This is a fertile time for FMS research. Two decades of research lead many researchers to believe that the cause of FMS lies in the brain. Several recent papers, however, that suggest the pain in FMS originates in the muscles, are causing some to reassess their findings.
Kim, S. Jang, T. and I. Moon. 2006. Increased expression of N-Methyl- D- Aspartate receptor subunit 2D in the skin of patients with Fibromyalgia. J. of Rhuematology 33: 785-8.
This small study has opened a new window in the question of whether peripheral not central sensitization exists in FMS. The last issue of Phoenix Rising discussed how NMDA receptor activation is an integral part of central sensitization. We learned that increased numbers of NMDA receptors on a neuron can make it hypersensitive to glutamate, the substance that ‘opens’ the neuron.
When high numbers of NMDA receptors are present, neurons respond to small levels of glutamate; the pain-producing neurons produce large amounts of pain enhancing substances such as substance P and nitric oxide.
Recent studies indicate that glutamate plays a role not only in central sensitization but in sensitization of the peripheral nerves as well. This could be a very important point. Researchers have found that the ‘pain’ neurons in the dorsal horn of the spinal cord respond to continued, repetitive pulses of pain in a rather unusual matter; instead of becoming de-sensitized to them, they become more sensitized to them.
A chronic pattern of excitation caused by over-sensitive neurons in the periphery could, therefore, ultimately cause the pain we see in FMS. Some support for this idea comes from the natural history of this disease; FMS often starts with a initial trauma (fall, car accident, etc.) and then spreads to the rest of the body.
Unlike previous studies which limited examination to the spinal cord, this study to examines whether NMDA receptors are abnormally abundant in the periphery, in this case, the skin from the shoulder region. This study found that a particular type of NMDA receptor called NR2D was significantly increased in FMS patients.
This receptor has a particularly high affinity for glutamate and exhibits a weaker magnesium MG2+ block than the other NMDA receptors. This indicates it responds more quickly to glutamate and more quickly sheds the agent, Mg, that plugs up the NMDA ion channels (and deactivates) them; i.e. the more abundant NR2D more quickly activates the NMDA ion channels and produces pain.
The prevalence of particularly active NMDA receptors in the skin of FMS patients suggests that pro-pain substances associated with NMDA activation might also be increased. The next study examined whether an integral pain factor, brain derived nerve factor (BDNF), was increased in the serum of FMS patients
Laske C, Stransky E, Eschweiler GW, Klein R, Wittorf A, Leyhe T, Richartz E, Kohler N, Bartels M, Buchkremer G, Schott K. 2006. Increased BDNF serum concentration in fibromyalgia with or without depression or antidepressants. J Psychiatr Res. 2006 Apr 3.
As noted in the last issue of Phoenix Rising, BDNF plays a major role in how the CNS processes painful stimuli. It is also, however, quite active in the periphery – its ability to regulate the mechanoreceptors in the skin means it plays an important role in how we respond to fine sensations. This study examined BDNF levels in the serum in order to determine whether it might contribute to the sensitization of the peripheral nerves in FMS.
It found that BDNF levels were indeed significantly increased in FMS compared to controls (p<.0001) (!). But where is the increased BDNF coming from? The authors suggest three possible sources; the endothelial cells, or the smooth muscles lining the blood vessels, or activated monocytes/macrophages.
But not the neurons? Perhaps because neurons produce substances that diffuse locally and not into the bloodstream? This suggests, of course, that just as with CFS, an immune disruption could play a role in FMS. The authors note that macrophages could produce BDNF themselves or they could induce BDNF production via production of the pro-inflammatory and pro-pain cytokine, IL-6.
When an injury occurs in the periphery, the nociceptors or pain receptors in that region are activated by various substances that become liberated during trauma (e.g. bradykinins, histamine, prostaglandins. etc.). These substances trigger the production pro-pain substances such as substance P and brain-derived nerve factor (BDNF) that further sensitize the neurons. All this activity contributes to the extreme sensitivity (hyperalgesia) found in an area surrounding a wound.
But where is the wound in FMS? If the pain in FMS originates in the muscles, they must have suffered from some sort of trauma. The lack of a consistently found lesion in the muscles has bedeviled FMS researchers. In the review article below Goff examines the evidence for and against the theory that a muscle disorder is responsible for the pain present in FMS.
Goff, Paul, P. 2006. Is fibroymalgia a muscle disorder? Joint Bone Spine.
Goff believes the Sprott paper in 2004 re-opened the debate on the possibility of muscle trauma in FMS. Sprott et al. found low numbers of often enlarged mitochondria as well as lipid and glycogen accumulations in the muscles of FMS patients. They believed these reflected problems with energy metabolism.
First Goff notes that after more than 30 studies a consensus on the role muscle pathology plays in FMS has still not been reached. Surprisingly, at least part of the reason appears to be the inability of researchers to agree on what constitutes a significant morphological abnormality. Goff cited one paper that concluded no morphological abnormalities were present in FMS but which had, Goff thought, illustrations clearly illustrating morphological abnormalities.
Some problems have to do with the varying types of irregularities thus far found in FMS. Since FMS is a distinctive disease, researchers want to see distinctive abnormalities. While studies have found muscle abnormalities, there has been little consistency in the type found. The fact that some of the irregularities found sometimes also occur in healthy people suggests some of them could be relatively minor.
Goff states, however, that two types of muscle abnormalities are not only consistently found in FMS but appear to be distinctive to it. These are lesions (injuries) in parts of the muscles called the ‘Z lines’ and that suggest mitochondrial problems may be present in FM.
Z line abnormalities were found in subjects suffering from ‘overexertion of the muscles and tendons’ in the late 1980’s but Goff reports that since then they have been found only in FMS patients (four studies). Z lines are bands of muscles that are aligned with each other.
When the muscle contracts the Z lines come together; when it relaxes they separate. This appears to suggest there could be a problem with cell-coordinated muscle contraction/relaxation in FMS. The mitochondrial abnormalities seen in FMS (5 studies) have only rarely been found in healthy subjects.
Goff believes that the mitochondrial abnormalities could account for the fatigue that is brought on by exercise in FMS. Since mitochondrial myopathies are usually quite debilitating, Goff believes that the lesser debility usually found in FMS suggests that the type of myopathy found in FMS might be observable only when an individual is exerting himself.
This has echoes of Chia’s theory of exercise induced enterovirus activation in CFS. Chia believes the pathogens in CFS become fully active during exercise. He further argues that the kinds of mitochondrial abnormalities seen in FMS are obscured in two ways; first he posits they are most observable only during exercise, and two, the types of muscles usually biopsied in FMS studies are the types where it is difficult to find mitochondrial abnormalities.
Critics of the idea of peripheral trauma in FMS state that many of the lesions found appear to be too minor to satisfactorily account for the extent of debility and pain found in many FMS patients. No signs of muscle degeneration and regeneration have been found.
Nor have signs of pathological process involving inflammation. Normal muscle strength suggests no gross abnormalities in muscle functioning are present. Electrical stimulation studies indicate that the muscles are receiving the appropriate inputs from the brain. Most indices of muscle functioning in FMS are normal.
It seems that most evidence would argue against a serious muscle injury in FMS. Examinations of muscle functioning have, have however, led to an intriguing finding that suggests the problem in FMS could be in the muscle circulation. This is the next study we look at.
*Sprott, H., Salem, S., Gay, R., Bradley, L, Alarcon, G., Oh, S., 2004. Increased DNA fragmentation and ultrastructural changes in fibromyalgic muscle fibers. Am. Rheum. Dis. 63: 245-51.
FMS is a microcirculatory disorder?
Morf, S., Amann-Vesti, B., Forster, A., Franzeck, U., Koppensteiner, R.,Uebelhart, D. and H.Sprott. 2005. Microcirculation abnormalities in patients with fibromyalgia – measured by capillary microscopy and laser fluxometry. Arthritis Res Ther. 7:R209-R216 (DOI 10.1186/art459).
Although the presence of overt histological or functional alterations in the muscles of FMS patients is controversial, several studies have now found alterations in microcirculatory blood flows. This study found that it took longer for the blood flow to return to normal in the FMS patients than in the controls after it was shut off by a cuff. It also found low normal levels of capillary density.
The decreased circulation was presumably due to increased sympathetic nervous system activity (tone) causing increased blood vessel vasoconstriction. Because the blood vessels are kept narrower than normal it takes longer for the blood flow to return to normal. Increased sympathetic nervous system activity could also account for the reduced capillary density found.
What might cause this microcirculatory dysfunction in FMS? Mawaka et. al. produced a much discussed paper in 2002 that posited it was due to a widespread sympathetic nervous system dysfunction.
Maekawa, K., Clark, G. and T. Kuboki. 2002. Intramuscular hypoperfusion, adrenergic receptors and chronic muscle pain. The Journal of Pain 3, 251-260.
Three researchers have posited that increased sympathetic nervous system (SNS) activity causes reduced blood flows to the muscles in FMS. Several lines of evidence suggest that an aberration in sympathetic nervous system activity could play a role in the pain found in FMS.
Blocking sympathetic nervous system (SNS) activity resulted in a dramatic reduction of pain in 5 of 8 FMS patients in one study. It also returned their ‘muscle relaxation rate’ from slow to near normal. High electromyography readings in tender points in FMS patients may be due to increased muscle sympathetic nerve activity.
One research group has proposed that the tender points in FMS are due to intrafusal muscle contractions within the muscle spindle that occur because of SNS overactivation.
The idea that the chronic muscle pain in FMS is caused by low blood flows to the muscles was raised over 30 years ago in a biopsy study that revealed swollen endothelial cells in the muscles of FMS patients. This study, amazingly, has never been repeated.
Three studies since then, however, have found indications of low muscle blood flows in FMS. Reduced blood flows have also been found in the jaw muscles of patients with chronic muscle pain.
How could reduced blood flows to a muscle cause muscle pain? One study has shown that states of ischemia (low blood flows) sensitize the pain receptors in muscles. Another has found that hypoxic states (low oxygen content) do the same.
But what could cause obstructed flows of blood to the muscles of FMS patients? One theory suggests an anatomical abnormality present in the blood vessels could, and indeed one study found significantly reduced capillary density in the thigh muscles of FMS patients. A larger study by a different researcher, however, did not.
Because cold stimulates the SNS, the cold pressor test which involves submerging a limb in ice water is commonly used to examine SNS activity. That patients with chronic muscle pain had abnormally reduced blood flows during the cold pressor test suggested they had impaired vasodilation.
Why the impaired vasodilation in these groups? Maekawa posits that chronically increased epinephrine production results in B2 AR desensitization. This suggests that when the signal for vasodilation occurs the receptors largely ignore it.
Thus, when muscle contraction during exercise occurs, the signal for increased blood flow (vasodilation) is ignored. This somehow locks the muscles spindles into a contracted position and activates the pain sensors in the muscles. This causes low blood flows to the muscles and pain in FMS and possibly other chronic pain diseases as well.
The sympathetic nervous system is a key regulator of blood flows to the tissues. This system, which uses norepinephrine (NE) and epinephrine (E) (adrenaline) to achieve its effects, operates differently depending on which receptors are present. If receptors called beta adrenoreceptors (B ARs) are present then NE will cause the blood vessels to dilate.
If receptors called alpha adrenoreceptors (A ARs) the NE will cause the blood vessels to vasoconstrict. Since B1 ARs are found mostly in the heart and A ARs are found mostly in the muscles, systemically increased NE levels will result in increased blood flows to the heart and decreased blood flows to the muscle tissues.
Ravings of a layman
Whether the blood flows in the brains of CFS/FMS patients are low enough to trigger ‘ischemia’ is unclear. Indeed the definition of ischemia is unclear; Stedman’s Medical Dictionary defines it as ‘local anemia’ due to an obstruction.
There is certainly no evidence as yet of an obstruction in CFS brains but several processes perhaps able to produce a low-level chronic ischemic state – e.g. low blood volume, low cerebral blood flows during standing (or otherwise) – have been documented in some CFS patients.
Baranuik’s stunning recent paper on the protein composition in the cerebral spinal fluid of CFS patients suggests a process of protein aggregation (amyloidosis) that is enhanced when blood flows are low could be occurring in the blood vessels in the brains of CFS patients.
Could reduced blood flows in the brains of FMS/CFS patients cause first increased glutamate, then NMDA receptor activation and finally pain in FMS patients? Are CFS and FMS circulatory conditions?
Even worse ravings
There are dramatic differences in the type of heart disease in men and women. Men tend to get heart disease earlier but tend to do better after being diagnosed. Women tend to get heart disease later but are often not diagnosed early and have poorer outcomes.
A recent article In the New York Times indicated the differences between the two may lie in the type of circulatory dysfunction they have. While men tend to have problems with the arteries, it is now believed that women have more problems with their microcirculation.
Unfortunately the technology is only now being developed that can adequately measure the microcirculation. This may have nothing to do with CFS but what an interesting finding it is given the increased rate of women with CFS. Could women’s susceptibility to microcirculatory problems be the cause of the gender bias present in CFS?
Conclusions
It is difficult to sum up such a complex field. Whereas FMS was for some time largely believed to be a disease of central sensitization several recent studies have suggested it is, in fact, a disease of both peripheral and central sensitization.
Research now implicates both the spinal cord and brain in FMS in the central sensitization occurring in FMS. Several lines of evidence including low blood flows to the thalamus and the muscles suggest, just as with CFS, that widespread circulatory problems may contribute to FMS.