Hindawi Publishing Corporation
Pain Research and Treatment
Volume 2012, Article ID 585419, 8 pages
Marta Ceko,1,2M.CatherineBushnell,1,2,3and RichardH.Gracely4
1Alan Edwards Centre for Research on Pain, McGill University, 3640 University Street, Room M19, Montreal,
QC, Canada H2A 1C1
2Department of Neurology & Neurosurgery, McGill University, 3640 University Street, Room M19, Montreal,
QC, Canada H2A 1C1
3Department of Anesthesia, McGill University, 3640 University Street, Room M19, Montreal, QC, Canada H2A 1C1
4Center for Neurosensory Disorders, University of North Carolina, CB No. 7280, 3330 Thurston Building, Chapel Hill,
NC 27599, USA
Correspondence should be addressed to Marta Ceko, email@example.com
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 the original work is properly cited.
Fibromyalgia is characterized by chronic widespread pain, clinical symptoms that include cognitive and sleep disturbances, and
otherabnormalities suchas increasedsensitivitytopainfulstimuli,increased sensitivitytomultiplesensorymodalities,andaltered
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 , suggested as an alternative
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 symptoms 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 types 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
1.1. Altered Pain Perception in FM Patients. 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
thepresenceof tenderness thathasbeen assessed clinicallyby
finding pain evoked by 4kg 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 individuals [4–7] and that FM patients
have an increased pressure sensitivity at non-tender-point
sites as well . Accumulating evidence now shows that FM
patients have increased sensitivity to many types of painful
stimulation, including pressure at non-tender-point sites
, heat and cold pain [6, 10–14], electrical 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
for heat [6, 10] or cold [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
control subjects . 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 range . 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 Perception.
Other types of evidence from experimental pain studies in
FM patients support the idea of a centrally mediated up-
regulation of nociceptive activity in the CNS. A central
pathophysiological process that appears to be disturbed in
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
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
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-
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
noxious stimuli are presented in conscious humans, other
systems that modulate pain, such as distraction, also are
Pain Research and Treatment3
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
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.
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 further
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
44, 48, 49, 51, 58, 59]. FM patients frequently display greater
impairments in the ability to actively retrieve past episodic
tests, which serve to evaluate the retrieval of remembered
information and are more resistant to the effects 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
dealing with complex, rapidly 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
this is not unique to FM .
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, and reduced slow wave 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
in several studies [67, 68, 71, 73].
3.BrainChanges 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 augmentation of sensory processing through-
out pain-related brain regions [9, 76–81]. This is important,
since laboratory findings of increased sensitivity 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
matter in FM patients is not known, it is possible that due to
4 Pain Research and Treatment
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 [11C] 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
partially 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. Neural 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 ,
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 parietal 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 evidence 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 function-
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 hypersensitivity 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].
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 functional 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
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 Treatment5
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
deduced from the available evidence, as it is correlational in
nature. Did 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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