THERAPEUTIC EFFECT OF EMFS ON NEURAL PROCESSES/FUNCTIONS

Grant Number: 5R01AT000483-02
PI Name: TUTTLE, JEREMY B.
PI Title: ASSOCIATE PROFESSOR
Project Title: THERAPEUTIC EFFECT OF EMFS ON NEURAL PROCESSES/FUNCTIONS

Abstract: Magnetic devices and therapies are gaining rapid acceptance among some groups, even in the absence of reliable outcome data. This Center is focused upon the potential treatment with electromagnetic fields (EMFs) of fibromyalgia and the sequelae to CVA and closed head trauma. Despite considerable effort, it is still not clear how biological systems might be responding to therapeutically applied EMFs. The development and refinement of this potential new mode of therapy will be advanced considerably by a more explicit understanding of what basic biological processes are responsible for the desired therapeutic effects. This project will examine the effect of therapeutic magnetic fields upon specific neural processes and functions, in the effort to outline potential biosensors for EMFs in the nervous system. The tests will be conducted in vitro upon reasonable cellular reductionist models of events in the nervous system. In each case, EMF effects under basal and stressed conditions will be examined. Specific aims will measure magnetic field effects upon: l) Fiber regeneration by peripheral and central neurons. Primary neurons in culture will be used and the rate of regeneration of neurites measured. 2) Synapse formation and maturation. Cultures of peripheral neurons and muscle, as well as central neurons, will be examined for synapse formation and function at various times after isolation. 3) Calcium signaling via cytosolic transients in nerve and muscle cells. Fura-2 imaging will be used to examine EMF effects on IP3-mediated calcium signaling in primary cultures of muscle and human neuroblastoma cells. 4) Synthesis and release of neurotrophins. The production of NGF at the cellular level by muscle, neuroblastoma and glial cells will be examined. 5) Cell death and neuroprotective gene expression. EMF effects on induction of apoptosis and expression of free-radical scavengers and bcl-2 will be tested. Each of these test areas relates to a biological process involved in the response of the nervous system to injury or disorder and thus may be involved in the therapeutic efficacy of magnetic fields. The results of these largely exploratory experiments will outline likely basic biological processes capable of responding to EMF with a desirable therapeutic effect.

Thesaurus Terms: alternative medicine, electromagnetic radiation, evaluation /testing, magnetic field, neural information processing, neurophysiology apoptosis, biological signal transduction, brain injury, fibromyalgia, free radical scavenger, nervous system regeneration, stroke, synapse laboratory rat, tissue /cell culture

Institution: UNIVERSITY OF VIRGINIA CHARLOTTESVILLE
Fiscal Year: 2001
Department: NEUROSCIENCE
Project Start: 01-JUN-2000
Project End: 31-MAR-2005
ICD: NATIONAL CENTER FOR COMPLEMENTARY & ALTERNATIVE MEDICINE
IRG: ZAT1

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SENSORY TESTING IN PATIENTS WITH CHRONIC MUSCULOSKELETAL PAIN SYNDROMES

Grant Number: 5M01RR000082-390650
PI Name: STAUD, ROLAND
PI Title:
Project Title: SENSORY TESTING IN PATIENTS WITH CHRONIC MUSCULOSKELETAL PAIN SYNDROMES

Abstract: The purpose of this study is to gain new information to improve current methods for diagnosing the condition of fibromyalgia.

Thesaurus Terms: fibromyalgia, muscle disorder diagnosis, sensorimotor system diagnosis design /evaluation clinical research, human subject

Institution: UNIVERSITY OF FLORIDA
Fiscal Year: 2001
Department:
Project Start:
Project End:
ICD: NATIONAL CENTER FOR RESEARCH RESOURCES
IRG:

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FOREBRAIN MECHANISMS IN CHRONIC NON-NEUROPATHIC PAIN

Grant Number: 1R01AR046045-01A1
PI Name: CASEY, KENNETH L.
PI Title: PROFESSOR
Project Title: FOREBRAIN MECHANISMS IN CHRONIC NON-NEUROPATHIC PAIN

Abstract: Psychophysical studies have shown that patients with fibromyalgia (FM) have cutaneous heat and pressure thresholds that are lower and ratings of these stimuli that are higher than normal. Patients with the chronic pain of arthritis (CPA) have similar, but less severe, hypersensitivity to cutaneous heat and pressure stimuli. These abnormalities may reflect an amplification of forebrain nociceptive processing due to continual nociceptive input (CPA), or primary adaptive changes in CNS nociceptive processing (FM). We will obtain psychophysical measurements of the thresholds and perceived intensities and unpleasantness of cutaneous heat and somatic pressure stimuli in all subjects. We will use H215O positron emission tomography (PET) to test the overall hypothesis that FM and CPA patients have correspondingly larger stimulus-evoked increases in regional cerebral blood flow (rCBF) within bilateral volumes of interest (VOI; thalamus, insula, and the sensorimotor (S1/M1), S2, anterior cingulate, and premotor (B6) cortices) than normal subjects. Because FM occurs primarily in women, we will study two groups of right-handed female patients: 20 with FM and 20 with CPA, and compare their rCBF responses to those of 20 normal women within the same age range (20-50 years). Patients will rate their clinical pain at or above 4 on a visual analog scale of pain (VAS; 0-10) and will complete a short-form McGill Pain Questionnaire (VAS, MPQ). Standard VOI will be developed in normal subjects from peak rCBF increases within the above structures in response to heat stimuli applied at 35EC, heat pain threshold (HPT), heat pain tolerance (Hptol), and at 3 additional intensities anchored symmetrically around HPT and below Hptol. These standard VOI and stimulus intensities will be used to determine the correlation between rCBF increases and applied stimulus intensity and perceived unpleasantness, as estimated with a VAS, in normal subjects and in patients with FM or CPA who have not been taking opioid analgesic or psychoactive medication for one month. We predict that the psychophysical responses, and the rCBF responses within one or more VOI will be larger in FM and CPA patients than in normal subjects. These same studies will be performed again after all patients have been taking nortriptyline (NT) and/or physical therapy (PT) for approximately one year. Normal subjects will take NT for 3 weeks before the second PET scan (1 year later). We predict that both patient groups, but not normal subjects, will show clinical pain scores, stimulus-evoked psychophysical responses, and rCBF responses, in one or more VOI, that are less than those obtained before NT or PT treatment. We will also examine differences between FM and CPA patients. Support for the overall and correlative hypotheses will constitute evidence that, in the absence of peripheral causes, the pain experienced by FM and CPA patients is due, at least in part, to abnormal central nociceptive processing mechanisms.

Thesaurus Terms: arthritis, brain circulation, brain scanning, chronic pain, fibromyalgia, pain threshold, prosencephalon heat stimulus, nortriptyline, psychophysics bioimaging /biomedical imaging, clinical research, female, human subject, positron emission tomography, questionnaire

Institution: UNIVERSITY OF MICHIGAN AT ANN ARBOR
Fiscal Year: 2000
Department: NEUROLOGY
Project Start: 30-SEP-2000
Project End: 31-AUG-2003
ICD: NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES
IRG: ZRG1

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BIOMARKERS OF HOMEOPATHY IN FIBROMYALGIA

Grant Number: 3R21AT000315-01S1
PI Name: BELL, IRIS R.
PI Title: ASSOCIATE PROFESSOR
Project Title: BIOMARKERS OF HOMEOPATHY IN FIBROMYALGIA

Abstract: DESCRIPTION (Adapted from Applicant's Abstract): Clinical researchers have not yet demonstrated therapeutic effectiveness of any single intervention that can target the polysymptomatic nature of FM, a chronic debilitating nonarticular rheumatic disorder. Classical homeopathy, a controversial alternative therapy, claims to provide such an integrative intervention to treat the totality of symptoms. This revised R21, 2-year exploratory effectiveness study will involve a 3-month parallel group (N=60), randomized, placebo-controlled, double-blind clinical trial, with an additional 3-month optional crossover, double-blind trial of individualized homeopathic treatment of FM. We will use self-report questionnaires, tender point examinations, and physiological markers of response to the homeopathic remedies and placebo (i.e., EEG alpha activity and orthostatic HRV. Specific aims and hypotheses are: 1) to evaluate the effectiveness of individually-chosen homeopathic treatment for the mental, emotional and somatic symptomatology of FM under double-blind conditions in which active and placebo-treated groups receive the same amount of attention using the same treatment procedures and differ only in the contents of the dispensed drug vials. The investigators hypothesize that individually chosen homeopathic remedies will lead to improvement in spiritual, mental, emotional, and somatic symptoms of FM than will placebo; 2) to determine the ability of acute changes in EEG alpha activity to differentiate active from placebo homeopathic remedies upon olfactory administration in FM patients and to predict subsequent responders and non-responders to treatment. The prediction is that active homeopathic remedies will lead to greater EEG alpha blocking than placebo; and 3) to assess resting EEG alpha power and orthostatic HRV as markers of global clinical improvement in FM over time. Global clinical improvement in FM will correlate with parallel improvements in resting EEG and orthostatic HRV.

Thesaurus Terms: alternative medicine, fibromyalgia, human therapy evaluation biomarker, clinical trial clinical research, electroencephalography, heart rate, human subject, questionnaire

Institution: UNIVERSITY OF ARIZONA
Fiscal Year: 2001
Department: PSYCHIATRY
Project Start: 01-AUG-2000
Project End: 31-MAY-2002
ICD: NATIONAL CENTER FOR COMPLEMENTARY & ALTERNATIVE MEDICINE
IRG: ZAT1

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MAPPING GENES FOR FIBROMYALGIA SYNDROME

Grant Number: 3N01AR092235-002
PI Name: OLSON, JANE
PI Title:
Project Title: MAPPING GENES FOR FIBROMYALGIA SYNDROME

Abstract: The purpose of the contract is to support a core facility dedicated to the collection and characterization of Fibromyalgia syndrome (FMS) families, uni and multiplex for FMS. The facility will operate two simultaneous activities. It will serve as a Registry of FMS pedigrees by collecting, validating and updating clinical, demographic and laboratory data on families with two or more members affected with FMS. Individuals will be considered to be affected with FMS if they meet the American College of Rheumatology criteria for primary FMS, including 11 of 18 tender points on examination and a history of widespread pain for at least three months, and absence of other heumatologic disease, chronic infection, or other concomitant disease, as evidenced by patient history, examination and routine Chemistry blood panel. Phenotype information collected will also include measurement of platelet serotonin level and the presence or absence and/or degree of FMS-related symptoms, including morning stiffness, sleep difficulty, fatigue, gastrointestinal symptoms, headache, depression, and stress. The facility will also operate as a repository of DNA and will store and manage genotyping data of the families enrolled. In addition, the investigators will also conduct genetic linkage analysis. The contents of the database, DNA samples and genotypes will be made available to basic and clinical researchers. The NIAMS expects that the availability of these resources will encourage and accelerate research in the genetic bases of FMS. The contract includes an option to extend the period of performance from 9/29/2000 to 9/29/2003

Thesaurus Terms: family genetics, fibromyalgia, genetic mapping, genetic registry /resource /referral center, patient /disease registry blood chemistry, case history, linkage mapping clinical research, human subject

Institution: CASE WESTERN RESERVE UNIVERSITY Fiscal Year: 2000 Department: EPIDEMIOLOGY AND BIOSTATISTICS Project Start: 30-SEP-1999 Project End: 29-SEP-2003 ICD: NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES IRG:

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BEHAVIORAL INSOMNIA THERAPY FOR FIBROMYALGIA PATIENTS

Grant Number: 5R21AR046094-03
PI Name: EDINGER, JACK D.
PI Title: ASSOCIATE CLINICAL PROFESSOR
Project Title: BEHAVIORAL INSOMNIA THERAPY FOR FIBROMYALGIA PATIENTS

Abstract: Fibromyalgia (FM) is a prevalent and debilitating condition which contributes to impaired occupational/social functioning and increased disability among affected individuals. The vast majority of FM patients present with persistent sleep disturbances (e.g. onset difficulty; repeated or extended awakenings; nonrestorative sleep) which worsen other FM-related symptoms (e.g. chronic pain, fatigue) and sustain their general dysfunction. Pharmacologic treatments (e.g. antidepressants, hypnotics) may produce symptom reduction for some FM patients but many FM patients display little enduring improvement in their sleep and other FM-related symptoms in response to such agents. Our clinical observations and initial pilot work have suggested that factors common among other insomnia subtypes such as conditioned bedtime arousal, erratic sleep/wake scheduling and spending too much time in bed likely perpetuate the sleep problems of these medication-refractory FM patients. Over the past decade, we have developed, refined, and repeatedly tested a cognitive-behavioral therapy (CBT) which has proven effective for reducing sleep disturbances perpetuated by such underlying cognitive/behavioral mechanisms. Moreover, as suggested by the case study reported herein, this treatment holds promise for addressing medication-refractory FM-related sleep disturbance. The proposed project's Specific Aims/Major Objectives entail conducting a prospective randomized clinical trial to confirm these preliminary findings and to determine the efficacy of CBT insomnia treatment for interrupting the disturbed nocturnal sleep/daytime pain, fatigue and distress symptom complex which defines FM. One arm of this study's 3 x 4 factorial design will compare CBT with both a contact control treatment and standard care. The other arm in the design is a repeated-measures factor consisting of 4 time points (i.e. baseline, mid-treatment, post-treatment, and 6 month follow-up periods) at which outcome is assessed. Subjects will be assessed at all 4 time points with objective (wrist actigraphy) and subjective (sleep logs, Insomnia Symptom Questionnaire) measures of sleep improvements, measures of subjective pain, and questionnaires which assess mood (State-Trait Anxiety and Beck Depression Scales) and general quality of life (SF-36). Multivariate statistics and tests of clinical significance will be conducted with these various measures. Exploratory analyses will also be conducted to determine if polysomnographically-derived sleep measures obtained prior to treatment correlate with initial levels of pain/distress or eventual treatment outcome. Results should provide information about the usefulness of CBT for treating FM-related sleep difficulties. Results should also improve understanding of the FM syndrome in general and provide new information about the potential role of behavioral therapy in the overall management of this disorder.

Thesaurus Terms: cognitive behavior therapy, fibromyalgia, human therapy evaluation, sleep disorder clinical trial, emotion, pain, personal log /diary, quality of life, wakefulness behavioral /social science research tag, clinical research, human subject, outcomes research, polysomnography, questionnaire

Institution: DUKE UNIVERSITY
Fiscal Year: 2001
Department: PSYCHIATRY AND BEHAVIORAL SCIS
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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EXERCISE INDUCED CHANGES IN HPA ACTIVITY IN FIBROMYALGIA

Grant Number: 5R01AR046016-02
PI Name: DEUSTER, PATRICIA A.
PI Title:
Project Title: EXERCISE INDUCED CHANGES IN HPA ACTIVITY IN FIBROMYALGIA

Abstract: Five to 10 percent of patients entering general practice centers report symptoms of fibromyalgia syndrome (FMS), a painful and debilitating condition of the musculoskeletal system. Although the cause(s) and pathophysiology of this disorder are poorly understood, FMS has been referred to as a syndrome of physical deconditioning and involves dysregulation of the hypothalamic- pituitary-adrenal (HPA) axis. Interestingly, regular exercise has been shown to confer benefit for some patients with FMS, as well as rheumatoid arthritis and depression. Importantly these health conditions all have the common element of reduced hypothalamic drive for pituitary adrenal function. Thus, exercise may confer benefit in FMS by upregulating hypothalamic drive to the pituitary and adrenal glands. The overall objective of this proposal is to determine whether aerobic training benefits FMS by inducing alternations in HPA axis regulation. The central hypothesis is that aerobic training serves to enhance hypothalamic drive, and thus pituitary-adrenal function. Specifically, 20 patients with FMS and 20 age-, gender-, weight-matched controls will be challenged at baseline; after 12 weeks with no intervention (control), and after 12 weeks of aerobic conditioning to evaluate whether aerobic training results in: (1) An increase in hypothalamic drive as evidenced by augmented adrenocorticotropin (ACTH) responses to a standardized exercise test (SET); (2) An increase in tonic and stimulated hypothalamic drive as evidenced by augmented ACTH responses following administration of metyrapone and dexamethasone (DEX) coupled with SET; (3) An increase in hypothalamic-pituitary responsiveness as evidenced by augmented ACTH responses stimulated by a bolus of ovine corticotropin releasing hormone (o-CRH) after pretreatment with DEX; and (4) Improved clinical and psychological profiles in FMS. Plasma ACTH will be used to assess hypothalamic drive during four challenge tests: (a) SET for control stimulation; (b) SET during enhancement of glucocorticoid negative feedback by DEX; (c) tonic and SET during attenuation of glucocorticoid negative feedback by metyrapone; and (d) responsivity of pituitary corticotropes following a bolus of o-CRH during enhancement of glucocorticoid negative feedback by DEX. Finally, disease activity (tender point index, tender point score, and myalgic score), and self-reported physical measures of function, depression and self efficacy will be used to assess clinical and psychological profiles over the course of the study. The information gained will provide an understanding of the pathology of FMS and the mechanisms by which exercise confers benefit in FMS. Given the important role exercise serves in the prevention of disease, this information will also contribute to our basic knowledge regarding how exercise modulates HPA axis reactivity in health and, in so doing suggest, mechanisms for HPA dysregulation in disease.

Thesaurus Terms: adrenocorticotropic hormone, aerobic exercise, fibromyalgia, hormone regulation /control mechanism, hypothalamic pituitary adrenal axis arginine vasopressin, corticotropin releasing factor, depression, dexamethasone, emotion, metyrapone, pain, self concept clinical research, human subject, human tissue, questionnaire, urinalysis

Institution: HENRY M. JACKSON FDN FOR THE ADV MIL/MED
Fiscal Year: 2000
Department:
Project Start: 15-SEP-1999
Project End: 31-AUG-2002
ICD: NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES
IRG: ZAR1

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HPA AXIS DYSREGULATION IN FIBROMYALGIA

Grant Number: 5R01AR043148-06
PI Name: CROFFORD, LESLIE J.
PI Title: ASSOCIATE PROFESSOR
Project Title: HPA AXIS DYSREGULATION IN FIBROMYALGIA

Abstract: DESCRIPTION: (Adapted from the Investigator's Application): Fibromyalgia (FM) and chronic fatigue syndrome (CFS) share many clinical features; however, we believe the difference in the dominant symptomatic manifestations, pain in FM and fatigue in CFS, reflect divergence of their biological phenotype. The onset and course of both syndromes appear to be influenced by physical or emotional stress. The physiologic response to stress is characterized by activation of the hypothalamic-pituitary-adrenal (HPA) axis. Ongoing studies of the HPA axis have uncovered perturbations of the pulsatile and circadian architecture of pituitary-adrenal secretion that may yield clues to the biologic divergence between FM and CFS. The findings in FM suggest psychophysiological arousal, while those in CFS suggest hypoarousal. Both syndromes are also characterized by non-restorative sleep, which is likely to be related, in a bi-directional manner, to the observed HPA axis disturbances. Analysis of the relationships between neuroendocrine secretory patterns and sleep-wake physiology provides a means to test the functional integrity of neural systems responsible for circadian rhythmicity, sleep regulation and hormonal release. The specific hypotheses to be tested in this proposal are: a) HPA axis abnormalities in FM and CFS are mediated centrally at the level of the hypothalamus through failure of integration of neurochemical systems controlling basal and stimulated hormone secretion, b) a relationship exists between mechanisms controlling sleep and HPA axis activity, such that correlations between neuroendocrine and sleep parameters will be present, and c) although abnormal HPA axis activity occurs in both FM and CFS, there are distinctions in the central inputs to the axis resulting in psychophysiological arousal in FM patients and hypoarousal in patients with CFS that may be revealed by close examination of specific components of the HPA axis and provocative testing of sleep architecture. The applicants propose to measure the dynamic pulsatile and circadian characteristics of the basal pituitary adrenal rhythm in FM and CFS patients under the influence of metyrapone, to inhibit glucocorticoid negative feedback and emphasize divergence in the central components of the HPA axis. they will examine the effects of the exogenously administered pituitary corticotroph secretagogues on pituitary-adrenal response in the study groups. They wll analyze sleep regulation and correlate sleep parameters with neuroendocrine hormone secretion. The results of these studies should further our understanding of the role of the HPA axis in the pathogenesis and clinical expression of FM and CFS, enlarge our understanding of the relationship between these two syndromes, and in so doing, make the informed development of reasonable diagnostic approaches and treatment interventions more likely.

Thesaurus Terms: chronic fatigue syndrome, fibromyalgia, hormone regulation /control mechanism, hypothalamic pituitary adrenal axis, pathologic process adrenocorticotropic hormone, arginine vasopressin, arousal, circadian rhythm, corticotropin releasing factor, endocrine disorder, melatonin, metyrapone, psychophysiology, secretion, sleep deprivation blood chemistry, clinical research, human subject, urinalysis

Institution: UNIVERSITY OF MICHIGAN AT ANN ARBOR
Fiscal Year: 2000
Department: INTERNAL MEDICINE
Project Start: 30-SEP-1994
Project End: 31-AUG-2001
ICD: NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES
IRG: ZRG5

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