Posts tagged spinal cord

A Queen’s University study is giving new insight into how the neurons in our brains control our limbs. The research might one day help with the design of more functional artificial limbs.

“We’ve taken a step closer to understanding how our arms and legs work and how we move our bodies,” says neuroscience researcher Tim Lillicrap, who worked with neuroscience professor Stephen Scott on the study.

The researchers used a novel network model, coupled with a computer biophysics model of a limb, to explain some of the prominent patterns of neural activity seen in the brain during movements.

The findings refine previous notions of how neurons in the primary motor cortex fire and drive muscles. The primary motor cortex is the region of the brain that sends the largest number of connections to the spinal cord.

When moving an arm or a leg, nerve impulses are sent along nerve fibres to control the movement of limbs. Different movements require different patterns of nerve impulses — the relationship between these neural patterns and the resulting movements is poorly understood.

The study demonstrates that the patterns of activity are related to specific details of limb physics — for example, the patterns of neural activity are tuned (or optimized) for muscle architecture and limb geometry.

Dr. Lillicrap, who did the study as part of his PhD thesis at Queen’s and is now a post-doctoral fellow at Oxford University in England, says better understanding of how the brain controls limbs will help develop artificial limbs in the future.

(Source: queensu.ca)

An experimental oral drug given to mice after a spinal cord injury was effective at improving limb movement after the injury, a new study shows.

The compound efficiently crossed the blood-brain barrier, did not increase pain and showed no toxic effects to the animals.

“This is a first to have a drug that can be taken orally to produce functional improvement with no toxicity in a rodent model,” said Sung Ok Yoon, associate professor of molecular & cellular biochemistry at Ohio State University and lead author of the study. “So far, in the spinal cord injury field with rodent models, effective treatments have included more than one therapy, often involving invasive means. Here, with a single agent, we were able to obtain functional improvement.”

The small molecule in this study was tested for its ability to prevent the death of cells called oligodendrocytes. These cells surround and protect axons, long projections of a nerve cell, by wrapping them in myelin. In addition to functioning as axon insulation, myelin allows for the rapid transmission of signals between nerve cells.

The drug preserved oligodendrocytes by inhibiting the activation of a protein called p75. Yoon’s lab previously discovered that p75 is linked to the death of these specialized cells after a spinal cord injury. When they die, axons that are supported by them degenerate.

“Because we know that oligodendrocytes continue to die for a long period of time after an injury, we took the approach that if we could put a brake on that cell death, we could prevent continued degeneration of axons,” she said. “Many researchers in the field are focusing on regeneration of neurons, but we specifically targeted a different type of cells because it allows a relatively long therapeutic window.”

An additional benefit of targeting oligodendrocytes is that it can amplify the therapeutic effect because a single oligodendrocyte myelinates multiple axons.

A current acute treatment for humans, methylprednisolone, must be administered within eight but not more than 24 hours after the injury to be effective at all. An estimated 1.3 million people in the United States are living with spinal cord injuries, experiencing paralysis and complications that include bladder, bowel and sexual dysfunction and chronic pain.

The experimental drug, called LM11A-31, was developed by study co-author Frank Longo, professor of neurology and neurological sciences at Stanford University. The drug is the first to be developed with a specific target, p75, as a potential therapy for spinal cord injury.

The research is published in the Jan. 9, 2013, issue of The Journal of Neuroscience.

Researchers gave three different oral doses of LM11A-31, as well as a placebo, to different groups of mice beginning four hours after injury and then twice daily for a 42-day experimental period. The scientists analyzed the compound’s effectiveness at improving limb movement and preventing myelin loss.

The spinal cord injuries in mice mimicked those caused in humans by the application of extensive force and pressure, resulting in loss of hind-limb and bladder function andexperimentally calibrated baseline difficulty in walking and swimming.

The researchers determined that the mice did not experience more pain than the placebo group at all the doses tested, suggesting that LM11A-31 does not worsen nerve pain after spinal cord injury.

Analysis showed that the extent of myelin sparing was dependent on the dose of the drug. Each dose – 10, 25 or 100 milligrams per kilogram of body weight – led to increasing myelin sparing, with the highest dose demonstrating the greatest effect.

The injury in the animals caused a loss of about 75 percent of myelinated axons in the lesion area in the placebo group. This loss was reduced so that myelinated axons reached more than half of the normal levels with LM11A-31 at 100 mg/kg. That was correlated with about a 50 percent increase in surviving oligodendrotcytes compared to those in the placebo group, Yoon said.

In behavior tests, only the highest dose of the compound led to improvements in motor function. Mice were tested in both weight-bearing and non-weight-bearing activities over the 42 days to evaluate their functional recovery.

Mice receiving the highest dose could walk with well-coordinated steps. In swimming tests, scientists saw similar improvements, with mice receiving the highest dose most able to coordinate hind-limb crisscross movement. The other treatment groups exhibited difficulty in walking and swimming.

Yoon said the findings may suggest that myelin sparing needs to reach a threshold of roughly 50 percent of normal levels before motor function improvements become measurable.

“The cellular analysis of the myelin profile detects small changes. Behavior is more complex, and we don’t think functional behavior necessarily improves in a linear fashion,” she said. “Still, these results clearly show that this is the first oral drug in spinal cord injury that works alone to improve function.”

(Source: researchnews.osu.edu)

Scientists at the Universities of Liverpool and Glasgow have uncovered a possible new method of enhancing nerve repair in the treatment of spinal cord injuries.

It is known that scar tissue, which forms following spinal cord injury, creates an impenetrable barrier to nerve regeneration, leading to the irreversible paralysis associated with spinal injuries. Scientists at Liverpool and Glasgow have discovered that long-chain sugars, called heparan sulfates, play a significant role in the process of scar formation in cell models in the laboratory.

Research findings have the potential to contribute to new strategies for manipulating the scarring process induced in spinal cord injury and improving the effectiveness of cell transplantation therapies in patients with this type of injury.

Scarring occurs due to the activation, change in shape, and stiffness of cells, called astrocytes, which are the major nerve support cells in the spinal cord. One possible way to repair nerve damage is transplantation of support cells from peripheral nerves, called Schwann cells. The team, however, found that these cells secrete heparan sulfate sugars, which promote scarring reactions and could reduce the effectiveness of nerve repair.

Scientists showed that these sugars can over-activate protein growth factors that promote astrocyte scarring. Significantly, however, they found this over-activation could be inhibited by chemically modified heparins made in the laboratory. These compounds could prevent the scarring reaction of astrocyte cells, opening up new opportunities for treatment of damaged nerve cells.

Professor Jerry Turnbull, from the University of Liverpool’s Institute of Integrative Biology, said: “Spinal injury is a devastating condition and can result in paralysis for life. The sugars we are investigating are produced by nearly every cell in the body, and are similar to the blood thinning drug heparin.

"We found that some sugar types promote scarring reaction, but remarkably other types, which can be chemically produced in the laboratory by modifying heparin, can prevent this in our cell models.

"Studies in animal cells are now needed, but the exciting thing about this work is that it could, in the future, provide a way of developing treatments for improving nerve repair in patients, using the body’s own Schwann cells, supplemented with specific sugars."

Professor Sue Barnett, from the University of Glasgow’s Institute of Infection, Immunity and Inflammation, said: “We had already shown that Schwann cells, identified as having the potential to promote nerve regrowth, induced scarring in spinal cord injury. Now that we know that they secrete these complex sugars, which lead to scarring, we have the opportunity to intervene in this process, and promote central nervous system repair.”

(Source: eurekalert.org)

I suddenly noticed I could move my pinkie. I was cruising towards the highway when this old guy tried to cross the 4-lane road really fast. He hit me and I ejected over to the opposite lane. Luckily someone found me before the traffic got to me.

Paralysis may no longer mean life in a wheelchair. A man who is paralysed from the trunk down has recovered the ability to stand and move his legs unaided thanks to training with an electrical implant.

Andrew Meas of Louisville, Kentucky, says it has changed his life. The stimulus provided by the implant is thought to have either strengthened persistent “silent” connections across his damaged spinal cord or even created new ones, allowing him to move even when the implant is switched off.

The results are potentially revolutionary, as they indicate that the spinal cord is able to recover its function years after becoming damaged.

Previous studies in animals with lower limb paralysis have shown that continuous electrical stimulation of the spinal cord below the area of damage allows an animal to stand and perform locomotion-like movements. That’s because the stimulation allows information about proprioception – the perception of body position and muscle effort – to be received from the lower limbs by the spinal cord. The spinal cord, in turn, allows lower limb muscles to react and support the body without any information being received from the brain (Journal of Neuroscience, doi.org/czq67d).

Last year, Susan Harkema and Claudia Angeli at the Frazier Rehab Institute and University of Louisville in Kentucky and colleagues tested what had been learned on animals in a man who was paralysed after being hit by a car in 2006. He was diagnosed with a “motor complete” spinal lesion in his neck, which means that no motor activity can be recorded below the lesion.

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ScienceDaily (July 6, 2012) — Yona Goldshmit, Ph.D., is a former physical therapist who worked in rehabilitation centers with spinal cord injury patients for many years before deciding to switch her focus to the underlying science.

"After a few years in the clinic, I realized that we don’t really know what’s going on," she said.

Now a scientist working with Peter Currie, Ph.D., at Monash University in Australia, Dr. Goldshmit is studying the mechanisms of spinal cord repair in zebrafish, which, unlike humans and other mammals, can regenerate their spinal cord following injury. On June 23 at the 2012 International Zebrafish Development and Genetics Conference in Madison, Wisconsin, she described a protein that may be a key difference between regeneration in fish and mammals.

One of the major barriers to spinal regeneration in mammals is a natural protective mechanism, which incongruously results in an unfortunate side effect. After a spinal injury, nervous system cells called glia are activated and flood the area to seal the wound to protect the brain and spinal cord. In doing so, however, the glia create scar tissue that acts as a physical and chemical barrier, which prevents new nerves from growing through the injury site.

One striking difference between the glial cells in mammals and fish is the resulting shape: mammalian glia take on highly branched, star-like arrangements that appear to intertwine into dense tissue. Fish glia cells, by contrast, adopt a simple elongated shape — called bipolar morphology — that bridges the injury site and appears to help new nerve cells grow through the damaged area to heal the spinal cord.

"Zebrafish don’t have so much inflammation and the injury is not so severe as in mammals, so we can actually see the pro-regenerative effects that can happen," Dr. Goldshmit explained.

Studies in mice have found that mammalian glia can take up the same elongated shape, but in response to the environment around the injury they instead mature into scar tissue that does not allow nerve regrowth.

Dr. Goldshmit and her colleagues have focused on a family of molecules called fibroblast growth factors (Fgf), which have shown some evidence of improving recovery in mice and humans with spinal cord damage. The Monash University group found that Fgf activity around the damage site promotes the bipolar glial shape and encourages nerve regeneration in zebrafish.

Preliminary results in mice show that Fgf injections near a spinal injury increase both the number of glia cells at the site and the elongated morphology. Their evidence suggests that Fgfs may work to create an environment more supportive of regeneration in mammals as well and could be a valuable therapeutic target.

Spinal injury patients usually have few options, Dr. Goldshmit emphasized, and development of new, biologically-based approaches will be critical.

"This is a nice example of how we can use the zebrafish model," she said. "When we learn from the zebrafish what to look at, we can find things that give us hope for finding therapeutic approaches for spinal cord injury in humans."

Source: Science Daily

ScienceDaily (June 26, 2012) — UCLA researchers discovered that a diet enriched with a popular omega-3 fatty acid and an ingredient in curry spice preserved walking ability in rats with spinal-cord injury. Published June 26 in the Journal of Neurosurgery: Spine, the findings suggest that these dietary supplements help repair nerve cells and maintain neurological function after degenerative damage to the neck.

Turmeric. (Credit: © Elzbieta Sekowska / Fotolia)

"Normal aging often narrows the spinal canal, putting pressure on the spinal cord and injuring tissue," explained principal investigator Dr. Langston Holly, associate professor of neurosurgery at the David Geffen School of Medicine at UCLA. "While surgery can relieve the pressure and prevent further injury, it can’t repair damage to the cells and nerve fibers. We wanted to explore whether dietary supplementation could help the spinal cord heal itself."

The UCLA team studied two groups of rats with a condition that simulated cervical myelopathy — a progressive disorder that often occurs in people with spine-weakening conditions like rheumatoid arthritis and osteoporosis. Cervical myelopathy can lead to disabling neurological symptoms, such as difficulty walking, neck and arm pain, hand numbness and weakness of the limbs. It’s the most common cause of spine-related walking problems in people over 55.

The first group of animals was fed rat chow that replicated a Western diet high in saturated fats and sugar. The second group consumed a standard diet supplemented with docosahexaenoic acid, or DHA, and curcumin, a compound in turmeric, an Indian curry spice. A third set of rats received a standard rat diet and served as a control group.

Why these supplements? DHA is an omega-3 fatty acid shown to repair damage to cell membranes. Curcumin is a strong antioxidant that previous studies have linked to tissue repair. Both reduce inflammation.

"The brain and spinal cord work together, and years of research demonstrate that supplements like DHA and curcumin can positively influence the brain," said coauthor Fernando Gomez-Pinilla, professor of neurosurgery. "We suspected that what works in the brain may also work in the spinal cord. When we were unable to find good data to support our hypothesis, we decided to study it ourselves."

The researchers recorded a baseline of the rats walking and re-examined the animals’ gait on a weekly basis. As early as three weeks, the rats eating the Western diet demonstrated measurable walking problems that worsened as the study progressed. Rats fed a diet enriched with DHA and curcumin walked significantly better than the first group even six weeks after the study’s start.

Next, the scientists examined the rats’ spinal cords to evaluate how diet affected their injury on a molecular level. The researchers measured levels of three markers respectively linked to cell-membrane damage, neural repair and cellular communication.

The rats that ate the Western diet showed higher levels of the marker linked to cell-membrane damage. In contrast, the DHA and curcumin appeared to offset the injury’s effect in the second group, which displayed equivalent marker levels to the control group.

Levels of the markers linked to neural repair and cellular communication were significantly lower in the rats raised on the Western diet. Again, levels in the animals fed the supplemented diet appeared similar to those of the control group.

"DHA and curcumin appear to invoke several molecular mechanisms that preserved neurological function in the rats," said Gomez-Pinilla. "This is an exciting first step toward understanding the role that diet plays in protecting the body from degenerative disease."

"Our findings suggest that diet can help minimize disease-related changes and repair damage to the spinal cord," said Holly. "We next want to look at other mechanisms involved in the cascade of events leading up to chronic spinal-cord injury. Our goal is to identify which stages will respond best to medical intervention and identify effective steps for slowing the disease process."

Source: Science Daily