(Numbers within the article refer to reference numbers
at the bottom of page) Taken from: JOURNAL OF CHRONIC FATIGUE SYNDROME, 1998;
4: 61-76. Richard L. Bruno, Ph.D.,1
Susan Creange, Ph.D.,1 Jerald R.
Zimmerman, M.D.,1 and Nancy M. Frick, M.Div, Lh.D.2
1 The Post-Polio Institute Englewood Hospital and Medical Center, Englewood, New Jersey 07631
2 Harvest Center Hackensack, New Jersey
This research was supported by grants from the George A. Ohl, Jr., Infantile Paralysis Foundation.
1 The Post-Polio Institute Englewood Hospital and Medical Center, Englewood, New Jersey 07631
2 Harvest Center Hackensack, New Jersey
This research was supported by grants from the George A. Ohl, Jr., Infantile Paralysis Foundation.
To
test the hypothesis that plasma prolactin and electroencephalographic (EEG)
slow wave activity are correlated with fatigue, (33) polio survivors without
medical or psychologic comorbidities were studied. Subjects were administered
the Post-Polio Fatigue Questionnaire (PFQ) and had resting measurement of both
plasma prolactin and bilateral temporal-occipital power across the EEG
frequency spectrum. Typical daily fatigue severity on the PFQ was significantly
correlated with daily difficulty with attention, staying awake and motivation,
but not with measures of acute polio severity or the number of limbs affected
by late-onset Post-Polio Sequelae symptoms. Prolactin was significantly
correlated with daily fatigue severity on the PFQ (r=.39; p<.05). EEG power
was equal between the two hemispheres across all frequency bands. However, EEG
slow wave power in the right hemisphere was significantly correlated with
daily fatigue severity and prolactin level (r=.37; p<.05).
Using multiple linear regression, age at acute polio, frequency of difficulty with attention on the PFQ, prolactin and right hemisphere slow wave power predicted 72% of the variance of the daily fatigue severity rating (r=.85; p<.0001). These data suggest that increased prolactin secretion and EEG slowing are related to the severity of post-polio fatigue, findings similar to those in patients with acute paralytic and non-paralytic poliomyelitis and with chronic fatigue syndrome. A primary role is suggested for a dopamine deficiency (versus serotonergic receptor supersensitivity) underlying impaired cortical activation and the symptoms associated with putative post-viral fatigue syndromes.
Using multiple linear regression, age at acute polio, frequency of difficulty with attention on the PFQ, prolactin and right hemisphere slow wave power predicted 72% of the variance of the daily fatigue severity rating (r=.85; p<.0001). These data suggest that increased prolactin secretion and EEG slowing are related to the severity of post-polio fatigue, findings similar to those in patients with acute paralytic and non-paralytic poliomyelitis and with chronic fatigue syndrome. A primary role is suggested for a dopamine deficiency (versus serotonergic receptor supersensitivity) underlying impaired cortical activation and the symptoms associated with putative post-viral fatigue syndromes.
Fatigue
is the most commonly reported and most debilitating of Post-Polio Sequelae
(PPS), the unexpected, late-onset symptoms affecting the more than 1.8 million
North American polio survivors (1). In the 1985 National Survey of polio
survivors, 91% reported new or increased fatigue, 41% reported fatigue significantly
interfering with performing or completing their work and 25% reported fatigue
interfering with self-care activities (2).
Importantly,
polio survivors differentiate between physical tiredness and what they describe
as "brain fatigue" that is associated with cognitive difficulties. In
the 1990 National Survey, between 70% and 96% of polio survivors with fatigue
reported concomitant problems with concentration, memory, attention,
word-finding, maintaining wakefulness and thinking clearly, with 77% percent
reporting moderateto severe difficulty with these problems (3). Despite their
multiple cognitive complaints, the only clinically significant deficits on
formal neuropsychologic testing in severely fatigued polio survivors were in
attention and information processing speed (4).
Postmortem
studies performed during the polio epidemics of 50 years ago demonstrated the
consistent presence of poliovirus lesions in the midbrain reticular formation,
hypothalamus, thalamus, putamen and globus pallidus, i.e. the reticular
activating system (RAS) (3,5). RAS lesions have been hypothesized to cause
late-onset fatigue and attention impairments in polio survivors (6). This
hypothesis is supported by studies in which magnetic resonance imaging of the
brain has revealed small discrete or multiple punctate areas of hyperintense
signal in the reticular formation, thalamus, putamen, and white matter tracts
only in those polio survivors reporting fatigue (3,7).
Postmortem
histopathology also documented that neurons secreting neurotransmitters known
to activate the brain, especially dopaminergic neurons in the substantia nigra
and arcuate nucleus, were also damaged or destroyed by the poliovirus (5-7).
The inability of polio survivors' damaged RAS to adequately activate the cortex,
thereby impairing attention and concentration and generating the subjective
symptoms of fatigue, has been hypothesized to result in part from reduced
secretion of dopamine(3,6,8). This hypothesis is supported by a double-blind,
placebo-controlled pilot study of bromocriptine mesylate, a direct-acting,
post-synaptic dopamine 2 (D2) receptor agonist (9). An increasing daily dose of
bromocriptine was significantly negatively correlated with subjective reports
of fatigue on awakening as well as difficulty with staying awake during the
day, attention, cognition, word finding and memory. It is notable that
bromocriptine was effective only in the most neurophysiologically impaired
subjects, i.e., those with more than twice as many lesions on brain MRI, a blunted
ACTH response to an overnight fast and a baseline plasma prolactin level nearly
double that of the drug non-responders.
If
there is a dopamine deficiency in polio survivors it should be physiologically
evident. Resting plasma levels of prolactin should be elevated since
dopaminergic neurons in the arcuate nucleus were damaged by the poliovirus and
arcuate dopamine secretion inhibits prolactin release via D2 receptor
stimulation (10). If a dopamine deficiency is preventing brain activation and
causing fatigue, elevated prolactin should be associated with impaired cortical
activation as evidenced by slowing of the electroencephalogram (EEG). This
study was undertaken to test the hypothesis that fatigue, plasma prolactin and
EEG slowing are significantly correlated in polio survivors with fatigue.
METHODS
Subjects. Subjects were recruited from patients treated by the Post-Polio Service
and from post-polio support groups. Potential subjects completed and mailed to
the laboratory polio and medical history form and the Post-Polio Fatigue
Questionnaire (PFQ) which rates typical daily fatigue severity on a six-point
scale from "none" through "severe" (3). The PFQ also rates
the severity and the frequency (on a four-point scale from "never"
through "always") of difficulty with motivation, attention, mind
wandering, thinking clearly, concentration, word finding, memory, muscle
weakness and staying awake during the day. A phone interview was conducted and
individuals were excluded if they were over 59 years of age, had any medical or
psychological condition that could cause fatigue or cognitive impairment (e.g.,
major depressive episode, thyroid, cerebrovascular or cardiac disease, anemia,
respiratory insufficiency, sleep apnea or hypopneas, lupus or diabetes) or if they
were taking medications that could cause fatigue or cognitive impairment (e.g.,
anti-depressants, benzodiazepines). Subjects were interviewed when they
reported for testing and their medical and psychiatric symptoms and history
were confirmed. Thirty-three subjects were selected, giving a power of
.80 at a two-tailed alpha level of Power
analysis of the EEG frequency spectrum using fast Fourier transformations was
performed using the Dantec NEUROSCOPE (Dantec, Inc.). Electrodes were
placed at T5-Oz (left hemisphere) and T6-Oz (right hemisphere) with reference
placed at FPZ of the International 10/20 System.
These placements have been found to be the most sensitive for identifying EEG activity associated with decreased attention and the least affected by eye movement and eye blink artifact (11,12). Scalp skin was wiped with isopropyl alcohol and scrubbed with an abrasive pad; 1.0 cm. diameter silver/silver chloride EEG electrodes were then attached with Ten20© EEG electrode paste to achieve an impedance of
Procedure. Subjects were asked to eat their usual morning meal and limit themselves to only two 8 oz. cups of a caffeine-containing beverage on the day of testing. On arriving at the Institute, the experimental procedure was described to the subjects who gave written informed consent. Subjects were then taken to the hospital's hematology laboratory where venous blood was drawn. Plasma prolactin was assayed by a commercial laboratory using CIBA-Corning ACS immunochemiluminometric kits. Pre-menopausal women were studied during their luteal phase to control for the effects of ovulation on prolactin. Blood was also drawn by finger-stick for a simultaneous study of blood glucose and post-polio fatigue (data to be presented elsewhere).
These placements have been found to be the most sensitive for identifying EEG activity associated with decreased attention and the least affected by eye movement and eye blink artifact (11,12). Scalp skin was wiped with isopropyl alcohol and scrubbed with an abrasive pad; 1.0 cm. diameter silver/silver chloride EEG electrodes were then attached with Ten20© EEG electrode paste to achieve an impedance of
Procedure. Subjects were asked to eat their usual morning meal and limit themselves to only two 8 oz. cups of a caffeine-containing beverage on the day of testing. On arriving at the Institute, the experimental procedure was described to the subjects who gave written informed consent. Subjects were then taken to the hospital's hematology laboratory where venous blood was drawn. Plasma prolactin was assayed by a commercial laboratory using CIBA-Corning ACS immunochemiluminometric kits. Pre-menopausal women were studied during their luteal phase to control for the effects of ovulation on prolactin. Blood was also drawn by finger-stick for a simultaneous study of blood glucose and post-polio fatigue (data to be presented elsewhere).
Subjects
were then escorted to the psychophysiology laboratory where EEG electrodes were
attached over the course of approximately 20 minutes. The subjects were then
requested to sit facing a white wall that was one meter away, with their eyes
open and their muscles relaxed, and to refrain from talking or moving. Muscle
(EMG) activity was monitored both visually and via the NEUROSCOPE's EMG
artifact rejection software. After one minute of sitting, the subjects' first
16 seconds of artifact-free EEG was recorded. Subjects then began taking
neuropsychologic tests of attention and word finding during which EEG was also
recorded (data to be presented elsewhere).
Data
analysis. Statview 4.5 was used to perform statistical
analyses. Descriptive statistics were calculated for all variables as were
product-moment intercorrelations. The p value for correlations of daily fatigue
severity with subjective symptoms on the PFQ was corrected for multiple
comparisons using the Bonferroni inequality. Multiple linear regressions was
performed to determine if the daily fatigue severity rating could be predicted
on the basis of the prolactin value and the demographic item, PFQ subjective
symptom of fatigue and EEG frequency band power most significantly correlated
with daily fatigue severity.
RESULTS
Eighteen
females and 15 males participated, ages 38 to 59 years, having a mean educational
level of 16 years (Table 1). On average, the patients contracted polio in 1951
when they were 5 years old, were hospitalized at polio onset and had one limb
permanently affected. This sample is typical of the population of American
polio survivors.(2) Subjects were tested between 8:15 and 14:45 (x =
11:00).
Subjects
had resting plasma prolactin values ranging from 2.7 to 16.3 ng/ml (x = 6.9 ±
3.7), typical of the resting prolactin levels measured in both healthy controls
and CFS patients and within the normal range (13-17). As opposed to other
studies, there were no significant correlations between prolactin and time of
blood drawing, age or gender (17). Prolactin was significantly correlated with
daily fatigue severity on the PFQ (r=.39;p<.05). Daily fatigue severity was
also significantly correlated with age at acute polio (r=.39; p<.05), the
severity of difficulty with attention, mind wandering, muscle weakness,
concentration, staying awake and motivation, and the frequency of difficulty with
attention and mind wandering (Table 2). Fatigue severity was not correlated
with measures of acute polio severity or the number of limbs affected by
current PPS symptoms (e.g., muscle weakness and pain). These relationships are
consistent with the symptom profile of polio survivors with fatigue seen in the
1990 National Post-Polio Survey (3).
EEG
power was equal between the two hemispheres across all frequency bands.
However, EEG power in the right hemisphere was significantly correlated with
daily fatigue severity (slow wave and delta power) and prolactin (slow wave and
theta power) (Table 3).
Using
multiple linear regression, the age when polio was contracted, frequency of
difficulty with attention on the PFQ, plasma prolactin and right hemisphere
slow wave power predicted 72% of the variance of the daily fatigue severity
rating (p<.0001) (Table 4).
DISCUSSION
These
findings suggest the hypothesis should be accepted: there are significant
correlations between fatigue, plasma prolactin and slowing of the EEG in polio
survivors. The correlation of fatigue and prolactin with EEG slow wave power
only in the right hemisphere may be related to the important role ascribed to
the right hemisphere in cortical activation (18). Since polio survivors have
impaired visual memory, a function also ascribed to the right hemisphere, they
may have an as yet unexplained tendency toward right hemisphere damage and
therefore a predisposition to impaired cortical activation and fatigue (4, 19).
The correlation of age at polio onset with fatigue severity may be indicative
of the brain's decreased ability to compensate for poliovirus-induced damage
inflicted at an older age because of decreased neural plasticity as the brain
develops.
EEG
slowing and fatigue. Slowing of the EEG has already been documented following
the acute episode of polio. Holmgren reported that 34% of 258 patients with
acute spinal, spinal/bulbar and even non-paralytic polio demonstrated
"mental changes" such as "disorientation, apathy, (and) irritability"
(20). These changes were significantly correlated with abnormal slowing of the
EEG (i.e., the emergence of theta and delta activity) in 42% of those with
spinal or bulbar symptoms as well as in 33% of those with non-paralytic polio.
Even
in healthy subjects, EEG slowing is indicative of impaired cortical activation
and has been associated with decreased arousal, "drowsiness" and
impaired performance on neuropsychologic tests of attention (11, 21-23). Since
EEG slowing similar to that documented in polio survivors and controls has also
been noted in patients with putative post-viral fatigue syndromes (PVFS), and
since 85% of CFS patients demonstrated "an excess of irregular slow wave
activity" on EEG, decreased cortical activation may be a common substrate
of impaired attention and fatigue (24-27).
Dopamine
and fatigue. The correlations of prolactin with daily
fatigue severity and EEG slow wave power suggest that a reduction in central
dopaminergic activity may underlie reduced cortical activation and the symptoms
of post-polio fatigue. This suggestion is supported by the finding that D2
receptor antagonists increase EEG slow wave power, cause subjective fatigue and
difficulty concentrating, and produce dose-related increases in subjective
"drowsiness" and impairments on neuropsychologic tests of attention
(28,29).
Buspirone,
a D2 receptor antagonist that is an even more potent serotonin (5-
HT) 1A
receptor agonist, was also found to increase EEG slow wave power, decrease
subjective alertness, impair performance on neuropsychologic tests of attention
and cause a nearly two-fold increase in prolactin release in healthy subjects
(30). Identifying whether these psychophysiological effects are caused by D2
receptor blockade or 5-HT1A receptor stimulation is important since buspirone
and other 5-HT mimetic agents have been employed to study the pathophysiology
of CFS. Buspirone has been found to produce at least a twofold greater release
of prolactin in CFS patients as compared to healthy controls and to generate "excessive
fatigue" in CFS patients (13, 16, and 31). Bakheit et al. concluded that
the prolactin elevation resulted from "increased sensitivity" of
hypothalamic 5-HT1A receptors in CFS patients (13).
A
5-HT releasing and reuptake blocking agent, d-Fenfluramine, was found in one
study to produce a 130% increase in prolactin in CFS patients as compared to
controls (14). Although the same researchers did not find a
d-fenfluramine-induced increase in prolactin in a second study of CFS patients,
they did find a significantly attenuated prolactin response to hypoglycemia
(15). The authors concluded that while impaired prolactin release during
hypoglycemia could have resulted from "subsensitivity" of
hypothalamic 5-HT1A receptors, the patients' intact ACTH/cortisol response to
hypoglycemia failed "to support a role for altered 5-HT
neurotransmission" in CFS. Further, when the authors compared their
failure to elicit a prolactin increase with d-fenfluramine to buspirone's
ability to release prolactin, they concluded that buspirone's D2 antagonist
properties may be "confounding the serotonergic effects on prolactin
secretion."
A
neurotransmitter of fatigue? Buspirone's combined
5-HT1A agonist and D2 antagonist properties confound any conclusions about
altered central 5-HT1A receptor sensitivity in CFS, since buspirone's blockade
of D2 receptor is the more likely cause of prolactin increases (32). But an
additional confound exists when using prolactin as an indicator of central 5-HT
receptor sensitivity following administration of 5-HT mimetics. In animals,
5-HT itself can directly inhibit dopaminergic neurons, reducing tyrosine
hydroxylase activity and dopamine release, suppressing nearly 70% of the
dopaminergic prolactin-inhibiting neurons in the arcuate nucleus and lowering
dopamine concentrations in portal blood (10, 33, and 34).
In
humans, a 5-HT mimetic drug (fluoxetine) has been seen to produce Parkinsonian
rigidity, akathisia and dystonia, while buspirone itself has been shown to
exacerbate Parkinsonian symptoms (34-39). These findings suggest that the
ability of 5-HT mimetics to trigger prolactin secretion, increase EEG slow wave
power, impair attention and alertness, and trigger symptoms of fatigue is more
likely due to 5-HT's "inhibitory influence on central dopamine mechanism
and functions" within an already dopamine-depleted RAS, rather than an
unspecified effect of unexplained increases in 5-HT1A receptor sensitivity (34;
cf 3, 6, 7). This conclusion would explain the failure of one 5-HT mimetic
agent (fluoxetine) to ameliorate symptoms of CFS in a randomized, double-blind,
placebo-controlled controlled study, and suggests that serotonin reuptake
blocking agents could actually reduce cortical arousal, decrease alertness and
induce fatigue via serotoninÕs inhibition of central dopamine mechanism and
functions (13,34,40,41).
In
this context it is noteworthy that Parkinson's patients, with their profound
dopamine depletion, demonstrate impaired attention and marked fatigue (42, 43).
"Excessive fatigue" was reported by 48% of Parkinson's patients while
nearly one-third reported that fatigue was their "most disabling
symptom" (43, 44). Indeed, one of the first descriptions of cognitive
dysfunction in Parkinson's disease (PD) could serve as a description of post-polio
fatigue or chronic fatigue syndrome, i.e., a syndrome "characterized by a
diminution of voluntary attention, spontaneous interest, initiative and the
capacity for effort and work, with significant and objective fatiguability, and
a slight diminution of memory" (45).
However,
if low central dopaminergic tone underlies the symptoms of chronic fatigue, why
was baseline prolactin found not to be related to chronic fatigue in any of the
buspirone and fenfluramine stimulation studies? One possibility is that dopaminergic
neurons are more severely damaged by the poliovirus than by other putative
PVFS-inducing agents, thus allowing a prolactin/fatigue relationship to be more
readily detected in polio survivors. While PD symptoms were seen acutely during
poliovirus infection, the extent and severity of brain stem damage in these
patients proved fatal in nearly all of the reported cases (46-50). In contrast,
survivable Parkinsonism was noted during PVFS outbreaks earlier in this century
and has even been documented recently in PVFS patients, suggesting that
dopaminergic neurons are damaged - albeit less severely - in PVFS (Behan, Lapp,
and Richardson, personal communications) (50, 51).
A
more readily testable explanation for the lack of elevated baseline prolactin
values in CFS patients is that the assayed blood was drawn following an
overnight fast. Although hypoglycemia is known to increase prolactin secretion,
this effect is significantly attenuated in CFS patients (15, 17). Fasting may
increase only the control subjects' baseline prolactin values and thereby
obscure an elevated baseline prolactin in CFS patients. This explanation is
supported by a study of circadian hormonal variations, in which non-fasting
prolactin levels were significantly higher in CFS patients, and a report that
25% of one group of PVFS patients had "high basal prolactin levels"
(51, 52).
Future
research. These findings provide a rationale for further
study of the role played by the brain stem's reticular activating system and
dopaminergic neurons, especially within D2 receptor-mediated systems, in the
genesis of fatigue and other fatigue-related cognitive symptoms (cf 53, 54).
For example, the word finding difficulty reported by 82% of poliosurvivors with
fatigue, which appears similar both to the "tip-of-the-tongue"
phenomenon in PD patients and word finding problems reported by CFS patients,
may be related to impaired dopaminergic neurotransmission (3,55,56, cf 57). For
example, the number of animals polio survivors could name in 60 seconds was significantly
positively correlated with their score on a neuropsychologic test of vigilance
but significantly negatively correlated with plasma prolactin (-.36; p<.05)
(58).
Further,
recent research suggests that the emerging relationship between chronic fatigue
and fainting in CFS patients, polio survivors and even in healthy subjects may
have a dopaminergic component that is related to RAS damage (cf 9, 59-62).
However, the interactions of many brain neurotransmitter systems - peptidergic,
cholinergic, glutaminergic, as well as monoaminergic - need to be considered
and studied simultaneously to determine whether neurotransmitter abnormalities
underlie any of the symptoms of fatigue in polio survivors, in those with CFS
or with other putative PVFS (3,6,8,62).
ACKNOWLEDGEMENTS
The
authors gratefully acknowledge the participation of the subjects, the
continuing support of the George Ohl, Jr., Infantile Paralysis Foundation, and
the efforts and expertise of Carol Diveny and Mary Ann Solimine, R.N., M.L.S.,
without whom this work would not have been possible. We also thank Drs. Charles
Lapp, Peter Behan, John Richardson and Jesse Kaysen for their comments and
criticism, and Virginia Tegue for her expeditious intervention and editorial
expertise.
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