Posts tagged spinal cord injuries
Articles and news from the latest research reports.
New Device Allows Brain To Bypass Spinal Cord, Move Paralyzed Limbs
For the first time ever, a paralyzed man can move his fingers and hand with his own thoughts thanks to an innovative partnership between The Ohio State University Wexner Medical Center and Battelle.
Ian Burkhart, a 23-year-old quadriplegic from Dublin, Ohio, is the first patient to use Neurobridge, an electronic neural bypass for spinal cord injuries that reconnects the brain directly to muscles, allowing voluntary and functional control of a paralyzed limb. Burkhart is the first of a potential five participants in a clinical study.
“It’s much like a heart bypass, but instead of bypassing blood, we’re actually bypassing electrical signals,” said Chad Bouton, research leader at Battelle. “We’re taking those signals from the brain, going around the injury, and actually going directly to the muscles.”
The Neurobridge technology combines algorithms that learn and decode the user’s brain activity and a high-definition muscle stimulation sleeve that translates neural impulses from the brain and transmits new signals to the paralyzed limb. In this case, Ian’s brain signals bypass his injured spinal cord and move his hand, hence the name Neurobridge.
Burkhart, who was paralyzed four years ago during a diving accident, viewed the opportunity to participate in the six-month, FDA-approved clinical trial at Ohio State’s Wexner Medical Center as a chance to help others with spinal cord injuries.
“Initially, it piqued my interested because I like science, and it’s pretty interesting,” Burkhart said. “I’ve realized, ‘You know what? This is the way it is. You’re going to have to make the best out of it.’ You can sit and complain about it, but that’s not going to help you at all. So, you might as well work hard, do what you can and keep going on with life.”
This technology has been a long time in the making. Working on the internally-funded project for nearly a decade to develop the algorithms, software and stimulation sleeve, Battelle scientists first recorded neural impulses from an electrode array implanted in a paralyzed person’s brain. They used that data to illustrate the device’s effect on the patient and prove the concept.
Two years ago, Bouton and his team began collaborating with Ohio State neuroscience researchers and clinicians Dr. Ali Rezai and Dr. Jerry Mysiw to design the clinical trials and validate the feasibility of using the Neurobridge technology in patients.
During a three-hour surgery on April 22, Rezai implanted a chip smaller than a pea onto the motor cortex of Burkhart’s brain. The tiny chip interprets brain signals and sends them to a computer, which recodes and sends them to the high-definition electrode stimulation sleeve that stimulates the proper muscles to execute his desired movements. Within a tenth of a second, Burkhart’s thoughts are translated into action.
“The surgery required the precise implantation of the micro-chip sensor in the area of Ian’s brain that controls his arm and hand movements,” Rezai said.
He said this technology may one day help patients affected by various brain and spinal cord injuries such as strokes and traumatic brain injury.
Battelle also developed a non-invasive neurostimulation technology in the form of a wearable sleeve that allows for precise activation of small muscle segments in the arm to enable individual finger movement, along with software that forms a ‘virtual spinal cord’ to allow for coordination of dynamic hand and wrist movements.
The Ohio State and Battelle teams worked together to figure out the correct sequence of electrodes to stimulate to allow Burkhart to move his fingers and hand functionally. For example, Burkhart uses different brain signals and muscles to rotate his hand, make a fist or pinch his fingers together to grasp an object, Mysiw said. As part of the study, Burkhart worked for months using the electrode sleeve to stimulate his forearm to rebuild his atrophied muscles so they would be more responsive to the electric stimulation.
“I’ve been doing rehabilitation for a lot of years, and this is a tremendous stride forward in what we can offer these people,” said Mysiw, chair of the Department of Physical Medicine and Rehabilitation at Ohio State. “Now we’re examining human-machine interfaces and interactions, and how that type of technology can help.”
Burkhart is hopeful for his future.
“It’s definitely great for me to be as young as I am when I was injured because the advancements in science and technology are growing rapidly and they’re only going to continue to increase.”
Testing method promising for spinal cord injuries, multiple sclerosis
A medical test previously developed to measure a toxin found in tobacco smokers has been adapted to measure the same toxin in people suffering from spinal cord injuries and multiple sclerosis, offering a potential tool to reduce symptoms.
The toxin, called acrolein, is produced in the body after nerve cells are injured, triggering a cascade of biochemical events thought to worsen the injury’s severity. Acrolein (pronounced a-KRO-le-an) also may play an important role in multiple sclerosis and other conditions.
Because drugs already exist to reduce the concentration of acrolein in the body, being able to detect and measure it non-invasively represents a potential treatment advance, said Riyi Shi (pronounced Ree Shee), a professor of neuroscience and biomedical engineering in Purdue University’s Department of Basic Medical Sciences, School of Veterinary Medicine, Center for Paralysis Research and Weldon School of Biomedical Engineering.
"If the acrolein level is high it needs to be reduced, and we already have effective acrolein removers to do so," Shi said. "Reducing or removing acrolein may lessen the severity of symptoms in people who have nerve damage, but there has not been a practical way to monitor acrolein levels in nervous system trauma and diseases."
The toxin is present in tobacco smoke and air pollutants. A method had been developed previously to detect and measure acrolein in the urine of smokers, but it has not been used in people suffering from conditions in which the body produces acrolein internally.
"Based on this method, it was revealed that acrolein is significantly elevated in smokers and decreases following the cessation of cigarette smoke," Shi said. "However, such a method has not been widely used for conditions in which acrolein is elevated due to central nervous system damage or disease."
The researchers tested the method in laboratory animals.
"We wanted to see if higher levels of acrolein corresponds to greater severity of spinal cord injury, and the answer is yes," said Shi, who is working with Bruce Cooper, director of the Metabolite Profiling Facility in the Bindley Bioscience Center of Purdue’s Discovery Park. "This means reducing acrolein may help to control symptoms."
New findings are detailed in a research paper that recently appeared online in the Journal of Neurotrauma. The paper, which also will appear in an upcoming print edition of the journal, was authored by doctoral students Lingxing Zheng, Jonghyuck Park, Michael Walls and Melissa Tully; Amber Jannasch, laboratory manager of the Metabolite Profiling Facility; and Cooper and Shi.
The method does not detect acrolein directly but determines the presence of a byproduct, or metabolite, of acrolein in the urine. The metabolite is a chemical compound called N-acetyl-S-3-Hydroxypropylcysteine, or 3-HPMA.
"Acrolein is very volatile, so it doesn’t remain stable long enough to monitor, but one molecule of acrolein will make one molecule of 3-HPMA, which is very stable in urine," Shi said.
Laboratory rats were injected with different doses of acrolein, and findings showed that the detection technique is able to accurately measure these differences in acrolein concentration in the urine. The technique might one day be performed routinely in a doctor’s office.
"The non-invasive nature of measuring 3-HPMA concentrations in urine allows for long-term monitoring of acrolein in the same animal and ultimately in human clinical studies," Shi said.
Two drugs have been shown to be effective in reducing acrolein levels in the body: hydralazine and phenelzine, which have been approved by the U.S. Food and Drug Administration for hypertension and depression, respectively.
The testing method could be used in conjunction with other measures to test patients for the progress of spinal cord disease.
"Nervous system trauma and diseases are like many other illnesses: A disease-associated marker can be critical for making a diagnosis, a therapeutic selection and a treatment evaluation," Shi said. "Therefore, determination of acrolein levels gives you more assurance that you have an intense biochemical imbalance and biochemical damage and that you should use an acrolein scavenger as a treatment. We used different levels of hydralazine to see if it causes a dose-dependent reduction of 3-HPMA and found that, in fact, it did. This shows that this method is capable of monitoring the decrease of acrolein through treatment with acrolein-removing medications."
Acrolein damages mitochondria, which provide energy for cells, and in multiple sclerosis compromises the myelin sheath surrounding a nerve cell’s axon, preventing nerves from properly conducting electrical impulses. The toxin has a possible role in other diseases, including Alzheimer’s disease, cancer and atherosclerosis.
"Due to widespread involvement of acrolein in the body, the benefits of this study have the potential to significantly enhance human health," Shi said. "For example, there is evidence that heightened levels of acrolein could diminish an individual’s ability to recover fully from stroke and cancer."
In laboratory animals, hydralazine has been shown to delay onset of multiple sclerosis for several days, which could mean several years in humans. Tests with animals also suggests the drug could help to reduce the most severe symptoms once the disease has progressed.
Acrolein has been found to be elevated by about 60 percent in the spinal cord tissues of mice with a disease similar to multiple sclerosis. The toxin causes harm by reacting with the proteins and lipids that make up cells, including neurons.
Laura Wong has coaxed damaged nerve cells to grow and send messages to the brain again
“An ailment not to be treated,” read the prescription for a spinal cord injury on an Egyptian papyrus in 1,700 B.C. Not much has changed in the intervening millennia. Despite decades of research, modern medicine has made little headway in its quest to reverse damage to the central nervous system.
That is not to say, however, that there isn’t a glimmer of hope. Laura Wong, an M.D./Ph.D. student in Professor Eric Frank’s molecular physiology lab at the Sackler School, has been able to coax damaged nerve cells known as sensory neurons to regenerate, growing as much as 10 times longer than previously documented. What’s more, the new neurons make organized connections with their counterparts inside the spinal cord and brain stem, ensuring information from the outside world paints an accurate picture inside the brain.
“All the regeneration in the world isn’t going to make any difference if they don’t reconnect. You’re still not going to get any function,” says Wong, who has worked since 2010 in Frank’s lab, which is trying to develop therapies for spinal cord injuries.
Her findings, which she presented at the annual meeting of the Society for Neuroscience in 2011 and 2012, shed light on the complex processes behind nerve cell growth and regeneration. If those results can be replicated in patients, it could prevent certain types of nerve damage and improve quality of life for some.
Going the Distance
Unlike tissues such as skin and bone, the cells of the central nervous system in an adult are notoriously resistant to healing. Not only does the supply of natural growth stimulants decline as we age, but the body also produces chemicals that discourage nerve cells from regenerating. Worse, the scar tissue that starts to form immediately after a spinal cord injury also contains compounds that hinder nerve cell growth.
Researchers in Frank’s lab have been seeking ways to either stimulate growth or block the mechanisms that inhibit nerve cell growth—or both—since 2005. Wong’s predecessor in the lab, Pamela Harvey, a 2009 graduate of the Sackler School, tested a synthetic version of a nerve cell growth factor, called artemin, on crushed sensory neurons that relay information from the hands, arms and shoulders to the brain.
The damage mimics a common injury called Erb’s palsy, which can occur when a baby’s shoulder gets caught behind the mother’s pelvis during labor and delivery, creating undue strain on nerves in the newborn’s neck. Riders thrown head first off a motorcycle or snowmobile can suffer similar injuries.
“Anytime the shoulder goes one way and the head and neck go the other, that’s when you see these injuries,” Wong says.
In earlier experiments, Harvey and Frank found that treating with artemin did indeed stimulate the sensory nerve fibers to regenerate and grow back into the spinal cord over the course of about six weeks. In her follow-up experiments, Wong showed that artemin could induce those nerve fibers to grow the 3- to 4-centimeter distance from there up to the brainstem, where the brain and the spinal cord meet. That’s a little more than an inch—or roughly 10 times longer than any other researchers have been able to demonstrate with artemin or any other growth factor.
“A lot of other researchers just haven’t seen this length,” notes Wong, who saw the artemin-induced growth occur over a period of three to six months.
That’s important, because while axons only have to grow across microscopic distances in a developing embryo, they would have to bridge much wider gaps—depending on the site of the injury—to heal a neural injury in an adult, Wong says. Nerves that extend from the spine to the foot or toe can reach lengths of about 60 centimeters, she adds.
But Wong’s artemin-treated nerve fibers achieved more than unprecedented growth. They also reestablished connections with correct regions in the brain stem, just as Harvey had seen the nerve cells do in the spinal cord. That is, the axons essentially plugged themselves back in just as they were prior to the injury, and, like an old-fashioned telephone switchboard, they sent the right messages to the right parts of the brain.
That’s crucial because should the sensory nerves that relay pain signals become crossed, for example, it could result in a patient feeling phantom pain or the sensation of pain from something that shouldn’t cause discomfort at all.
“With some other growth-promoting compounds you get regeneration, but you see those axons growing kind of willy-nilly,” says Wong. “You can see where it would be just as detrimental to have things wired incorrectly as it would be to have things not wired at all.”
Just a Start
Artemin isn’t a panacea for spinal cord injuries, Wong and Frank stress. To work its cellular magic, the compound must be administered within a day or two, and the sooner the better. Also, artemin promotes growth only in sensory neurons—and so far, only in rats—which means such growth wouldn’t improve motor function for someone who had been paralyzed by a spinal cord injury, for example.
But if the findings, which Wong presented at the Society for Neuroscience meetings in 2011 and 2012, prove applicable to humans, restoring sensation alone could still improve quality of life, even for those living with paralysis. Giving these people the ability to sense heat, cold and pain could help them avoid other accidental injuries, says Frank.
Wong hopes her work with sensory neurons will help unlock the secrets to promoting regeneration of other, more obstinate types of neurons in the brainstem and spinal cord. While she demonstrated that the sensory nerves plugged themselves back into the spinal cord precisely where they should have, it’s not clear how they did that.
Frank speculates that chemical cues guided the cells back into place. Should researchers be able to identify those cues, they potentially could use that knowledge to spark regeneration of other classes of neurons, such as motor neurons.
“There is hope—not proof—that even in humans these guidance molecules will persist into adulthood,” says Frank. “That means if we are able to get neurons to regenerate in patients, we might be able to make them go back to the right place. These experiments suggest we have some reason to believe it may work.”
Neuronal regeneration and the two-part design of nerves
Researchers at the University of Michigan have evidence that a single gene controls both halves of nerve cells, and their research demonstrates the need to consider that design in the development of new treatments for regeneration of nerve cells.
A paper published online in PLOS Biology by U-M Life Sciences Institute faculty member Bing Ye and colleagues shows that manipulating genes of the fruit fly Drosophila to promote the growth of one part of the neuron simultaneously stunts the growth of the other part.
Understanding this bimodal nature of neurons is important for researchers developing therapies for spinal cord injury, neurodegeneration and other nervous system diseases, Ye said.
Nerve cells look strikingly like trees, with a crown of “branches” converging at a “trunk.” The branches, called dendrites, input information from other neurons into the nerve cell. The trunk, or axon, transmits the signal to the next cell.
"If you want to regenerate an axon to repair an injury, you have to take care of the other end, too," said Ye, assistant professor in the Department of Cell and Developmental Biology at the U-M Medical School.
The separation of the nerve cell into these two parts is so fundamental to neuroscience that it’s known as the “neuron doctrine,” but how exactly neurons create, maintain and regulate these two separate parts and functions is still largely unknown.
While the body is growing, the neuronal network grows rapidly. But nerve cells don’t divide and replicate like other cells in the body (instead, a specific type of stem cell creates them). Adult nerve cells appear to no longer have the drive to grow, so the loss of neurons due to injury or neurodegeneration can be permanent.
Ye’s paper highlights the bimodal nature of neurons by explaining how a kinase that promotes axon growth surprisingly has the opposite effect of impeding dendrite growth of the same cell.
In the quest to understand the fundamentals of nerve cell growth in order to stimulate regrowth after injury, scientists have identified the genes responsible for axon growth and were able to induce dramatic growth of the long “trunk” of the cell, but less attention has been given to dendrites.
There are technical reasons that studying axons is easier than studying dendrites: The bundle of axons in a nerve is easier to track under the microscope, but to get an image of dendrites would require labeling single neurons.
Ye’s lab circumvented that obstacle by using Drosophila as a model. Using this simple model of the nervous system, the scientists were able to reliably label both axons and dendrites of single neurons and see what happened to nerve cells with various mutations of genes that are shared between the flies and humans.
One of the genes shared by Drosophila and people is the one that makes a protein called Dual Lucine Zipper Kinase, or DLK. As described previously by other groups, DLK is a product of the gene responsible for axon growth. Cells with more of the protein had very long axons, and those without the gene or protein had no regeneration after nerve injury. The DLK kinase seemed a promising target for therapies to regenerate nerve cells.
However, Ye’s lab found that the kinase had the opposite effect on the dendrites: Lots of DLK leads to diminished dendrites.
"This in vivo evidence of bimodal control of neuronal growth calls attention to the need to look at the other side of a neuron in terms of developing new therapies," Ye said. "If we use this kinase, DLK, as a drug target for axon growth, we’ll have to figure out a way to block its effect on dendrites."
Research determines how the brain computes tool use
With a goal of helping patients with spinal cord injuries, Jason Gallivan and a team of researchers at Queen’s University’s Department of Psychology and Centre for Neuroscience Studies are probing deep into the human brain to learn how it manages basic daily tasks.
The team’s most recent research, in collaboration with a group at Western University, investigated how the human brain supports tool use. The researchers were especially interested in determining the extent to which brain regions involved in planning actions with the hand alone would also be involved in planning actions with a tool. They found that although some brain regions were involved in planning actions with either the hand or tool alone, the vast majority were involved in planning both hand- and tool-related movements. In a subset of these latter brain areas the researchers further determined that the tool was in fact being represented as an extension of the hand.
“Tool use represents a defining characteristic of high-level cognition and behaviour across the animal kingdom but studying how the brain – and the human brain in particular – supports tool use remains a significant challenge for neuroscientists” says Dr. Gallivan. “This work is a considerable step forward in our understanding of how tool-related actions are planned in humans.”
Over the course of one year, human participants had their brain activity scanned using functional magnetic resonance imaging (fMRI) as they reached towards and grasped objects using either their hand or a set of plastic tongs. The tongs had been designed so they opened whenever participants closed their grip, requiring the participants to perform a different set of movements to use the tongs as opposed to when using their hand alone.
The team found that mere seconds before the action began, that the neural activity in some brain regions was predictive of the type of action to be performed upon the object, regardless of whether the hand or tool was to be used (and despite the different movements being required). By contrast, the predictive neural activity in other brain regions was shown to represent hand and tool actions separately. Specifically, some brain regions only coded actions with the hand whereas others only coded actions with the tool.
“Being able to decode desired tool use behaviours from brain signals takes us one step closer to using those signals to control those same types of actions with prosthetic limbs,” says Dr. Gallivan. “This work uncovers the brain organization underlying the planning of movements with the hand and hand-operated tools and this knowledge could help people suffering from spinal cord injuries.”
The research was recently published in eLife.
(Source: queensu.ca)
Human brain treats prosthetic devices as part of the body
People with spinal cord injuries show strong association of wheelchairs as part of their body, not extension of immobile limbs injuries.
The human brain can learn to treat relevant prosthetics as a substitute for a non-working body part, according to research published March 6 in the open access journal PLOS ONE by Mariella Pazzaglia and colleagues from Sapienza University and IRCCS Fondazione Santa Lucia of Rome in Italy, supported by the International Foundation for Research in Paraplegie.
The researchers found that wheelchair-bound study participants with spinal cord injuries perceived their body’s edges as being plastic and flexible to include the wheelchair, independent of time since their injury or experience with using a wheelchair. Patients with lower spinal cord injuries who retained upper body movement showed a stronger association of the wheelchair with their body than those who had spinal cord impairments in the entire body.
According to the authors, this suggests that rather than being thought of only as an extension of the immobile limbs, the wheelchairs had become tangible, functional substitutes for the affected body part. As Pazzaglia explains, “The corporeal awareness of the tool emerges not merely as an extension of the body but as a substitute for, and part of, the functional self.”
Previous studies have shown that people with prosthetic devices that extend or restore movement may make such tools part of their physical identity, but whether this integration was due to prolonged use or a result of altered sensory input was unclear. Based on the results of this study, the authors suggest that it may be the latter, as the brain appears to continuously update bodily signals to incorporate these tools into a sense of the body. The study concludes that this ability may have applications in rehabilitation of physically impaired people.
(Image: University of Miami)
Research advances understanding of the human brain
Advanced neuroimaging techniques are giving researchers new insight into how the human brain plans and controls limb movements. This advance could one day lead to new understanding of disease and dysfunction in the brain and has important implications for movement-impaired patient populations, like those who suffer from spinal cord injuries.
Randy Flanagan (Psychology and Centre for Neuroscience Studies), working with colleagues at Western University, used functional magnetic resonance imaging (fMRI) to uncover what regions of the human brain are used to plan hand actions with the left and right arm. This study, spearheaded by Jason Gallivan, a Banting postdoctoral fellow at Queen’s found that by using the fMRI signals from several different brain regions, they could predict the limb to be used (left vs. right) and hand action to be performed (grasping vs. touching an object), moments before that movement is actually executed.
“We are trying to understand how the brain plans actions,” says Dr. Gallivan. “By using highly sensitive analysis techniques that enable the detection of subtle changes in brain activity patterns, we can reveal which of a series of actions a volunteer is merely intending to do, seconds later. Mapping and characterizing these predictive signals across the human brain allows us to pinpoint the key brain structures involved in generating normal, everyday behaviours.”
In another study, Dr. Flanagan and doctoral student Jonathan Diamond examined how the brain learns object mechanical properties, knowledge that is essential for skilled manipulation. They found that, through experience, humans use mismatches between predicted and actual fingertip forces and between predicted and actual object motions to build internal representations, or models, of the mechanical properties of the objects.
“The goal of this work is to understand the representations underlying skilled manipulation,” explains Dr. Flanagan. “This is important because it will enable us to better characterize deficits in manipulation tasks that often result from stroke and neurological diseases.”
Dr. Flanagan, Dr. Gallivan, and Ingrid Johnsrude (Psychology and Centre for Neuroscience Studies) have recently been awarded a CIHR operating grant to support ongoing neuroimaging work.
Both research papers were published in the Journal of Neuroscience. Read Dr. Flanagan’s paper here and read the joint paper here.
(Image: Getty Images)
Scientists behind groundbreaking research that enabled rats with severed spines to run again after two weeks have outlined their plans for human trials.
The technology brings fresh hope to sufferers of spinal cord injuries, and the team say they hope the first humans could be implanted with the technology within months.
Using a cocktail of drugs and electrical impulses, researchers hope to begin testing the project to ‘regrow’ nerves linking the spinal cord to the brain in five patients in a Swiss clinic.
Last June in the journal Science, Grégoire Courtine, of the École Polytechnique Fédérale de Lausanne (EPFL), reported that rats in his lab are not only voluntarily initiating a walking gait, but they were sprinting, climbing up stairs, and avoiding obstacles after a couple of weeks of neurorehabilitation with a combination of a robotic harness and electrical and chemical stimulation.
At the 2013 Annual Meeting of the American Association for the Advancement of Science (AAAS) in Boston, Courtine revealed the next step for the research.
He has since repeated the study in rats with bruised spines, which more closely resembles human trauma patients, and after a few weeks they could walk with no assistance.
He now believes that the technique could help people who have been immobile for up to two years.
Although full human trials are still a few years off, he plans to attempt electrical stimulation on five patients who have limited leg movement in the coming months.
‘We know that spinal cord stimulation is safe, we know that training is good, so we want to start the first trial in people who can move their legs but cannot walk independently.
'So we will implant five patients, we have a new technology which allows us to stimulate the spinal cord of humans just like we do in the rats.’
Once they have refined the technique, they hope to fully rehabilitate patients with moderately damaged spines, while others would regain some movement.
‘We already have preliminary data from the rats with these clinically relevant lesions is that a number of them would recover at the end of the training and could walk without any help. It depends on the severity of the damage,’ he said.
‘But if you talk to the patient and you tell them at least you could use it at home to cook, to watch TV and have normal activity, they say their life would be so different. So it is less ambitious, but we are talking about improving the quality of life, allowing people to stand and take a few steps at home with a walker.’
Scientists describe the genetic signature of a vital set of neurons
Scientists at NYU Langone Medical Center have identified two genes involved in establishing the neuronal circuits required for breathing. They report their findings in a study published in the December issue of Nature Neuroscience. The discovery, featured on the journal’s cover, could help advance treatments for spinal cord injuries and neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), which gradually kill neurons that control the movement of muscles needed to breathe, move, and eat.
The study identifies a molecular code that distinguishes a group of muscle-controlling nerve cells collectively known as the phrenic motor column (PMC). These cells lie about halfway up the back of the neck, just above the fourth cervical vertebra, and are “probably the most important motor neurons in your body,” says Jeremy Dasen, PhD, assistant professor of physiology and neuroscience and a member of the Howard Hughes Medical Institute, who led the three-year study with Polyxeni Philippidou, PhD, a postdoctoral fellow.
Harming the part of the spinal cord where the PMC resides can instantly shut down breathing. But relatively little is known about what distinguishes PMC neurons from neighboring neurons, and how PMC neurons develop and wire themselves to the diaphragm in the fetus.
The PMC cells relay a constant flow of electrochemical signals down their bundled axons and onto the diaphragm muscles, allowing the lungs to expand and relax in the natural rhythm of breathing. “We now have a set of molecular markers that distinguish those cells from other populations of motor neurons, so that we can study them in detail and look for ways to selectively enhance their survival,” Dr. Dasen says. Degeneration of PMC neurons is the primary cause of death in patients with ALS and spinal cord injuries.
To find out what distinguishes PMC neurons from their spinal neighbors in mice, Dr. Philippidou injected a retrograde fluorescent tracer into the phrenic nerve, which wires the PMC to the diaphragm, and then looked for the spinal neurons that lit up as the tracer worked its way back to the PMC. He used transgenic mice that express green fluorescent protein (GFP) in motor neurons and their axons in order to see the phrenic nerve. After noting the characteristic gene expression pattern of these PMC neurons, Dr. Philippidou began to determine their specific roles. Ultimately, a complicated strain of transgenic mice, based partly on mice supplied by collaborator Lucie Jeannotte, PhD, at the University of Laval in Quebec, revealed two genes, Hoxa5 and Hoxc5, as the prime controllers of proper PMC development. Hox genes (39 are expressed in humans) are well known as master gene regulators of animal development.
When Hoxa5 and Hoxc5 are silenced in embryonic motor neurons in mice, the scientists reported, the PMC fails to form its usual, tightly columnar organization and doesn’t connect correctly to the diaphragm, leaving a newborn animal unable to breathe. “Even if you delete these genes late in fetal development, the PMC neuron population drops and the phrenic nerve doesn’t form enough branches on diaphragm muscles,” Dr. Dasen says.
Dr. Dasen plans to use the findings to help understand the wider circuitry of breathing—including rhythm-generating neurons in the brain stem, which are in turn responsive to carbon dioxide levels, stress, and other environmental factors. “Now that we know something about PMC cells, we can work our way through the broader circuit, to try to figure out how all those connections are established,” he says.
"Once we understand how the respiratory network is wired we can begin to develop novel treatment options for breathing disorders such as sleep apneas," adds Dr. Philippidou.
In late October Dr. Dasen lost many of his transgenic mice when Hurricane Sandy flooded the basement of the Smilow building at NYU Langone Medical Center. But just before the hurricane hit, he sent an important group of these mice back to Dr. Jeannotte in Quebec, “so we didn’t lose everything,” he says.
(Source: eurekalert.org)
A step forward in regenerating and repairing damaged nerve cells
A team of IRCM researchers, led by Dr. Frédéric Charron, recently uncovered a nerve cell’s internal clock, used during embryonic development. The discovery was made in collaboration with Dr. Alyson Fournier’s laboratory at the Montreal Neurological Institute. Published in the prestigious scientific journal Neuron, this breakthrough could lead to the development of new tools to repair and regenerate nerve cells following injuries to the central nervous system.
Researchers in Dr. Charron’s laboratory study neurons, which are the nerve cells that make up the central nervous system (brain and spinal cord). They want to better understand how neurons navigate through the developing embryo to arrive at their correct destination.
“To properly form neural circuits, developing axons (long extensions of neurons that form nerves) follow external signals to reach the right targets,” says Dr. Frédéric Charron, Director of the Molecular Biology of Neural Development research unit at the IRCM. “We discovered that nerve cells also have an internal clock, which changes their response to external signals as they develop over time.”
For this research project, IRCM scientists focused on the Sonic Hedgehog (Shh) protein, which gives cells important information for the embryo to develop properly and plays a critical role in the development of the central nervous system.
“It is known that axons follow the Shh signal during their development,” explains Dr. Patricia Yam, research associate in Dr. Charron’s laboratory and first author of the study. “However, axons change their behaviour once they reach this protein, and this has been a mystery for the scientific community. We found that a nerve cell’s internal clock switches its response to external signals when it reaches the Shh protein, at which time it becomes repelled by the Shh signal rather than following it.”
“Our findings therefore showed that more than one system is involved in directing axon pathfinding during development,” adds Dr. Yam. “Not only do nerve cells respond to external signals, but they also have an internal control system. This discovery is important because it offers new possibilities for developing techniques to regenerate and repair damaged nerve cells. Along with trying to modify external factors, we can now also consider modifying elements inside a cell in order to change its behaviour.”