On Assignment for Mayo's Clinic's Discovery's Edge magazine, reposted with permission.
Summary: Spinal cord injuries, like the one that actor Christopher Reeve endured, are the focus of two dedicated researchers at Mayo Clinic. Rather than asking how they can make a severely injured patient walk again, this accomplished scientist and practicing anesthesiologist are collaborating in the laboratory to understand how to restore breathing function to patients who would otherwise be tethered to mechanical ventilators for life. Using an animal model of spinal cord injury (SCI), they are the first researchers to show enhancement of spontaneous recovery of breathing by infusing neurotrophins into the spinal cord; a novel therapy that could translate to newfound independence for thousands of SCI patients.
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Breathing After Spinal Cord Injury
Strengthening Remaining Connections to the Spinal Cord
By Nikolas Charles
February 2009
Breathing. It’s something that most of us take for granted. It happens so easily and so naturally. The rhythmic movement that sends oxygen into our bloodstream—it is the rhythm of life. However, for more than 5,000 new cervical SCI patients each year, the precious gift of breath is made possible only with the aid of a mechanical ventilator since descending connections are disrupted between the brain areas that generate and transmit the rhythmic signal to breathe and motor neurons in spinal cord that cause the diaphragm muscle to contract and pump air into the lung. Yet, there is hope since most SCI do not completely sever the spinal cord. Some of the descending connections are spared but their input is insufficient to drive activity in the motor neurons. Strengthening these spared connections is possible and with it there may be recovery of breathing.
At Mayo Clinic, Gary C. Sieck, Ph.D. and Carlos B. Mantilla, M.D., Ph.D., are working together to improve the efficacy of spared connections between the brain and spinal cord. This area of research is called neuroplasticity, which means the brain’s natural ability to strengthen synapses in order to adapt or in this case compensate for injury.
“In most patients with cervical SCI, the communication between the respiratory pattern generator in the brain and the spinal cord motor neurons that effect diaphragm contraction is not completely disrupted,” says Dr. Sieck. “Our research is focused on strengthening those connections that remain. If these remaining connections can take over the work of those that were lost, rhythmic activation of the diaphragm muscle may be restored, which means patients on mechanical ventilators could learn to breathe on their own.”
Neuroplasticity and functional recovery of breathing
All muscles are controlled the same way. They have a motor neuron, which makes the muscles move by making contact with a group of muscle fibers. Collectively those muscle fibers are called motor units. Every time a motor neuron becomes active, it activates a group of muscle fibers. This is how the nervous system controls muscles. For almost 30 years, Dr. Sieck has studied the neural control of the diaphragm muscle, the most important muscle involved in breathing. His studies (more than 150 published papers) have characterized the basic elements of neural control called motor units. “Since the time of Charles Sherrington, it has been known that motor units are the building blocks for neural control of muscles. A motor unit is a single motor neuron in the spinal cord and the group of muscle fibers it innervates. In the diaphragm muscle, like other skeletal muscles, motor units range in their mechanical properties. There are slow twitch motor units that are very fatigue resistant and are ideally suited to accomplish breathing. There are also fast twitch motor units that are more fatigable and thus more appropriate for shorter duration activation of the diaphragm as occurs during sneezing and coughing. The nervous system recruits these motor units to accomplish a range of motor behaviors.”
Control of the breathing muscles starts with the generation of a respiratory rhythm. This occurs in the brain stem and is communicated down to the spinal cord where it activates phrenic motor neurons. These are the neurons that activate the diaphragm muscle. In upper cervical SCI, the connections between the brain stem and spinal cord are disrupted causing phrenic motor neurons to become inactive and the diaphragm muscle is paralyzed.
But after SCI, some descending connections from the brain stem may be spared even though they are insufficient to activate phrenic motor neurons. Drs. Sieck and Mantilla want to be able to strengthen these spared connections called synapses. A synapse is a connection between a neuron and its target cell. Strengthening synaptic connections in the brain is very common; it is called neuroplasticity and this process forms the basis for memory and learning. “Over the past 20-30 years, we have learned a considerable amount about the molecular basis for neuroplasticity and how synapses can be strengthened to promote better neurotransmission of signals between neurons. If synapses between the brain stem and phrenic motor neurons can be strengthened, this could promote functional recovery of breathing in SCI patients.”
Brain derived neurotrophic factor
Basic research on neuroplasticity and functional improvement in brain areas responsible for memory learning has implicated a class of growth promoting compounds called neurotrophins that are naturally in the body. Neurotrophins are chemicals that can be released either by neurons or surrounding cells (such as glial cells) in response to normal stimuli or injury. Although neurotrophins exist naturally within the nervous system, they can also be added artificially as drugs.
“In our studies, we’ve shown that we can strengthen neuromuscular synapses by exogenous treatment with neurotrophins,” says Dr. Sieck. “These substances include brain derived neurotrophic factor (BDNF) and neurotrophin 4 (NT-4), both of which act on a common TrkB receptor, which stands for tropomyosin related kinase.”
“Our studies have shown that the TrkB receptor is present in phrenic motor neurons and that its expression changes in response to SCI. This is important because these neurotrophins and their TrkB receptor are implicated in neuroplasticity and strengthening synaptic transmission.”
In order to see if neurotrophins are effective in strengthening spared neural connections after SCI and thereby restoring breathing function, Drs. Sieck and Mantilla conducted animal studies in which a catheter was inserted into the space surrounding the spinal cord. This allowed controlled infusion of neurotrophins and other compounds that affect TrkB activation.
“We do similar procedures during spinal blocks in anesthesiology,” says Dr. Mantilla. “Both anesthesiologists and pain medicine specialists, routinely perform these procedures during surgery and in patients with chronic pain. We thread a catheter into the intrathecal space in order to infuse drugs. In the operating room we infuse anesthetics that cause the patient to become numb so surgery can be performed. In patients with chronic pain, we infuse substances that can provide pain relief while minimizing side effects. In our animal studies, we infused BDNF and NT4 into the cervical spinal cord after SCI. We found that BDNF and NT4 treatment markedly enhanced recovery of rhythmic phrenic nerve and diaphragm muscle activity after SCI. Conversely, if we blocked TrkB receptors at phrenic motor neurons, using pharmaceuticals, a blocking antibody or a silencing RNA to reduce TrkB receptor expression in phrenic motor neurons, we found that spontaneous recovery of breathing after SCI was significantly delayed or completely blocked.”
“To date, no one has used this method to promote functional recovery of breathing after cervical SCI,” says Dr. Sieck. “Our study is the first to show that neurotrophins can enhance functional recovery of breathing. So, we’re not going to make SCI patients walk again, but if you ask these patients the one thing they would like to have back in their life—it would be the freedom to breathe on their own.”
But neurotrophin treatment may have significant side effects, most notably increased pain. “Although we are very excited about our results so far, we recognize that intrathecal neurotrophin treatment is not the final answer,” says Dr. Mantilla. “More recently we’ve explored whether we can enhance TrkB receptor expression in phrenic motor neurons using gene therapy. Such an approach would enhance neurotrophin signaling in phrenic motor neurons while avoiding the negative side effects.”
“Our evidence so far clearly indicates that the neurotrophins and signaling through the TrkB receptor may be involved in promoting functional recovery of breathing in SCI patients,” says Dr. Sieck. “For us, that’s very exciting because it presents a therapeutic strategy that might be important in the future.”