Fibromyalgia Syndrome: A Central Role for the Hippocampus ­- A Theoretical
Construct

J of Musculoskeletal Pain, Vol. 12(1) 2004, pp. 19-26

Patrick B. Wood

Patrick B. Wood, MD, is Assistant Professor. Department of
Fami]y Medicine, Louisiana State Health Science Center-Shreveport, 150]
Kings Highway. Shreveport, LA 71103 (E-mail: mailto:pwood@lsuhsc.edu ).


Submitted: April 29, 2003.
Revision accepted: August 7. 2003.


ABSTRACT. Objective: A growing body of evidence implicates the central
nervous system as playing a primary role in the diverse phenomena
associated with fibromyalgia, including hyperac­tivity of stress systems
and enhanced nociception. The objective of this review is to propose a
unifying theory to explain a majority of these.

Findings: Stress exposure causes deleterious changes within the central
nervous system, the hippocampus being particularly vulnerable. The
hippocampus is perhaps best known for its role in memory and cognition, two
functions which are impacted by elevated glucocorticoid levels such as
occur in prolonged stress. The hippocampus also provides inhibitory drive
to brain centers asso­ciated with the stress response, i.e., the
hypothalamic paraventricular nucleus, central amygdala, and locus
coeruleus. In addition, the hippocampus has been demonstrated to
participate in nociception, a function positively correlated with the
activity of hippocampal N-methyl-D­aspartate [NMDA] subtype glutamate
receptors. A variety of stress-related hormones are known to enhance the
activity of hippocampal NMDA receptors, thereby increasing excitatory
neuro­transmission within the hippocampus. While the impact of
stress-related hormones on hippocampal NMDA receptor function is adaptive
in the acute scenario, exposure to chronic stress eventually leads to
hippocampal dysfunction and atrophy secondary to excessive excitatory
neurotransmission [i.e., excitotoxicity].

Conclusion: Fibromyalgia is characterized by abnormalities that appear to
be related to hippocampal dysfunction, including hyperactivity of both
corticotropin-releasing hormone neurons and the sympathetic nervous system,
impaired declarative memory, and enhanced NMDA receptor-mediated
nociception. It is therefore postulated that stress-induced, NMDA
receptor-mediated dysfunction within the hippocampus plays a central role
in the etiopathogenesis and clinical phe­nomena of fibromyalgia.


KEYWORDS. Fibromyalgia, hippocampus, stress-related disorder, corticotropin
releasing hor­mone, N-methyl-D-aspartate receptor


BACKGROUND: FIBROMYALGIA AND STRESS

Fibromyalgia [FMS] has been character­ized as a "stress-related disorder"
due to its frequent onset after acute or chronic stressors and apparent
exacerbation of symptoms dur­ing periods of physical or emotional stress
(1). Factors associated with the onset of FMS in­clude severe infectious
illness, physical trauma, and severe emotional distress (2). The two
principal arms of the stress response system are the
corticotropin-releasing-hormone [CRH] system and the locus
coeruleus-norepinephrine [LC-NE] system, and their peripheral effectors,
the hypothalamic-pituitary-adrenal [HPA] axis and the sympathetic nervous
system. Prolonged exposure to either stress or the hormones asso­ciated
with it, particularly adrenal glucocorti­coids [GC, i.e., cortisol in man,
corticosterone in the rat] has been associated with adverse changes within
the central nervous system. The hippocampus [HC] is particularly
vulner­able, inasmuch as exposure to both stress and to stress-related
hormones is known to result in atrophic change and dysfunction within the
HC (3). Of what relevance might this be to FMS?

While FMS has long been associated with abnormalities in the stress
response system, the status of CRH in the disorder has been the matter of
some confusion. In an earlier review, Demitrack and Crofford suggested that
some of the symptoms associated with FMS were likely due to low CRH levels
(2), while later clinical investigations by Riedel et al. demon­strated
that many of the neuroendocrine phe­nomena associated with the disorder are
the consequence of hyperactivity of CRH neurons (4). In a subsequent review
by Neeck and Crofford, it was concluded that hyperactivity of CRH neurons
was indeed the case in FMS (5), a position that was lent further credence
by additional investigations, again by Riedel and colleagues (6).

In addition to increased CRH, a number of studies have demonstrated
phenomena associ­ated with hyperactivity of the sympathetic nervous system.
Martinez-Lavin et al. first demonstrated a deranged sympathetic response to
orthostatic stress in patients with FMS (7). Cohen et al. later
demonstrated the same, concluding that an imbalance of
sympathetic/para­sympathetic tone was related to the abnormal sympathovagal
response that characterizes the disorder (8). Individuals with FMS have
diminished 24-hour heart rate variability, an index of autonomic activity,
which is thought to be due to increased sympathetic activity resulting in
an exaggerated nocturnal sympathetic modulation of the sinus node (9).
Although not correlated with measures of tenderness or other FMS symptoms,
an association between heart rate variability changes and measures of
quality of life, physical function, anxiety, depression, and perceived
stress has been found (10). Together, these findings have led to the
conclusion that hyperactivity of the sympa­thetic component of the
stress-response sys­tem might explain many of the phenomena as­sociated
with FMS (11).

It would therefore appear that FMS may be characterized by sustained
hyperactivity of both the CRH system and the sympathetic nervous system.
Given that CRH is a potent stimulator of the sympathetic nervous system
(12), the latter is, perhaps, not surprising. What remains to be
determined, however, is the basis for such sustained hyperactivity. One
possibility relates to the experience of adverse early life events,
inasmuch as studies in both human subjects and nonhuman models have
demon­strated that adverse early life experience in­duces long-term
hyperactivity of CRH systems and, thus, dysregulation of the stress axis,
resulting in increased stress responsiveness (13,14). However, while these
data resonate with the increased incidence of adverse early life events in
FMS patients (15,16), they do not fully explain the dysregulation of the
stress axis observed in FMS, given the lack of a one-to-one correlation
between the develop­ment of FMS and the experience of childhood adversity.

What else might then explain these phenomena?


© 2004 by The Haworth Press, Inc. All rights reserved.