A Case-Controlled Study of Proton Spectroscopy in Fibromyalgia
Principal Investigator: Patrick Wood, M.D.
Louisiana State University at Shreveport (LSU)
Award Amount: $37,450
Fibromyalgia has long been associated with abnormalities in the body's stress response mechanisms and is believed to be due to problems in brain function. Symptoms often surface for the first time after a stressful insult to the body that may include trauma, infectious agents or a prolonged time of severe duress. Once symptoms have developed, stress also tends to make the symptoms worse. Researchers have shown that those parts of the body responsible for handling stress may be overactive in patients with FMS (e.g., hyperactivity of the corticotropin-releasing hormone neurons, which are believed to blunt growth hormone secretion during exercise, and a sympathetic nervous system that is pushed into hyper-drive so that it can't respond appropriately to common daily stressors). These hormonal and nervous system problems could explain many of the symptoms of FMS, including widespread pain, but the search for the root cause of this situation is essential in order to better understand how to treat FMS.
The hippocampus is part of the limbic system of the brain which is best known for its role in memory and learning—but it has many other functions. The hippocampus is also responsible for "putting the brakes" on the stress response network, to prevent it from running out of control. Ironically, the same chemicals that characterize the stress response (namely cortisol, corticotropin-releasing hormone, and adrenaline) are also known to damage the hippocampus, making it less able to do its job. In addition, the hippocampus also handles pain signals by routing them from the spinal cord to the brain. Exposure of the hippocampus to stress chemicals may therefore be associated with the development of chronic pain, such as that found in FMS and CFS patients.
Magnetic resonance spectroscopy (MRS) is a technique used to characterize the chemical content of living tissue without having to take a sample. Using this technique, researchers Patrick B. Wood, M.D., and James C. Patterson, M.D., Ph.D., at Louisiana State University Health Science Center in Shreveport, will investigate whether or not patients with FMS have a lower concentration of n-acetylaspartate, or NAA, in their hippocampus. NAA is a marker of integrity and function within the brain, and a decrease in its concentration is associated with a variety of illnesses. In fact, a short communication published in The British Journal of Radiology in November of 2000 (volume 73, pages 1206-08) indicated that patients with CFS exhibited a substantial decrease in their hippocampal concentration of NAA. The study only assessed seven CFS patients, but this preliminary report presents a strong case for the measurement of NAA levels in both CFS and FMS patients on a larger scale. Wood and Patterson will also be evaluating the effects of depression and anxiety in FMS patients because they may often coexist in people with chronic illnesses.
Other cerebral metabolites will be measured by MRS to provide more knowledge about FMS. Creatine (Cr) levels are predictive of the rate of cellular metabolism and choline (Cho) levels are thought to be a marker of glial cell function. Glial cells surround the neurons in the brain to assist in regulating transmissions and the transfer of nutrients. Hippocampus volumes will be measured as well because a decreased size has been found in patients suffering from combat-related post-traumatic stress disorder (PTSD). People with PTSD not only have impaired memory functions similar to FMS/CFS; they also have higher than normal levels of stress hormones circulating within their brain.
If patients with FMS (and possibly CFS) are found to have a lower concentration of NAA in their hippocampus compared to those without FMS, this might explain the hyperactive stress response, widespread pain, "fibro fog," and many other symptoms. Medications are available to protect the integrity of the hippocampus, but they are not prescribed for patients with FMS/CFS because there is currently no basis for their use. However, if the NAA concentrations are low in patients, then this study will open up a new avenue of drug therapies that will enable the hippocampus to recover from its stressful environment. In addition, abnormal concentrations of NAA, Cr, or Cho in the hippocampus, as well as a smaller hippocampus size, could prove to be of benefit diagnostically for patients.
Dr. Wood is an Assistant Professor at LSU Health Science Center and also serves as co-director of their Primary Care Pain Management Clinic. He recently completed a research fellowship in Psychopharmacology and was honored as one of the nation's most promising New Investigators by the National Institutes of Mental Health (NIMH) for his work involving a novel treatment for patients with FMS. NIMH is one of the major Institutes involved in brain research. He is eager to use his special training in neuropharmacology to help identify novel drugs or potential new classes of medications that will benefit patients with FMS and CFS. Dr. Patterson is director of the neuroimaging research center at LSU and is working with Dr. Wood to bring MRS technology to the field of FMS.
EBV Transformation for Genetic Studies on FMS
Principal Investigator: Laurence Bradley, Ph.D.
University of Alabama at Birmingham (UAB)
Award: $28,049 - January 2002
In the August 2001 issue of the AFSA Update, we mentioned that AFSA was in the process of approving a research project that would be awarded in memory of Laura Skalla, an FMS patient who died tragically in an automobile accident last year. What follows is a description of the award that we alluded to in that Update. Unlike most projects that are funded in the biomedical field, this particular AFSA study will lay the groundwork for an unlimited number of future genetic studies on FMS. In simple terms, the "EBV transformation" in the title above is a process that takes blood samples and immortalizes the genetic material in the cells to generate a replenishable supply of DNA that can be used for qualified AFSA applicants at anytime well into the future. The usefulness of this project will span many years and, in like fashion, we hope that this facet of the study helps to preserve the memory of Laura for the hundreds who contributed on her behalf.
Evidence for a sex-dependent genetic predisposition for the development of FMS is slowly accumulating. The first published study in the 1980s by Mark Pellegrino, M.D., hinted that the genetic predisposition of FMS may be strong, but that the expression of the condition was more likely to occur in female offspring. Many studies since have implicated a strong genetic role in FMS, including studies showing the high incidence of FMS-like sleep disturbances in school-aged children of mothers with FMS and a genetic abnormality pertaining to the way the nervous system in FMS patients regulates the production of serotonin ... an important transmitter involved in pain and sleep.
Laurence Bradley, Ph.D. and his team of FMS experts at UAB plan to compare several measures of pain sensitivity, blood serum serotonin levels, and the frequency of a specific polymorphism in the promoter region of the serotonin transporter gene (5-HTT) in eight (8) groups of subjects. This will build on recently published genetic findings on polymorphism of 5-HTT in FMS patients (polymorphism means more than one structural abnormality occurring in the gene, and in this case, the gene that regulates serotonin production). The eight groups of subjects are: 80 female FMS probands, 80 sex-matched control subjects, 40 sisters and 40 brothers of the FMS probands, 40 sisters and 40 brothers of the control subjects, 40 male spouses/partners of the probands, and 40 male spouses/partners of the controls. These procedures will be performed over a 5-year period as the core part of a larger genetic study.
Bradley anticipates a rank ordering of pain sensitivity across the eight subject groups with the greatest pain sensitivity among the FMS probands, followed by their sisters, followed by their brothers, and then among the remaining groups (controls, sisters and brothers of the controls, and the two spouse/partner groups). He anticipates similar relationships among these subject groups and serum serotonin levels. It is also believed that serum serotonin levels will be found to make a significant contribution to the group differences in pain sensitivity. Finally, the UAB team suspects that the polymorphism in 5-HTT will be found significantly more frequently in the FMS probands compared to the controls. Exploratory analyses will be performed to determine if the polymorphism is found more frequently in the sisters of the FMS probands compared to all of the other sibling groups.
Support from AFSA will allow UAB to create a replenishable supply of genomic DNA from the flood serum donated by the participants using a procedure called EBV transformation. This will ensure that Bradley's team has a sufficient supply of DNA to test their hypotheses concerning the 5-HTT polymorphism. It will also allow them to perform future genetic studies regarding the causes of abnormal pain sensitivity among women with FMS as other candidate genes are identified by basic science investigators (in other words, as genetic technology expands, so too can the genetic basis of FMS increase). Moreover, genetic DNA material will be kept in frozen storage to be made available to other qualified investigators with promising research ideas concerning the causes of FMS. Long delays to recruit 400 samples and the corresponding massive amount of clinical data on each sample will be circumvented by the AFSA project. As Bradley explains in his grant proposal, it will take five years to collect the samples and data, but once the project is completed, future investigators can swiftly obtain the genetic material at a very minimal cost of shipping and handling!
"This project will contribute to more rapid advances in our understanding of the causes of abnormal pain sensitivity in women with FMS, and thus lead to significant advances in treatment," says Laurence Bradley, Ph.D. The genetic glitches that are the most substantial can be targets for early therapy. Currently, there are so many abnormalities in FMS that it is difficult, if not impossible, to know which ones appear first, and then cause other abnormalities to develop. Genetic studies will greatly clarify this confusion. As science progresses, there is also the hope that genetic knowledge can lead to genetically based treatments. Also commenting of the significance of this AFSA-funded project, medical advisor Robert Bennett, M.D., says, "This project will hopefully establish AFSA as a `major player' in FMS research."