Scientists continue to investigate new ways to better understand and treat spinal cord injuries.
Much of this research is supported by the National Institute of Neurological Disorders and Stroke (NINDS), a part of the National Institutes of Health (NIH). Other NIH components, as well as the Department of Veterans Affairs, other Federal agencies, research institutions, and voluntary health organizations, also fund and conduct basic to clinical research related to improvement of function in paralyzed individuals.
Many hospitals have developed specialized centers for spinal cord injury care. Many of these bring together spinal cord injury researchers from a variety of disciplines for partnerships regarding basic and clinical research, clinical care, and knowledge translation.
Current research is focused on advancing our understanding of four key principles of spinal cord repair:
- Neuroprotection—protecting surviving nerve cells from further damage
- Regeneration—stimulating the regrowth of axons and targeting their connections appropriately
- Cell replacement—replacing damaged nerve or glial cells
- Retraining CNS circuits and plasticity 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 stages of the injury.
Strategies involving neuroprotection are aimed at preventing cell death, limiting or reducing inflammation, and stopping over-excitability of certain cells and their functions. Investigators are looking at ways to reduce inflammation within or near the injured spinal cord, which can restrict blood flow, affect nerve signal transmission, and increase cell death. One approach is using steroid drugs to reduce nerve cell damage and suppress activities of immune cells. One clinical trial identified slight improvement in motor function among some individuals who were given a steroid within 8 hours after injury. However, other trials showed the drug’s modest benefit did not outweigh serious side effects. Steroid therapy has not been approved by the U.S. Food and Drug Administration (FDA) for the treatment of acute spinal cord injury.
Antibiotics, which can cross the protective blood-brain barrier, have been shown to improve motor function, restoration, decrease lesion size, and reduce cell death in animal models of SCI.
The kidney hormone erythropoietin promotes the growth of new red blood cells and increases oxygen levels in the blood. Studies in animal models have shown that erythropoietin can reduce inflammation in the brain, improve blood flow to the brain, and reduce nerve cell death following brain injury. It also aids in the recovery of motor function. However, other trials in animal models show conflicting results regarding the drug’s usefulness in preventing inflammation and cell death. Researchers continue to study the drug in preclinical models.
Therapeutic hypothermia (controlled lowering of the body’s core temperature) can protect cells from damage following cardiac arrest, stroke, and traumatic brain injury. Therapeutic hypothermia has been shown to reduce the swelling and inflammation that presses on the spinal cord following injury in animal models and in small, limited human studies. It also can reduce damage to susceptible neurons following the primary injury, reduce damage to spinal cord microvasculature, and improve functional outcome. Researchers are studying the safety and effectiveness of different durations of hypothermia following spinal cord injury.
Researchers are trying to manipulate macrophages—a type of white blood cell that travels to the injury site during the inflammatory response—to promote nerve cell growth without causing further tissue damage. Following a spinal cord injury, macrophages at the site of injury begin to remove cellular debris and receive signals that help them promote the growth of axons. But, within a few days post-injury, the collection of macrophages increases inflammation, scarring, and toxicity, which can worsen the damage. Scientists hope to learn how to signal macrophages to continue their restorative function while turning off their damaging consequences.
The buildup of sodium and glutamate in cells following a spinal cord injury can lead to cell damage and impaired or blocked cell signaling. The drug riluzole, which slows the progression of the disease amyotrophic lateral sclerosis, has shown in animal models to improve motor function and reduce cell death loss caused by decreased blood flow following spinal cord injury. The experimental drug HP 184 blocks the entry of sodium into cells (which can impair nerve function) and may enhance cell signaling in surviving axons that have had their protective myelin cover either destroyed or damaged following spinal cord injury. Other scientists are examining drugs that target glutamate, whose release is greatly increased following a spinal injury. Excess glutamate leads to cell death and blocked transmission of signals across nerve synapses. Researchers are studying different drugs that may reduce glutamate binding among cells following spinal cord injury, which could reduce secondary cell death, improve motor function outcome, and reduce long-term hypersensitive pain post-injury.
Neurons have a limited capacity to regenerate. As nerve cells are either damaged or destroyed by injury, and as others die naturally during development, the number of chemical interactions between adjacent nerve cells (synapses)decreases. Nerve cells can die when they do not make enough synapses, leaving large numbers of supporting glial cells in the area of damage. Glial cells are thought to support tissue after injury to the spinal cord but also inhibit the growth of axons.
Approaches to repairing damaged axons through remyelination and new growth include:
Some anti-inflammatory drugs have been shown to encourage axonal regeneration by stimulating CNS nerve axons to grow and by inhibiting amino acid toxicity and cell death that occurs after the initial injury. Two such nonsteroidal anti-inflammatory drugs are ibuprofen and indomethacin. The drug rolipram was shown to encourage axonal regeneration in an animal model of spinal cord injury. Preclinical studies are examining the effectiveness of rolipram in combination with other drugs given at different delivery times post-injury.
Antibodies are proteins made by immune cells and are designed to attach themselves to specific foreign proteins (called antigens) and disable them. Therapeutically, antibodies can be made that target specific proteins that inhibit repair of the body after injury. Monoclonal antibodies, produced in a laboratory, may promote nerve fiber regeneration by blocking proteins in the myelin debris that inhibit regeneration after spinal cord injury. Scientists are testing monoclonal antibodies at the site of the spinal cord injury in animal models in an attempt to block anti-regeneration activity of cells in the damaged central nervous system and improve nerve function and recovery. For example, researchers are using a Nogo-A monoclonal antibody to block proteins that inhibit the sprouting and regeneration of axons following a spinal injury. Other antibodies, called anti-MAG (myelin associated glycoproteins), are designed to counteract protein-sugar molecules on myelin-forming debris at the site of injury.
A number of other targets are being tested to overcome inhibition to regeneration. Cethrin, a recombinant protein that blocks activation of rho (a protein that inhibits axon regeneration), has been tested clinically. A drug that targets Nogo-receptors is being developed to promote regeneration after spinal cord injury and stroke. Recent animal studies showing that inhibition of the tumor-suppressing gene PTEN can promote growth of upper motor neurons has led to active research into strategies to promote regeneration after spinal cord and optic nerve injuries. Finally, the histone deacetylases (HDAC) are a class of compounds that are involved in the regulation of gene expression and negatively affect cell structure following a traumatic spinal cord injury. Preclinical studies are examining ways to inhibit HDAC activity as a way to protect and allow axons to overcome inhibition in regions of a spinal injury.
To get past the glial scar that forms after a spinal cord injury and be able to transmit signals from the cell body, an axon has to advance between the tangles of long, branching molecules made up of inhibitory proteins and sugars that surround the cells. Experiments have successfully used a bacterial enzyme, chondroitinase ABC, to clear away the tangles so that axons could grow in animal models of injury. Researchers are looking at ways to combine chondroitinase ABC with other treatments, such as cell transplants, to increase functional recovery.
Other researchers are using a tissue-engineered highway-like matrix that is implanted onto the spinal cord to help axons “bridge” the lesion that forms at the injury site and to rebuild neural circuits. They also will look at using the matrix as a way of delivering growth factors that can promote nerve cell survival and inhibit proteins associated with the glial scar.
Controversy exists over potential benefits and possible harmful consequences of cell replacement and cell transplants. The potential of several cell types, including stem cells and glial cells, 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. Preclinical research results are limited but show cell transplants can regenerate neuronal growth and create new connections between neurons.
Scientists are experimenting with a variety of cells for effectiveness and safety in increasing connectivity and restoring function following a spinal cord injury:
- Human oligodendrocyte progenitor cells have been shown to reduce secondary damage following a spinal cord injury and promote functional recovery and remyelination. Researchers are expanding trials to better determine optimal cell delivery windows and evaluate potential risks of transplants, such as the formation of tumors and inflammatory reactions.
- Schwann cells surround and insulate peripheral nerves, and often grow into the spinal cord after injury. Schwann cells that have been transplanted at the site of the spinal cord injury can produce growth factors and reinsulate damaged nerve axons. They are not stem cells in that their fate as Schwann cells is determined before transplantation. Schwann cells can be taken from the individual’s own body, which reduces the need for immune-suppressing drugs and the risk of tumor formation, but this requires several weeks after injury before grafting can be done. Preclinical studies are examining their potential in safely treating both acute and chronic spinal cord injury.
- Bone marrow stromal cells, taken from the tissue found inside bones, have been shown in some studies to increase recovery from an injury to the spinal cord. Scientists are studying the injection of these cells into the cerebrospinal fluid (fluid that bathes the brain and spinal cord) to promote proteins needed to grow and maintain nerves and increase nerve signaling across the glial scarring that forms post-injury.
- Nasal olfactory ensheathing cells, taken from the lining of the nose, are special types of glial cells that have been shown to promote axon regeneration and remyelination at the injury site. The transplanted cells have been shown to permit regrowth of axons in both the peripheral and central nervous systems, and improve functional outcome in animal models of spinal cord injury. Early-stage trials in humans are being conducted overseas.
Retraining CNS circuits and plasticity
Recovery from a spinal cord injury may occur for quite some time after the initial injury, as part of the brain’s ability to reorganize or form new nerve connections and pathways following injury or cell death (called neuroplasticity).
Active rehabilitation and exercise
Specific training can improve function, coordination of fine muscle movements, and overall strength and health. Scientists are comparing the relative effectiveness of an intensive task-specific motor training program added to standard rehabilitation compared with standard rehabilitation alone for improving hand function and clinical outcomes in people with recent tetraplegia.
Much as in the general population, cardiovascular disease (CVD) is a leading cause of death in persons with spinal cord injury. After the injury, the opportunity to actively exercise large muscles affected by paralysis is limited or may require assistive technologies. Researchers have recently shown that such injuries increase the risk of CVD, along with other muscle atrophy and effects of deconditioning. Since CVD occurs earlier in life for those with a spinal cord injury, researchers are assessing the impact of acute exercise, conditioning, and dietary supplementation on measures of fitness, function, and CVD risk factors/modifiers in individuals with tetraplegia. Other scientists are examining an add-on group exercise program to the usual physical therapy delivered in the hospital to see if it improves the participant’s overall outlook on exercise and recovery, and to promote physical activity as part of a healthy lifestyle.
In May 2011, scientists funded in part by the National Institutes of Health reported that after intensive physical therapy and electrical stimulation to the spine, a man with a paralyzing spinal cord injury from the chest down had recovered the ability to stand and move paralyzed muscles at will when the stimulator is active. The man participated in a pilot study that combined epidermal stimulation and locomotor training—involving his being suspended for hours a day in a harness, walking on a treadmill while physical therapists moved his legs in stepping motions. Two years of locomotor training following his injury did not improve his ability to walk or stand. But he did improve after December 2009, when electrodes were surgically implanted over the paralyzed area of his spinal cord and began sending rhythmic electrical bursts to neurons in the spinal cord during the locomotor training sessions. This epidural simulation imitates the brain’s sending signals to the spinal cord to begin movement. He gradually became able to stand and fully bear his own weight for a few minutes at a time. Although he can’t walk without assistance, he can bend one leg at the knee and flex his ankle when the stimulator is active. Locomotor training without any epidural stimulation is routinely used as a rehabilitative technique for people with spinal cord injuries—which allows some individuals to retain the ability to move and feel below the injury. Meanwhile, a form of epidural stimulation is used to relieve pain for some individuals. The researchers and NIH scientists caution that this finding was in only one person, and further study is required to confirm these early, promising results and to understand exactly how the stimulation is working.
Functional Electric Stimulation
Exciting and promising results in restoring or assisting function in individuals with chronic spinal cord injury have been shown in studies using functional electric stimulation (FES). FES devices use a computer system and electrodes to deliver small bursts of a low-level electrical current to paralyzed muscles, to generate muscle contractions. Researchers are working to improve the electrode and computer interfaces so they can produce more natural yet complex movements. FES is being used to restore breathing without a ventilator, cough unassisted, enhance bladder and bowel control, increase hand movement and grasping, and improve blood flow to the skin.
Several studies continue to investigate the use of FES in restoring or improving function following a spinal cord injury. Researchers are using FES to help individuals with tetraplegia move paralyzed muscles to restore voluntary grasping function. Others are attempting to stimulate recovery with the goal of being able to grasp objects without stimulation once the treatment program is completed. This approach has been shown to be useful for people who have had a stroke.
A NINDS-supported clinical trial demonstrated that FES of the diaphragm and intercostal muscles (muscles between adjacent ribs that help move the chest wall) can produce effective cough in persons with high tetraplegia. The ability to cough at will eliminates the need for assistance in suctioning secretions and reduces the risk of lung disease. These researchers are now working to improve electrode design to allow for a less invasive surgical implantation.
One study is using a surgically implanted FES to facilitate exercise, standing, stepping, and/or balance in people with various degrees of paralysis. A related study is using a surgically implanted FES to facilitate stability of the trunk and hips, and to evaluate how stabilizing and stiffening the trunk can change the way spinal cord injured volunteers sit, breathe, reach, push a wheelchair, or roll in bed.
Transcranial Direct Current Stimulation (tDCS) is another form of electric stimulation that is being tested experimentally to improve patient outcomes after a spinal cord injury. tDCS is a noninvasive procedure that delivers continuous low electrical current to areas of the brain involved with movement via small electrodes placed on the scalp. Researchers are investigating if combining tDCS with exercise therapy for the affected hand will increase performance over exercise therapy alone. Other researchers hope to determine if tDCS can decrease chronic pain in people with spinal cord injury.
Most recovery following SCI takes place within six months after injury. Substantial recovery after 12 months is unusual, but researchers continue to test ways to restore function in persons with chronic paralysis. In one very small study involving patients one year after injury, scientists are testing the safety and efficacy of a type of robotic therapy device known as the AMES device. The aim of this study is to investigate the use of assisted movement and enhanced sensation (AMES) technology in the rehabilitation of the legs of participants with incomplete spinal cord injury. The AMES device rotates the ankle over a range of 30 degrees while vibrators stimulate the tendons attached to muscles that move the leg. The subject’s task is to assist the motion of the device.
In another study, researchers will determine the effect of using body-weight supported treadmill training and a robotic gait trainer on functional movement from place to place (ambulation) in people with an incomplete spinal cord injury. The person is suspended in a harness and onto a treadmill, and the robotic legs are strapped to the person. A computer controls the pace of the walking. The effect of the therapy will be evaluated by analyzing changes in ambulation and gait patterns during walking.
Brain-computer interfaces (BCI)
The goal of brain-computer interface technology is to bypass the damaged nerve circuits in the spinal cord and establish a direct link between the brain and an assistive implanted device which may restore an individual’s control of voluntary muscle movement and coordination of paralyzed muscles.
Most individuals with tetraplegia have intact brain function but are unable to move due to injury or disease affecting the spinal cord. Brain-computer interface technology is based on the finding that with intact brain function, neural signals for movement are generated in the brain and can be used to control computer-assisted devices. By implanting electrodes in the brain, individuals can be trained to practice thoughts and thereby generate neural signals that are interpreted by a computer and translated to movement which can then be used to control a variety of devices or computer displays.
Researchers are working to develop BCI technology to offer individuals with upper limb paralysis a natural and rich control signal for prosthetic arms or FES device to re-animate paralyzed arms. The study uses electrocorticographic (ECoG) electrodes that interface with neurons in the brain’s cortex (the part of the brain that is responsible for higher thought and motor control) to measure brain activity. Participants will learn to control computer cursors, virtual reality environments, and assistive devices such as hand orthotics and FES devices using neural activity recorded with the ECoG sensor.
Another preliminary study is assessing the safety and effectiveness of a brain-computer interface to give people with tetraplegia the ability to control a computer cursor and other assistive devices with their thoughts. A small electrode array is inserted into the part of the brain’s surface that controls movements. Using the very precise signals this device records, researchers are working to improve the computer’s ability to interpret the person’s intent and transfer that to the display screen.