Central Pain press release from the Univ. of Maryland



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.”

Breakthrough in Central Pain Understanding

Painonline has at times been hardpressed to explain why central pain patients have so much muscle pain.  Both kinesthetic dysesthesia (pain with muscle loading) and confinement cramps, aka isometric dysesthesia (the largely spontaneous sensation of cramps in the muscles) are exceedingly common in central pain. Although often glossed over because the patient complains of such agony from burning sensation on the skin, as Beric has pointed out, the muscle pains may be so severe that a person with an intact motor unit may be functionally paralyzed. Muscle pains have been the stepchild of CP.

They also confound cliniicans who often confront ACTUAL musculoskeletal pain in post spinal cord injury patients, which pain is NOT neuropathic. Devising treatment strategies is much more difficult because verbal descriptors are lacking by which the clinician may distinguish between Central Pain in the muscles and the musculoskeletal pains which are to be expected whenever there is alteration anatomically at any motion segment of the spine. The former is neuropathic, and may be utterly resitant to opiates, while the latters is nociceptive and should respond to conventional pain therapies, such as opiates.

In a prior article here, the increasing focus on the posterior nucleus of the thalamus was discussed. This largely ignored nucleus is at the very back of the thalamus. The prior article dealt with connections being uncovered between pain tracts and the posterior nucleus or PoT (also called PO)

Now Masri, Keller and others at the University of Maryland have published a landmark study in the online J. Neurophysiology April edition ** which suggests that the PoT has inhibitory input from the zona incerta. The zona incerta is part of a nucleus which sits BELOW the thalamus, known as the Subthalamic nucleus. The Subthalamic nucleus is itself divided into areas. Nothingi n the brain seems to do just one thing. One neurophysiologist suggested that no area of the brain does just one thing, and that no nucleus has more than thirty percent of its neurons devoted to any one function.

Zona Incerta has always been a mystery as to its function. Its very name means in Latin, the zone of uncertainty, meaning no one had a clue what it did. (If you want a little look at this area, go to Brainmaps.com) Now, the ZI is turning out to be massively important to Central Pain patients. Its failure to inhibit the PoT may be the actual mechanism of CP.

This multifunctional aspect is revealed in the zona incerta. However, proximity often means some RELATION between the various functions should be suspected, or at least looked for. The posterior part of the Zona Incerta is the area of interest. The very most posterior part of the ZI is the area which is sometimes lesioned in Parkinson’s because there are links to the cerebellum and hence the motor functions of the body. (Coordination etc) The forward part of the most posterior region of the ZI was discovered to serve the function of INHIBITING the POT. When Central Pain is present, the inhibitory signal from the ZI is missing.

This leads to the rather logical conclusion that without input from the ZI, the PoT cannot distinguish between something like a breeze on the skin and a burn. (The University of Maryland news release on the discovery called Central Pain a mysterious disease. Perhaps an analogy might be made to color blindness. The color blind cannot distinguish between red and green. Thus, the brain of a person with Central Pain cannot distinguish between a breeze on the skin and a burn)  

The clinical description is hardly surprising, since most of those in the survey here attest to the fact that anything bringing a temperature change, especially a blast of cold air< will evoke burning pain powerfully. However, the more the press refers to Central Pain as “mysterious”, the less mysterious it becomes. This alone is a help to CP subjects. Even more help is the notice that attention and focus must be given to the surprising role of an allegedly ”MOTOR” area, the Zona Incerta, plays in interpretation of pain signal. Perhaps we should say “sensory signal” since most of what causes agony in CP is not inherently a pain stimulus at all.

Carl Saab, noted for identifying an area in the cerebellum which inhibits central pain, ie the vermis, has written here of the unexpected cerebellar link between that structure and pain inhibition. His first paper on the subject was so unexpected that it caused not only an uproar, but anger, at the Ninth World Congress of Pain, when Dr. Saab presented it. However, we now have more backing for the former author at painonline in yet another link between the cerebellum and pain. Namely, the area which connects to the cerebellum, and is a point of interest in Parkinson’s, is immediately adjacent to the pain interepreting area of the posterior region of the ZI which inhibits the PoT.

Look for more material on this, as some Parkinson’s patients have pain. It may be a touch of central pain, given this recent finding. We congratulate the authors (there are a number) and feel this may be the most significant article ever published on Central Pain.

**We are indebted to Mary Simpson for first noting this article when it appeared.