How Is Research Helping Spinal Cord Injury Patients?
Can an injured spinal cord be rebuilt? This is the question that drives basic research in the field of spinal cord injury. As investigators try to understand the underlying biological mechanisms that either inhibit or promote new growth in the spinal cord, they are making surprising discoveries, not just about how neurons and their axons grow in the CNS, but also about why they fail to regenerate after injury in the adult CNS. Understanding the cellular and molecular mechanisms involved in both the working and the damaged spinal cord could point the way to therapies that might prevent secondary damage, encourage axons to grow past injured areas, and reconnect vital neural circuits within the spinal cord and CNS.
There has been successful research in a number of fields that may someday help people with spinal cord injuries. Genetic studies have revealed a number of molecules that encourage axon growth in the developing CNS but prevent it in the adult. Research into embryonic and adult stem cell biology has furthered knowledge about how cells communicate with each other.
Basic research has helped describe the mechanisms involved in the mysterious process of apoptosis, in which large groups of seemingly healthy cells self-destruct. New rehabilitation therapies that retrain neural circuits through forced motion and electrical stimulation of muscle groups are helping injured patients regain lost function.
Researchers, many of whom are supported by the National Institute of Neurological Disorders and Stroke (NINDS), are focused on advancing our understanding of the four key principles of spinal cord repair:
- Protecting surviving nerve cells from further damage
- Replacing damaged nerve cells
- Stimulating the regrowth of axons and targeting their connections appropriately
- Retraining neural circuits to restore body functions
A spinal cord injury is complex. Repairing it has to take into account all of the different kinds of damage that occur during and after the injury. Because the molecular and cellular environment of the spinal cord is constantly changing from the moment of injury until several weeks or even months later, combination therapies will have to be designed to address specific types of damage at different points in time.
Discoveries in Basic Research
A decade ago, researchers demonstrated a small but significant neuroprotective and anti-inflammatory effect from an adrenal corticosteroid drug called methylprednisolone if it was given within 8 hours of injury. It is the only treatment currently available to limit the extent of spinal cord injury and its risks are relatively low. Researchers continue to search for additional anti-inflammatory treatments that might prove even more effective.
Preliminary clinical trials of another compound, GM-1 ganglioside, indicate that it could be useful in preventing secondary damage in acute spinal cord injury. A large, randomized clinical trial suggested that it might also improve neurological recovery from spinal cord injury during rehabilitation.
These observations and others have led to optimism that recovery can be improved by altering cellular responses immediately after injury. Using what they know about the mechanisms that cause secondary damage - excitotoxicity, inflammation, and cell suicide (apoptosis) - researchers are creating and testing additional neuroprotective therapies to prevent the spread of post-injury damage and preserve surrounding tissue.
Some of the findings in these three different areas follow:
When nerve cells die, they release excessive amounts of a neurotransmitter called glutamate. Since surviving nerve cells also release glutamate as part of their normal communication process, excess glutamate floods the cellular environment, which pushes cells into overdrive and self-destruction. Researchers are investigating compounds that could keep nerve cells from responding to glutamate, potentially minimizing the extent of secondary damage.
Recently, investigators tested agents called receptor antagonists that selectively block a specific type of glutamate receptor that is abundant on oligodendrocytes and neurons. These agents appear to be effective at limiting damage. Some of these receptor antagonists have already been tested in human trials as a therapy for stroke. Similar agents could enter clinical trials within several years for patients with spinal cord injury.
Some time within the first 12 hours after injury, the first wave of immune cells enters the damaged spinal cord to protect it from infection and clean up dead nerve cells. Other types of immune cells enter afterwards. The actions of these immune cells and the messenger molecules they release, called cytokines, are the hallmarks of inflammation in the spinal cord.
Researchers have discovered that these inflammatory processes aren't entirely bad for the injured spinal cord. Although cytokines can be toxic to nerve cells because they stimulate the production of free radicals, nitric oxide, and other inflammatory substances that cause cell death, they also stimulate the production of neurotrophic factors, which are beneficial to cell repair.
Currently researchers are looking for ways to control these immune system cells and the molecules they produce by encouraging their potential for neuroprotection and reining in their neurotoxic effects. One approach being tested clinically is to exploit the ability of the PNS to mount a healing response in macrophages by injecting macrophages already stimulated by injured peripheral nerves into injured spinal cords. Recent experiments have indicated that selectively boosting the T-cell response to spinal cord injury could reduce secondary damage. Because of the possibility that these cells can also damage tissue, they must be very carefully controlled if they are to be used therapeutically.
Clinical investigators are also looking at how cooling the body protects surviving spinal cord tissue and nerve cells. Experiments have shown that cooling the body to a state of mild hypothermia (about 92° F) for several hours immediately following the injury limits damage and promotes functional recovery. Researchers aren't yet sure why mild hypothermia is neuroprotective, but the ability of body temperature to affect many different kinds of physiological mechanisms may be one of the reasons.
Days to weeks after the initial injury, apoptosis sweeps through oligodendrocytes in damaged and nearby tissue, causing the cells to self-destruct. Although genes have been identified that appear to regulate apoptosis, researchers still don't know enough to be able to specify the exact biochemical events that cause a cell to switch it on - or turn it off. Further studies are aimed at understanding these cellular mechanisms more fully. These studies will provide an opportunity to develop neural protective strategies to combat apoptotic cell death.
By understanding the process of apoptosis, researchers have been able to develop and test apoptosis-inhibiting drugs. In rodent models, animals given a drug that blocks a known apoptotic mechanism retained more ambulatory ability after traumatic spinal cord injury than did untreated animals.
Once the secondary wave of damage ends, the spinal cord is left with areas of scar tissue and fluid-filled gaps, or cysts, that axons can't penetrate or bridge. Unless these areas are reconnected by functioning nerve cells, the spinal cord remains disabled. Discovering how to bridge the gap between functioning axons and figuring out how to encourage axons to grow and make new connections could be the key to spinal cord repair.
Researchers are experimenting with cell grafts transplanted into the injured spinal cord that act as bridges across injured areas to reconnect cut axons, or that supply nerve cells to act as relays. Several types of cells have been studied for their potential to promote regeneration and repair, including Schwann cells, olfactory ensheathing glia, fetal spinal cord cells, and embryonic stem cells. In one group of experiments, investigators have implanted tubes packed with Schwann cells into the damaged spinal cords of rodents and observed axons growing into the tubes.
One of the limitations of cell transplants, however, is that the growth environment within the transplant is so favorable that most axons don't leave and extend into the spinal cord. By using olfactory ensheathing glia cells, which are natural migrators in the PNS, researchers have gotten axons to extend out of the initial transplant region and into the spinal cord. But it remains to be seen whether or not regenerated axons are fully functional.
Fetal spinal cord tissue implants have also yielded success in animal trials, giving rise to new neurons, which, when stimulated by growth-promoting factors (neurotrophins), extend axons that stretch up and down several segments in the spinal cord. Animals treated in these trials have regained some function in their limbs. Some patients with long-term spinal cord injuries have received fetal tissue transplants but the results have been inconclusive. In animal models, these transplants appear to be more effective in the immature spinal cord than in the adult spinal cord.
Stem cells are capable of dividing and yielding almost all the cell types of the body, including those of the spinal cord. Their potential to treat spinal cord injury is being investigated eagerly, but there are many things about stem cells that researchers still need to understand. For example, researchers know there are many different kinds of chemical signals that tell a stem cell what to do. Some of these are internal to the stem cell, but many others are external - within the cellular environment - and will have to be recreated in the transplant region to encourage proper growth and differentiation. Because of the complexities involved in stem cell treatment, researchers expect these kinds of therapies to be possible only after much more research is done.
Researchers are also looking at ways to compensate for axons that, having lost their myelin sheaths, have a decreased ability to conduct the electrical impulses essential for axonal communication. Preliminary studies with compounds known as potassium channel blockers, which block the flow of ions through the demyelinated membrane and increase the potential for messages to get through, have shown some success, but mostly in terms of reducing spasticity in muscles. Further studies might show how remyelinating axons could also improve function.
Stimulating regrowth of axons
Stimulating the regeneration of axons is a key component of spinal cord repair because every axon in the injured spinal cord that can be reconnected increases the chances for recovery of function.
Research on many fronts reveals that getting axons to grow after injury is a complicated task. CNS neurons have the capacity to regenerate, but the environment in the adult spinal cord does not encourage growth. Not only does it lack the growth-promoting molecules that are present in the developing CNS, it also contains substances that actively inhibit axon extension. For axon regeneration to be successful, the environment has to be changed to turn off the inhibitors and turn on the promoters.
Investigators are looking for ways to take advantage of the chemicals that drive or halt axon growth: growth-promoting and growth-inhibiting substances, neurotrophic factors, and guidance molecules.
In the developing CNS, thread-like axons grow and lengthen behind the axonal growth cone, an active tip only a few thousandths of a millimeter in diameter, which interacts with chemical signals that encourage growth and direct movement. But the environment of the adult CNS is hostile to axon growth, primarily because growth-inhibiting proteins are embedded in myelin, the insulating material around axons. These proteins appear to preserve neural circuits in the healthy spinal cord and keep intact axons from growing inappropriately. But when the spinal cord is injured, these proteins prevent regeneration.
At least three growth-inhibitory proteins operating within the axonal tract have been identified. The task of researchers is to understand how these inhibitory proteins do their job, and then discover ways to remove or block them, or change how the growth cone responds to them.
Growth-inhibiting proteins also block the glial scar near the injury site. To get past, an axon has to advance between the tangles of long, branching molecules that form the extracellular matrix. A recent experiment successfully used a bacterial enzyme to clear away this underbrush so that axons could grow.
A treatment that combines both these approaches - turning off growth-inhibiting proteins and using enzymes to clear the way - could create an encouraging environment for axon regeneration. But before trials of such a treatment can be attempted in patients, researchers must be sure that it could be controlled well enough to prevent dangerous miswiring of regenerating axons.
Neurotrophic factors (or neurotrophins) are key nervous system regulatory proteins that prime cells to produce the molecular machinery necessary for growth. Some prevent oligodendrocyte death, others promote axon regrowth and survival, and still others serve multiple functions. Unfortunately, the natural production of neurotrophins in the spinal cord falls instead of rises during the weeks after injury. Researchers have tested whether artificially raising the levels post-injury can enhance regeneration. Some of these investigations have been successful. Infusion pumps and gene therapy techniques have been used to deliver growth factors to injured neurons, but they appear to encourage sprouting more than they stimulate regeneration for long distances.
Axonal growth isn't enough for functional recovery. Axons have to make the proper connections and re-establish functioning synapses. Guidance molecules, proteins that rest on or are released from the surfaces of neurons or glia, act as chemical road signs, beckoning axons to grow in some directions and repelling growth in others.
Supplying a particular combination of guidance molecules or administering compounds that induce surviving cells to produce or use guidance molecules might encourage regeneration. But at the moment, researchers don't understand enough about guidance molecules to know which to supply and when.
Researchers hope that combining these strategies to encourage growth, clear away debris, and target axon connections could reconnect the spinal cord. Of course, all these therapies would have to be provided in the right amounts, in the right places, and at the right times. As researchers learn more and understand more about the intricacies of axon growth and regeneration, combining therapies could become a powerful treatment for spinal cord injury.
Discoveries in Clinical Research
Advances in basic research are also being matched by progress in clinical research, especially in understanding the kinds of physical rehabilitation that work best to restore function. Some of the more promising rehabilitation techniques are helping spinal cord injury patients become more mobile.
Restoring function through neural prostheses and computer interfaces
While basic scientists strive to develop strategies to restore neurological connections between the brain and body of spinal cord injured persons, bioengineers are working to restore functional connections via advanced computer modeling systems and neural prostheses. Discovering ways to integrate devices that could mobilize paralyzed limbs requires a unique interface between electronics technology and neurobiology. A functional electrical stimulation (FES) system is one example of this kind of innovative research.
FES systems use electrical stimulators to control muscles of the legs and arms to encourage functional walking and to stimulate reaching and gripping. Electrodes are taped to the skin over nerves or surgically implanted and then controlled by a computer system under the command of the user. For example, to assist reaching, electrodes can be placed in the shoulder and upper arm and controlled by movements of the opposite shoulder. Through a computer interface, the spinal cord injured person can then trigger hand and arm movements in one arm by shrugging the opposite shoulder.
These systems are useful not just for restoring functional movements. They also help people exercise paralyzed muscle systems, which can provide significant cardiovascular benefits. So far, relatively few people utilize them because the movements are so robotic, they require extensive surgery and electrode placement, and the computer interface systems are still limited. Bioengineers are working to develop more natural interfaces.
Because the brain plans voluntary movements several seconds before the command is sent out to the muscles, people whose spinal cords no longer carry signals to their limbs might still be able to complete the planning phase in their brains but use a robotic device to carry out the command. A recent experiment used microwires implanted in the motor cortex area of the brain (in this case a monkey's brain) to record brain-wave activity, which was then relayed to a computer that analyzed the data, predicted the movement, and sent the command to a robotic arm. A device such as this could be used to control a wheelchair, a prosthetic limb, or even a patient's own arms and legs.
In the future, researchers expect that these kinds of brain-machine interfaces could be planted directly into the brain using microchips that would do the processing and transmit the results without wires. Work is already being done with hybrid neural interfaces, implantable electronic devices with a biological component that encourages cells to integrate into the host nervous system.
Retraining central pattern generators
Scientists have known for years that animals' spinal cords contain networks of neurons called central pattern generators (CPG) that produce rhythmic flexing and extension of the muscles used in walking. They assumed, however, that the bipedal walking of humans was more dependent on voluntary control than on CPG activation. Therefore, scientists thought that without control from the brain, movements produced by a spinal CPG weren't likely to be useful in restoring successful walking without regulation from the brain. Current research is showing, however, that these networks can be retrained after spinal cord injury to restore limited mobility to the legs.
Using a technique called sensory patterned feedback, researchers are attempting to retrain CPG networks in spinal cord injured patients with special programs that break down walking movements into their component patterns and force paralyzed limbs to repeat them over and over again. In one of these programs, the patient is partially supported by a harness above a moving treadmill while a therapist moves the patient's legs in a stepping motion. Other researchers are experimenting with combining body weight support and electrical stimulation with actual walking rather than treadmill training.
Another technique uses an FES bicycle in which electrodes are attached to hamstrings, quadriceps, and gluteal muscles to stimulate the pedaling motion. Several studies have shown that these exercises can improve gait and balance, and increase walking speed. NINDS is currently funding a clinical trial with paraplegic and quadriplegic subjects to test the benefits of partial weight-supported walking.
Relieving pressure through surgery
The timing of surgical decompression (alleviating pressure on the spinal cord from fractured or dislocated vertebrae or disks) is a controversial topic. Animal studies have shown that early decompression can reduce secondary damage, but similar results haven't been reliably reproduced in human trials. Other studies have shown neurological improvement without decompression surgery, which has led some to believe that either avoiding or delaying surgery, and using pharmacologic interventions instead, is a reasonable (and non-invasive) treatment for spinal cord injuries. Additional research is needed to determine if early surgical intervention is sufficiently beneficial to offset the risk of major surgery in acute trauma.
Two thirds of people with spinal cord injury report pain and a third of those rate their pain as severe. Nonetheless, both diagnosis and treatment of post-injury pain still remain a clinical challenge. There is no universally recognized scheme for classifying pain from spinal cord injury, nor is there a uniformly successful medical or surgical treatment to prevent or reduce it. The mainstays of neuropathic pain treatment are antidepressants and anticonvulsants, even though they are not uniformly effective.
Research suggests that spinal cord pain syndromes stem from the spread of secondary damage to spinal cord segments above and below the injury site. Pain can be at the level of the injury or below the level of the injury, even in areas where sensation is limited or absent. Findings indicate that at-level (junctional) pain probably results from damage to grey and white matter one or more segments above the injury site, whereas pain below the injury results from the interruption of axon pathways and the formation of abnormal connections within the spinal cord near the site of injury.
Studies suggest that functional changes in neurons, which make them hyperexcitable, could be a cause of chronic pain syndromes. Consequently, giving more aggressive treatment for spinal cord injury in the first few hours after injury could limit secondary damage and prevent or reduce the development of chronic pain afterwards.
Investigators are currently testing neuroprotective and anti-inflammatory strategies to calm overexcited neurons. Other studies are also looking at pharmacological options, including sodium channel blockers (such as lidocaine and mexiletine), opioids (such as alfentanil and ketamine), and a combination of morphine andclonidine. Drugs that interfere with neurotransmitters involved in pain syndromes, such as glutamate, are also being investigated. Other researchers are exploring the use of genetically engineered cells to deliver pain-relieving neurotransmitters. These treatments appear to alleviate pain in animal models and in preliminary clinical studies with terminally ill cancer patients.
The mechanisms of muscle spasticity after spinal cord injury are not well understood. Recent studies indicate that the loss of particular descending axonal pathways most likely results in the decreased activity of inhibitory interneurons, which causes the overreaction of motor neurons to excitatory stimuli.
Unlike treatments for post-injury pain, medical and surgical treatments for spasticity are established and highly successful. These include oral medications that act within the central nervous system (baclofen and diazepam) and one that acts directly on skeletal muscle (dantrolene). For spasticity that is resistant to drug interventions, surgical rhizotomy or myelotomy is sometimes performed to sever reflex pathways.
Investigators are currently exploring neuromodulation procedures based on preliminary results showing that electrical spinal cord stimulation below the injury can modulate spasms. Other techniques used clinically and experimentally involve implanting pump systems that continuously supply antispasmodic drugs such as baclofen.
Improving bladder control
A promising area of research on treatments for bladder dysfunction involves using electrical stimulation and neuromodulation to achieve bladder control. The current treatment for reflex incontinence includes a surgical procedure that cuts the sacral sensory nerve roots from S2 to S4. With the hope that a cure for spinal cord injury could be imminent, and the reluctance among men to lose any of their already compromised sexual function, few patients are willing to have these nerves cut.
Development of a sacral posterior and anterior root stimulator implant is being explored to better coordinate bladder and sphincter contractions. In preliminary studies people were able to achieve suppression of reflex incontinence and clinically useful increases in bladder volume with the use of the implanted stimulator.
Researchers hope that by combining neuromodulation for reflex incontinence with neurostimulation for bladder emptying, the bladder could be completely controlled without having to cut any sacral sensory nerves.
Understanding changes in sexual and reproductive function
Sperm count in men may or may not change due to spinal cord injury, but sperm motility often does. Researchers are investigating whether or not spinal cord injury causes changes in the chemical composition of semen that make it hostile to sperm viability. Preliminary studies show that the semen of men with spinal cord injury contains abnormally high levels of immunologically active leukocytes, which appear to have a negative impact on sperm motility.
Recent animal studies have revealed what appears to be a neural circuit within the spinal cord that is critical for triggering ejaculation in animal models and may play the same role in humans. Triggering ejaculation by stimulating these cells might be a better option than some of the current, more invasive methods, such as electroejaculation.