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7
Arousal States, Symptoms, Behaviour,
Sleep and Body Temperature
Rhonda Brown and Einar Thorsteinsson
7.1 Arousal States and Elevated Body
Temperature
In this section, we explore the extent of the co-occurrence between arousal
states (e.g. stress, anxiety), certain symptoms (e.g. fatigue, chronic pain)
and changes in BT. Depression comorbidity is discussed in regard to BT
in Chapter 6.
Autonomic arousal states (e.g. psychological stress) have been shown
to be functionally related to an elevated BT via the production of body
heat, which occurs as a natural by-product of the autonomic arousal [1].
For example, examination stress and anxiety were linked to an elevated
BT, prior to (i.e. anticipatory stress) and during an exam (e.g. increase in
R. Brown (
B
)
Australian National University, Canberra, ACT, Australia
e-mail: rhonda.brown@anu.edu.au
E. Thorsteinsson
University of New England, Armidale, NSW, Australia
e-mail: ethorste@une.edu.au
© The Author(s) 2020
R. Brown and E. Thorsteinsson (eds.), Comorbidity,
https://doi.org/10.1007/978-3-030-32545-9_7
179
180 R. Brown and E. Thorsteinsson
mean oral temperature of 0.6 °C 10–15 minutes prior to the exam) [2].
Similarly, young boxersshowed an elevated BT (1.06°F) before competing
in a boxing contest, relative to mean BT values obtained prior to training,
which was 1.44 °F higher than mean at-home BT values [3]. Medical
residents have also shown higher axillary BT 5–10 minutes before an
annual exam, relativeto a calm situation 2–3 weekslater (37.0 vs. 36.4 °C)
in all 22 participants, in a room with ambient temperature set at 23 °C.
This elevation in BT was mirrored by an elevation in heart rate (90.6 vs.
67.9 beats/min) and diastolic (72.2 vs. 67.6 mmHg) and systolic blood
pressures (120.4 vs. 104.1 mmHg) [4].
Taken together, theresults indicate that anelevated BT (byabout 0.6°C)
is functionallylinked to autonomicarousal states andan elevated heart rate
and bloodpressure [5], althoughfew studies have examined stress/affective
distress in regard to BT. However, it is apparent that any state, emotional
or otherwise, that is linked to an increase in autonomic arousal (e.g. rapid
heart rate, butterflies in stomach, muscle tension) will tend to have ther-
mogenic effects. For example, as detailed in Sect. 7.2, physical activity
is linked to autonomic arousal (e.g. elevated heart rate) and an elevated
BT. Thus, the perceptions of stress/anxiety will result in activation of the
physiological processes thatunderpin autonomic arousal (e.g.sympathetic
nervous system activation) [6], which, in turn, leads to increased energy
expenditure to result in the production of body heat, translating into an
elevated BT [1]. As discussed in detail in Chapter 2, an elevated nocturnal
BT can potentially interrupt a person’s sleep.
In contrast, social exclusion has been shown to be related to the percep-
tion of low ambient temperature aswell as the experienceof stress/affective
distress. For example, Zhong and Leonardelli [7] showed that people who
recalled a social exclusion experience tended to provide lower estimates of
room temperature than those who recalled a social inclusion experience.
Similarly, participants who were socially excluded from an online virtual
interaction task reported a greater desire for warm food and drinks, rela-
tive to those who were socially included. Somewhat differently, IJzerman
and Semin [8] showed that warmer conditions (i.e. warm vs. cold bev-
erage or room) induced greater social proximity in the participants than
colder ambient conditions.Finally, IJzermanand colleagues [9] foundthat
7 Arousal States, Symptoms, Behaviour, Sleep … 181
social exclusion (from an online ball-tossing game) reduced the partici-
pant’s finger temperature, whereas the negativeaffect induced by the social
exclusion was alleviated by holding a cup of warm tea. Taken together, this
interesting research suggests that the experience of coldness is integral to the
experience of social exclusion. However, it is unclear exactly how this
biopsychosocial phenomenon is best explained, especially as social exclu-
sion is typically linked to stress/affective distress, which in turn is linked
to an elevated BT. Nonetheless, the perception of cold in these studies was
mirrored by a real fall in peripheral BT [9], suggesting that a drop in skin
temperature (but perhaps not core BT) underpins the phenomenon.
7.2 Symptoms and Elevated Body
Temperature
Fatigue (i.e. pervasive sense of tiredness or lack of energy that is not
related exclusively to exertion) [10] is reported to be linked to an elevated
BT. Fatigue commonly coexists with depression, impaired sleep and over-
weight/obesity. For example, in multiple sclerosis patients, fatigue severity
is correlated with physical disability (r = .3) and depression (r = .4),
but only depression independently predicted fatigue, not age or disease
or treatment factors [11]. Similarly, Brown et al. [12] found that depres-
sion strongly predicted fatigue severity 3 months later in multiple sclerosis
patients, and fatigue also predicted later depression. Further, in a prospec-
tive population-based study, Addington and colleagues [13] showed that
a history of dysphoric episode and the number of somatization symp-
toms strongly predicted new-onset fatigue and recurrent/chronic fatigue
over 13 years, whereas a history of unexplained fatigue at baseline and
follow-up was linked to the greater risk of new depression onset (Major
Depressive Disorder), relative to patients who did not have fatigue.
However, fatigue has received relatively little attention as an indepen-
dent symptom of impaired sleep or in relation to impaired sleep, and it
is frequently confused with tiredness/sleepiness [14]. However, Lichstein
and colleagues [14] showed that fatigue was related to sleep disorders,
especially insomnia, in 206 people with severe fatigue. Fatigue severity at
12 months was predicted by low per cent sleep efficiency but not daytime
182 R. Brown and E. Thorsteinsson
sleepiness, suggesting that daytime sleepiness and fatigue are independent
phenomena. However, in another study, a change in insomnia severity
predicted fatigue changes 1 year later, after 3.5 weeks of inpatient psycho-
logical therapy; but when anxiety and depression changes were included in
the model, they (but not sleep) predicted the fatigue [15]. The results may
indicate that affective distress (e.g. anxiety, depression) and impaired sleep
together contribute to fatigue, although affective distress may make the
greater contribution.This assertion is corroborated byrecent results show-
ing that non-depressive rumination mediated the relationships between
stress, anxiety and depression to poor sleep quality, and poor sleep quality
mediated the relationship between rumination to fatigue [16]; although
the results were only cross-sectional. Nevertheless, the results suggest that
rumination may at least partly explain the tendency of stress/affective
distress to impair sleep, and together with poor sleep, they may at least
partly explain the fatigue in some individuals. However, as discussed in
Chapter 6, a bidirectional relationship is not always evident between low
mood and sleep; for example, depressed mood in adolescent students pre-
dicted less total sleep time on school nights and longer sleep onset latency
on weekends 1 year later,but impaired sleep didnot predict later depressed
mood [17]. As detailed below, these inconsistent study results may be at
least partly due to the overlap in (or comorbidity between) depressed
mood, fatigue and impaired sleep.
Fatigue is also known to be linked to overweight/obesity and proxy
measures of it; for example, it is predicted by higher BMI [18]. In a
study of 103 truck drivers, of whom one-half (53.4%) were obese, the
obese drivers were 1.22–1.69 times more likely to be rated as fatigued,
using two fatigue measures, and 1.99 times more likely to be fatigued
while involved in an at-fault safety-critical incident, relative to non-obese
drivers [18].Thus, obesity is linked to fatigue, sleep problemsand reduced
satisfaction with general health functioning and vitality [19], although it
is noteworthy that a diagnosis of severe obesity (BMI ≥ 40 kg/m
2
) can
actually preclude a patient from receiving a fatiguing illness (e.g. chronic
fatigue syndrome) diagnosis [20].
Taken together, the results suggest that fatigue is rarely experienced on
its own;rather, itis likely to beconcurrent with other symptomsand disor-
ders, including impaired sleep/insomnia, depression, overweight/obesity
7 Arousal States, Symptoms, Behaviour, Sleep … 183
and chronic illness diagnoses [21–23]. Bidirectional relationships have
also been documented between depression and fatigue, and fatigue and
impaired sleep, but it is unclear exactly how the symptoms (or disorders)
are related to each other. That is to say, in practice, it is often difficult to
disentangle anxiety, depression, fatigue and impaired sleep in longitudinal
predictive studies, as they often strongly and bidirectionally predict each
other; their symptoms overlap to some degree; and further complicating
this situation, anxiety, depression and impaired sleep can manifest as the
greater severity of somatic complaints, including fatigue, as detailed in
Chapter 6 and this chapter.
Clinically, fatigue is the most frequently reported symptom by multi-
ple sclerosis (MS) patients (53–87%) [23–26] which is typically persistent
and moderate tosevere in intensity [27]. It is also one of the most common
symptoms reported by primary care patients (e.g. 25% with some degree
of fatigue) [28]. Further, moderate-to-severe fatigue is typically present in
chronic fatigue syndrome (CFS; Centre for Disease Control and Preven-
tion [CDC], 2012) patients [29]. CFS is a relatively rare condition (e.g.
prevalence estimates = 37.1 cases/100,000 people) [30] that is charac-
terised by severe chronic fatigue that lasts at least 6 months and which is
not significantly relieved by rest. It is a highly debilitating condition that
can negatively impact upon daily living, employment and quality of life
in affected individuals [31]. For a CFS diagnosis to be made, the fatigue
must be accompanied by other symptoms including unrefreshing sleep,
joint and muscle pain, tender lymph nodes and/or cognitive or mood
disruption [29]. Clients with depressed mood [28] and anxiety [32]also
often report significant fatigue, as do patients with medical conditions
such as cancer and diabetes mellitus type-II [33, 34]. Finally, fatigue is
reported by a significant proportion of otherwise healthy adults (e.g. 17–
22%) [35–40] including community samples [37, 40], healthy working
adults [38, 39] and university students [35, 36], although the fatigue is
typically transient and mild to moderate in intensity [35, 36]. Similarly,
about two-thirds of adolescents report experiencing morning fatigue that
can impair their waking more than once/week, which peaks in the tran-
sition to high school [41]; in this case, the fatigue is generally attributed
to an imbalance between educational, social, other (e.g. sports) demands
and physiological debt due to rapid growth and sexual development.
184 R. Brown and E. Thorsteinsson
As detailed below, many different factors have been advanced to explain
the cause/s of fatigue in the scientific literature: It is variously explained
by infection, post-viral syndrome, cytokines, medical illness, impaired
sleep, stress (e.g. perceived stress, life event stressors, work stress) and
certain cognitions and behaviour (e.g. all-or-nothing behaviour, catas-
trophizing, somatic preoccupation, neuroticism, fear-avoidance, escape-
avoidance) and genetic factors. For example, in a Norwegian twin study
(746 monozygotic & 770 dizygotic twins, aged 50–65 years), the heri-
tability of fatigue was found to be moderate (.53), but it had both genetic
and environmental risk factors. In particular, shared anxiety/depression
symptoms were reported to be genetically related to fatigue (r = .73),
whereas individual-specific environmental correlations with fatigue were
only moderately correlated (r = .33) [42].
Stress/affective distress (i.e. perceived stress, negative life events, nega-
tive affect) at the onset of infection has been shown to be related to fatigue
development in the acute phase of parvovirus B19 infection in primary
care patients; it predicted chronic fatigue and arthritis 1–3 years later and
CFS/myalgic encephalomyelitis (CFS/ME)caseness 1–3 years later.Taken
together, the results suggest that the stress/affective distress–fatigue rela-
tionship may at least partly reflect the effects of intercurrent infection [43,
44]. For example, stress/distress at the onset of infection may be an early
unrecognised symptom of the infection (e.g. irritability). However, it is
also appreciated that psychological stress results in stress hormone (e.g.
cortisol) release that can suppress immune system functioning, thereby,
potentially increasing a person’s susceptibility to infection [45–47], which
may then induce the fatigue. That is, fatigue may result from the effects
of stress-induced immune suppression that increases the risk of infection,
which then causes fatigue.
Consistent with this assertion, acute fatigue is known to be a common
manifestation of certain viral infections such as Epstein–Barr virus (EBV)
infection. Forexample, a Norwegian study [48] examined 195 adolescents
and young adults (12–20-year-olds) at baseline and 6 months after EBV
infection. At6 months,91 of 195(46.7%) participantshad chronic fatigue
using the Chalder fatigue questionnaire, 27 (13.8%) had chronic fatigue
based on the Fukuda definition, and 20 (10.3%) had it based on the
Canadian definition. Fatigue severity 6 months later was predicted by
7 Arousal States, Symptoms, Behaviour, Sleep … 185
prior negative life events, high plasma C-reactive protein levels, clinical
symptoms, functionalimpairment and negative emotions[48]. Thus,viral
infection is likely to contribute to the development of chronic fatigue, but
it may be perpetuated by other factors; for example, as detailed below, it
might be perpetuated by infection-related cytokine release, physical de-
conditioning and/or sleep disturbance.
Symptoms of infection (e.g. fever, gastrointestinal [GIT] symptoms) are
also observed to precede or co-occur with fatigue onset in CFS patients
[49–52] which likely indicates that an infection has caused the fatigue
[53], possibly via an abnormal host response to infection [44]. Simi-
larly, cytokines (i.e. immune transmitters), including the expression of
tumour necrosis factor-
α
mRNA, have been shown to be elevated in MS
patients with significant fatigue (Fatigue Severity Score > 4), relative to
non-fatigued MS patients. Results suggest that inflammatory mediators
such ascytokines, which are known tobe activatedin response toinfection,
may be involved in causing MS-related fatigue [54].
However, in contrast, Hickie et al. [55]. found that only the initial
symptoms of infection (i.e. EBV, Q fever or Ross River virus)—not the
infection itself or the host immune response to it —predicted later CFS onset
in their study. CFS caseness was predicted by the severity of the acute
infective illness, especially fatigue, but not demographics, psychological
symptoms or serology. A prolonged fatiguing illness (i.e. disabling fatigue,
musculoskeletal pain, neurocognitive difficulties, mood disturbance) was
evident in 12% of the 253 patients at 6 months, of whom most met
diagnostic criteria for CFS, although cytokine assays were not performed
in this study.
Taken together, the results of this study suggest that severe infection
symptoms are most pertinent to the experience of chronic fatigue rather
than serological (or possibly other) immune evidence of infection. Inter-
estingly, gastrointestinal (GIT) [51, 56], glandular fever-like [53, 57], and
cardiac symptoms and signs [58, 59] have all been reported to reliably pre-
cede or co-occur with fatigue in CFS patients. Similarly, glandular fever
symptoms predicted fatigue in infectious mononucleosis patients [57];
generalised symptoms (e.g. chills) were related to fatigue risk in dengue
fever patients [60]; GIT symptoms were related to worse fatigue in uni-
versity students [61]; and flu-like illness and gastroenteritis were related
186 R. Brown and E. Thorsteinsson
to fatigue onset in healthy working adults [62]. Taken together, the results
suggest that infections with certain features—that is, flu-like/generalised,
glandular fever-like and/or GIT symptoms—may be especially likely to
cause fatigue in clinical and non-clinical populations.
However, there is substantial evidence that a combination of biological
(e.g. infection), physical (e.g. physical de-conditioning) and psychological
(e.g. stress) factors may contribute to the development of fatigue, includ-
ing sleep disturbance, which in turn is a symptom of fatiguing illness and
stress/affective distress [32, 63–66]. This assertion is consistent with prior
study results showing that high perceived stress [67–71] and stressful life
events [12, 35, 68] are related to worse fatigue in MS patients and uni-
versity students, respectively; work-related stress predicts fatigue severity
in healthy working adults [38, 69, 70]. Thus, acute and chronic stress
has been shown to be linked to fatigue [68]. Additionally, the assertion
is consistent with results showing that fatigue is related to stressful life
events, lower social support satisfaction, poor sleep quality and the use of
sleep medications [16, 35]; poor sleep quality mediates the stress–fatigue
relationship in people with undiagnosed fatigue; and the relationship was
additionally mediated by low social support in females [35]. Finally, the
assertion is consistent with results showing that the key risk factors for
fatigue in a sample of 2494 Indian women included low BMI, socio-
economic hardship (e.g. feeling hunger in past 3 months, less education,
family debt), domestic violence from the husband and poor mental health
[72]. Taken together, the results suggest that many different factors may
predispose an individual to experience fatigue (e.g. work stress, impaired
sleep), and these and other factors (e.g. viral infection, physical inactivity)
may also precipitate and/or perpetuate the fatigue [35, 38, 55, 57, 71].
Fatigue is known to be integrally linked to an elevated BT;forexam-
ple, fatigue tends to precede or be concurrent with infection symptoms
that include fever, as well as post-exertional malaise, pharyngitis, myal-
gia, adenopathy (i.e. swollen and painful lymph nodes), GIT symptoms,
sleep problems, cognitive impairment [49, 58, 73] and depression [74], in
medical patients [75] and CFS/ME patients [51, 73]. Fever is an adaptive
compensatory mechanism that activates the immune system, decreases
bacterial and viral growth rates and improves host survival in response to
7 Arousal States, Symptoms, Behaviour, Sleep … 187
infection; in the case of mild-to-moderate systemic infection, it can accel-
erate recovery from the infection. It (or an elevated BT) can be induced
by neuroendocrine, neurological, immunological and behavioural mech-
anisms, and in some cases, the fever is correlated with the severity of the
infective illness [76]. Furthermore, even in the non-clinical setting, hyper-
thermia that was induced in healthy cyclists who wore water-perfused
jackets heated to 40.1–40.2 °C was correlated with high heart rate and
feelings of fatigue/exhaustion [77], suggesting that autonomic arousal and
an elevated BT may at least partly explain the presence of post-exertional
fatigue.
Mechanistically, cytokines (i.e. small protein immune transmitters) that
are secreted in response to infection can directly induce infection symp-
toms, including fatigue [78, 79]. However, cytokines are not exclusively
secreted in response to infection; theyare also released in response to other
thermogenic stimuli,including exercise [80],physical stress [81],cold [82]
and heat stimulation [83–85]. Furthermore, cytokine responses that are
mounted in response to infection are reported to be largely indistinguish-
able from those that are activated in response to heatstroke/overheating,
stress/autonomic arousal and exercise/physical activity [84–86]. In con-
trast, core temperature ‘clamping’ (e.g. immersion to mid-chest in a cold
18 °C water bath) has been shown to abolish these plasma cytokine and
stress hormone (e.g. cortisol) responses [83].
In simplelanguage, the stresshormone and cytokineresponses to hyper-
thermia are similar, whatever their proximal cause; whether it is an emo-
tional stressor, thermal stressor, physical activity or infection [86]. How-
ever, in febrile patients, the hypothalamic thermal balance point is reset
to a higher level such that peripheral and central BT is sensed as cold
temperature signals bythe thermoregulatory circuitry. In contrast,in heat-
stroke/hyperthermia, the BT is elevated withouta corresponding elevation
in thethermal balance point. Thus,in the caseof fever, andto meetthe new
balance point, heat loss is inhibited via skin vasoconstriction, potentially
leading to chills, piloerection and behavioural adaptations (e.g. seeking
a warmer environment); heat gain mechanisms are activated, potentially
leading to rigours. Thus, fever is often characterised by chills, rigours,
elevated BT and after the infection, later sweating and a fall in BT [76,
188 R. Brown and E. Thorsteinsson
87]. Nonetheless, as detailed above, the immune response to hypother-
mia is largely similar whatever its cause, and a persistently elevated BT
can switch on both stress hormone and cytokine pathways. Therefore,
in addition to the putative effects of BT on sleep, it is possible that the
activation of these inflammatory pathways via an increase in BT, whatever
its cause, could directly contribute to ill-health. The potential role played
by stress hormones and cytokines in contributing to depressed mood is
discussed in detail in Chapter 6, and their potential rolein contributing to
the development of diabetes in overweight/obese individuals is discussed
in Chapter 4.
Finally, chronic pain is related to perturbations in BT and it is highly
comorbid with sleep problems, anxiety, depressed mood and obesity. For
instance, people who frequently experience pain tend to report sleep dif-
ficulties [88, 89]; for example, in a community-based study of Australian
adults, pain most strongly predicted impaired sleep, then anxiety, age,
somatic health, and annual low household income (i.e. proxy measure
of financial stress) [90]. In particular, arthritis and rheumatic pain are
reported toespecially disrupta person’s sleep—contributing to longersleep
onset latency, poorer sleep quality and fragmented sleep [91, 92]—with
similar results obtained in chronic pain outpatients. However, pre-sleep
cognitive arousal, rather than pain severity, was shown to best predict
poor sleep quality [93], suggesting that the extent to which pain causes
hyper-arousal impacts the most on sleep, not pain severity.
Longitudinal studies have consistently shown a significant predictive
relationship between pain and impaired sleep; for example, a significant
relationship was detected between pain severity at night and shorter sleep
and more awakenings and nightmares in 28 burns patients, but not all
of them experienced impaired sleep every day, suggesting that effective
pain management at night can help to maintain a patient’s sleep [94].
Similarly, Nicassio and Wallston [95] showed that greater baseline pain
intensity predicted worse sleep disturbance 2 years later in 242 patients
with rheumatoid arthritis, after controlling for demographics, depression
and functional impairment, but impaired sleep did not predict later pain
severity.Thus, it is unclearwhether a reciprocal relationshipexists between
impaired sleep and pain, although several studies have indicated that sleep
deprivation, especially a change in slow-wave sleep, can adversely impact