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Asaf Keller, Ph.D.
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Thalamic mechanisms of central pain.
Funded for two years, total $150,000. Principal investigator, Asaf Keller, Ph.D., University of Maryland
Spinal cord damage often results in chronic, debilitating pain. As many as 80 percent of people with spinal cord injuries develop steady, unrelenting central pain syndromes (CPS); these are highly resistant to medications or surgery.
Research from the Keller lab has identified a critical pathway in the brain that plays a major role in the development of central pain. Using a unique rodent model, he discovered a malfunction in a normally pain-blocking area of the brain known as the zona incerta (ZI). This is in turn related to altered activity in the thalamus, a key brain region for processing sensory information.
Pain information travels from the limbs through the spinal cord to the brain. Keller has previously shown that under normal conditions, the zona incerta allows only certain pain information to be experienced by the brain; the ZI filters or inhibits the pain information that passes to the thalamus. In the current project, spinal cord injured animals with CPS show reduced inhibition from the ZI, and abnormally high activity in the thalamus. This unrestricted flow of sensory information causes pain.
There may be ways to modify the zona incerta so it inhibits pain as it should. Keller's lab has shown that, after SCI, the ZI gradually stops working over a period of several weeks. He and his colleagues hope to find a way to intervene during that time to keep the zona incerta active. Drug therapies are a possibility. "We're also considering options such as non-invasive brain stimulation, stem cell implants or even occupational therapy -- exercises patients could do to stimulate the zona incerta," Keller says. "We're hopeful we'll find relief for these patients, at last."
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Soheila Karimi, Ph.D.
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A combinatorial strategy to optimize neural repair and plasticity after chronic spinal cord injury. Funded for two years, $149,494 total. Principal investigator, Soheila Karimi, Ph.D., Toronto Western Hospital Research Institute
"Considering the substantial number of paraplegic individuals who sustain lifetime disabilities," said scientist Soheila Karimi, "new therapies need to be developed to facilitate repair and regeneration of the chronically injured spinal cord."
Karimi's lab proposes to attack chronic SCI with a four-part combination: transplantation of adult neural stem cells to replace lost neural cells; promotion of neural stem cell survival and differentiation into oligodendrocytes using a growth factor cocktail; using the enzyme chondroitinase ABC to block the inhibitory components of the glial scar; and lastly, intensive rehabilitation therapy to stimulate the activity-dependent repair of spinal cord circuits.
"The discovery of neural stem cells in adult central nervous system has offered tremendous hope for new treatments for SCI," said Karimi. Recent findings from her team have shown that a strategy using these neural stem cells, along with growth factors, has potential for the repair of injured spinal cord. But using neural stem cells remains a challenge, mainly due to the inhibitory properties of the scar tissue surrounding the lesion site.
"Based on our preliminary findings, we anticipate that our combined therapeutic strategy would have a significant impact on the outcome of neural stem cell transplantation in the chronically injured spinal cord. The experiments proposed here could represent a major advance in the application of regenerative medicine to the treatment of patients with chronic SCI," she said.
"People ask, is there hope. I tell them, we're working hard; there are many promising results and I believe there is good reason for hope. But it's a very long road to get there."
Modulation and activation of excitatory spinal interneurons necessary for walking movements.
Funded for two years, $150,000; principal investigator, Martyn D. Goulding, Ph.D., The Salk Institute for Biological Studies, La Jolla, CA
Interneurons in the spinal cord play a key role in generating the complex patterns of muscle activity that enable us to walk. These interneurons, together with motor neurons, form a neural network known as the central pattern generator (GPG). The CPG is able to function independently of the brain to generate the coordinated and rhythmic firing of motor neurons needed for walking.
Goulding's lab has studied the function of many of the cell types in the CPG, including a class of excitatory neurons that connect with motor neurons. These cells, the V3 interneurons, are important for maintaining the overall excitability of the locomotor network.
Goulding found that removing V3 cells from motor circuits in the spinal cord causes a loss of organized "walking" activity. This has led to the working hypothesis that enhanced V3 neuronal activity is important to maintain ambulation.
Goulding, therefore, proposes to see whether certain drugs known to modify locomotor activity in the spinal cord can directly activate V3 cells. He further plans to test whether V3 interneurons are direct targets of descending pathways that are already known to activate the CPG. Said Goulding, "These studies will help us devise new therapies and approaches that are aimed at activating V3 interneurons and the locomotor network in the injured spinal cord," and therefore improved walking ability.
For more on individual grants, see ChristopherReeve.org/research
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