Neurophysiopathogenesis of Fibromyalgia Syndrome: A Unified Hypothesis
Section snippets
Nociception, pronociception, antinociception, descending inhibition
A simple model of normal centrally regulated nociception can be envisioned with an outlying block of peripheral tissue, an afferent neuron, the spinal cord, the brainstem, and the brain (Fig. 1).10, 11 Nociception can be viewed as being composed of two opposed components—pronociception and antinociception. A sensory signal generated by a stimulus to the peripheral tissue is carried to the dorsal horn of the spinal cord by an unmyelinated afferent nerve (a-delta and c-fibers). In the dorsal
Spinal fluid levels of neurochemicals in fibromyalgia
Abnormal levels of key neurotransmitters and neuromodulators (or their metabolites) in the cerebrospinal spinal fluid (CSF) of persons with FMS provide a molecular mechanism for the observed neurofacilitation. For example, there is documentation of lower than normal levels of CSF biogenic amine metabolites (Fig. 3)14 and elevated levels of CSF substance P (facilitator of pronociception) (Fig. 4)15 and NGF (facilitator of substance P production) (Fig. 5).16 An attempt to document elevated levels
Medication therapy
These abnormal findings have predicted the responses of FMS patients to medications that now have been extensively tested in FMS cohorts and have been approved by the US Food and Drug Administration for the treatment of patients with FMS. One of these agents (pregabalin) is believed to reduce the magnitude of the enhanced pronociception process in FMS,19, 20, 21 whereas the other two (duloxetine and milnacipran) are believed to promote antinociception in the compromised descending inhibition
Medical imaging documents allodynia in fibromyalgia
Studies using functional MRI have provided objective support for clinical allodynia in patients with FMS.31 In one study, the amount of pressure was determined (the stimulus to a peripheral tissue, the thumbnail bed of the dominant hand) that would create the same clinical experience of moderately severe pain for patients with FMS and HNC volunteers. The stimulus was about 2.4 kg of pressure for FMS patients and about 4.5 kg of pressure for HNCs (illustrating subjective allodynia). The extent
Comorbidities in fibromyalgia
The FMS is more complicated than its pattern of pain. Many other manifestations of FMS accompany the pain in subgroups of patients. They include dysfunctional sleep, cognitive insecurity (difficulty remembering, foggy thinking, list making), mood or affective disorders, chronic daily headache, clumsiness (accident prone/stumbling/falling), compromised stress management, autonomic nervous system dysfunction, irritable bowel syndrome, and irritable bladder, to name only a few of the most
Cognitive insecurity in fibromyalgia
A common complaint of patients with FMS is that their minds are not functioning normally. They perceive that, since the onset of their symptoms, they cannot remember names, dates, events, or responsibilities as they had before FMS. A celebrated manifestation of this insecurity is evidenced by an FMS patient going to see her physician. She fears that she will forget to report important symptoms to the doctor, so she writes extensive lists of concerns and questions that would take considerably
Loss of gray matter with time in fibromyalgia
A dramatic new objective finding in FMS has been derived from voxel morphometric examination of brain MRI in FMS patients when compared with HNCs.37 The FMS patients exhibited significantly smaller than normal volumes of brain gray matter, and the loss of gray matter mass rapidly progressed with time. It was clear from the data that the FMS gray matter volume was comparable to that of controls before the symptoms began but then decreased progressively with time thereafter. The HNCs who
Seeking possible causes of gray matter atrophy in fibromyalgia
The voxel morphometric method has been used extensively for examination of brain atrophy in a variety of diseases, with the hope of developing disease pattern recognition.44 Brain atrophy could occur as a result of an insidious chronic infection, with chemically induced brain cell injury, by loss of inhibition by gamma amino butyric acid,42 or by some form of misguided apoptosis. Another possible cause might be ischemia resulting from premature atherosclerotic vascular disease. Elevated
Consequences of oxidative stress and atrophy
The presence of gray matter atrophy and oxidative stress in patients with FMS appears to be a real phenomenon; therefore, the implications of these abnormal findings must be carefully considered. One could ask how these changes would relate to the pain and other manifestations of FMS. NGF is a trophic factor whose synthesis is increased not only during development but also in response to tissue damage. With central neuronal loss, NGF would be produced in excess, as reported in patients with
Premature aging
Several findings in FMS are suggestive of premature aging. Observations have included a decline in the prevalence of FMS after age 70 years,71, 72 fragmented sleep in both,33, 73 aching stiffness in both, dyscognition in both, and loss of cortical gray matter in both (but progressing more rapidly in FMS37).
The concept of sleep dysfunction as a manifestation of premature aging of the brain in FMS came about in the following way. A population study of sleep dysfunction in normal aging adults33, 73
Genetic predisposition to develop fibromyalgia
It would be negligent not to mention the potential role of genetics in the pathogenesis of FMS. It is not our intent in this treatise to detail the variety of genetic associations with FMS because that is the subject of another scholarly offering in this issue. It is reasonable to indicate that FMS is familial. About one third of patients with FMS have a close relative who is similarly affected and, strategically, that affected other person is usually a female. Genetic associations with FMS
Unifying model of central nervous system pathogenesis in fibromyalgia
Together, these findings have led to a unified hypothesis regarding the pathogenesis of FMS (Fig. 6). The model begins with one or more of the genetic associations that might predispose the individual to undergo brain degeneration or atrophy in response to an undefined stimulus. Time and a variety of cofactors, including age, physical trauma, febrile illness, inflammation, dysfunctional sleep, and antipolymer antibody, may contribute to this process. The degeneration of cortical tissue,
Hypothetical sites for experimental intervention
The model helps to identify some sites at which experimental testing or therapeutic intervention might be fruitful. In a small clinical trial, an alternative medicine preparation was used as antioxidant therapy in FMS, but the sample size and effect size were small.47 If oxidant stress is the cause of FMS, lifestyle changes should be aggressively coupled with effective antioxidant and lipid-lowering therapies.
Potent inhibitors of the NK1 receptor are beneficial in controlling the depression of
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2020, Journal of Bodywork and Movement TherapiesCitation Excerpt :Studies suggest that the main factors causing FM are related to atypical processing of pain, dysfunctions of nociceptive components of skeletal muscle, and changes in the hypothalamic-pituitary-adrenal axis (Abeles et al., 2007). At the molecular level, a possible explanation would be the imbalance between the excitatory and inhibitory neurotransmitters of pain, causing a decrease in the pain threshold of individuals with FM (Russell and Larson, 2009). Given that FM presents as a multifactorial pathology, its treatment should be multidisciplinary and presents physical exercise as a strong evidence intervention (level 1A) (Clauw, 2014) for improving pain, general function, and quality of life (Busch et al., 2007; Gavi et al., 2014; Giannotti et al., 2014; Latorre et al., 2013; Sañudo et al., 2011).
Effects of an Extract of Salmon Milt on Symptoms and Serum TNF and Substance P in Patients With Fibromyalgia Syndrome
2019, Clinical TherapeuticsCitation Excerpt :Various studies have reported problems with allergens, central sensitization, chemical exposures, infectious agents, inflammation, irritants, and stress.8–12 Some neuroimmune mediators have been reported to be abnormal in patients with FMS, but the findings have been inconclusive.13–15 TNF was most often elevated in the serum of patients with FMS.16
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Dr. Russell is supported, in part, by the RGK Foundation of Austin, Texas. This work was also supported, in part, by Award Number UL 1RR025767 from the National Center for Research Resources. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources of the National Institutes of Health.