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Abstract

Fibromyalgia is characterized by chronic widespread pain, clinical symptoms that include cognitive and sleep disturbances, and other abnormalities such as increased sensitivity to painful stimuli, increased sensitivity to multiple sensory modalities, and altered pain modulatory mechanisms. Here we relate experimental findings of fibromyalgia symptoms to anatomical and functional brain changes. Neuroimaging studies show augmented sensory processing in pain-related areas, which, together with gray matter decreases and neurochemical abnormalities in areas related to pain modulation, supports the psychophysical evidence of altered pain perception and inhibition. Gray matter decreases in areas related to emotional decision making and working memory suggest that cognitive disturbances could be related to brain alterations. Altered levels of neurotransmitters involved in sleep regulation link disordered sleep to neurochemical abnormalities. Thus, current evidence supports the view that at least some fibromyalgia symptoms are associated with brain dysfunctions or alterations, giving the long-held "it is all in your head" view of the disorder a new meaning.
Hindawi Publishing Corporation
Pain Research and Treatment
Volume 2012, Ar ticle ID 585419, 8 pages
doi:10.1155/2012/585419
Review A rticle
Neurobiology Underlying Fibromyalgia Symptoms
Marta Ceko,
1, 2
M. Catherine Bushnell,
1, 2, 3
and Richard H. Gracely
4
1
Alan Edwards Centre for Research on Pain, McGill University, 3640 University Street, Room M19, Montreal,
QC, Canada H2A 1C1
2
Department of Neurology & Neurosurgery, McGill University, 3640 University Street, Room M19, Montreal,
QC, Canada H2A 1C1
3
Department of Anesthesia, McGill University, 3640 University Street, Room M19, Montreal, QC, Canada H2A 1C1
4
Center for Neurosensory Disorders, University of North Carolina, C B No. 7280, 3330 Thurston Building, Chapel Hill,
NC 27599, USA
Correspondence should be addressed to Marta Ceko, marta.ceko@mail.mcgill.ca
Received 27 April 2011; Accepted 23 August 2011
Academic Editor: Muhammad B. Yunus
Copyright © 2012 Marta Ceko et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided t he orig inal work is properly cited.
Fibromyalgia is characterized by chronic widespread pain, clinical sy mptoms that include cognitive and sleep disturbances, and
other abnormalities such as increased sensitivity to painful stimuli, increased sensitivity to multiple sensory modalities, and altered
pain modulatory mechanisms. Here we relate experimental findings of fibromyalgia symptoms to anatomical and functional
brain changes. Neuroimaging studies show augmented sensory processing in pain-related areas, which, together with gray matter
decreases and neurochemical abnormalities in areas related to pain modulation, supports the psychophysical evidence of altered
pain perception and inhibition. Gray matter decreases in areas related to emotional decision making and working memory suggest
that cognitive disturbances could be related to brain alterations. Altered levels of neurotransmitters involved in sleep regulation
link disordered sleep to neurochemical abnormalities. Thus, current evidence supports the view that at least some fibromyalgia
symptoms are associated with brain dysfunctions or alterations, giving the long-held “it is all in your head” view of the disorder a
new meaning.
1. Introduction
In order to examine the neurobiology underlying the
symptoms of fibromyalgia, we must first determine what
those symptoms are. Until recently, fibromyalgia (FM) was
diagnosed based on the ARC1990 criteria [1], which were
widespread pain in combination with tenderness at 11 or
more of 18 specific tender point sites. The provisional ACR
2010 FM diagnostic criteria [2],suggestedasanalternative
method of diagnosing FM, do not require the presence of
tenderness, but rather include a list of several other symp-
toms, including fatigue, unrefreshing sleep, and cognitive
symptoms, as well as a mix of some other s ymptoms that
could include headache, depression, and lower abdominal
pain/cramping. The hallmark symptom is still widespread
pain, and a diagnosis of fibromyalgia requires this symptom.
However, a patient must also have some of the other symp-
toms that are common among FM patients in order to reach
a composite score that would lead to a diagnosis of FM. In
addition to clinical symptoms that make up the diagnosis of
FM, experimental studies have identified a number of other
abnormalities in FM patients, including increased sensitivity
to multiple t ypes of painful stimuli, increased sensitivity to
other sensory modalities, and alterations in pain modulatory
mechanisms. Further, neuroimaging studies have found
functional, anatomical, and neurochemical dierences in the
brains of FM patients compared to healthy control subjects.
Most of the clinical symptoms associated with FM have
not been systematically studied in the experimental setting,
but there are a number of studies that have provided an
objective evaluation of the altered cognitive functioning
and sleep disturbances reported in FM patients. Thus, this
paper will focus on the experimental evidence related to FM
symptoms and connect these perceptual and cognitive signs
to abnormalities observed in the brains of FM patients.
2 Pain Research and Treatment
1.1.AlteredPainPerceptioninFMPatients.The hallmark
symptom of FM is widespread ongoing musculoskeletal
pain. In addition, FM patients have been distinguished from
other patients with widespread pain syndromes primarily by
the presence of tenderness that has been assessed clinically by
finding pain evoked by 4 kg manual pressure in at least 11 of
18 defined tender points. This tender point concept was not
based on an understanding of the underlying pathophysiol-
ogy, but rather on empirical observation. Thus, although the
ARC-90 diagnostic criteria provided an important uniform
tool for defining the FM syndrome, they did not validate the
tender point concept, due to the circular evidence on which
the criteria were based [3]. In fact, much evidence indicates
that tender points are just sites normally more sensitive to
pressure pain in all indiv iduals [47] and that FM patients
have an increased pressure sensitivity at non-tender-point
sitesaswell[8]. Accumulating evidence now shows that FM
patients have increased sensitiv ity to many types of painful
stimulation, including pressure at non-tender-point sites
[9], heat and cold pain [6, 1014], elec trical stimulation [6],
and intramuscular hypertonic saline injection [15]. Despite
the plethora of evidence for hypersensitivity to painful
stimuli, there is less evidence that FM patients are more
sensitive to innocuous somatosensory stimuli. Detection
thresholds for tactile and electrical stimuli are not altered
in FM [6, 12, 13], but Hollins et al. [16] found that FM
patients rated innocuous pressure as more intense than did
healthy controls, although the eects in the innocuous range
were weaker than in the noxious range. The evidence for
changes in cool or warm detection also is mixed, with most
investigators finding no dierences between FM and controls
for heat [6, 10]orcold[10, 12], whereas one study found
FM patients to have reduced heat detection thresholds [12],
and one study found patients to have reduced cold detection
thresholds [6]. Thus, it appears that the altered sensitivity
within the somatosensory system is more profound in the
noxious range than in the innocuous range.
1.2. Evidence for Generalized Hypersensitivity to Unpleasant
Stimuli. The hypersensitivity of FM patients to painful
stimuli has led some investigators to propose that fibromyal-
gia involves a hypervigilance to pain and pain-associated
information [1719]. However, there is now evidence that
the hypersensitivity to unpleasant stimuli extends beyond
the somatosensory system, which has led to the hypothesis
that there is a generalized hypervigilance for sensory stimuli
in FM [16, 20, 21]. A few studies have examined the
sensitivity of FM patients in modalities other than pain
and found perceptual amplification. FM patients have been
shown to have decreased tolerance of unpleasant noise [20]
and increased sensitivity to loud unpleasant auditory stimuli
that parallels their increased pressure pain sensitivity [22].
Similarly, FM patients perceive unpleasant olfactory stimuli
to be more intense and more unpleasant than do matched
controlsubjects[23]. On the other hand, when pleasant
odors were tested, FM patients and controls perceived the
odors as equally intense, consistent with another evidence
that the hypersensitivity across perceptual modalities may be
confined to stimuli in the unpleasant ra nge [24]. Neverthe-
less, for pleasant odors, although FM patients did not rate
them as more intense, they did evaluate the pleasant odors
as less pleasant than did control subjects. Further, a range of
auditory stimuli were rated as more intense by FM patients
than by controls, and auditory stimuli rated as mildly pleas-
ant by healthy subjects were rated as somewhat unpleasant
by FM patients [16]. The finding of hypersensitivity in mul-
tiple modalities of stimulation, particularly for unpleasant
stimuli, suggests that the evoked pain sensitivity of FM may
be related to an altered hedonic appreciation for sensory
stimuli, rather than to peripheral tissue abnormalities.
1.3. Other Phenomena Related to Altered Pain Percepti on.
Other types of evidence from experimental pain studies in
FM patients support the idea of a centrally mediated up-
regulation of nociceptive activit y in the CNS. A central
pathophysiological process that appears to be disturbed in
FM patients is the “w indup” of central nociceptive processing
of C-fibre input to the spinal cord, resulting in the perceptual
phenomenon of temporal summation of pain. Windup of
nociceptive activity is dependent on activation of the NMDA
receptor complex in the spinal cord by input from C-
nociceptors [25, 26]. Some FM patients show increased
temporal summation of pain and increased aftersensations at
the termination of noxious stimulation [27]. These enhanced
responses could be related to one or more of several possible
factors: (1) an ongoing peripheral source of input from C
nociceptors other than the applied stimulus; (2) sensitized
NMDA receptors on central nociceptive neurons; (3) abnor-
malities in descending modulation; (4) abnormal processing
at supraspinal levels. Evidence of increased sensitivity in mul-
tiple sensory modalities suggests that ongoing C-nociceptor
input cannot alone account for FM symptoms, indicating
that there probably also are either sensitized NMDA recep-
tors, abnormalities in modulatory systems in the brain, or
abnormal sensory processing at spinal or supraspinal levels.
Increased sensitivity has been demonstrated at the spinal
level in FM [11]. Staud et al. [28] showed that an NMDA
inhibitor reduced temporal summation in both healthy peo-
ple and FM patients, suggesting that NMDA receptors prob-
ably are not sensitized in FM. On the other hand, experimen-
tal evidence shows that there are abnormalities in pain mod-
ulatory systems in FM patients that could account for altered
temporal summation and other putative spinal eects.
1.4. Altered Pain Inhibition in FM Patients. For hundreds of
years, clinicians have known that pain inhibits pain, a phe-
nomenon termed “counterirritation. More recently, a phys-
iological basis of this phenomenon has been identified; the
application of noxious stimulation activates an endogenous
analgesic system involving supraspinal descending control
of dorsal horn nociceptive activity. This system is termed
“diuse noxious inhibitory control” or DNIC and its physio-
logical basis in the spinal cord has been studied extensively in
anesthetized animals [29, 30]. Nevertheless, w hen competing
noxious stimuli are presented in conscious humans, other
systems that modulate pain, such as distraction, also are
Pain Research and Treatment 3
probably in eect, so that care must be taken in inferring
that perceptual eects are due to DNIC. Accordingly, a
group of interested researchers has suggested that the term
conditioned pain modulation be used in humans studies
to avoid the mechanistic implication [31]. Studies that have
examined conditioned pain modulation in FM patients show
that conditioning stimuli that produce an analgesic response
to experimental pain stimuli in healthy control subjects
fail to have an eect on FM patients [13, 3234]. One of
these studies controlled for the eects of distraction and
habituation and found a similar lack of conditioned pain
modulation in FM patients [33], suggesting the possibility
that the DNIC system is in fact impaired in these individuals.
Alternatively, DNIC and other descending inhibitory systems
could be activated by the widespread pain of FM, and the
failure to demonstrate DNIC in FM could represent a ceiling
eect in which these activated systems cannot be fur ther
engaged by the experimental manipulations [8]. In addition,
distraction can have a powerful pain-inhibiting eect [35
39], and some researchers have suggested that FM patients
have altered attentional focusing, with a hypervigilance to
unpleasant stimuli (see discussion above).
2. Other Symptoms of FM
2.1. Altered Cognitive Function in FM Patients. In addition
to pain, many patients with fibromyalgia complain of prob-
lems with memory and concentration, often referred to
as “fibrofog” [4043]. This clinical symptom has received
a large amount of experimental study, and studies using
objective cognitive tests substantiate patients’ subjective
reports of cognitive dysfunctions, most commonly related
to speed of information processing, attention, and memory
[4356]. The most robust deficits in tests of memory and
attention have so far been observed in paradigms involv-
ing a prominent distraction from a competing source of
information, wherein FM patients are less capable than
healthy controls to retain new information when rehearsal
is prevented by a distraction [49, 50, 57]. Milder deficits have
been observed in memory free of distraction at encoding [43,
44, 48, 49, 51, 58, 59]. FM patients frequently display greater
impairments in the ability to actively retrie ve past episodic
events in the absence of a cue (free recall) than on recognition
tests, which serve to evaluate the retrieval of remembered
information and are more resistant to the eec ts of impaired
attention and concentration [43, 44, 48, 51]. It has thus been
proposed that memory impairments in FM are more highly
related to attentional factors that modulate the eciency of
memory functioning than to primary memory processes per
se [48, 60, 61]. Thus, the inability to manage distraction
seems to be a particular problem in fibromyalgia patients and
is reflected in patients’ reports of diculty concentrating and
dealing with complex, ra pidly changing environments [61]
and by memory tests showing performance decrements in
the presence of distraction. Impaired cognitive performance
is evident even after controlling for anxiety and depression
and the influence of medications that might aect cognitive
functioning [ 43, 50, 52, 58]. Another area of cognitive
functioning that has been shown to be abnormal in FM is
that of emotional decision making [ 62, 63]. A similar deficit
has been shown in chronic back pain patients, suggesting that
thisisnotuniquetoFM[64].
2.2. Sleep Disturbances in FM Patients. Many FM patients
complain of unrefreshed sleep. Several laboratory studies
using objective measures of sleep physiology such as EEG
substantiate these reports by showing disordered sleep
architecture in FM patients, including delayed onset to sleep,
altered sleep stage dynamics, a nd reduced slow w ave sleep
(deep sleep) and rapid-eye movement (REM) sleep [6568].
The intrusion of EEG frequencies characteristic of wakeful-
ness (alpha waves) in the deep non-REM sleep (delta waves)
seems to be a prominent feature of the nonrestorative sleep
of FM patients [65, 6971]. Further, patients with FM often
have fragmented sleep resulting from periodic intrusions
such as involuntary limb movements (restless legs), sleep
apnea, and arousal disturbances [68, 72
74]. Although FM
patients tend to report greater disturbances in sleep duration
and quality than shown in laboratory studies, and their
subjective reports correlate better with the severity of clinical
symptoms [75], objectively measured sleep disturbances
have been associated with pain and subjective daily sleepiness
in several studies [67, 68, 71, 73].
3. Brain Changes That Could
Underlie Symptoms
3.1. Neural Basis of Pain Amplification and Altered Pain
Modulation. Functional brain imaging studies support psy-
chophysical findings of increased pain perception in FM, in
that there is an aug mentation of sensory processing through-
out pain-related brain regions [9, 7681]. This is important,
since laboratory findings of increased sensitiv ity could be
interpreted as a reporting bias, rather than evidence of
increased activation in pain pathways. The functional imag-
ing studies have found that fibromyalgia patients show sig-
nificantly more activity in response to pressure and thermal
stimuli compared to controls in a number of brain regions.
Increased activations were observed not only in limbic
structures, but also in brain regions involved in sensory-
discriminative processing, such as primary and secondary
somatosensory cortices, which supports the view that neural
responses to aerent signals are amplified in fibromyalgia.
Although the increased pain-evoked brain activations
corroborate patients’ reports, the correlation between in-
creased brain activity and increased pain perception does
not explain how the aerent signal is amplified. As discussed
above, there is psychophysical evidence of dysfunctions in
pain modulation as well as pain perception. There is now
much evidence that the activation of descending control cir-
cuitry is involved in pain modulation and that this circuitry
includes parts of prefrontal, cingulate, and insular cortices
[23, 36, 37, 82, 83]. A number of anatomical imaging studies
in FM patients reveal decreased brain gray matter in these
regions [8490]. Although the cellular basis of decreased gray
matter in FM patients is not known, it is possible that due to
4 Pain Research and Treatment
neuronal loss, decreased dendritic arborisation, or changes in
glial activation, pain inhibitory systems do not work in FM
patients as well as in healthy individuals.
Consistent with the idea that pain modulatory systems
may be disturbed in fibromyalgia are data showing that some
FM patients have abnormalities in neurochemical systems
involved in pain control, including the forebrain opioid and
dopamine systems. A positron emission tomography (PET)
competitive binding study using the D2/D3 receptor antag-
onist [
11
C] raclopride showed that striatal dopamine is
released in response to painful muscle stimulation in healthy
subjects, but not in FM patients [15, 91], which might
partial ly explain the increased sensitivity of FM patients to
the painful muscle stimulation. For the opioid system, inves-
tigators using PET found that FM patients had decreased
binding potentials at rest for the exogenously administered
µ-opioid receptor agonist carfentanil in several brain areas,
including the ventral striatum, the anterior cingulate cortex,
and the amygdala [92]. These areas are implicated in pain
and its emotional modulation, and correspondingly, the
binding potentials showed a negative relationship with the
magnitude of aective pain scores relative to the sensory
scores. Although results of this study do not tell us whether
levels of endogenous opioids were increased or whether
receptor availability was decreased, the findings support the
notion that disturbances in the opioidergic system might be
related to the increased pain sensitivity in fibromyalgia. For
both dopamine and opioids, the ongoing widespread pain
of FM could lead to a tonic activation within these systems
and thus be a main factor in altering receptor availability
and associated responsiveness to externally applied painful
stimuli.
3.2. Ne ural Basis of Cognitive Symptoms. It is well known
that cognitive capabilities such as attention and memory
functions decline continuously across the adult lifespan
[93], which, together with findings of accelerated age-related
decline of brain gray matter observed in FM patients [84],
suggests that there may be a relationship between gray matter
reductions in FM and cognitive deficits in these patients.
Two recent studies have linked FM to impaired emotional
decision making [62, 63]. Anatomical imaging studies have
reported that FM patients have decreased gray matter in
the medial prefrontal and insular cortices [84, 85, 89], areas
implicated in emotional decision making [9499]. Together,
these data suggest a possible association between gray matter
loss and emotional decision making in FM. One study has
directly examined the relationship between performance on
working memory tasks and gray matter in FM patients
and found that an individual’s performance was positively
correlated with gray matter values in medial frontal and
anterior cingulate cortices, thereby providing direct evidence
for an association between altered working memory and
gray matter morphology in fibromyalgia [51]. Both of these
brain regions, together with lateral premotor cortex, lateral
prefrontal cortex, frontal poles, and posterior par ietal cortex,
are areas known to be related to working memory processes
[100105]. In terms of the neurochemical abnormalities
in FM discussed above, dopamine plays an important role
for cognitive functioning. Multiple lines of ev idence demon-
strate the importance of mesocortical and striatal dopamin-
ergic pathways in memory tasks, perceptual speed, and
response inhibition (see [106] for review). Thus, there is an
overlap between tasks in which fibromyalgia patients per-
form poorly and tasks that are related to dopamine func tion-
ing, suggesting that a dysfunctional dopamine system could
contribute to the cognitive symptoms of fibromyalgia.
3.3. Neural Basis of Sleep Disturbances. While many studies
have used EEG and related methods to show various aspects
of disordered sleep physiology in FM patients, little is known
about the neurobiology underlying these disturbances. Sev-
eral neurotransmitters have been proposed to influence
CNS hypersensitivit y associated with sleep alterations. For
example, inhibition of the CNS serotonin synthesis has been
linked to insomnia and increased pain sensitivity [107].
Accordingly, in FM there is evidence for low serum and
cerebrospinal fluid serotonin levels [108, 109]. Injecting
amounts of substance P into the CNS of rats has been shown
to reduce sleep eciency, increasing latency to onset to sleep
and provoking awakenings from sleep [110], and there is
evidence for elevated cerebrospinal fluid levels of substance
P in FM patients [111, 112].
3.4. What Do the Psychophysical, Cognitive, and Neuroimaging
Studies Tell Us about the Neurobiology Underlying FM
Symptoms? The wealth of experimental evidence showing
that FM patients are hypersensitive to painful stimuli, as
well as unpleasant stimuli from other sensory modalities,
in conjunction with func tional brain imaging data showing
increased stimulus-evoked activation throughout nocicep-
tive pathways, shows that the defining symptom of FM—
increased pain—is in fact real and not just a response bias
of the patients. The finding that perception is increased in
multiple modalities speaks against the hypothesis that FM
pain is due to an upregulation of peripheral nociceptive
processes. Further, psychophysical evidence that descending
modulatory systems are altered in FM patients supports the
opposing idea that FM symptoms are at least in part caused
by alterations in CNS processing of the pain signal, including
a dysregulation of pain modulatory systems. Nevertheless,
the apparent dysregulation within these systems could be
caused and/or perpetuated by a tonic activation related to the
presence of ongoing widespread pain, so that the systems are
saturated and cannot regulate further in response to external
stimuli.
Since similar descending control systems, including
attentional and emotional regulatory circuitry, aect mul-
tiple sensory modalities [113119], a dysfunction (or satu-
ration) in these systems could lead to the hypersensitivity
in multiple sensory modalities. FM patients show reduced
habituation to nonpainful tactile stimuli and increased
cortical response to intense auditory stimuli, both of which
have been linked to deficient inhibition of incoming sensory
stimuli [120, 121]. Also in support of the idea of a central
dysregulation or saturation of pain modulation are changes
Pain Research and Treatment 5
in the opioid and dopamine neurotransmitter systems, both
known to be involved in hedonic regulation [122].
Finally, the findings that FM patients not only perceive
themselves to have altered memory and concentration
(“fibrofog”), but also in fact perform poorly on multiple
cognitive tests, even when depression is excluded as a
contributing factor, suggest that there are alterations in
brain function. The anatomical brain imaging studies that
show reductions in gray matter in frontal regions important
for cognitive function further indicate that this common
symptom of FM is based on altered brain function. Together,
the experimental evidence provides strong support for the
idea that FM symptoms are related to dysfunctions in the
central ner vous system. The cause of these changes cannot be
deduced from the available evidence, as it is correlational in
nature. D id long-term ongoing pain cause the changes or did
the changes cause the pain? Without a relevant animal model
or long-term longitudinal studies, we cannot answer these
questions. Nevertheless, we can at least say that fibromyalgia
is real and that it is associated with multiple changes in the
brain.
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... Likewise, the relationship between WM performance and other clinical symptoms apart from pain in FM patients is not clear. It has been suggested that depressed mood (Seo et al., 2012;Gelonch et al., 2017Gelonch et al., , 2018Wu et al., 2018), anxiety (Munguía-Izquierdo et al., 2008;Seo et al., 2012;Wu et al., 2018), fatigue (Suhr, 2003) and sleep disturbance (Ceko et al., 2012;Aasvik et al., 2018) may be relevant to explain dyscognition in FM (Gelonch et al., 2013;Pidal-Miranda et al., 2018). However, other studies confirmed the presence of dyscognition even after ruling out the effect of those symptoms (Dick et al., 2008). ...
... Likewise, lack of differences between patients with high and low pain threshold in any of the WM tasks does not support the hypothesis of an overlap between pain and cognition networks as an explanation for the cognitive dysfunction in FM (Buhle and Wager, 2010;Schmidt-Wilcke et al., 2014;Sturgeon et al., 2015). Previous studies reported morphological (Luerding et al., 2008;Cánovas et al., 2009;Robinson et al., 2011;Ceko et al., 2012), functional (Napadow et al., 2010;Glass et al., 2011;Seo et al., 2012;Schmidt-Wilcke et al., 2014;González-Villar et al., 2017) and neurotransmission alterations in the dopaminergic (Albrecht et al., 2015;Ferrera et al., 2020), glutamatergic and GABAergic systems (De Paepe et al., 2020), which could be associated with pain in patients with FM. Future studies should clarify whether the WM functioning in FM can be explained by pain-mediated structural and functional neural reconfiguration. ...
... Finally, we attempted to examine which of the clinical selfreported variables were the best predictors of WM performance. The results of the linear regression analyses suggest that sleep problems and fatigue were the variables that best predicted WM performance in FM patients, as found in previous research (Suhr, 2003;Ceko et al., 2012;Aasvik et al., 2018;Pidal-Miranda et al., 2018;Andrade et al., 2020). In addition, both pain threshold and pain tolerance appear to predict performance on the ACT task at 9 s, as already indicated by the correlation analysis. ...
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Working memory (WM) is a critical process for cognitive functioning in which fibromyalgia (FM) patients could show cognitive disturbances. Dyscognition in FM has been explained by interference from pain processing, which shares the neural substrates involved in cognition and may capture neural resources required to perform cognitive tasks. However, there is not yet data about how pain is related to WM performance, neither the role that other clinical variables could have. The objectives of this study were (1) to clarify the WM status of patients with FM and its relationship with nociception, and (2) to determine the clinical variables associated to FM that best predict WM performance. To this end, 132 women with FM undertook a neuropsychological assessment of WM functioning (Digit span, Spatial span, ACT tests and a 2-Back task) and a complete clinical assessment (FSQ, FIQ-R, BDI-1A, HADS, PSQI, MFE-30 questionnaires), including determination of pain thresholds and tolerance by pressure algometry. Patients with FM seem to preserve their WM span and ability to maintain and manipulate information online for both visuospatial and verbal domains. However, up to one-third of patients showed impairment in tasks requiring more short-term memory load, divided attention, and information processing ability (measured by the ACT task). Cognitive performance was spuriously related to the level of pain experienced, finding only that pain measures are related to the ACT task. The results of the linear regression analyses suggest that sleep problems and fatigue were the variables that best predicted WM performance in FM patients. Future research should take these variables into account when evaluating dyscognition in FM and should include dynamic measures of pain modulation.
... Regarding the mechanisms underlying the effects of DLPFC/tDCS, while no studies have specifically explored them, it is plausible that the cognitive and affective effects of DLPFC stimulation could be induced through the connections with the limbic system (fronto-limbic network) [55], whilst the effects on pain relief could be due to connectivity with the diffuse noxious inhibitory controls (DNIC) pathways that are involved in the inhibitory modulation of nociceptive input [56,57]. ...
... Different methods have been designed to optimize the configuration of MtCS montage for stimulation of brain networks, represented by spatially extended cortical targets [58]. In this sense, MtCS could be more effective in modifying the functioning of the networks that are altered in patients with FM [55][56][57]. Previous studies with tDCS in FM have focused on the DLPFC; however, the effects of modulating the activity of this area with MtCS have not yet been explored. ...
... In recent years, abundant evidence has been obtained regarding the implication in FM of an abnormal cerebral process primarily mediated by the Central Nervous System (CNS) that forms part of the so-called Central Sensitization Syndromes [4,14]. Aided by advances in neuro-imaging [15], this concept of pain experience, which differs from nociception, defends the leading role of the brain in the intensity and perception of pain, leaving the relationship with body tissues in second place [16]. In this setting, we find a permanently "hyperalert" nervous system that amplifies sensory stimuli, accompanied by a comprehensive autonomic and/or neuroendocrine motor cortex. ...
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Background Very positive effects have been described in the application of pain neuroscience education (PNE) to chronic pain and migraine. However, there are few data on the applicability of this therapeutic approach in actual clinical practice in a primary care (PC) setting. The aim of this study was to explore the efficacy in fibromyalgia (FM) of an intervention based on PNE and exercise compared to treatment as usual (TAU). Methods Pragmatic nonrandomised controlled trial set in 5 healthcare centres and one physiotherapy centre in PC. Fifty-three women with FM (2010 American College of Rheumatology Diagnostic Criteria for Fibromyalgia) were studied, 35 in the intervention group (IG) and 18 in the control group (CG). The women in the IG were interviewed individually and then received 6 weekly sessions plus one review session (1 month later): those in the CG received their TAU. The subject assignation to the CG or the IG was determined according to their availability to attend the sessions. They all filled in several questionnaires (prior to and 1 year after the intervention) to evaluate the impact of FM in their daily lives, catastrophism, anxiety and depression, severity and impact of pain in daily personal performance and functional capacity. Results The reductions (improvements) in the scores of all tests (baseline-final) were greater in the IG (p < 0.05) when adjusted for age and baseline values, with moderate or high effect size. After 1 year, 20% (CI − 1 to 42%) more women in the IG, compared to the CG, had a FIQ score < 39 (mild functional impairment). 17/38 (49%) women in the IG no longer met FM criteria at the end of follow-up. Conclusions An intervention based on PNE and exercise in patients with FM is feasible and seems effective in PC. Trial registration The study was retrospectively registered at ClinicalTrials.gov (Trial Registration NCT04539171), on 04/09/2020.
... 75 This phenomenon might extend to the other senses as well like auditory perception 76 and smell. 77,78 Beyond that, migraine, tinnitus, and dizziness are common comorbidities in fibromyalgia. [79][80][81] Similar to patients with VSS, tinnitus, and PPPD, patients with fibromyalgia report triggers such as stress, trauma, or environmental changes associated with the onset of the syndrome and flares. ...
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Objective: The aim of this narrative review is to explore the relationship between visual snow syndrome (VSS), migraine, and a group of other perceptual disorders. Background: VSS is characterized by visual snow and additional visual and nonvisual disturbances. The clinical picture suggests a hypersensitivity to internal and external stimuli. Imaging and electrophysiological findings indicate a hyperexcitability of the primary and secondary visual areas of the brain possibly due to an impairment of inhibitory feedback mechanisms. Migraine is the most frequent comorbidity. Epidemiological and clinical studies indicate that other perceptual disorders, such as tinnitus, fibromyalgia, and dizziness, are associated with VSS. Clinical overlaps and parallels in pathophysiology might exist in relation to migraine. Methods: We performed a PubMed and Google Scholar search with the following terms: visual snow syndrome, entoptic phenomenon, fibromyalgia, tinnitus, migraine, dizziness, persistent postural-perceptual dizziness (PPPD), comorbidities, symptoms, pathophysiology, thalamus, thalamocortical dysrhythmia, and salience network. Results: VSS, fibromyalgia, tinnitus, and PPPD share evidence of a central disturbance in the processing of different stimuli (visual, somatosensory/pain, acoustic, and vestibular) that might lead to hypersensitivity. Imaging and electrophysiological findings hint toward network disorders involving the sensory networks and other large-scale networks involved in the management of attention and emotional processing. There are clinical and epidemiological overlaps between these disorders. Similarly, migraine exhibits a multisensory hypersensitivity even in the interictal state with fluctuation during the migraine cycle. All the described perceptual disorders are associated with migraine suggesting that having migraine, that is, a disorder of sensory processing, is a common link. Conclusion: VSS, PPPD, fibromyalgia, and chronic tinnitus might lie on a spectrum of perceptual disorders with similar pathophysiological mechanisms and the common risk factor migraine. Understanding the underlying network disturbances might give insights into how to improve these currently very difficult to treat conditions.
... There have been correlations between CD and structural MRI changes such as reduced gray matter volume, a dysfunctional dopamine system as well as correlations with central sensitisation. [27][28][29] ...
Article
Fibromyalgia presents with symptoms of widespread pain, fatigue, sleeping and cognitive disturbances as well as other somatic symptoms. It often overlaps with other conditions termed ‘central sensitivity syndromes’ such as irritable bowel syndrome, chronic fatigue syndrome and temporomandibular disorder. Central sensitisation, mediated by amplified processing in the central nervous system, has been identified as the key pathogenic mechanism in these disorders. The term ‘central sensitivity’ can be used to collectively describe the clinical presentation of these disorders. Fibromyalgia is highly prevalent in most rheumatic diseases as well as non-rheumatic chronic diseases and if unrecognised results in high morbidity. It is diagnosed clinically after excluding important differential diagnoses. Diagnostic criteria have been developed as tools to help identify and diagnose fibromyalgia. Such tools can fulfill an important need when managing patients with rheumatic disease and other chronic diseases as a way to identify fibromyalgia and improve patient outcomes. Treatment involves an integrated approach including education, exercise, stress reduction and pharmacological therapies targeting the central nervous system. This approach is suitable for all presentations of central sensitivity and some central sensitivity syndromes have additional treatment options specific to the clinical presentation. This article is protected by copyright. All rights reserved.
... The morphometric abnormalities in white and grey matter in the cerebellar and frontal cortical area contribute to enhanced pain in fibromyalgia subjects (Kim et al. 2015;Kuchinad et al. 2007). Moreover, evidence also suggests that the brain regions involved in emotional decision making, such as the medial prefrontal cortex and insular cortices have reduced gray matter (Clark et al. 2008;Ceko et al. 2012). Furthermore, studies have also shown that fibromyalgia subjects have increased activity response to pressure and thermal stimulus compared to normal subjects in limbic structures and sensory discriminative regions of the brain such as somatosensory cortices . ...
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Fibromyalgia is a common, chronic, and generalized pain syndrome that is often associated with comorbid depression. The etiology of fibromyalgia is complex; most researchers have documented that the hallmark symptoms are due to the central nervous system’s abnormal functioning. Neurotransmitters such as serotonin, norepinephrine, and glutamate, have been reported to be key regulators of fibromyalgia syndrome. Daphnetin is a 7, 8 dihydroxy coumarin widely distributed in Thymelaeaceae family plants, possessing various activities such as anti-arthritic, anti-tumor, anti-malarial, and anti-parasitic. The present study was designed to explore the potential of daphnetin against reserpine-induced fibromyalgia in mice. In mice, a fibromyalgia-like state was achieved by injecting reserpine (0.5 mg/kg, s.c) continuously for 3 days. All behavioral tests were conducted on the 4th and 6th day of experimentation. Reserpine administration significantly increased the mechanical hypersensitivity in electronic von Frey (eVF) and pressure application measurement (PAM) tests. It also increased the immobility period and time to reach the platform in force swim test (FST) and Morris water maze (MWM) test, respectively. In the biochemical analysis, reserpine treatment upregulated the monoamine oxidase-A (MAO-A) activity and level of glutamate, tumor necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1β), and thiobarbituric acid reactive substances (TBARS). Whereas, it decreased the level of glutathione (GSH), dopamine, serotonin, and norepinephrine. Daphnetin pretreatment attenuated the behavioral and biochemical changes induced by reserpine. Thus, the current investigation results delineate that daphnetin might exert its protective effect by inhibiting inflammatory stress and MAO-A-mediated neurotransmitter depletion and oxidative stress.
... However, they do not entirely explain all the cognitive symptoms of FM [65]. Nevertheless, morphological investigations show decreases of grey material in FM in regions related to cognitive components [66,67]. As we expected, the values obtained in depression and cognitive impairment were worse in the FM group than the HC group, being in line with previous studies that obtained similar results [13,59,68,69]. ...
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Patients with fibromyalgia (FM) show widespread pain associated with other symptoms such as cognitive problems, depression, and anxiety among others associated with alterations in the central nervous system. The hippocampal subfields had differences in function, histology, and connectivity with other brain regions, and are altered in different diseases. This study evaluates the volumetric differences between patients with FM compared with a healthy control group. A total of 49 women with, and 43 healthy women completed this study. T1-weighted MRI was used to assess brain volume, and FreeSurfer software was used to segment the hippocampal subfields. Women with FM had a significant reduction in most of the hippocampal subfields. The regression equation models were obtained to predict the volume of specific subfields of the right and left hippocampus. These findings provide that women with FM have lower hippocampal subfields volumes compared with healthy women. Besides, regression models show that different covariates, such as age, cognitive impairment, or depression, are related to specific subfields.
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Objetivo: Este estudo objetivou mapear as contribuições disponíveis sobre o uso da liberação miofascial como estratégia terapêutica auxiliar na fibromialgia. Métodos: Trata-se de uma scoping review (revisão de escopo) da literatura científica indexada e não indexada (área cinza) nas bases SciELO (Scientific Electronic Library Online), LILACS (Literatura Latino-Americana e do Caribe em Ciências da Saúde), PubMed e PEDro (Physiotherapy Evidence Database) e na “área cinzenta da literatura” por meio do buscador Google Scholar, pela combinação de palavras-chave “myofascial release" AND “fibromyalgia”, sem restrições de ano de publicação, idioma, ou qualquer outra restrição. Resultados: O corpus totalizou oito artigos, prevalentemente com ocorrência na PubMed, com delineamento de ensaios clínicos realizados na Espanha, com diagnóstico da fibromialgia pelos critérios de Wolfe et al. (1990), com desfecho relacionado à “qualidade de vida” e à “dor”. Conclusão: Conclui-se que, em geral, os trabalhos disponíveis sobre liberação miofascial como estratégia terapêutica auxiliar na fibromialgia indicam resultados positivos para os vários desfechos investigados, ainda que sejam poucos os estudos acerca da temática, explicitando lacuna expressiva no contexto acadêmico- científico nacional e internacional.
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Objectives With the International Classification of Diseases 11th revision (classifying fibromyalgia as a primary pain disorder) soon to be implemented, the importance of pain physicians being able to identify patients with fibromyalgia is emphasized. The diagnostic criteria proposed in 2016 are based on self-reported pain distribution and symptom severity. The study aimed to evaluate the diagnostic accuracy of the 2016 diagnostic criteria for fibromyalgia applied in a population of patients with high impact chronic pain referred for pain rehabilitation. Methods The study was performed as a diagnostic accuracy study at two Danish interdisciplinary pain rehabilitation centers, including 215 participants. All participants were evaluated clinically to identify patients with fibromyalgia. The diagnosis was based on expert opinion, but the minimum requirements were: (1) pain in all four body quadrants and axially for at least three months and (2) minimum 8 of 18 positive tender points. Participants filled in the fibromyalgia survey questionnaire, the patient version of the 2016 diagnostic criteria. Sensitivity, specificity, likelihood ratios, and positive and negative post-test probabilities were calculated using a clinical diagnosis of fibromyalgia as the reference standard. Results Based on clinical diagnosis 45% of the participants were diagnosed with fibromyalgia; of these, only 19% had been diagnosed previously. The 2016 diagnostic criteria demonstrated a sensitivity of 88.5%, a specificity of 81.5%, a positive likelihood ratio of 4.79, a negative likelihood ratio of 0.14, a positive post-test probability of 79.4%, and a negative post-test probability of 10.2%. Conclusions Fibromyalgia was severely under-diagnosed among patients with high impact chronic pain referred to tertiary care in two pain rehabilitation centers in Denmark. The 2016 diagnostic criteria showed sufficient discriminatory properties suggesting that the fibromyalgia survey questionnaire can be used as a screening tool assisting the identification of fibromyalgia in this patient population.
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Objective: We hypothesized that change in pain threshold to pressure reflects a generalized change in the pain system affecting both tender and control points. Methods: We assessed 18 tender points and 4 control points using an algometer in 60 patients with generalized fibromyalgia/fibrositis syndrome, 60 patients with localized chronic pain syndromes, and in 60 pain-free subjects. Results: A significant correlation was found between myalgia scores at tender points and control points in these subjects. Conclusion: These results suggest that there is a diffuse change in pain modulation in fibromyalgia, as hypothesized, but the tender point is still clinically useful.
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Objective: The present study assessed the relationship of depression, pain, and fatigue to subjective cognitive complaints and objective impairment in patients with fibromyalgia (FM), patients with other chronic pain disorders, and healthy controls.Method: Neuropsychological assessment was conducted on 28 FM patients, 27 chronic pain patients, and 21 healthy controls. Five FM patients and five chronic pain patients were excluded due to poor effort on cognitive tasks. Assessment included measures of depression, pain, fatigue, subjective cognitive complaints, memory, executive functioning, intellect, attention, and psychomotor speed. Analysis of covariance was used to assess group differences in cognitive complaints and cognitive test performance, after controlling for depression, pain, and fatigue. Hierarchical regression was used to assess whether objective test performance was related to subjective cognitive complaints, after controlling for depression, pain, and fatigue.Results: FM patients had more memory complaints and reported more fatigue, pain, and depression than other groups. Groups were not different in cognitive performance, after controlling for fatigue, pain, and depression; depression was related to memory performance and fatigue was related to psychomotor speed. Neuropsychological test results did not add significantly to the variance accounted for in subjective cognitive complaints, after accounting for depression, pain, and fatigue.Conclusion: Psychological factors, particularly effort, depression, and fatigue, are important in understanding both subjective cognitive complaints and objective cognitive impairment in FM and other chronic pain disorders.
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Objective. We hypothesized that change in pain threshold to pressure reflects a generalized change in the pain system affecting both tender and control points.Methods. We assessed 18 tender points and 4 control points using an algometer in 60 patients with generalized fibromyalgia/fibrositis syndrome, 60 patients with localized chronic pain syndromes, and in 60 pain-free subjects.Results. A significant correlation was found between myalgia scores at tender points and control points in these subjects.Conclusion. These results suggest that there is a diffuse change in pain modulation in fibromyalgia, as hypothesized, but the tender point is still clinically useful.
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To develop criteria for the classification of fibromyalgia, we studied 558 consecutive patients: 293 patients with fibromyalgia and 265 control patients. Interviews and examinations were performed by trained, blinded assessors. Control patients for the group with primary fibromyalgia were matched for age and sex, and limited to patients with disorders that could be confused with primary fibromyalgia. Control patients for the group with secondary-concomitant fibromyalgia were matched for age, sex, and concomitant rheumatic disorders. Widespread pain (axial plus upper and lower segment plus left- and right-sided pain) was found in 97.6% of all patients with fibromyalgia and in 69.1% of all control patients. The combination of widespread pain and mild or greater tenderness in ⩾ 11 of 18 tender point sites yielded a sensitivity of 88.4% and a specificity of 81.1%. Primary fibromyalgia patients and secondary-concomitant fibromyalgia patients did not differ statistically in any major study variable, and the criteria performed equally well in patients with and those without concomitant rheumatic conditions. The newly proposed criteria for the classification of fibromyalgia are 1) widespread pain in combination with 2) tenderness at 11 or more of the 18 specific tender point sites. No exclusions are made for the presence of concomitant radiographic or laboratory abnormalities. At the diagnostic or classification level, the distinction between primary fibromyalgia and secondary-concomitant fibromyalgia (as defined in the text) is abandoned.
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To measure, and seek clinical correlates with, levels of substance P (SP) in the cerebrospinal fluid (CSF) of fibromyalgia syndrome (FMS) patients. CSF from 32 FMS patients and 30 normal control subjects was tested for SP by radioimmunoassay. Clinical measures included tender point examination and standardized questionnaires. CSF SP levels were 3-fold higher in FMS patients than in normal controls (P < 0.001), but they correlated only weakly with tenderness found on examination. SP is significantly elevated in FMS CSF, but other abnormalities must exist in FMS to more fully explain the symptoms.
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Objective To characterize the patterns of alpha electroencephalographic sleep and their associations with pain and sleep in patients with fibromyalgia.Methods Pain and sleep symptoms of 40 female patients with fibromyalgia and 43 healthy control subjects were studied before and after overnight polysomnography. Blinded analyses of alpha activity in non–rapid eye movement (non-REM) sleep were performed using time domain, frequency domain, and visual analysis techniques.ResultsThree distinct patterns of alpha sleep activity were detected in fibromyalgia: phasic alpha (simultaneous with delta activity) in 50% of patients, tonic alpha (continuous throughout non-REM sleep) in 20% of patients, and low alpha activity in the remaining 30% of patients. Low alpha activity was exhibited by 83.7% of control subjects (P < 0.01). All fibromyalgia patients who displayed phasic alpha sleep, activity reported worsening of pain after sleep, compared with 58.3% of patients with low alpha activity (P < 0.01) and 25.0% of patients with tonic alpha activity (P < 0.01). Postsleep increase in the number of tender points occurred in 90.0% of patients with phasic alpha activity, 41.7% of patients with low alpha activity, and 25.0% of patients with tonic alpha activity (P < 0.01). Self ratings of poor sleep were reported by all patients with phasic alpha activity, 58.3% of patients with low alpha activity (P < 0.01), and 12.5% of patients with tonic alpha activity (P < 0.01). Patients with phasic alpha activity reported longer duration of pain than patients in other subgroups (P < 0.01). Additionally, patients with phasic alpha sleep activity exhibited less total sleep time than patients in other subgroups (P < 0.05), as well as lower sleep efficiency (P < 0.05) and less slow wave sleep (P < 0.05) than patients with a tonic alpha sleep pattern.Conclusion Alpha intrusion during sleep can be of different patterns. Phasic alpha sleep activity was the pattern that correlated better with clinical manifestations of fibromyalgia.