Journal Volume 4 - January 2010
Article 2
Neurorestorative Principles of Rehabilitation Today’s field of neuro-rehabilitation is transforming from a focus on social rehabilitation to life-long restoration of function through regeneration. Many readers likely remember seeing Christopher Reeve’s video during Super Bowl XXXIV in 2000. It showed the actor, Christopher Reeve, standing up and walking; intentionally looking real. Despite the uproar in the field of rehabilitation this 30-second video generated, it served its purpose; people started believing that recovery from spinal cord injury is achievable. We feel that there is hope today for recovery for almost everyone with a neurological injury, no matter how long ago the injury occurred. Traditional rehabilitation is almost exclusively associated with the acute phase of injury. There is very limited rehabilitation available for people living with chronic spinal cord injury. We believe that we now have the tools to optimize recovery of function, through a number of approaches that we will present below. Spinal cord injury is our main focus, however we want to emphasize that these approaches, including regeneration and restoration of function, are going to be applicable to all disorders of the nervous system. It doesn’t matter whether it is Alzheimer’s disease, Parkinson’s disease, stroke, traumatic brain injury, spinal cord injury, or transverse myelitis. Although these conditions have different mechanisms of injury, the end result is similar. Christopher Reeve demonstrated that recovery of function is possible in the worst case scenario, long after an injury.1 In 2002 we were unable to determine the mechanism that accounts for why this recovery occurred. Here we will discuss today’s approaches to regeneration. There are common goals and mechanisms for both regeneration and activity-based restoration therapy (ABRT). The International Center for Spinal Cord Injury (ICSCI) at Johns Hopkins and The Kennedy Krieger Institute in Baltimore, MD are centers that are dedicated to people living with paralysis. We have a sub-focus on pediatric spinal cord injury. We take care of young children from onset of injury through lifelong care. We design an individualized, lifelong, in-home restoration therapy rehabilitation program. The only realistic way for a person to maintain a therapy program for a long period of time is by doing it at home. There are simply not enough rehabilitation centers in the country, and the information takes years to disseminate throughout the rehabilitation community. The vision of our center is to provide meaningful recovery and life improvement for every person with paralysis. What is our mission? We are translating today’s science to near-term therapeutic applications. We are very interested in what can be done that immediately and positively affects our patients. The ICSCI is developing and applying advanced rehabilitation restoration strategies for optimizing spontaneous recovery in those living with paralysis. Image #1 illustrates the problem. This is a T2 MRI of someone who had a cervical spinal cord injury from trauma over 20 years ago. Spinal cord injury from transverse myelitis can look identical. The end result is the same whether you have TM or a trauma to the spinal cord. The cord swells which is followed by a secondary infarct. The spinal cord tissue usually dies from the inside out, and one is left with a donut-like rim of tissue. What is important is the outer rim. That is the part of the spinal cord that carries the fibers to and from all parts of the body. Except for certain areas in the neck, one can lose the entire middle piece of the spinal cord and can have near normal function. That is because those nerves that leave the cord at one level originate from at least three spinal levels. This person, whose MRI is depicted, although completely paralyzed for years, now can do triathlons. This proves that we do not need to cure or repair the entire nervous system. We do not even need to come close. Similar to the data demonstrated in animals, only 5-10% of connections that a person without spinal cord injury has are probably enough for people to run and walk.2 Up until a few years ago, we felt that a severe complete or ASIA A spinal cord injury typically had a poor prognosis. This statement was correct in its day. In today’s world, this is no longer true. What is different today? We have advanced imaging techniques. For example, diffusion tensor imaging (DTI) can actually visualize the tracts in the spinal cord. This enables us to identify and obtain an index of axons that cross the spinal cord lesion. With the individual in the case above, about 20% of the neural connections across the lesion are functioning. This is a person who can run and walk. The animal models are not as far off as some people have believed, as this phenomenon is exactly what the data from these studies suggested. A primary goal of restorative therapy used to be to try to fill the cavity in the spinal cord that forms following a spinal cord injury. We now understand that there is plenty of tissue remaining after injury and we do not really need to bridge this gap. A major problem that does need to be addressed, however, is the surrounding scar. As a scar, it expresses chemicals that prevent axons from growing into it. The broken neural connections are constantly trying to re-grow. In the scar tissue, there are incurring signals that communicate, “Stop, turn around, and go back the other way.” It is as if one had rearranged the road signs. Scientists are using enzymes to break up these signals. They are using multiple molecular approaches to overcome them or to inhibit their development. Another approach being used is the delivery of growth factors to that area that will create favorable conditions for neural cell growth. We believe that even the scar is not as critical a barrier as once suspected. There are ways to circumvent this problem. Usually, there are connections that exist across the lesion that are not functioning properly, because they are missing their appropriate insulation, myelin, resulting in short circuiting. This is what usually happens in transverse myelitis (TM) or multiple sclerosis (MS). There are many connections that exist across the lesion. Even in ASIA A or complete spinal cord lesions, probably about 3 – 5% of the connections across the lesion sites are functioning; they are just not functioning properly. Scientists, therefore, are trying to promote remyelination. This can be done through transplantation, stimulation of endogenous stem cells, or by delivering growth factors. It is important to note that successful results from all three of these techniques are highly dependent on activity. One can release brain-derived neurotrophic factor (BDNF) microscopically to the precise appropriate location through neural activity. Oligodendrocyte myelination can be stimulated through activity3. We are hypothesizing that loss of activity plays a major role in chronic spinal injury. These neural circuits need to be active. Most of this knowledge is derived from observations in early development. The nervous system needs constant activity to grow and to form the appropriate connections. We know that stem cells have many functions besides simply replacing cells that are lost. They can replace neurons, astrocytes and oligodendrocytes. They can form chimeric blood vessels; meaning they can integrate into normal blood vessels. They are also an important growth factor production and delivery system. They reduce and interact with the inflammatory response following SCI, and they break down inhibitors in the glial scar through enzymatic mechanisms and phagocytosis. There are many mechanisms that contribute to recovery. We do not know which ones are most important, but probably multiple factors are involved. Is it possible for these cells to create an organ? Yes it is. Organogenesis has already been shown in other organs, such as the pancreas and liver. How can this knowledge be applied to the nervous system? Researchers can get nervous system cells to grow, to connect, and even to appear to function appropriately. However, it does not look like the normal nervous system. It does not form all of the complex structures that the normal nervous system does. So, is the concept of growing or restoring the nervous system achievable? Years ago, we stumbled across something very interesting: neural induced stem cells can spontaneously make embryoid bodies. These amazing little formations contain neural tube-like structures in them, which are almost identical to neural tubes that occur during normal development. These cells can spontaneously become neurons and form circuits in tissue culture dishes. They also form oligodendrocytes that will function appropriately. This tissue is indistinguishable from the immature nervous system at the light and electron microscopy level. In one experiment, we injected the cells as small clumps in the space around the spinal cord of normal animals and then waited 4 months. We saw that the graft grew outside the spinal cord and resembled a highly similar architecture to the spinal cord.5 Another exciting topic of neuron-restoration is the concept of activity-based restorative therapies (ABRT). This concept is based on the hypothesis that neural activity is critical for the nervous system to not only maintain itself, but also to support regeneration and for recovery of function. To enhance regeneration, we need to increase neural activity. Activity is dramatically decreased below the level of the injury following SCI. If activity is reduced in the developing nervous system, then development is dramatically impaired. Mechanisms that are important for cell development, migration, path-finding, fate-choice, and myelination, are all dependent on activity. All of these mechanisms would be negatively affected by reducing activity during normal development; this is also the case in the normal, adult nervous system. We used to believe that the nervous system did not turn over or replace itself. We now know that there is significant turnover of cells, mainly of glial cells. Replacement of oligodendrocytes is important and it is regulated by activity. How can we achieve this replacement in individuals with SCI? We can simulate SCI in the laboratory and add functional electrical stimulation (FES) with the prediction that we are going to enhance regeneration. We have been able to show that FES can dramatically enhance regeneration6. We measured indices, such as cell birth, migration, myelination and formation of circuits. By adding FES to rats with SCI, we have demonstrated enhanced cell birth and survival selective to the spinal cord area that is stimulated. Adding more activity to a normal area did not show any differences. FES also enhances neural differentiation of embryonic stem cells, shifting differentiation from oligodendrocytes and astrocytes to neurons.8 Oligodendrocyte myelination can be enhanced by increasing neural activity. Is it possible to speculate that some of our traditional interventions, for example the use of Baclofen, a drug commonly used in patients with spasticity, may have been inhibiting spontaneous recovery of function? We demonstrated that the use of Baclofen not only inhibited a return of function, it resulted in a worsening of function7. By using Baclofen in animals at clinically relevant concentrations following simulation of SCI, using the same standards we would use clinically, we showed that recovery is dramatically impaired.7 When we took chronically injured animals and started them on Baclofen, they lost function. Even after stopping the drug, the deficit persisted. This implies that whether given early or late in the course of treatment, Baclofen is not necessarily a good thing. We feel that activity is a better treatment of spasticity than any medication. How can we apply this knowledge to humans? At our center, we are using an FES bike system. With the FES bike, we stimulate muscles of the legs and buttocks using a small computerized control system. The bike is very easy to use and can be used at the patient’s home. Patients can use their own wheelchair and can connect themselves very easily. During the early phase, muscles are usually weak. With continued exercise, they become stronger and will require different settings. Changing the program is automated to make it as simple as possible for the patient. The concept that serves as the foundation for ABRT is that the cycling motion results in the stimulation of the leg muscles. The contraction of these muscles produces patterned neural activation within the spinal cord that goes up the cord and activates a central pattern generator (CPG). The CPG is comparable to a minicomputer within the spinal cord that knows the program for walking. When activated, it sends volleys of activity up the spinal cord. Activity usually cannot cross the injury zone. However, what happens over time is that increased activity in the spinal cord can actually stimulate regeneration. It can stimulate axonal outgrowth, but mostly it stimulates remyelination of those connections that already exist across the lesion but are not functioning properly. Additionally, activity results in the release of growth factors. ABRT can achieve all these things and it does so in largely the appropriate way. The benefits of exercise are well documented for reduction of cardiovascular risk factors, including diabetes, hypertension and hyperlipidemia. People who are paralyzed have an even greater need for exercise because they simply cannot move. Activity in these patients, in addition to the above mentioned benefits, results in increased muscle mass, the maintenance of bone density, enhanced blood flow, and a decrease in the complications that frequently occur in this population. Ordinarily, one of the limitations of these treatments is the time and effort it takes to come to a rehabilitation center. Few people have the time to go to a center three times a week. We solved this problem by putting the FES bike into the patients’ homes. We were able to show that just the health benefits of exercise alone result in long-term cost savings. Everyone remembers the case of Christopher Reeve. He did not recover any substantial function within his first 5 years following the injury. However, following the initiation of ABRT, he went from no motor function to 20 percent of normal function within three years. Also in those three years, he recovered from 7 percent of normal sensory function to 70 percent normal sensory function. He enhanced his physical body fitness. He had a tenfold reduction in infections and associated use of antibiotics. The reduced major medical complications and improved quality of life gave him hope to live. Initially, he had no hope and was not given any chance of recovery. With therapy, he was on the road to recovery from a worst case scenario injury. Using his example, we want to emphasize that delayed substantial recovery is possible. At the time, we did not understand the mechanisms that led to these positive changes. We did have a few hypotheses which led to the design of further studies. For example, in a prospective cohort analysis, we looked at the benefits of three hours of FES biking a week. The physical benefits were enormous. Following spinal cord injury, muscle mass shrinks and is replaced by fat tissue leading to an unchanged size of the limb. The loss of muscle causes early diabetes. The increased fat causes the reduction of HDL’s (the “good cholesterol”), increasing the cardiovascular risk. Other scientists have already shown that reversing these changes can significantly decrease those complications. FES cycling can do just that following a couple months of therapy. We were able to show in a group of 60 patients who had experienced a spinal cord injury at least 2 years prior that we can reduce fat by 50% and double muscle mass with FES cycling. In this group, 70 percent of people recovered major neurological function.9 The other 30% might not have gained function, but they also did not lose any. The patients in the control group who did not receive treatment, lost function on an average of 11 points over a period of 3 years on their ASIA scale. Of the 70 percent that did recover, function improved on average 40 points on their ASIA scale. This is a very significant gain. To put this into perspective,: that is a larger gain than the administration of steroids achieves as an acute injury treatment. We made some additional and very interesting observations: 50% of people in the treatment group were able to discontinue use of Baclofen; 90% were able to reduce Baclofen or change from polytherapy to monotherapy for the management of spasticity. There were also significant improvements in functional independence measures. In summary, we are able to reverse physical deterioration, and enhance muscle volume and strength while reducing spasticity. We are able to reduce complications, achieve functional gains and obtain recovery of neurological function. Our real goal now is to try to understand the molecular mechanisms that are involved and how to optimize this process. We hope to maximize the physical integrity and benefits by using what we know from animal models in terms of stimulation of regeneration and recovery of function. We believe that the analog of regeneration in humans is recovery of function, which is much easier to measure. FES cycling is just one aspect of ABRT. The FES bike is probably the most effective and efficient first step in ABRT, because it has been designed for that purpose. However, it is just a small part of ABRT. The same concepts can be applied all over the body. We think that today there really is hope. We believe that the old days of being told that you have a bad spinal cord injury, life is over, and get used to a wheelchair, are over. Currently, there are hardly any treatments for chronic neurological disease. Activity-based restorative therapies may become one of the first. Reference List 1. McDonald JW, Becker D, Sadowsky CL, Jane JA, Sr., Conturo TE, Schultz LM. Late recovery following spinal cord injury. Case report and review of the literature. J Neurosurg 2002;97:252-265. |