UM SCHOOL OF MEDICINE SCIENTISTS DISCOVER KEY BRAIN MECHANISM INVOLVED IN POORLY UNDERSTOOD CENTRAL PAIN SYNDROME
Findings Could Lead to Treatment for Painful Condition Common in Spinal Cord Injury, Multiple Sclerosis and Stroke Patients
Scientists at the University of Maryland School of Medicine have discovered a key mechanism in the brain related to a devastating, painful condition that affects people who suffer from spinal cord injury, multiple sclerosis and stroke. The condition, called Central Pain Syndrome, causes chronic pain that patients compare to being stabbed with a thousand burning knives. The pain can be severe and untreatable and suicide is a leading cause of mortality among those who have the syndrome. Now, a team led by University of Maryland School of Medicine researchers has traced the syndrome to a malfunction in the zona incerta, or “zone of uncertainty,” an area of the brain about which little was known until now. Their study has been published in the online version of The Journal of Neurophysiology.
“We hope that by understanding this underlying mechanism of Central Pain Syndrome, we can begin to think about potential treatments or preventive techniques,” says lead author of the study Asaf Keller, Ph.D., a professor of anatomy and neurobiology at the University of Maryland School of Medicine. “We are continuing our research into how the zona incerta is related to Central Pain Syndrome, and we hope to begin studying spinal cord injury patients who suffer from the condition very soon.”
“This study is an example of the kinds of discoveries that are possible in an interdisciplinary environment like our School of Medicine, where world class researchers from every discipline have easy access to each other’s expertise,” says E. Albert Reece, M.D., Ph.D., M.B.A., John Z. and Akiko K. Bowers Distinguished Professor and dean of the University of Maryland School of Medicine. “We hope this work will lead to a solution for the patients who suffer so terribly from this now-untreatable pain condition,” say Dean Reece, who also is vice president for medical affairs of the University of Maryland.
Pain travels from the limbs to the spinal cord to the brain. The zona incerta reduces pain by filtering out or inhibiting sensory cues it deems unimportant before they pass on to the rest of the brain. The zona incerta allows only certain pain information to be experienced by the brain. The study, called “Zona Incerta: A Role in Central Pain,” traced Central Pain Syndrome back to a malfunctioning zona incerta. The scientists found that the zona incerta in animals with Central Pain Syndrome is not inhibiting pain as it should. The zona incerta in these animals is allowing too much pain information through to the rest of the brain, causing the animals to experience unusually high levels of pain.
Central Pain Syndrome affects as many as 80 percent of patients with spinal cord injury, about 30 percent of multiple sclerosis patients and almost 10 percent of patients who have suffered a stroke. The pain associated with the syndrome can be a heightened sensitivity to ordinarily painless activities as simple as putting on clothes or feeling the wind on the skin. The syndrome also causes spontaneous pain that occurs for no apparent reason and can be unrelenting. There is no treatment for the condition, and scientists have known little about the source of the pain until now. Dr. Keller published a paper five years ago that found the zona incerta was a filter that allows only certain pain information to move on to the thalamus, where it is processed. From the thalamus, the pain information goes to the cerebral cortex, where sensations are perceived.
Dr. Keller collaborated on the new study with Radi Masri, Ph.D., an assistant professor at the University of Maryland Dental School and the Department of Anatomy and Neurobiology at the School of Medicine, and their colleagues Raimi Quiton, Ph.D., and Peter Murray, Ph.D., both postdoctoral fellows the Department of Anatomy and Neurobiology, and Jessica Lucas, a graduate student in the Program in Neuroscience, as well as Scott M. Thompson, Ph.D., a professor of physiology at the School of Medicine. The study was funded by the National Institute of Neurological Disorders and Stroke, part of the National Institutes of Health, and the Christopher & Dana Reeve Foundation.
Co-investigator Dr. Thompson recently completed a study with his associate Gexin Wang, Ph.D., a post-doctoral fellow in the Department of Physiology at the School of Medicine, showing that animals with Central Pain Syndrome respond to a drug called ethosuximide, a U.S. Food and Drug Administration-approved treatment for childhood epilepsy. Dr. Thompson’s study found that ethosuximide appeared to calm the over-activity and excitability in the thalamus that seems related to Central Pain Syndrome. Some of that excessive activity may be a result of inactivity in the zona incerta, according to Dr. Keller’s and Dr. Thompson’s latest joint study. “Our two studies examine areas of the brain that are very near each other, very similar and clearly related,” says Dr. Thompson. “We believe our two studies are basically indicating the same thing — that there is some imbalance of activity in the thalamus. These studies could finally mean relief for these patients for whom there is really no treatment. They’re desperate for anything.”
The scientists plan to continue their research to investigate new treatments and ways to prevent Central Pain Syndrome. Dr. Thompson will begin a study of ethosuximide in human patients very soon. Since that drug already has earned FDA approval for treating epilepsy, if it proves effective in Central Pain Syndrome it could be approved for treating that condition far more quickly than a new drug.
Dr. Keller is planning to investigate other avenues as well. His study showed that, after an injury to the spinal cord, the zona incerta gradually stops working properly over a period of several weeks. Dr. Keller and his colleagues hope to find a way to intervene during those weeks and keep the zona incerta active. “We’re considering options such as non-invasive brain stimulation, stem cell implants or even occupational therapy — exercises patients could do to stimulate the zona incerta,” Dr. Keller says. “A successful treatment regimen one day could include a combination of exercises and drug therapy. We’re hopeful we’ll find relief for these patients, at last.”