue -- obtaining fetal tissue and genetically engineering the fetal tissue. Investigators also have information of, well if these cells are cloning, what are we going to do in terms of transplanting them? We don’t want them to continue to clone when there is a transplant.

So, in genetic engineering, you have been able to achieve some control over the cells, in terms of the cells in a dish are cloning, but now we need them to stop, cloning because we want to transplant them and have these cells incorporate into the nervous system. And they are able to achieve that.

The other thing about neuronal cell lines is that some of them can be designed so that they secrete substances. In this case, this particular cell line RN 46A, when it’s put with brain-derived nerve growth, factor becomes a serotonergic cell and it pumps out serotonin.

In the case down here when GAD is added, then it becomes a gabonergic cell. And the potential of these cells is that they may be able to be used for cell replacement, but they may also serve as pumps to the nervous system. One of the roles that these cells may take -- and we’ve investigated this with some animal models -- is in the treatment of neuropathic and neurogenic pain.

Neuropathic pain -- often the patient is describing this as a burning sensation below their injury, and there are a few good treatments, so the current drug of choice is Neurontin. That seems to be effective in some cases, but, in many cases, is not enough.

So investigators at the Miami Project, we formed a pain research group, and one of the goals of that group is to understand the mechanisms of neuropathic pain. We can understand the mechanisms, and we may be able to design treatments for this type of pain.

One of the treatments that has been suggested, is using these neuronal cell lines that secrete the serotonin and secrete GABA -- injecting them or transplanting those cells to serve as mini pumps of the drug, of the neurotransmitter, and see if that affects the pain. And in the animal studies, there have been some encouraging results.

The other possibility, in terms of pain treatment, is we are looking at the possible use of chromophen.  Cell transplantation in and near the spinal cord.  And chromophen?  Cells come from the adrenal gland and they also secrete these analgesic substances, actually a cocktail of analgesic substances, and the chromophen cells. There may be a possibility of transplanting these.

Adrenal cells, chromophen cells are being transplanted in cancer patients in Europe, and investigators are very interested in getting the approval to test these cells also in spinal cord injury pain.  So we are going through the process of getting IRB approval to try to do this type of study. So this may be a clinical study that we will begin to enroll individuals in in the next year or so. We hope.

I want to mention here some work that has been done as a multi-center study, which the Miami Project is just beginning to get involved with. When a nerve cell survives and has its axon, but has lost its myelin, there is still a potential that that nerve cell could transmit the message. It is difficult because the myelin is not there, but the possibility of that cell transmitting the message exists.

There is a drug called 4AP, which is being tested in a multi-center trial at the present time. It is a clinical study. They are enrolling individuals with chronic spinal cord injury who are classified as Asia C and D, and they are giving this drug to look at whether individuals can recover some of their function with the use of 4AP.

4AP -- its action may help nerves like this to improve the transmission of their message. It doesn’t replace the myelin. It’s not trying to remyelinate the axon, but it is a drug that they believe is helping to promote the transmission of the message so that individuals perhaps are gaining some functional recovery with this drug. That drug is currently under investigation. Again, a multi-center study that the Miami Project is just getting involved with.

The other aspect of the injury, of course, is the loss of the axon. With nerves like this that have the nerve cell body, they have lost their axonal connection, investigators want to know, are there ways to encourage these cells to regenerate and promote regeneration? There are some promising approaches to regeneration. This is a list of a few of them. I will talk in a little more detail about one or two.

There is a possibility of implanting cells that naturally make, or can be altered to make, growth promoters and regenerator promoters, applying growth-promoting molecules directly, growth factors and cell surface molecules.

Blocking or removing the growth inhibition in the spinal cord is another approach -- and I’ll mention that work, part of that work is coming out of Switzerland -- decreasing immunological processes and then stimulates the nerves to reinitiate growth.

One approach that is being taken, mainly through the work of Dr. Mary Bartlett Bunge, who is one of our principle investigators at the Miami Project, is the potential use of PNS cells, peripheral nerve cells. We know that the brain and spinal cord are inhibitory to regeneration. One of the reasons why people don’t recover from spinal cord injury and other central nervous system diseases is that the nerve, though it may have potential for regeneration, is not in an environment that really allows it to regenerate.

The peripheral nervous system, on the other hand, is an environment that supports regeneration. Nerves in the peripheral nervous system will regenerate. They are supported by glial cells that support regeneration.

The glial cell in the peripheral nervous system is the Schwann cell. So, in the peripheral nervous system, we can isolate, take nerve cell grafts, peripheral nerve grafts and isolate Schwann cells in a culture dish. Taking a peripheral nerve graft, what I’ve been told by the scientists is to take a two-inch peripheral nerve graft and through the processes of expanding these Schwann cells, they can get millions of cells in a four-week period. They suspect that the number of cells that they are able to obtain would be enough to transplant.

So the idea here is to take peripheral nerve grafts, isolate the Schwann cells that are the supportive cells for regeneration, and then transplant them back into the central nervous system in an effort to provide an environment for the neurons that have lost their axons -- provide an environment for the axons to regenerate.

The studies that we have been doing with animals is to remove a portion of the spinal cord, creating a gap here and then forming a bridge. It is a synthetic tube that goes in-between the cut ends of the spinal cord. Inside this bridge they are placing Schwann cells and nerve growth factors.

So we are placing a peripheral nerve environment into the area of injury. And the peripheral nerve environment, Schwann cells help to support the regeneration. And what we are finding is when this injury is made and the bridge is put in immediately, then we go back 30 days later.

What they found is that thousands of axons were growing in this bridge. And this is work from the early 1990s that we learned this. These nerve fibers will grow. They do grow into and across the bridge, and we can get substantial growth in these bridges.

One of the problems that we’ve seen, however, with this approach is that we can get the fibers to grow quite nicely in the bridge, but what happens is the fibers don’t want to leave the bridge and go into the environment that is hostile, I like to call it unfriendly environment, of the spinal cord.

In the spinal cord, there are proteins that inhibit regeneration, and the environment is hostile. Martin Schwabb at the University of Zurich is one investigator who has identified at least one protein in the spinal cord that inhibits regeneration. And he named the protein Nogo. It kind of fits its function of these fibers that don’t want to go there. But the protein is named Nogo, and in studies that Dr. Schwabb and his colleagues have done, is that they have been able to develop an antibody against the Nogo protein.

So, when they introduce the antibody, the Nogo is inactivated and then the fibers can grow. So they’ve had some evidence that regeneration within the spinal cord can be encouraged, by stopping the inhibition -- by turning off the protein that is causing the inhibition.

There are other proteins in the spinal cord that may also be inhibitory, and one of the keys that researchers throughout the world are interesting in doing is understanding, well, what are all the sharks and the alligators in here? I use an analogy that I’ve actually heard a scientist use -- that the environment of the spinal cord is like there are sharks and alligators. There are these different proteins, and these fibers don’t want to grow there, because they are going to gobbled up by the sharks and the alligators, and investigators want to understand what are the sharks, what are the alligators. How do we deal with those? Stop and, namely, to look at how do we stop the inhibition that occurs. How do we make this a friendlier environment?

Using the peripheral nerve grafting, we are making a friendly environment there, but we need to help these nerves to be able to leave their friendly environment and go into the environment that is not to friendly. So we hopefully can make it friendly. But also, if we can’t make it friendlier, we may be able to give it an escort -- give the nerve fibers an escort into the spinal cord tissue.

So work of Dr. Mary Bartlett Bunge and her colleagues continues to use an approach where they use the bridge of Schwann cells in the area of the injury to promote the growth across the gap. But the other thing they are doing is putting another glial cell, a helper cell, for regeneration.

Transplanted on each side of the bridge, these helper cells here in blue are the ensheathing glia, and they are found, at the present time they are taking these cells from the olfactory bulb from the nose, and these are cells that naturally support regeneration throughout our lifetime in our nervous system. The nose is the only place that we have new nerves being born. We have new nerves being turned over and replaced in the olfactory bulb.

When the new nerves have grown and developed, they need to be able to make their connection from the peripheral nerve system in the olfactory bulb into the brain. And it is the olfactory ensheathing glial cell, this cell here, that helps to promote that growth from peripheral nerve environment to the central nervous environment.

When we take those cells and transplant them on each side of this bridge, what we are hoping to do is have these fibers here, that are in a peripheral nerve environment, grow beyond the bridge and into the central nervous system environment. So these cells are placed here to help escort the growth outside the bridge and into the central nervous system. And these are approaches that investigators are hoping will eventually result in connections.

At the present time we can work with Schwann cells, and we are working with human Schwann cells. Our laboratories have been able to obtain peripheral nerve graft from humans, from organ donors that are donating their kidneys, their hearts. We get some peripheral nerve from those individuals, and we are growing human Schwann cells at this time.

So, in the future, if we are able to take this type of an approach to clinical trial, Schwann cells, we expect, we’ll be able to obtain quite easily. The nice thing about that is, then, this could be an autotransplantation -- where the individual serves as their own donor of those cells -- utilize those cells for transplantation.

The other types of cells -- it is a challenge right now to be able to get olfactory ensheathing glial. So investigators are trying to understand are there other cells that could promote regeneration across the bridge from within the bridge out to ends of the spinal cord.

And the evidence we are still looking for are whether these fibers can get outside the bridge, and I didn’t mention what our results with the animals are yet, when we combine the Schwann cells and olfactory ensheathing glial, so far we are seeing some regeneration beyond the bridge up to about two centimeters, but no proof yet that connections are occurring.

So scientists still have a lot to do to try to understand how to really get connections and, basically, investigators are working together to try to understand what combinations of these approaches do we need.

There are the bridging strategies that I have pointed out -- the possibility of cellular transplantations, adding growth factors to promote some of the regeneration. The anti-inhibitory agents try to make the spinal cord a friendlier place for regeneration.

Adding neuroprotection to that, of course, and trying to improve the axonal function; getting those fibers that the axons are there to be able to utilize those axons better, and then another part of a future cure. Investigators at this time are looking at these various approaches. The Miami Project collaborates with scientists throughout the world.

I mentioned Martin Schwabb, and he is a collaborator directly with Dr. Mary Bartlett Bunge, who is one of our principle investigators. They sit on committees. The Christopher Reeve Paralysis Foundation has a consortium and several laboratories throughout the world that are working together and discussing the possibilities of the combinations. What combinations do we need to promote regeneration?

An important part of a cure, however, we expect, is going to also involve rehabilitation.

I like to show this slide too. It kind of gives a visual of what it is that the investigators are trying to do and where we are at this point.

This is a hotshot neurosurgeon standing here next to the boiling pot, which is labeled the cure. You can’t see this very well, but these are anti-inflammatory freeze-dried peripheral nerves. We have olfactory ensheathing glia here. We have stem cells here -- spinal cord puree, Schwann cells, Nogo noodles. So there are various things. As you can see all of the things are at this time under investigation by various laboratories throughout the world, and all of them have some potential that they could be part of a cure and part of trying to reestablish the axonal connections, the regeneration and the connections.

I was happy to see a basic scientist put this cartoon together, and I was happy to see that he did include a door here for rehab -- that rehab will be an important part of a cure.

So we are quite optimistic in terms of basic science to be able to see the progress from before 1980 -- scientists not being able to say nerves in the central nervous system regenerate. They regenerate. We can promote regeneration in the animal models. We’re seeking to find the way to get the fibers to connect, and when those fibers connect, we then will be seriously considering whether these investigations could then go to the clinical laboratory and be testing these in the clinic.

There are several considerations when we are wanting to take animal studies to clinical trial in our patients, and I hear it almost every day from patients. People with spinal cord injury saying, “Well when can I get into a study that is going to transplant cells? When are we going to be able to see that Schwann cells are transplanted? When or this? When or that?”

Really one of the biggest issues is going to be safety. The other issue is can we reliably, can we confidently say, that the animal studies give us the evidence to be able to confidently move to the clinical trials? So those are important considerations. And the effectiveness, the reliable outcome -- there is the aspect of functional, versus statistical significance. We may see statistical significance in some outcome, but does that do anything for function?

Statistically if we can get 20 percent of the neurons to connect, have we proven that that is effective? That may be statistically significant, but does it mean that it is functionally significant? Does it mean that, in this case with the animal studies, that the animal got better? So there are many questions the investigators are having to look at to really confidently go to the clinical trials.

One of my roles at the Miami Project is to help families and the individuals with spinal cord injury understand the scientific process. They always want to know, “Well, how come it is taking so long? You’ve been talking about this for years.”

It is a challenge to try to help them to understand that this process is very tedious, it is pain staking, and it does take time. The initial trials, of course, are going to have to be looking at safety. And, actually, I’ll mention here that there have been discussions to begin a Phase I clinical trial with the transplantation of glial cells. So we may, in the next three to five years, I’ll guess, see that some clinical trials, cell transplantation trials, will begin with some of the glial cells that I mentioned, the supportive cells that I mentioned.

At this point, I want to switch and go into some of the clinical and rehab studies that the Miami Project is doing. Our basic science studies, of course the mission and the goal, is to understand can we develop new cellular therapies, drug therapies, to promote function, promote regeneration of the nervous system and repair of the nervous system.

But other goals that we have are in the rehabilitation field. What can we do to improve rehab? What can be done today to have people living better? Have people been maintaining their nervous systems? Maintaining their musculoskeletal systems? Maintaining their health? So these are important questions that we are working on at the Miami Project.

We are also working on a few clinical studies that I’ll mention now. Dr. Greene is one of our principle investigators and is the chairman of the Department of Neurosurgery. He is overseeing the work of his faculty and his students, and is interested in understanding there are better ways to treat the injury from the surgical perspective.

Questions he has had in chronic injury, there may be compression resulting from the bone or instrumentation, and chronically there may be pressure in a chronic injury. And he has asked the question, “Well, if we remove that pressure, does that help the individual?”

And he has been doing studies on delayed decompression. The person may have had an injury for ten years, and there are certain cases that he has found. He and his colleagues have found and published on this -- that removing the bony pressure or the instrumentation pressure on the spinal cord may help to preserve some function or re-establish some function.

Now it is not anything that is going to get people. It is not a cure. It is not something that an individual would come to Miami and get this decompression surgery to walk home. It is something, let’s say for an example, a quadriplegic has bony pressure on the spinal cord, and by removing that pressure, they can get their triceps or more of their tricep function. One level or at the zone of the injury getting a little more function, and in a quadriplegic, that might be significant.

So Dr. Greene has done some work on that. He has also been in syringomyelia and how to treat the cysts that can form after spinal cord injury. A cyst is a fluid-filled cavity, and sometime the fluid expands, and that can become a problem that causes loss of function in some cases, pain, spasticity and increased dysreflexia.

And Dr. Greene, his colleagues and others of his colleagues throughout the nation have been interested in understanding what is the best treatment for syringomyelia and have been looking at the use of shunting the cyst but also been looking at tethering of the spinal cord. Sometimes tethering, which is a scarring of the dura, and the scar gets caught up against the bone or the soft tissue.

That scarring, or the syringomyelia, can cause the same kinds of problems clinically. And an approach that he has been looking at is detethering the spinal cord, alone or in combination with shunting a cyst. But typically what he has found is, when he detethers the spinal cord, the cysts collapse, and they don’t need to use the shunt, but they have the shunt ready if they need it. This is the spinal cord here, and this is tissue that has scarred and adhered to the dura.

What is done is he cuts this away and then creates a patch, and this is a duroplasty patch. So it helps to free the spinal cord. So it’s free within the casings, the dura, and the cerebral spinal fluid flow is restored. That is just an example of a couple of the things that Dr. Greene has been involved with, with clinical and surgical treatments.

We also have surgeons who are collaborating with neurophysiologists to try to make spinal surgery safer. A group of our investigators have developed two different intraoperative monitoring techniques.

One of the monitoring techniques has been used in the case, of let’s say for example, pedical screw placement, where screws are going to be drilled into the vertebra. When they are doing this procedure, there is the potential that there could be impingement of the nerve roots or the spinal cord itself.

The intraoperative monitoring technique they have developed is to use stimulation. When the screw hole is being positioned, they can stimulate here and learn how close to, if any, stimulation is reaching the nervous system. If it does, then they can reposition the screw hole, so it is not impinging on the spinal cord, and that is making the surgery safer.

They first did these investigations in pigs and then moved to clinical trial. They are finding, when the study was going on, the cases that involved the intraoperative monitoring had less adverse effects following the surgery. We find that this is a way to make the surgery safer. Keep the nervous system safe during the injury.

The other procedure that has been develop. Oh, I should give you an example here so something like this doesn’t happen. So this kind of intraoperative monitoring can be utilized so inaccurate positioning of the instrumentation doesn’t occur. With intraoperative monitoring, the monitoring I just mentioned, this wouldn’t have occurred. They would have known that the nervous system was being impinged on.

The other intraoperative monitoring technique that is utilized is using evoked potentials, where stimulation of the brain occurs during the surgery, and EMG recordings are done on the muscles below the surgical site. So continuous stimulation is going on. It helps to guide the surgeon. If a clamp is put on or bone is pressing against the spinal cord or the nerve root, and they lose signals to the EMG, then they are able to stop and see what is going on at that time. Waiting until the person is in the recovery room is too late.

If the person wakes up and they are weak or they’ve got pain or they’re paralyzed, then it is too late to go back and fix that. It needs to be taken care of at the time of the surgery. And these intraoperative monitoring techniques are assisting the surgeons and guiding them.

The Battle Center is a facility at the University of Miami. It is part of the Miami Project. It is a place where we are able to conduct rehabilitation research. Some of the goals that we have are to improve our understanding of human physiology, to ask questions of when spinal cord injury occurs. What happens to the spinal cord? Do nerve pathways change? Do we have resprouting going on? What happens in people who show spontaneous recovery? Is their nervous system changing? Is that the reason we are having those people see recovery?

So we hope to have a better understanding of the physiology. It will help us to understand what interventions we can use and what patients perhaps to use for those interventions and help us to quantitate and evaluate what kinds of responses we are getting from the rehab that we deliver or, in the future, from a cell transplantation that we deliver.

The other goal we have is to improve the quality of life after spinal cord injury, and we are looking at things like strengthening and conditioning, assisting reproduction. I mentioned our pain research group, and we’ve done some work with spasticity.

So we’ll go through a little bit of this. This is a neurophysiologist here. This is an incomplete quadriplegic, who was brought to the laboratory, and the investigator is using magnetic cortical stimulation. This is a device that can stimulate through the skull to the cortex of the brain. When the neuron receives that stimulation, it sends its message down the spinal cord.

Now those individuals, it’s pretty obvious, if they have voluntary control, that they are getting some messages from their brain to control the toe movement. Our investigators want to know, will these people recover? Will they be the ones to have spontaneous recovery? To what extent will they recover? Why are they recovering? And by doing physiological testing like this, we can follow these people over time. We will do this type of testing a couple of days after the injury, a couple of weeks after the injury, a couple of months after the injury. Follow them over time and gather the EMG information, which we hope will correlate with the functional recovery and help to explain the functional recovery we see.

If we can understand how people recover spontaneously, we may understand how to then influence that recovery. And these physiological tests will help us with that. So spontaneous recovery is of much interest to us.

We are also interested in understanding -- from a physiological perspective -- does the spinal cord change? Does the spinal cord regenerate? Is there plasticity or is there the ability of the nervous system to resprout after injury?

The investigator you saw pictured there is neurophysiologist Blaire Clancy, by the way. He has done some studies where he took a group of individuals and did some stimulation studies. Stimulated sensory nerve in the ankle.

In the group of individuals that were complete injuries at C6 or above and who had been injured at least a year, he found a curious response when he did this stimulation at the ankle. What he found is these individuals, when he stimulated the ankle, had a motor response in the opposite hand. That is not a normal connection. If you stimulate there, you are not going to get that response in able-bodied people.

This is a diagram of what he feels has happened. The nerve pathway for the sensory neuron ascends the spinal cord and it is interpreted in the nucleus grasilus. You can’t see it up here, but the motor control of the muscles in the hand is coming from the cortex, so descending to the muscles in the hand.

Spinal cord injury disrupts those pathways. So now you have muscles over here that have lost their connection to the cortex, and you have sensory neurons down here that have lost their connection to the brain.

What he feels happens over this period, a year, is that these sensory neurons try to resprout and regenerate but because of the injury are unable to make their way to their natural target in the brain. And what happens is they resprout and redirect to muscles that have lost their nerve connection from the brain.

So, if this theory is correct, this would explain why stimulating sensory neuron in the ankle would result in a motor response in the hand. And this is some evidence that the human nervous system is plastic. That resprouting can occur.

Again, if we can understand how this occurs, in this case, this was not a functional resprouting. We are not going to sit and stimulate somebody’s ankle and get their thumb to move, and it is not very functional movement anyway. But if we can understand how to harness this sprouting and get it to occur in an organized fashion and perhaps in pathways that be able to utilize, then we may be able to understand how to influence recovery.

Another neurophysiological observation we have made is walking may not come from the brain. Control of walking may not come from the brain. Control of walking is partly controlled by what is known as a spinal rhythm generator. A network of nerves in the lower lumbosacral cord that coordinate the flexor and extensor muscles for reciprocating gait, alternating gait.

We have evidence in animals that this spinal rhythm generator, that’s also known as the central pattern generator that it exists. We have some evidence also that it may exist in humans. The idea here is that -- I like to explain it this way -- the brain is the pilot. When I get up to take some steps, my brain initiates the activity but it may turn over the control of that activity to the central pattern generator. My brain probably doesn’t control every step that I take.

So investigators hope to have a better understanding of locomotion. What is the physiology? What’s the nervous system control of locomotion?

Now we had a very curious case that led investigators to believe that humans do have alternate pathways or pathways outside the brain that control walking. This case study was in an individual who was a quadriplegic. He was injured back in 1975. It was a football accident, I believe. And within six months after his injury, he was incomplete, showing incompleteness. He was a C5 burst fracture. He had finger movement, which is C8, and he had some toe movement.

So he had some of this function. Six months after his injury to 12 years after his injury, he had no changes in motor recovery. But 12 years after his injury, he noticed that he could move his leg a little better, and gradually over a five-year period with some rehabilitation at that point, he was able to get to a point of standing and walking with Lofstrand crutches.

Up until 12 years after his injury, he was still in a wheelchair. Seventeen years after his injury, he could get out of his wheelchair. He could walk with Lofstrand crutches.

Now this individual was of great interest to our physiologists because they were saying, “Well gee, how is this happening? We expect recovery to occur in the first couple of years,” and that is what most doctors will tell their patient, and I think that is mostly what we see. But we have seen a few cases where we see late changes. We see changes in functional capability even years after the injury.

And, of course, this individual we brought to the laboratory. The physiologist wanted to do some studies with him, to try to understand why did he have this recovery. Can we learn from his nervous system?

When he was in Miami for this type of physiology testing, he decided, “Well I’m going to stand up. I’m going to use the parallel bars, work with the therapists. I’m on vacation, I’m going to try to improve my gait.”

After about four or five days of self-imposed therapy, intensive therapy, he came back to the laboratory and said, “You know what? I’m having trouble sleeping at night. Every time I roll over onto my back I wake up because my legs are moving and its like they are walking.” 

And this was all involuntary movement that he was experiencing. Mind you, he couldn’t get up and walk voluntarily, but in a certain position, lying supine in the bed, his legs started moving involuntarily in a walking pattern.

What we have here is a slide of one of the steps that occurs. We got some videotape of this. You see here the left knee comes up. It goes back down. Then the right knee comes up and goes back down, and that one step takes about three seconds, but it would continue and have this alternating walking movements. And, of course, at that point the physiologists are saying, “What is going on in his nervous system? What is controlling this? Why is this occurring? Can we learn something from this?”

And they have concluded that this particular case study is probably the first evidence that we have a central pattern generating -- that humans have this spinal rhythm generator. If we do, if humans have this network of nerves that controls walking activity or locomotion, and that pathway or those pathways are apart from the brain, can we design rehabilitation techniques to help improve the walking in certain cases?

We also have some studies going on in collaboration with what we are looking at in the human laboratory. Our basic scientists are looking at the animal models, so some work is being done with animals to try to map out the tracing studies of what are the neurons from the brain, down to the cord, and out to the muscles that control locomotion. What are the pathways that are normally used?

Some of the rehabilitation techniques that we are investigating -- are looking at -- in this case, the use of body weight support to see if this is a method that would help to encourage recovery -- either encourage the use of alternate pathways, not from the brain or to improve the strength or function of the individual. We hope to learn more about this.

We are currently funded by the National Institutes of Health to conduct a randomized study, using this body weight support training, gait training. This is a person in a harness that goes around the torso, and they are suspended from a device on the ceiling, and he is walking on ground. There are other groups of patients that we put over the treadmill and we want to understand how these two interventions compare to conventional gait training.

The individuals that we enroll in this particular study have to meet specific criteria. They must have an injury at T10 or above, and it must be incomplete where they have the ability to stand and initiate some steps on their own. So this fellow, his movements are voluntarily. The therapist is here guiding, but his movements, he initiates the movements. He is able to bring the leg forward, and we want to know if this body weight support training has any better effect on locomotion as compared to conventional gait training.

So at this time, we have people coming from various places to enroll in this particular study, and I will talk more about that in a moment.

Treadmill training, versus the over ground, versus conventional therapy -- the other applications that we’re interested in, and have been interested in looking at, are the use of functional electrical stimulation devices. How can these devices help to improve function? How can they help to improve quality of life?

Some of the things that have been under investigation are devices that help with reaching and grasp, such as the bionic glove and the freehand. Freehand is currently FDA approved, and there are several clinics throughout the United States that will provide the surgery.

What freehand is they will put a switch in the shoulder and electrodes in the arm to promote grasp, and the electrodes in the arm will help to cause a grip. The position controls that with a switch in the shoulder. They shrug their shoulder, and that turns the device on. They get the grip. Shrug their shoulder again, turns it off and the grip is released. So there are devices like that that are available.

Bladder and bowel control -- there is a device called VoCare that has been under investigation, and if it is not already FDA approved, I think it is soon to be FDA approved.

We have done some work with strengthening and using arm ergometry with functional stimulation. Also with stepping and cardiovascular exercise. So I will review those things for you now.

This is a Saratoga cycle, which most rehabs have. This is readily available. Patients can order these from catalogs, but what our investigators did was to modify this device, put electrical switches in the handle that control neuromuscular stimulation so the person receives stimulation of the weak tricep muscle.

What that does is to stimulate the tricep for arm extension, that helps to assist them with extension of their arm against the crank, and then they use their bicep to pull, and we wanted to see this combination how it would help and if it would help the strength of the tricep muscle. And basically we found that those individuals that did receive the stimulation, we did find that they were able to increase the strength of their muscle.

This device is an FDA approved device. The Miami Project was part of a multi-center study in the early 90s, and Sigmetics, Inc. has gotten FDA approval for the device. Its called Parastep. It consists of a neuromuscular stimulator that the subject is wearing here in a fanny pack.

There are wires that come from the stimulator, that connect to electrodes that are taped to the skin over the muscle. The muscles that are stimulated are the quadricep muscles, the lower back or the gluteal muscles, and then there is an electrode on the lower part of the leg, which stimulates a nerve for stepping action.

The person controls, sorry you can’t see this very well, but there are controls on the walker. When they want to take a step, they will press this button on the walker that creates a withdrawal reflex of the leg, and the quadriceps are then turned on and stimulated from the computer. They bring their hip forward and take a step. So this is a device we’ve studied quite a bit, and we looked at it to understand, well, how functional is it. How realistic is it for people to get up, get out of their wheelchair and utilize this device for walking?

Now we’ve learned that it’s not a very functional device in terms of community ambulation. Nobody would take this out and try to cross a city street with it, but you could use it, the individuals are able to use it in their homes, for short distances in the community. It is slow walking, so there are some functional capabilities of the device.

But our investigators found that, more than a functional device, that it really is a very good exercise device. We did physiological testing, exercise physiology testing, to see how the hearts and muscles of these individuals, who had trained with the Parastep system, how they had done. What kind of advantages did they have in using a device like this?

And these are the conclusions that we found from the studies -- that the cardiac function and exercise capacity increased. We looked at bone density to see if the weight-bearing and electrical stimulation had any effect on the bones and, fortunately, it didn’t have a significant effect on bone loss in these individuals.

We looked at lower extremity blood flow in the muscle mass -- their physiological well-being. We found that they felt good about the device, in using it, and also looked at some of the blood lipid concentrations and the effect that this type of exercise has on cardiovascular function and cholesterol levels -- general health.

There are some problems associated with exercise. If we look at the electrical stimulation cycling or ambulation, one of the problems with this is the equipment. The equipment is expensive. People don’t have the resources to utilize it, and it is not universally available.

It is difficult to find clinicians who are offering the devices and training people with the devices. It is also questionable as to whether, you know, are people going to use the device? If somebody gets Parastep, how long are they going to use it? Are they going to use it for a year and then say, “Well this isn’t doing what I wanted it to do,” and then put it in the closet? So there are issues like that.

So some of our investigators have been looking at voluntary exercise -- exercise that is more available to individuals. It doesn’t involve a device or uses a device that is very easy to access.

Some of the problems we can see with voluntary exercise is that it might cause injuries to the upper extremities and hasten the dysfunction. Looking at shoulders, people are pushing their wheelchairs and maybe damaging their shoulders. Adding exercises to that might not be beneficial.

So some of our investigators have been looking at, well, what types of exercises would be beneficial? How can we balance the strength needed for wheelchair propulsion? They use a certain group of muscles for wheelchair propulsion, and we don’t get a lot of the back muscle strengthened.

What series of exercises perhaps could be designed so that people are maintaining their shoulders, maintaining their health? And we are providing some preventative rehabilitation techniques -- techniques to prevent the complications that we see in long-term wheelchair use and in aging.

So our exercise physiologist designed a circuit weight-training program where paraplegics were put into an exercise program, and they would do each of the stations that are on a universal gym -- a certain number of repetitions. Move to the next station --certain number of repetitions. Move immediately to the next station and the repetitions.

They would combine this with arm crank ergometry, which is like riding a bike with the arm, and basically have a program that was being tested to see what the results were and would this be helpful.

With this circuit weight training that was designed and studied, basically we found people’s shoulder strength improved -- pain decreased. They had improvements in their adrenalin levels, and their cholesterol levels improved. So we saw some good effects with this type of exercise. And the nice thing about this is most people can get to a place where the universal gym is accessible to them.

I have just a few more slides.

We are also involved with some male fertility research. Men, but not women, have problems with fertility. Women are able to achieve pregnancy after their injury, but men have a difficulty fathering children. Two reasons for that -- one is, most of the times, anejaculatory. Devices have been designed to help them to obtain their semen samples. Vibratory stimulation is available, as well as electroejaculation.

The other problem that they experience is after spinal cord injury their semen qualities usually are impaired. What we see is their counts are usually normal, but their motilities are decreased. So the number of sperm that are swimming is decreased, and that impairs their fertility. And work that has been done through the last 15 years is helping to identify what, perhaps, are the problems.

We have looked at lifestyle factors. We are now looking at abnormalities in the semen. But also, over the years, the technology in the assistive-reproduction field has improved the chances for men with spinal cord injury to be fathers.

And this is just a picture of the first six couples that we worked with at the Miami Project that have achieved pregnancy. We currently have 25 couples, with 37 babies, as a result of the work and the technologies that are available.

Just to end here, I’ve given you an overview of the type of research we do. We have the goals to try to find better treatment and repair for spinal cord injury and a cure, improve the treatments, but we are also looking at the other side of it -- rehabilitation. What can we do today to improve the function, and also keep people prepared for the possibility of a cell transplantation for example in the future? So we are a multidisciplinary team.

The individuals that come to the Miami Project are people who volunteer their time. If they come to the Miami Project, it’s because an investigator has invited them to a specific protocol. And individuals get into these protocols, basically, because they call the Miami Project, and we learn that they fit the criteria.

They e-mail us and they come by for a visit. Another way that they may get involved is they register and fill out an intake form that we maintain in a database, and that database is then used, as we start new studies, as a way to identify potential volunteers for the particular studies.

Any of your clients that are interested in getting information or you, yourselves, in getting more information about the Miami Project, our website is available, which is listed here. If people aren’t using the Internet, they can call our 800 number, and a packet of information would be sent out to them, which includes some of the information from the website. There are ways for people to contact us and talk with us, and they do. I usually talk to at least a thousand people a year who want to know about the progress, and they want to know how can they be involved. Can they be part of a research study? And they are also asking me, well, when.

“When are you going to have me come for a cell transplantation?”
So part of my role is helping them understand really where we are at in terms of the progress for research.

So I’ll close here, and we’ll open the floor to questions.

Q: I have a question actually. You had talked about the multi-center study that you guys were working with, to enhance the transmission in a cell with damage to the myelin sheath and the drug that you are using. Are they also, in that study, looking at that drug in relationship to MS and the possibility of assistance…?

Amador: Yes, they have studied that particular drug. It is 4AP and the initial studies were done with MS patients. They saw some promising results with it in MS and decided to look at spinal cord patients, a small group of spinal cord patients for safety and then took it to a multi-center study. So yes, that has been potential use for MS disease as well.

Q:  You talked about your multi-center studies. What are the centers that you are using in your studies?

Amador: The 4AP study is one of the multi-center studies that we are involved with. The 4AP study is sponsored by a biotechnical company called Acorda Therapeutics, and they are based out of New York, and they have selected centers throughout the United States that are part of that multi-center study, and we are one of the sites for that study. Acorda has more information, the individual sites, and the location of those sites, and Acorda can be contacted via the Internet, and their website is pretty easy, it is http://www.acorda.com/.

Thank you very much.