Neurobiology Underlying Fibromyalgia Symptoms
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
Review A rticle
Neurobiology Underlying Fibromyalgia Symptoms
M. Catherine Bushnell,
1, 2, 3
and Richard H. Gracely
Alan Edwards Centre for Research on Pain, McGill University, 3640 University Street, Room M19, Montreal,
QC, Canada H2A 1C1
Department of Neurology & Neurosurgery, McGill University, 3640 University Street, Room M19, Montreal,
QC, Canada H2A 1C1
Department of Anesthesia, McGill University, 3640 University Street, Room M19, Montreal, QC, Canada H2A 1C1
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, firstname.lastname@example.org
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
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 , 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 ,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 diﬀerences 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
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 . In fact, much evidence indicates
that tender points are just sites normally more sensitive to
pressure pain in all indiv iduals [4–7] and that FM patients
have an increased pressure sensitivity at non-tender-point
sitesaswell. Accumulating evidence now shows that FM
patients have increased sensitiv ity to many types of painful
stimulation, including pressure at non-tender-point sites
, heat and cold pain [6, 10–14], elec trical stimulation ,
and intramuscular hypertonic saline injection . 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.  found that FM
patients rated innocuous pressure as more intense than did
healthy controls, although the eﬀects 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 diﬀerences between FM and controls
for heat [6, 10]orcold[10, 12], whereas one study found
FM patients to have reduced heat detection thresholds ,
and one study found patients to have reduced cold detection
thresholds . 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 [17–19]. 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 
and increased sensitivity to loud unpleasant auditory stimuli
that parallels their increased pressure pain sensitivity .
Similarly, FM patients perceive unpleasant olfactory stimuli
to be more intense and more unpleasant than do matched
controlsubjects. 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 . 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 . 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 . 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 . Staud et al.  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 eﬀects.
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
“diﬀuse 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 eﬀect, so that care must be taken in inferring
that perceptual eﬀects 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 . 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 eﬀect on FM patients [13, 32–34]. One of
these studies controlled for the eﬀects of distraction and
habituation and found a similar lack of conditioned pain
modulation in FM patients , 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
eﬀect in which these activated systems cannot be fur ther
engaged by the experimental manipulations . In addition,
distraction can have a powerful pain-inhibiting eﬀect [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” [40–43]. 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
[43–56]. 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 eﬀec 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 eﬃciency 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 diﬃculty concentrating and
dealing with complex, ra pidly changing environments 
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 aﬀect 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
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 [65–68].
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, 69–71]. 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 , 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
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, 76–81]. 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 aﬀerent 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 aﬀerent 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 [84–90]. 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-
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 . These areas are implicated in pain
and its emotional modulation, and correspondingly, the
binding potentials showed a negative relationship with the
magnitude of aﬀective 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
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
, which, together with ﬁndings of accelerated age-related
decline of brain gray matter observed in FM patients ,
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 [94–99]. 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 . 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
[100–105]. 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  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 .
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 eﬃciency, increasing latency to onset to sleep
and provoking awakenings from sleep , 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
Since similar descending control systems, including
attentional and emotional regulatory circuitry, aﬀect mul-
tiple sensory modalities [113–119], 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 .
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
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