NEUROENDOCRINOLOGY OF MASTICATORY MUSCLE DISORDERS

Grant Number: 5R01DE011972-05
PI Name: YOUNG, ELIZABETH A.
PI Title: PROFESSOR
Project Title: NEUROENDOCRINOLOGY OF MASTICATORY MUSCLE DISORDERS

Abstract: DESCRIPTION: The temporomandibular disorders (TMDs) are a complex group of conditions involving masticatory muscles and/or temporomandibular joints and characterized by chronic facial pain. The etiology and pathogenesis of TMDs are multifactorial, including a strong association with depression and the occurrence of environmental stressors, with a strong predominance of women with these disorders (75-84%). It is known that dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, the main stress hormone axis, occurs in both depression and stress-related disorders. Recent evidence also demonstrates HPA dysregulation in other conditions related to TMDs: in particular, in fibromyalgia. This is a condition of generalized myalgia with a great deal of clinical overlap with masticatory muscle disorders (MMDs), a major sub-group of TMDs. Fibromyalgia also shows a similar high female predominance and is associated with high rates of depression and stress. Furthermore, there is evidence of important gender differences in HPA axis function resulting in an increased stress responsiveness and susceptibility to HPA dysregulation in women, thus providing an explanation for the high female predominance of fibromyalgia, depression and MMD. This study will examine the comorbidity of MMD and disorders associated with HPA stress axis dysregulation including fibromyalgia and stress-related psychiatric disorders, including depression, and test the hypothesis that women with MMD have an underlying HPA axis abnormality similar to that which occurs in fibromyalgia, namely HPA axis hypofunction, which is the underlying pathophysiological basis of both disorders. HPA function will be studied in women with MMD, (with and without comorbid fibromyalgia and depression) compared to normal controls, in terms of circadian and pulsatile patterns of basal cortisol secretion, using an intensive 24-hour plasma cortisol sampling paradigm. Women will be studied during both follicular and luteal phases of the menstrual cycle to test the hypothesis that there will be menstrual cycle-phase related fluctuations in symptoms and HPA axis function. These multidisciplinary studies will provide an understanding of the pathophysiological basis of the relationship of MMD to seemingly disparate conditions such as fibromyalgia and depressive disorders, as well as the higher prevalence in women, leading to a more rational basis for diagnosis and treatment of MMD.

Thesaurus Terms: female, hormone regulation /control mechanism, hypothalamic pituitary axis, major depression, mastication, muscle disorder circadian rhythm, cortisol, fibromyalgia, menstrual cycle, oral facial pain, pathologic process, posttraumatic stress disorder, psychological stressor, secretion, sign /symptom, striated muscle, temporomandibular joint, temporomandibular joint syndrome clinical research, human subject

Institution: UNIVERSITY OF MICHIGAN AT ANN ARBOR
Fiscal Year: 2000
Department: PSYCHIATRY
Project Start: 15-SEP-1996
Project End: 14-JUL-2002
ICD: NATIONAL INSTITUTE OF DENTAL & CRANIOFACIAL RESEARCH
IRG: ZDE1

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NORADRENERGIC DYSFUNCTION--A MODEL OF FIBROMYALGIA PAIN

Grant Number: 5R21AR046085-03
PI Name: JASMIN, LUC
PI Title:
Project Title: NORADRENERGIC DYSFUNCTION--A MODEL OF FIBROMYALGIA PAIN

Abstract: The goal of this project is to develop a rat model of fibromyalgia pain which could provide the basis for future research into this complex disease. The difficulty in finding an etiology for this painful condition is in part because fibromyalgia is not a discrete or unique disease, but patients also a display number of different symptoms in addition to the widespread tenderness, including fatigue, sleep disturbances, headaches, gastrointestinal symptoms, etc. As such, fibromyalgia overlaps conditions such as Chronic Fatigue Syndrome, Irritable Bowel Syndrome, tension and migraine headaches. These conditions share several features, including a female predominance, initiation or exacerbation in response to several different types of "stressors", and response to similar types of pharmacologic and non-pharmacologic modalities (e.g. tricyclic drugs, aerobic exercise). A dysfunction of the noradrenergic system, the basis for the proposed model, presents a unifying explanation for many seemingly disparate findings in fibromyalgia by accounting for the neuroendocrine and autonomic abnormalities, in addition to the chronic pain. Our guiding hypothesis is that in fibromyalgia, chronically decreased noradrenergic input to the spinal cord facilitates substance P release and subsequent hyperalgesia (decreased threshold for pain). This hypothesis is based on both clinical evidence of decreased noradrenaline and increased substance P in the spinal cord of fibromyalgia patients, as well as evidence from basic research demonstrating that acute decreases in spinal noradrenaline allow for greater release of substance P and sustained hyperalgesic effects of this neurotransmitter. These alterations in turn result in greater expression and redistribution of the substance P receptor in the spinal cord, contributing to the chronicity of the hyperalgesia. In the female rat, we will apply a novel technique of selective immunolesion of brainstem noradrenergic input to nociceptive areas of the spinal cord. The first aim will test the hypothesis that lowered nociceptive thresholds in rats with decreased spinal noradrenaline depend on substance P neurotransmission. This hypothesis will be tested by determining the contribution of spinal SP neurotransmission in alterations of nociceptive behavioral and neuronal responses to noxious and innocuous stimuli. The second aim will test the hypothesis that chronically decreased spinal noradrenaline chronically increases basal levels, and facilitates evoked release of substance P, by measuring levels of substance P in the CSF, primary afferent neurons, and spinal cord, both basal and following noxious and innocuous stimulation. In the third aim, we will test the hypothesis that decreased spinal noradrenaline facilitates stimulus-induced increased expression and redistribution of the substance P receptor (NK1 receptor) in the spinal cord by measuring basal and noxious stimulus-induced alterations in the expression of this receptor.

Thesaurus Terms: disease /disorder model, fibromyalgia, model design /development, norepinephrine, pain threshold cerebrospinal fluid, chronic pain, endocrine disorder, hyperalgesia, neuroendocrine system, neuropeptide receptor, receptor expression, spinal cord, substance P female, laboratory rat

Institution: UNIVERSITY OF CALIFORNIA SAN FRANCISCO
Fiscal Year: 2001
Department: NEUROLOGICAL SURGERY
Project Start: 01-JUL-1999
Project End: 30-JUN-2002
ICD: NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES
IRG: ZAR1

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Assessment of psychological distress in fibromyalgia

Grant Number: 5P60AR030701-200039
PI Name: WINFIELD, JOHN B.
PI Title: PROFESSOR
Project Title: Assessment of psychological distress in fibromyalgia

Abstract: The bases for the decreased pain threshold and pain tolerance that is characteristic of people with fibromyalgia remain to be clarified. In addition to biological variables, such as gender, central sensitization, "wind-up" (abnormal temporal summation of pain), and central dysregulation of several axes of the stress response, cognitive, behavioral, emotional, environmental, and cultural variables appear to contribute importantly to the chronic pain experience and associated symptomatology in this disorder. A common denominator linking both biological and psychosocial contributors in this regard may be psychologic distress. The applicant's preliminary data are consistent with the hypothesis that psychological distress lowers pain threshold and, therefore, contributes to widespread allodynia and hyperalgesia in fibromyalgia. The immediate objective of this proposal is to use established databases from a cohort of patients with fibromyalgia and other rheumatologic conditions to define some of the individual differences that underlie the development and perpetuation of chronic widespread pain. This will be accomplished through the following Specific Aims: Aim 1, to determine the association of psychological distress with pain threshold and tolerance using thermal and ischemic pain techniques; Aim 2, to determine whether helplessness, optimism, and pessimism are associated with defined patterns of self-reported pain, pressure pain threshold and distress in patients with fibromyalgia and other rheumatologic disorders; and Aim 3, to determine whether our preliminary data showing an inverse relationship of distress and pressure pain threshold in fibromyalgia and other rheumatic disease patients receiving care in an academic medical center also obtain for patients in the community. Aim 3 will allow us to determine the generalizability of our preliminary data through comparisons of the UNC Arthritis Clinic Database, which consists of information on consecutive patients obtained from completion of a self-report questionnaire, Activities and Lifestyle Index and pressure pain threshold by algometry at 4 fibromyalgia tender points and the NC Rheumatologists Database also based on the Activities and Lifestyle Index completed by patients of rheumatologists in private practice in North Carolina; in addition, cross-sectional - data concerning the relationship of psychological distress and pressure pain threshold by algometry will be obtained in a subset of patients with fibromyalgia and other diagnoses under the care of NC rheumatologists.

Thesaurus Terms: chronic pain, fibromyalgia, pain threshold, psychological adaptation, psychological stressor attitude, life style behavioral /social science research tag, clinical research, human subject

Institution: UNIVERSITY OF NORTH CAROLINA CHAPEL HILL
Fiscal Year: 2001
Department:
Project Start:
Project End:
ICD: NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES
IRG: ZAR1

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PILOT STUDY OF ACUPUNCTURE IN FIBROMYALGIA

Grant Number: 5R01AT000004-02
PI Name: CLAUW, DANIEL J.
PI Title: ASSOCIATE PROFESSOR
Project Title: PILOT STUDY OF ACUPUNCTURE IN FIBROMYALGIA

Abstract: Fibromyalgia is the second most common rheumatic disorder, affecting approximately 8 - 10 million persons in the U.S. This condition is characterized by the presence of widespread musculoskeletal pain, and of soft tissue tenderness on examination. Although there are several therapeutic modalities that have been demonstrated to be somewhat effective in relieving the symptoms of fibromyalgia, despite these treatments most persons with this illness continue to be quite debilitated. Acupuncture, although considered an alternative therapy in the West, has been demonstrated to be effective in treating several conditions, and a growing data base suggests that acupuncture may be a particularly effective and safe intervention for a variety of pain syndromes. Since the cardinal manifestation of fibromyalgia is pain, and current treatments are frequently ineffective, fibromyalgia is an ideal disorder to examine for efficacy with this treatment modality. Although there have been anecdotal reports of the efficacy of fibromyalgia, there has only been one randomized controlled trial, and there are numerous methodological problems with this study that limit the interpretation of these data. This pilot study will examine numerous issues regarding the use of acupuncture as a therapeutic modality in fibromyalgia, so that a full scale randomized controlled trial (RCT) could be performed in this condition. The issues which will be examined include: 1) the optimal duration and frequency of treatment, 2) the independent and synergistic effects of needle placement and needle stimulation on efficacy, and 3) appropriate control strategies. The present proposal utilizes a randomized, blinded, sham-controlled design that incorporates several unique aspects to accomplish these aims. A 2 X 2 factorial design will be used examine the individual and synergistic effects of both needle placement and of needle stimulation on the efficacy of acupuncture. The four arms of the trial will include: 1) active site, with stimulation, 2) active site, without stimulation, 3) sham site, with stimulation, and 4) sham site, without stimulation. In each of the four arms of the trial, subjects will receive acupuncture in escalating frequency, beginning at once weekly and culminating in three times weekly. This "forced-titration" design is commonly used in the preliminary phases of drug (development, to examine the optimal dose of a medication for each person in a trial. In this manner, we will be able to determine the "dose-effect" for the analgesic effect of acupuncture in each person, and in each group. This design allows the detection of inter-patient differences in responsiveness to acupuncture, as well as the factors which may predict responsiveness (or a lack thereof). Secondary goals of the study are to collect pilot data on the mechanism, safety, and cost-effectiveness of acupuncture in fibromyalgia, and to determine the optimal outcome measures, for a full-scale RCT.

Thesaurus Terms: acupressure /acupuncture, fibromyalgia, human therapy evaluation analgesic, clinical trial, dosage, health care cost /financing, pain alternative medicine, clinical research, human subject

Institution: GEORGETOWN UNIVERSITY
Fiscal Year: 2000
Department: MEDICINE
Project Start: 30-SEP-1999
Project End: 31-JUL-2002
ICD: NATIONAL CENTER FOR COMPLEMENTARY & ALTERNATIVE MEDICINE
IRG: ZRG7

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CONTROLLED FAMILY STUDY IN PATIENTS WITH FIBROMYALGIA

Grant Number: 5R01AR046054-03
PI Name: ARNOLD, LESLEY M.
PI Title: ASSOCIATE PROFESSOR
Project Title: CONTROLLED FAMILY STUDY IN PATIENTS WITH FIBROMYALGIA

Abstract: Fibromyalgia, a chronic musculoskeletal pain disorder of unknown etiology, is a significant public health problem. Evidence from studies of phenomenology, comorbidity, family history, and pharmacologic treatment response suggest that fibromyalgia may be associated with major mood disorder, and possibly to a proposed group of conditions known as affective spectrum disorders. Prior psychiatric research has demonstrated that major mood disorder is highly familial. Family history studies provide a method by which to assess how medical disorders co-aggregate in families and, therefore may share a common risk factor or pathophysiologic mechanism. To date, few studies have explored the morbid risk of major mood disorder (and other proposed affective spectrum disorders) in probands with fibromyalgia and their first- degree relatives. All of these studies have used the family history method, which entails interviewing probands regarding their knowledge of psychiatric illness in relatives. Although most of these studies have provided important preliminary data suggesting an association between fibromyalgia and major mood disorder, this method has been demonstrated to be less sensitive in detecting illness in relatives than direct interview (the family interview method). In order to provide further evidence of a relationship between fibromyalgia and major mood disorder, we propose to study the prevalence of psychiatric and rheumatologic disorders in probands with fibromyalgia and their first-degree relatives as compared to probands with rheumatoid arthritis and their relatives using the family interview method. In addition to assessing the degree of co-aggregation of these disorders within families, we will also study the occurrence of other conditions within the proposed group of affective spectrum disorders in relation to fibromyalgia, and the association between the severity of fibromyalgia symptoms and the presence of major mood disorder within families.

Thesaurus Terms: comorbidity, family genetics, fibromyalgia, mood disorder, rheumatoid arthritis anxiety disorder, bipolar depression, chronic fatigue syndrome, interview, irritable bowel syndrome, major depression, mental health epidemiology, migraine clinical research, human subject

Institution: UNIVERSITY OF CINCINNATI
Fiscal Year: 2001
Department: PSYCHIATRY
Project Start: 01-JUL-1999
Project End: 30-JUN-2002
ICD: NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES
IRG: ZAR1

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RENEWAL OF THE NEW JERSEY CFS CRC

Grant Number: 5U01AI032247-10
PI Name: NATELSON, BENJAMIN H.
PI Title:
Project Title: RENEWAL OF THE NEW JERSEY CFS CRC

Abstract: We propose to continue the work of our CFS CRC. The central theme and goal of the Center is to stratify CFS patients based on differences in cardiovascular and neuropsychological function. The purpose of our Center will be to continue to use the syndromic approach to identify subgroups of patients with different putative organic causes for their fatiguing illness. In the past grant cycle, we have identified two such -- one implicating the brain and another implicating abnormalities in peripheral cardiovascular function. We plan to bring in CFS patients and categorize them based on the variables that track these putative organic causes -- namely cognitive dysfunction and cardiac stroke volume. By using a median split approach, we will have data from 4 groups of patients and can make a priori hypotheses about which group will show the biggest differences from our sedentary healthy controls during experimental testing. The work we propose begins at the molecular level of serotonin receptor function and spinal fluid constitution, moves on to the physiological level in experiments on brain blood flow, on the structure and function of the heart, and on orthostatic intolerance and continues to the system level in a longitudinal study that follows the illness patterns of different subsets of CFS patients over time. Thanks to prior NIAID support, we have put together a broad team of experts -- all with major interests in understanding CFS. The group is headed by a neurologist-scientist and is comprised of psychologists, physiologists expert in behavioral medicine, exercise and activity assessments, and a superb statistician. New collaborations were initiated - one with a physician in Germany who is expert in autoantibodies and another with an NIMH researcher expert in central factors in fatiguing illness. We propose a three tiered strategy for the next 5 years of our Center's activities. First, we will use ideas synthesized from data generated from our original Center to fuel new studies aimed at understanding the abnormalities and/or causes of CFS. The second tier uses probes known to uncover subtle abnormalities in brain and cardiovascular function. The third tier is a longitudinal study of CFS to determine the pattern of illness over time and how illness and psychosocial factors interact over time.

Thesaurus Terms: chronic fatigue syndrome, cooperative study

Institution: UNIV OF MED/DENT NJ NEWARK
Fiscal Year: 2000
Department: NEUROSCIENCES
Project Start: 30-SEP-1990
Project End: 31-JUL-2003
ICD: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
IRG: ZAI1

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RBC MASS, ANS INTEGRITY & SYNCOPE SUSCEPTIBILITY IN CFS

Grant Number: 1R01HL065668-01
PI Name: HURWITZ, BARRY E.
PI Title: ASSOCIATE PROFESSOR
Project Title: RBC MASS, ANS INTEGRITY & SYNCOPE SUSCEPTIBILITY IN CFS

Abstract: The pathogenesis of the chronic fatigue syndrome (CFS) includes severe and debilitating fatigue, orthostatic intolerance, and the disruption of hematological, autonomic, and cardiovascular function. Our preliminary findings suggest that: 1) reduced red blood cell (RBC) mass is a critical hematological marker of CFS; and 2) RBC mass expansion improves orthostatic tolerance and fatigue beyond that ascribed to plasma volume expansion alone. However, the physiologic mechanisms underlying the RBC mass treatment effect and the relationship of such mechanisms to individual differences in treatment response have not been elucidated. This proposed 5-year study will screen 150 CDC-defined CFS men and women and classify them into low and normal RBC mass groups. The CFS subjects (90 of 105 enrolled) will be studied before and after a 3-month intervention in a randomized double-blind, placebo-controlled study of pharmacotherapy to expand RBC mass; specifically, two CFS groups with low RBC (RBC-treated and placebo-treated) will be compared to another CFS group with normal RBC mass (standard and usual care). To assess whether the diminished cardiac function, characteristic of CFS orthostatic intolerance, is a consequence of myocardial origin, echocardiographic evaluation of left ventricular structure and function (left ventricular mass and wall thickness, compliance, and contractility) will be performed. In addition, autonomic integrity will be assessed during a standardized battery of tests (supine rest, paced respiration, Valsalva maneuver, lying-to standing, and sustained handgrip); baroreceptor sensitivity and alpha- and beta-adrenoceptor sensitivity will he tested using adrenoceptor pharmacologic challenge (phenylephrine, isoproterenol). To determine orthostatic susceptibility, a 70 head-up tilt (HUT) test combined with beta-adrenoceptor infusion at 2 mug/min (and then again at 5 mug/min, if the previous HUT failed to induce orthostatic hypotension) will be performed. We will further examine the treatment effect on exertional fatigue and hemodynamic and autonomic physiologic response to the HUT tests. Finally, the relation between the criterion (orthostatic hypotension susceptibility) and the predictors (hemodynamic, autonomic, cardiac structure/function and baroreceptor, alpha-adrenoceptor and beta-adrenoceptor sensitivities) will be evaluated to determine the extent to which the predictors are mediating the treatment effects on orthostatic hypotension susceptibility.

Thesaurus Terms: blood volume, cardiovascular disorder chemotherapy, cell volume, chronic fatigue syndrome, erythrocyte, human therapy evaluation, postural hypotension, syncope

Institution: UNIVERSITY OF MIAMI
Fiscal Year: 2000
Department: PSYCHOLOGY
Project Start: 27-SEP-2000
Project End: 31-JUL-2004
ICD: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
IRG: ZRG1

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5-HT1 RECEPTORS AND PROTEIN SYNTHESIS PATHWAYS

Grant Number: 5R01MH060100-02
PI Name: COWEN, DANIEL S.
PI Title: ASSISTANT PROFESSOR
Project Title: 5-HT1 RECEPTORS AND PROTEIN SYNTHESIS PATHWAYS

Abstract:
This abstract is not available.

Thesaurus Terms: G protein, protein biosynthesis, receptor coupling, serotonin receptor adenylate cyclase, antidepressant, biological signal transduction, hippocampus, mitogen activated protein kinase, nuclear factor kappa beta, pertussis toxin, receptor expression, second messenger tissue /cell culture, transfection

Institution: UNIV OF MED/DENT NJ-R W JOHNSON MED SCH
Fiscal Year: 2000
Department: PSYCHIATRY
Project Start: 01-AUG-1999
Project End: 31-JUL-2003
ICD: NATIONAL INSTITUTE OF MENTAL HEALTH
IRG: ZRG1

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CHRONIC FATIGUE SYNDROME COOPERATIVE RESEARCH CENTERS

Grant Number: 5U19AI038429-06
PI Name: BUCHWALD, DEDRA S.
PI Title: PROFESSOR
Project Title: CHRONIC FATIGUE SYNDROME COOPERATIVE RESEARCH CENTERS

Abstract: The University of Washington (UW) Chronic Fatigue Syndrome Cooperative Research Center (CFS CRC) continues an integrated, multi- faceted research program that capitalizes on several large, well-organized data bases already collected and addresses a number of practical and theoretical issue sin the epidemiology, clinical assessment, etiology and pathophysiology of CFS. The 4 Projects reflect our central theme: the examination of genetic and environmental influences on the biological and psychosocial characteristics of CFS. Our research has sought to operationalize an explanatory model of CFS that emphasizes 5 dynamic elements and their interaction with respect to risk, onset and course. These elements referred to as the "5 Ps" include predisposing, precipitating, predictive, perpetuating and perceptual factors. CFS may occur in a vulnerable individual in whom genetic, environmental or other predisposing factors are present. Subsequently, an acute or chronic stressor precipitates illness. During a transition period, predictors of chronically become apparent. Symptoms lead to disability, which is both due to, and results in, psychological distress, social dysfunction and other factors that perpetuate illness. Lastly, the individual's perceptual style serves as a context in which the other 4 factors affect the illness. With this model in mind, the objectives of the next period of support for this CFS CRC are to: 1) further characterize CFS using monozygotic twins discordant for CFS and to expose subjects to biological and behavior "stressors" in a theoretically guided fashion to investigate predisposition and perceptions in CFS; 2) confirm the clinical and laboratory abnormalities seen in our current intensive study of CFS-discordant monozygotic twins in sleep, neuropsychological function, immunological parameters and exercise capacity by re-examining these twins and adding a new comparison group of health twin pairs; 3) to define the relative contributions of predispositional genetic or common environmental effects using biometrical genetic analyses of population-based twin study; 4) compare the children of CFS cases and the children of healthy controls to determine the impact of parental illness and to examine if predispositional and perceptual styles are vertically transmitted across generation; 5) explore the role of perpetuators and perceptions in the context of an observational study of interactions between CFS patients and their partners; and 6) to follow-up a well-characterized patient sample to further describe the natural history, prognosis and predictors of outcome of CFS.

Thesaurus Terms: chronic fatigue syndrome, cooperative study, family genetics, genetic susceptibility

Institution: UNIVERSITY OF WASHINGTON
Fiscal Year: 2000
Department: MEDICINE
Project Start: 30-SEP-1995
Project End: 31-JUL-2003
ICD: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
IRG: ZAI1
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