ARTHRITIS & RHEUMATISM

Vol. 40, No. 11, November 1997, pp 1928-1939

1928 0 1997. American College of Rheumatology

CONFERENCE SUMMARY

THE NEUROSCIENCE AND ENDOCRINOLOGY OF FIBROMYALGIA

STANLEY R. PILLEMER, LAURENCE A. BRADLEY, LESLIE J. CROFFORD,

HARVEY MOLDOFSKY, and GEORGE P. CHROUSOS

Fibromyalgia syndrome (FMS) is characterized Chronic pain segment

by widespread pain and tenderness in reproducible,
characteristic anatomic locations (1). The syndrome is
associated with chronic pain and dysregulation of neu-
roendocrine function and of sleep. In addition, patients
often experience high levels of fatigue and other symp-
toms, such as irritable bowel or bladder.
Recently, researchers in fields other than the
rheumatic diseases have made considerable progress in
studying the individual component manifestations of
FMS. Therefore, several experts in the fields of pain,
neuroendocrine function, and sleep research were in-
vited to meet with a small group of expert FMS investi-
gators at an interdisciplinary workshop held July 16-17,
1996 at the National Institutes of Health, Bethesda,
Maryland. The major goals of the meeting were to
heighten awareness among rheumatologists regarding
advances in clinical and basic research in chronic pain,
neuroendocrine function, and sleep, and, conversely, to
inform investigators in these research areas about FMS.
This report summarizes the material presented at the
workshop, which was organized into 3 segments corre-
sponding to the research areas noted above.
Cosponsors of the Workshop on the Neuroscience and En-
docrinology of Fibromyalgia: National Institute of Arthritis and Mus-
culoskeletal and Skin Diseases; National Institute of Nursing Re-
search; Office of Behavioral and Social Sciences Research; Office of
Research on Women’s Health; and National Center on Sleep Disor-
ders Research, National Heart, Lung, and Blood Institute.
Stanley R. Pillemer, MD: National Institute of Arthritis and
Musculoskeletal and Skin Diseases, National Institutes of Health,
Bethesda, Maryland; Laurence A. Bradley, PhD: The University of
Alabama at Birmingham; Leslie J. Crofford, MD: University of
Michigan, Ann Arbor; Harvey Moldofsky, MD: Toronto Western
Hospital, Toronto, Ontario, Canada; George P. Chrousos, MD, PhD:
National Institute of Child Health and Human Development, National
Institutes of Health, Bethesda, Maryland.
Address reprint requests to Stanley R. Pillemer, MD, Office
of the Director, National Institute of Arthritis and Musculoskeletal
and Skin Diseases, Building 45, Room 5As-37G, 45 Center Drive MSC
6500, Bethesda, MD 20892-6500.
Submitted for publication March 26,1997; accepted in revised
form June 10, 1997.
Pain mechanisms and physiology. Pain percep-
tion initiated by a noxious peripheral stimulus is medi-
ated by ascending neural pathways, as shown in Figure
1A (2). However, the transmission of nociceptive signals
from peripheral tissues to the brain is modulated by
endogenous and exogenous processes. For example,
several descending pain inhibitory fibers originate in
brain stem sites and inhibit spinal nociceptive transmis-
sion (Figure 1B). In addition, various psychological,
pharmacologic, and physical interventions can attenuate
or promote nociceptive processing and thus affect pain
perception. These modulating effects may be mediated
by the activation or suppression of a complex network of
cerebral, bulbar, and spinal neurons. For example, elec-
trical stimulation or destruction of central nervous sys-
tem (CNS) structures and pathways can produce pain or
analgesia. In addition, physical trauma and diseases that
directly affect the CNS, such as stroke or multiple
sclerosis, can produce central pain syndromes. Investi-
gators are beginning to examine the mechanisms and
physiology of pain with new imaging methods for study-
ing nociceptive processing in animals and in the con-
scious human brain. These methods, which include
positron emission tomography (PET), single-photon
emission computed tomography (SPECT), and func-
tional magnetic resonance imaging, may clarify neuro-
logic processes involved in chronic pain disorders such as
FMS (3,4).
Spinal cord and brain plasticity. Peripheral tis-
sue or nerve injury often results in hyperalgesia, in which
innocuous stimuli such as light touch may be perceived
as painful. Hyperalgesia is related to changes at the site
of injury as well as to CNS hyperexcitability that leads to
long-term changes in the nervous system, referred to as
plasticity (5-7).
Animal models of hyperalgesia produced by in-
flammation or nerve injury mimic persistent pain condi-
tions. These models suggest that, after nerve injury, new
FMS NEUROSCIENCE AND ENDOCRINOLOGY WORKSHOP 1929

r-7
Limbic forebrain
Frontal lobe
Limbic forebrain

Thalamus/ Thalamus/
Hypothalamus Hypothalamus

Sl/S2/ lnsula
Cortex \ Cortex

Midbrain Midbrain

Medulla

Spinal cord
-
(C3 C4)

Figure 1. A, Ascending neural pathways for pain. Pain perception is normally initiated by activation of
nociceptors in peripheral tissues. Primary nociceptive afferents ascend contralaterally and excite spinothalamic
and spinoreticular neurons in the dorsal horn of the spinal cord through neurotransmitters such as glutamate,
aspartate, substance P, and calcitonin gene-related peptide. The signals generated in these neurons are then
transmitted to the brain via their axons, which travel in 3 primary ascending tracts that project to the thalamus
and the reticular formation. Direct spinothalamic tract projections to the ventral posterior lateral thalamus excite
neurons with connection to the primary (Sl) and secondary (S2) somatosensory and insular cortex. The S l cortex
mediates the discrimination of intensity and spatial and temporal aspects of pain. The limbic system is also
involved in nociceptive input. The above pathways are also interconnected with neurons involved in mediating
autonomic, endocrine, mnemonic, and hedonic components. B, Descending pathways for pain inhibition.
Corticothalamic neurons from the S1 and S2 somatosensory cortex modulate the excitability of neurons in the
ventral posterior lateral thalamus. Frontal lobe and limbic forebrain projections activate medial thalamic,
hypothalamic, and brain stem reticular formation neurons, which modulate the spinal (and trigeminal) dorsal
horn through the dorsolateral spinal cord. (Adapted, with permission of the American Academy of Neurology,
from Casey KL, Gonzales GR, Max MB, Price DD, Portenoy RK, Rowbotham MC: Continuum; Pain 2, 1996.)

axon sprouts that are sensitive to stimulation often
develop in the injured zone. Spontaneous discharges
from these damaged nerves, as well as from the dorsal
root ganglion, increase the neuronal barrage into the
CNS and contribute to increased pain after injury.
The responses of CNS neurons also change after
injury. After inflammation, spinal dorsal horn nocicep-
tive neurons often exhibit an increased excitability that is
characterized by an enlargement of their peripheral
receptive fields and an increased responsiveness to
mechanical, thermal, and chemical stimuli (Figure 2).
This hyperexcitability of CNS neurons, called central
sensitization, leads to increased activity at higher brain
centers. It is likely perceived as more intense and
prolonged pain. The hyperexcitability is mediated by the
activation of neurons with N-methyl-D-aspartate
(NMDA) receptor sites by excitatory amino acids. The
release of these amino acids from presynaptic sites and
their effects on dorsal horn neurons are enhanced by
neuropeptide transmitters such as dynorphin, substance
1930
Tissue or Nerve Injury
Excitatory amino acid release
neuropeptide release
and Hyperexcitability
Loss of Inhibition
Increased Pain
Figure 2. Changes in the nervous syatem after injury. The hyperexcit-
ability involves activation of neurons at N-methyl-u-aspartate
(NMDA) receptor sites by excitatory amino acids. The release of
excitatory amino acids from prcsynaptic sites and their effects on
dorsal horn neurons are enhanced by neuropeptide transmitters such
as dynorphin, substance P (SP), and calcitonin gene-related peptide
(CGRP).
P (SP), and calcitonin gene-related peptide. However,
the dorsal horn neuron hyperexcitability and behavioral
hyperalgesia may be attenuated in a dose-dependent
manner by selectively acting NMDA receptor antag-
onists.
Descending projections from brain stem sites
dampen or counteract the spinal cord hyperexcitability
produced by tissue or nerve injury (Figure 1B). The net
descending effects are greater after inflammation than
in the absence of inflammation.
These findings have important implications re-
garding treatment, because the pain of tissue or nerve
damage can be attacked at the site of the injury where it
is initiated, as well as at CNS sites where it is maintained.
New treatment strategies for controlling persistent pain
following injury have been developed based on these
new research advances.
Fibromyalgia as a model for chronic pain. There
is increasing behavioral and biologic evidence that,
similar to nerve injury pain, the pathogenesis of FMS
pain is related to altered CNS processing of nociceptive
stimuli. For example, the pain thresholds of FMS pa-
tients and nonpatients (individuals who meet critcria for
FMS but who do not seek medical treatment) in re-
sponse to pressure stimulation at diagnostic tender
points (1) and anatomic control sites are 2-3 times lower
than those of healthy persons (8,9). Patients and nonpa-
tients also have significantly higher scores than controls
on an index of sensory discrimination ability during
PILLEMER ET AL
stimulation of tender and control points (9), indicating
greater sensitivity to this stimulation. In addition, pa-
tients with FMS tend to meet diagnostic criteria for
multiple lifetime psychiatric diagnoses, especially major
depression, whereas nonpatients do not differ from
healthy controls in psychiatric morbidity. Thus, persons
with FMS, regardless of their behavior in seeking health
care and their psychiatric histories, differ from healthy
persons in neurosensory processing of stimulation at
numerous anatomic sites.
Substance P, regional cerebral blood flow, and
FMS pain. The behavioral evidence of altered CNS
processing of nociceptive stimuli in persons with FMS is
supported by evidence of biologic abnormalities. For
example, SP, which is an important nociceptive neuro-
transmitter at the dorsal horn level, is elevated in the
cerebrospinal fluid (CSF) of both patients and nonpa-
tients with FMS (10,ll). The high CSF levels of SP are
stable and are associated with high CSF concentrations
of nerve growth factor. Certain anti-nociceptive peptide
mediator levels are also abnormal in the CSF of FMS
patients. Met-enkephalin-arg-phe levels are low, while
the N-terminal peptide fragment of SP (SP,-,) is in-
creased 2-fold (12). There is also indirect evidence of a
decrease in the availability of serotonin to down-
regulate nociception in FMS (12).
Finally, both patients and nonpatients with FMS
are characterized by significantly lower levels of regional
cerebral blood flow (rCBF) in the caudate nucleus, as
compared with controls (1 1). Low thalamic rCBF also
has been observed in FMS patients, as well as in patients
with other disorders associated with chronic pain, such
as chronic neuropathic pain, metastatic cancer, and
mononeuropathy (13-17). The caudatc nucleus and
thalamus are both involved in signaling the occurrence
of noxious events. It may be that low rCBF, which
indicates decreased functional activity, is a marker for
impaired inhibition of nociceptive transmission by these
brain structures. The findings reviewed above suggest
that chronic pain in FMS is associated with several
behavioral and biologic abnormalities indicative of al-
tered CNS processing of nociceptive signals.
Animal models of sex differences in pain and
analgesia. The high prevalence of chronic pain condi-
tions, such as FMS, in women compared with men may
be related to sex differences in pain sensitivity. Studies in
both animals and humans indicate that males show
higher pain thresholds and tolerance when exposed to
noxious stimuli ( 17-21). Furthermore, females discrim-
inate better among painful stimuli than males, indicating
a higher sensitivity to these stimuli (17).
FMS NEUROSCIENCE AND ENDOCRINOLOGY WORKSHOP
Animals also exhibit profound sex differences in
the magnitude and mechanisms of analgesia produced
by pharmacologic (administration of opioid agonists),
electrical (brain stimulation-produced analgesia), or en-
vironmental (stress exposure) manipulations (22). For
example, stress-induced analgesia (SIA) often occurs at
higher levels in male rodents than in females (19). SIA
may be mediated by opioid or non-opioid neurotrans-
mitters. As determined by sensitivity to specific receptor
antagonists, non-opioid SIA in male mice appears to be
mediated by the NMDA subtype of excitatory amino
acid receptors. In contrast, female mice display equipo-
tent non-opioid SIA that is dependent on estrogen for its
expression and is not sensitive to NMDA antagonist
(22). The presence of such qualitative sex differences in
brain neurochemistry related to analgesia processes
indicates possible sex differences in the clinical efficacy
of analgesic agents that may activate these mechanisms.
Cognitive processes and the pain experience.
Patients with rheumatic diseases such as FMS vary in
their responses to persistent pain. Three important
cognitive variables may explain how FMS patients adjust
to persistent pain. First, a high level of self-efficacy, or
the belief in one’s ability to engage in actions sufficient
to attain a desired health outcome, is associated with
reports of lower pain and disability among patients with
arthritis ( 2 3 ) . Increases in self-efficacy following coping
skills training interventions have been associated with
long-term improvements in pain and function. Second,
patients who rate their ability to control and decrease
pain as high and who avoid the use of catastrophizing
coping strategies report low levels of pain and disability.
Third, frequent use of adaptive, cognitive coping strate-
gies is also associated with lower levels of pain and
disability.
Newly developed treatment protocols for rheu-
matic disease patients use cognitive-behavioral inter-
ventions such as cognitive restructuring and self-
instructional training to increase self-efficacy beliefs and
to reduce overly negative and maladaptive cognitions.
These protocols have been shown to be effective for
patients with rheumatoid arthritis and osteoarthritis in
randomized, controlled clinical trials (24,25). Recent
studies of cognitive-behavioral therapy (CBT) protocols
have shown positive findings in patients with FMS (26).
One randomized, controlled trial of a CBT protocol
showed no clinical or economic benefits of treatment for
FMS (27); however, these findings appear to have been
associated with poor patient adherence to the study
protocol. Thus, the effects of CBT for patients with FMS
have not been established. Controlled research is
1931
needed to determine whether CBT protocols can reducc
maladaptive cognitions, decrcase pain and utilization of
health care, and enhance psychological and physical
function in persons with FMS.
Pain studies: methodologic issues. The evalua-
tion of pain and pain mechanisms in FMS is problem-
atic. Tenderness at each anatomic site is usually mea-
sured by determining the pain threshold to a single
pressure stimulus of increasing intensity. This method
may be influenced by factors such as variation in rate of
increases in pressure; thus, results are easily biased.
Moreover, the evaluation of tenderness in patients with
generalized body pain lacks the power of comparison
with a contralateral or baseline control. Dynamic designs
that include evaluation of physiologic response3 during
baseline and stimulation conditions may be useful both
to increase experimental power and to evaluate mean-
ingful disease factors; for example, measurement of
brain rCBF by PET or SPECT during both baseline and
ipsilateral exposure to a controlled stimulus may de-
crease measurement problems.
Neuroendocrine function segment
Neuroendocrine alterations associated with al-
tered sleep, mood, and pain perception. FMS is associ-
ated with alterations in pain perception, mood, and
sleep, and may be a “stress-related illness” since it., omet
often coincides with physical or psychological stress.
During stress, CNS and peripheral functions generally
are altered to reestablish homeostasis and to preserve
life. The physiology of stress is complex and is subserved
by a dedicated stress system (28,29). This consists of
CNS and peripheral components and includes the
hypothalamic-pituitary-adrenal (HPA) axis and the au-
tonomic (sympathetic) system (Figure 3). In the brain,
corticotropin-releasing hormone (CRH) neurons are
located in the paraventricular nucleus of the hypothala-
mus, the brain stem, the amygdala, and other sites. The
sympathetic system centers include the locus ceruleus,
which regulates arousal, and other brain stem nuclei
responsible for regulation of central and peripheral
sympathetic functions.
The principal regulator of the HPA axis, CRH, is
secreted into the hypophyseal portal system, where it
increases adrenocorticotropic hormone (ACTH) secre-
tion, which in turn stimulates cortisol secretion by the
adrenal cortex. Cortisol then feeds back negatively to the
pituitary, the hypothdamus, and higher centers of the
CNS that control HPA axis activity. The systemic sym-
pathetic system primarily secretes norepinephrine, while
1932
Circadian
~ BEHAVIORAL ADAPTATION (&
_- * - GABAJBZD ----__-
\ ACTH I stress system. In contrast, there are disorders in which a
1
Gluc:oz&oids Epiriephrine
Norepinephrine
PERIPHERALADAPTATION
Figure 3. Interactions between the 2 major components of the stress
system, the hypothalamic-pituitary-adrenal axis system (left) and the
locus ceruleusinorepinephrine sympathetic system (LCINEC Symp.
Syst.) (right). CRH = corticotropin-releasing hormone; AVP = argi-
nine vasopressin; ACTH = adrenocorticotropic hormone; GABA =
y-aminobutyric acid; BZD = benzodiazepines; POMC = pro-
opiomelanocortin; SP = substance P. (From ref. 28.)
the adrenal medulla secretes epinephrine and norepi-
nephrine.
T h e H P A axis and the locus ceruleusi
norepinephrine sympathetic nervous system innervate
and interact with each other and other systems in the
brain (Figure 3). Thus, CRH neuron projections activate
catecholaminergic sympathetic nuclei and vice versa,
resulting in a positive reverberating loop. Also, neuro-
transmitters and neuropeptides inhibit the neurons that
produce them, via ultrashort feedback loops; tricyclic
antidepressive and central antihypertensive agents exert
their effects at this level. Some neurotransmitters, such
as serotonin and acetylcholine, activate both the HPA
axis and the sympathetic system, whereas y-
aminobutyric acid, the benzodiazepines, and several of
PILLEMER ET AL
the opioid peptides inhibit both systems. Pro-
opiomelanocortin-derived peptides, such as a-
melanocyte-stimulating hormone and p-endorphin, in-
hibit both the HPA axis and the sympathetic system and
may be involved in peripheral stress-induced analgesia.
Interestingly, while SP is a potent inhibitor of CRH, it
stimulates the central sympathetic system. In addition,
the HPA axis inhibits the reproductive axis, growth, and
the immune system.
In the classic stress response, CRH and arginine
vasopressin (AVP) work synergistically to cause ACTH
secretion. Neurons secrete CRH and AVP with 2-3
pulses per hour. Approximately 75% of these pulses are
secreted together, producing a synergistic effect on
ACTH secretion.
Pathophysiologic manifestations tend to occur
when the stress response is chronically hyperactive or
hypoactive. Individuals with melancholic depression
have a chronically hyperactive and hyperresponsive
hyporesponsive stress system is noted. These include
seasonal affective disorder, chronic fatigue syndrome,
postpartum depression, and FMS (30-33). An under-
standing of the neurotransmitters and neuropeptides
that are stimulatory or inhibitory to the stress system
may suggest possible candidate genes for defining the
genetic predisposition to hyperactivity or hypoactivity of
this system. SP, a potent inhibitor of CRH, may partic-
ipate in causing the low activity of the CRH neuron
found in patients with FMS.
Stress system plasticity: neural adaptations to
neonatal pain and stress. Genetic and environmental
factors interact throughout development to shape the
phenotype of an individual. Adverse early experiences,
including abuse, neglect, or severe childhood illness, and
associated medical treatment may influence vulnerabil-
ity to a variety of physio- and psychopathologies, and
possibly to disorders such as FMS. Changes in adult
behavior, HPA axis function, central gene expression,
pain threshold, and drug-seeking behavior have been
characterized in male Long Evans rats exposed to either
repeated pain (forelimb needle puncture) or maternal
separation (180 minutes daily) as neonates in the first 2
weeks of life (34). Neonatal exposure to either maternal
separation or pain resulted in increased pre- and post-
pubertal pain thresholds in a standard hot-plate test and
reduced resistance to infection. Neonatal rats exposed to
maternal separation and pain demonstrated enhanced
central CRF neurocircuit activity, HPA axis responsive-
ness, anxiety-like behavior, and reactivity of the mesen-
cephalic dopaminergic system. A detrimental cascade
FMS NEUROSCIENCE AND ENDOCRINOLOGY WORKSHOP
may be initiated by adverse early experience that occurs
within a critical period corresponding to a particular
dcvelopmental level of the CNS. This cascade may be
initiated by the morphogenic actions of serotonin and
other neurotransmitters in the developing CNS in re-
sponse to incoming stimuli.
Hypothalamic-pituitary-gonadal (HPG) axis:
stress-induced gonadal compromise. Interactions be-
tween the HPA and HPG axes in FMS patients have yet
to be thoroughly investigated. However, stress has been
shown to compromise fertility (35,36). In women, stress-
related increases in cortisol secretion suppress hypotha-
lamic gonadotropin-releasing hormone (GnRH) input
to the pituitary-ovarian axis. Profound and persistent
loss of GnRH input manifests as amenorrhea, whereas
episodic or milder interruptions in GnRH secretion can
bc clinically occult and may present only as decrements
in luteal-phase progesterone secretion in the setting of
preserved menstrual cycle intervals. Stress management
and reduction (such as CBT techniques) may possibly
restore GnRH drive, as well as ovulation, menses, and
fertility; this is currently under investigation (Berga S:
personal communication).
Sympathetic nervous and adrenomedullary hor-
monal systems: differential responses to stressors. The
major stress response systems, the HPA axis and the
sympathetic nervous system, do not necessarily respond
in the same way to particular stressors (37). In addition,
the 2 major sympathetic nervous system pathways can be
regulated differentially. Interactions between the HPA
axis and the components of the sympathetic nervous
system in FMS have not been delineated.
Neuroendocrine findings in patients with FMS.
Patients with FMS exhibit disturbances of the major
stress-response systems, the HPA axis and the sympa-
thetic nervous system. integrated basal (24-hour urine)
free cortisol levels are low in FMS patients, while plasma
cortisol levels obtained at discrete times of the day are
normal (peak) or elevated (trough) (33). Research on
alterations in basal HPA axis activity is directed toward
observing the pulsatile characteristics of ACTH and
cortisol secretion. A unique pattern of stimulated HPA
axis activity has been noted in patients with FMS. It is
characterized by exaggerated ACTH response to exog-
enous CRH, or to endogenous activators of CRH re-
lease such as insulin-induced hypoglycemia (33,38). The
cortisol response to increased ACTH in these stress
paradigms, and to exercise, is blunted (33,38).
Patients with FMS may also have disturbed sym-
pathetic system activity. For example, levels of plasma
neuropeptide Y, a peptide co-localized with norepineph-
1933
rine in the sympathetic nervous system, are low in
patients with FMS (33,39). Another neuroendocrine
system, the growth hormone axis, is abnormal in FMS
patients (40,41). However, our understanding of how the
growth hormone and HPA axes are interrelated in FMS
is incomplete.
Clinical features of FMS, such as widespread pain
and fatigue, could be related to these observed neuroen-
docrine and sympathetic nervous system perturbations.
This hypothesis is supported by the observation that
interventions found to be useful in FMS patients affect
the function of stress-response systems. Further clarifi-
cation of neuroendocrine axis function and the relation-
ship of these systems to clinical symptoms may lead to
improved therapeutic strategies for FMS.
Sleep segment
Sleep control mechanisms. Falling asleep is char-
acterized by an advance through stages I, 11,111, and IV
of non-rapid eye movement (non-REM) sleep. As sleep
progresses, there is a series of brief REM periods; sleep
becomes more shallow and REM sleep predominates.
During waking, alpha waves appear as rapid oscillations
on electroencephalogram (EEG). As sleep is initiated,
the amplitude becomes much smaller, and there is a
mixed-frequency oscillation. In contrast, during the
deepest stage of sleep (stage IV), large slow (delta)
waves occur.
i n recent years, a rapid increase in knowledge of
basic mechanisms has revolutionized our understanding
of sleep (42). Initially, REM sleep was more readily and
extensively studied. Transection experiments in animals
demonstrated that the basic rhythmic generator for
REM sleep is in the mammalian brain stem (Figure 4).
In FMS, slow-wave sleep abnormalities appear to
be more important than REM sleep. Sleep researchers
are interested in the role of the hypothalamus in slow-
wave sleep, how REM sleep and slow-wave sleep are
linked, and the mechanisms of slow-wave sleep produc-
tion. Hypothalamic lesions may cause insomnia, tumors
may cause hypersomnia, and cells recorded sporadically
throughout the hypothalamus and basal forebrain are
selectively active during slow-wave sleep. However, the
specific cells responsible have not been identified.
Because FMS may be associated with frequent or
early awakening, an increased understanding of the
mechanisms involved in awakening may have implica-
tions with regard to FMS. In animal studies, ventrolat-
era1 preoptic (VLPO) neurons may be important in the
control of forebrain waking mechanisms, especially in
1934
Plane of Pontine Forebrain
Transection Cortex
’\
/ Brain Stem
Figure 4. Rapid eye movement (REM) slecp regulation: representa-
tion of a mammalian brain, demonstrating nuclei involved in REM
sleep. Oblique line represents the plane of transection that preserves
the signs of REM caudally. The REM-promoting neurons primarily
contain the neurotransmitter acetylcholine. Two nuclei found at the
junction of the midbrain and pons, the laterodorsal tegmental (LDT)
and pendunculopontine tegmental (YPT) nuclei, project to target areas
in the reticular formation that control the rapid eye movements of
REM sleep, and the muscle atonia zones that control the muscle
atonia of REM sleep. Cholinergic agonists placed in this region
produce a state that simulates REM sleep. Firing of serotonergic
dorsal raphc nucleus (DRN) neurons and norepinephrinergic locus
ceruleus (LC) neurons slows during slow-wave sleep and virtually
ceases just before and during REM sleep. This suggested that these
neurons might disinhibit the cholinergic LDTiPPT neurons, a theory
that was later tested and shown to be correct. At sleep onset,
cholinergic, REM-on neurons are initially quiescent, then become
active, and at a certain threshold, REM sleep occurs. The cycle repeats
throughout the night, and the increasing duration of REM periods
reflects circadian modulation. REM-suppressive neurons, containing
norepinephrine and serotonin, have an opposite discharge pattern, and
as they turn off, the cholinergic neurons bccome active. BRF, PRF,
and MRF = bulbar, pontine, and mesencephalic reticular formation.
(Adapted, with permission, from Serninurs in the Neurosciences [42].)
histaminergic tuberomamillary nucleus cells (43). The
Fos protein, which accumulates in recently activated
neurons, has been used in immunocytochemical studies
to show that sleep-activated VLPO neurons innervate
the tuberomammillary nucleus. These studies suggested
that sleep-wake states may be regulated by this mono-
synaptic pathway in the hypothalamus. Ongoing struc-
tural studies suggest the exciting possibility that these
neurons may coordinate other functions including brain
stem nuclei, such as those involved in pain perception,
and perhaps endocrine projections, such as those in-
volved in the stress system.
Animal models of sleep. Sleep is regulated in part
by humoral agents (44). Sleep-promoting substances
accumulate in CSF during wakefulness and induce sleep
PILLEMER ET AL
when transferred to normal animals. Several sleep-
regulatory humoral agents have been identified, includ-
ing interleukin-1 (IL-1) and tumor necrosis factor a
(TNFa). Administration of IL-1 or TNFa increases
intensity and duration of non-REM sleep in mice. In
contrast, IL-1 or TNFa blockade inhibits spontaneous
non-REM sleep in rabbits. Blockade of IL-1 or TNFa
prior to experimental manipulations of sleep depriva-
tion, acute mild increases in ambient temperatures, or
injection of microbial products abolishes the expected
sleep responses. TNFa and IL-lP and their receptors
are normal brain products. Further, their messenger
RNA (mRNA) levels or protein levels vary with the
sleep-wake cycle (e.g., rat hypothalamic TNFa and
TNFa mRNA are highest just after light onset) (45).
Knockout strains of mice lacking either the 1L-1 type I
receptor or the 55-kd TNFa receptor sleep less than
their strain controls. In addition, changes in sleep regu-
lation that may be beneficial to the host occur during
infection. These sleep responses are induced by specific
microbial components, e.g., bacterial cell wall muramyl
peptides and lipopolysaccharide or influenza vital
double-stranded RNA. These microbial products also
induce cytokine production, and their somnogenic ac-
tions are attenuated if IL-1 or TNFa is inhibited. The
findings cited above strongly implicate the immune
response modifiers IL-1 and TNFa in sleep regulation.
The humoral regulation of sleep involves com-
plex cascades of biochemical events within the brain,
analogous to events involved in immune cell regulation.
For example, IL-1 induces TNFa and growth hormone-
releasing hormone (GHRH) production, while anti-
GHRH inhibits IL-1-induced sleep (46). Both IL-1 and
TNFa induce nitric oxide (NO) production. In contrast,
inhibition of NO synthase inhibits spontaneous sleep
and IL-1-induced sleep. Administration of exogenous
NO donors, such as S-nitroso-N-acetylpenicillamine or
molsidomine, enhances sleep. Data such as these, cou-
pled with the recent availability of knockout strains of
mice lacking one or more of the genes included in the
IL-1 and TNFa families of molecules, will facilitate
research into the biochemical events and pathways in-
volved in sleep regulation.
Sleep deprivation influences on behavior and
immune function in animals. The effects of profound
sleep deprivation resemble the effects of loss of a vital,
physical requirement, such as food (47). In young
healthy humans, short-term sleep deprivation results in
1) profound decrements in cognitive function, 2) pro-
gressive decreases in oral temperature, 3) behavioral-
psychiatric changes (irritability, delusions), 4) nonspe-
FMS NEUROSCIENCE AND ENDOCRINOLOGY WORKSHOP
cific neurologic signs, and 5) increased sensitivity to pain
(48). The specific organic changes due to sleep depriva-
tion or disruption in individuals with compromised
health have not been elucidated, but may exacerbate
disease and hinder recovery.
Prolonged sleep deprivation in rats produces
syndromic physical changes that occur in 2 stages over
time, and culminate in death. The first stage is longer
and is marked by a progressive negative energy balance,
accompanied by a mild elevation in body temperature
and its subsequent return to baseline. The second phase
is heralded by a breakdown in host defense, manifested
as systemic infection by lethal opportunistic organisms
and a mild drop in body temperature. This second stage
is acute and is characterized by a cachectic-like state of
dwindling health, suggestive of cytokine- and endotoxin-
mediated septicemia and shock.
Detection of lethal opportunistic organisms in
the blood of sleep-deprived rats is diagnostic of a
functional impairment that implicates the immune sys-
tem (49). Despite systemic infection, sleep-deprived rats
do not exhibit fever or marked tissue inflammatory
reactions typical of most infectious disease states, indi-
cating that sleep deprivation is immunosuppressive.
Whether such immunosuppression is a primary or a
secondary effect of sleep deprivation is unknown, al-
though several signs of sleep deprivation are consistent
with early changes in immunocompetency. Furthermore,
responses by immunomodulators to host defense chal-
lenges during sleep deprivation may mediate part of the
deep negative energy balance that leads to a cachectic-
like state.
Thermal regulation and sleep-wake physiology.
Thermal stress has an extremely important influence on
sleep (50,51). RBM sleep is sensitive to ambient tem-
perature. Basal forebrain lesions in rats cause insomnia
and interfere with thermoregulation, although at higher
ambient temperatures REM sleep may appear normal.
Pharmacologic interventions may also interfere with
sleep; phentolamine, an a1 -noradrenergic antagonist,
decreases sleep in rats in a similar way to that seen in the
presence of lesions in the basal forebrain, when ambient
temperature is not taken into account (52).
Experiments in female rats have demonstrated
that aging is also associated with thermal and sleep
rhythm disturbances (53). However, when old anestrous
female rats were compared with young oophorecto-
mized rats, the oophorectomized animals did not show a
deterioration of rhythm (54). In contrast, they showed
more precisely regulated rhythms, suggesting that the
instability of thermal and sleep rhythms developing in
1935
old rats could not be accounted for by sex steroid
hormones in females. Similar studies in male rats also
excluded the possibility of a hormonal role. Further
investigation demonstrated that the instability of ther-
mal and sleep rhythms with aging occurs independently,
i.e., the unstable thermal and sleep regulatory rhythms
are not linked to one another (55). Thus, although sleep
is linked to temperature regulation in younger animals,
this may change under certain conditions, including
aging.
Roles of sleep and circadian rhythm in neuro-
endocrine function. Circadian rhythmicity is an intrinsic
endogenous signal that, in mammals, is generated by the
hypothalamic suprachiasmatic nucleus (56). Although
the circadian rhythm is an endogenous signal, it is
influenced by environmental periodicities, such as light-
dark cycle (56,57). The sleep-wake cycle can also exert
synchronizing effects on the suprachiasmatic nucleus,
which integrates environmental and sleep-wake infor-
mation and drives a variety of endocrine, behavioral,
and metabolic rhythms. Measurement of hormones at a
single time of day has little meaning, since the endocrine
system displays intricate temporal organization and re-
alizes different states of endocrine function at different
times of day (58).
In FMS, slow-wave sleep may be interrupted by
intrusions of alpha activity (59). These intrusions may be
important, because most of the endocrine and cardio-
vascular effects of sleep are observed during deep sleep,
including secretion of growth hormone and prolactin
and inhibition of corticotropic activity and thyroid-
stimulating hormone secretion.
Understanding sleep control mechanisms may
ultimately lead to a better understanding of the sleep
disorder associated with FMS. The timing, duration, and
quality of sleep are controlled by 2 major components,
the homeostatic and circadian components (60). The
homeostatic component reflects the amount of sleep
required to compensate for the duration of wakefulness
and may primarily control slow-wave sleep. In contrast,
the circadian component is thought to primarily regulate
REM sleep, as well as to exert a modulatory effect on
the timing and duration of sleep. Regardless of the
presence or timing of sleep, the cortisol pattern shows
little modification (circadian dependent). In contrast,
growth hormone disappears when there is no sleep, and
reappears with the replacement of sleep (sleep depen-
dent). The circadian system may be involved in the
waking function and altering the expression of the
homeostatic component; intrusion of physiologic waking
during sleep in FMS could be related to an altered
1936
relationship between the homeostatic and circadian
components.
Sleep, particularly slow-wave sleep, has a role in
controlling the release of growth hormone (61). In
normal young subjects, the amount of growth hormone
secretion demonstrates a dose-response relationship to
the amount of slow-wave sleep. In contrast, awakening
during sleep while growth hormone is being secreted
results in a rapid inhibition o f growth hormone secre-
tion. In FMS, sleep fragmentation that manifests as
awakening, arousal, or perhaps alpha intrusion would be
expected to inhibit growth hormone secretion (62).
Studies in patients with FMS have shown a decrease in
insulin-like growth factor 1, the hormone secreted by the
liver, which could possibly occur in response to de-
creased growth hormone stirnulation (40.63).
Aging has differential effects on sleep and endo-
crine system components (55,56). In terms of slow-wave
sleep decline and growth hormone secretion, we are old
by age 40; whereas REM sleep and the progressive rise
of evening cortisol levels change at a slower ratc over a
lifetimc (64). Restoration of deep (slow-wave) sleep and
its endocrine correlates has been studied in healthy
volunteers. The majority of currently available hypnotic
agents do not increase slow-wave sleep. It may be worth
investigating whether alpha suppression in FMS can be
overcome by stimulation of slow-wave \leep, and
whether such stimulation has a beneficial effect.
FMS as a model for sleep dysregulation. Disor-
dered sleep physiology is accompanied by nonrestorative
sleep, fatigue, diffuse musculoskeletal pain, and
cognitive-behavioral symptoms in patients with FMS
(59). Clinical studies show that measures of pain and
fatigue are related to ratings of poor sleep. Also, non-
rcfreshing sleep in patients with FMS is commonly
associated with altered sleep physiology. These physio-
logic disturbances include the alpha (7-12-IIz) EEG
sleep anomaly and sleep-related features of periodic
involuntary limb movements, periodic K-alpha EEG,
and apnea-hypopnea in subgroups of patients. Experi-
mental disruption of slow-wave sleep with noise artifi-
cially induces the alpha EEG sleep anomaly, nonrefresh-
ing sleep, diffuse myalgia, and fatigue in healthy
subjects. Patients with FMS have diurnal impairment in
cognitive performance functions that arc sensitive to
sleep deprivation. They show a reduction in the speed,
but not the accuracy, of complex performance tasks
carried out hourly throughout the day, and ratc them-
selves as sleepy and fatigued. In comparison with FMS
patients, patients with chronic somatoform pain disorder
do not show the alpha EEG sleep anomaly or describe
PILLEMER ET AL
unrefreshing sleep, but they report more depressive
symptoms and psychological distre
studies show that the alpha EEG sleep anomaly and
symptom5 may follow a febrile episode.
The theoretical model that FMS patients have
disordered chronobiologic functions that are linked to a
dysregulation of their sleep-waking brain is based on the
following evidence (65-67): 1) research finding\ on the
disordered sleep-wake physiology, symptoms, and be-
havior in patients with FMS and chronic fatigue syn-
drome; 2) cxperimcntal studies that link the neurochem-
ical, eytokine-immune-neurocndoerine thermal systems
and the sleep-wake cycle in animals and humans; 3)
studies and preliminary data on the interrelationships of
sleep-wakefulness, IL-1 , and aspects of the peripheral
immune and neuroendocrine functions in healthy men
(in women t h e w sleep-wake-related immune-
neuroendocrine functions differ between high and low
progesterone phases of the menstrual cycle); and 4) the
observations of alterations in aspects of neurochemical
(serotonin, SP), immune, neuroendocrine, and auto-
nomic functions in patients with FMS.
Time series analyses o f measures of the circadian
patterns of the sleep-wakefulness, neurochemical, and
cytokine-immune-neuroendocrine-thermal functions in
patients with FMS and chronic fatigue syndrome should
determine whether alterations in aspects of these bio-
logic operatiom accompany the disordered sleep-wake
physiology that results in nonrefreshing sleep, chronic
pain, fatigue, and cognitive and behavioral symptoms.
There is evidence, based on diary reports, of a bidirec-
tional within-person association between sleep quality
and pain in women with FMS (68), i.e., nights of
relatively poor 4eep are followed by significantly greater
pain the next day, and more painful days are followed by
poorer sleep at night. However. the biologic changes
underlying this relationship have not been determined.
Conclusion
Fibromyalgia has been regarded by many as a
diffuse and nebulous syndrome that is “all in the pa-
tient’s head.” There is mounting evidence that these
impressions have an element of truth in them-not in a
way that disparages FMS patients, but at the physiologic
level. Much of the symptomatology of FMS is familiar in
other contexts to researchers in the areas of pain,
neuroscience, endocrinology, and sleep, particularly
where centrally mediated mechanisms are concerned.
During the workshop, many of the intricate in-
teractions between components of the central nervous
FMS NEUROSCIENCE AND ENDOCRINOLOGY WORKSHOP
and endocrine systems were discussed in relation to
pain, circadian rhythms, and sleep. These systems are
responsive to stressors and are functionally, anatomi-
cally, and physiologically intertwined. Furthermore,
there is clear evidence of sex differences in the
regulation of pain and sleep, as well as in circadian
rhythms. Also, circadian rhythms and their relation-
ship to homeostatic mechanisms of sleep appear to
alter with increased age.
In the field of pain related to FMS, we must
devote more effort to the development of animal models
and to the understanding of CNS functions. In addition,
the psychosocial factors involved in pain vulnerability
and pain expression require clarification. Better under-
standing of pain transmission and pain inhibition may
lead to new treatments in FMS.
Questions regarding neuroendocrine function in
FMS remain unanswered. How do we distinguish vul-
nerability in neuroendocrine function leading to the
development of FMS versus abnormalities that might
result from FMS? How are gonadal hormones and aging
related to FMS? Findings from neuroendocrine and
pain research must be integrated in order to understand
how they interact in FMS. Neuroendocrine function
studies should take into account the importance of the
complex temporal variations in hormone levels.
In the field of sleep research, we are beginning to
address the fundamental mechanisms involved in sleep-
wake physiology, the rhythms of the body, and the
effects of the dysregulation of these rhythms on FMS.
Researchers are shifting attention from the brain stem
to the hypothalamus as an area of importance in
regulation.
The rhythms of the body and sleep-wake physi-
ology are intimately connected to cytokines and aspects
of neuroendocrine functioning. Further investigation
into the ways in which sleep deprivation is involved in
problems of repair or lack of repair may be useful in
understanding FMS. Additional research is needed to
clarify the role of thermal factors and their intimate
linkage to sleep-wakefulness, the rhythms of the body,
and aging in the development of sleep abnormalities in
FMS. Future investigation may involve differences in
males and females, and estrus versus nonestrus systems
involved in animal models. Little information is avail-
able, not only with regard to normal physiology of
thermal mechanisms, but also with regard to how these
mechanisms might be impaired in FMS. Finally, there is
much work to be done in the area of sleep physiology
and its alterations; the findings of such investigations
may allow associations with the results of studies on
1937
neuromechanisms of pain, neuroendocrine functioning,
and immune alterations that might relate to FMS.
The workshop generated considerable excite-
ment among the participants from diverse fields, who
developed some mutual understanding regarding the
interrelationships among pain, neuroendocrine func-
tions, circadian rhythms, and sleep. We believe that an
interdisciplinary approach will accelerate progress in
research into FMS and other related disorders.
ACKNOWLEDGMENTS
The authors and cosponsors thank the following pre-
senters for their materials and efforts that contributed to this
Workshop Summary: Dr. Sarah L. Berga, Dr. Daniel J. Clauw,
Dr. Ronald Dubner, Dr. Richard H. Gracely, Dr. Carol A.
Everson, Dr. David S. Goldstein, Dr. Francis J. Keefe, Dr.
Robert W. McCarley, Dr. Paul M. Plotsky, Dr. 1. Jon Russell,
Dr. Evelyn Satinoff, Dr. Wendy F. Sternberg, and Dr. Eve Van
Cauter. We also thank Dr. Kenneth Casey, Dr. James M.
Krueger, and Dr. Susana A. Serrate-Sztein, who served with
the authors on the Planning Committee. We are grateful for
the assistance of the Conference Logistics Team of the Na-
tional lnstitute of Arthritis and Musculoskeletal and Skin
Diseases.
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