Handbook of Clinical Neurology, Vol.

157 (3rd series)

Thermoregulation: From Basic Neuroscience to Clinical Neurology, Part II
A.A. Romanovsky, Editor
https://doi.org/10.1016/B978-0-444-64074-1.00035-5
Copyright © 2018 Elsevier B.V. All rights reserved

Chapter 35

Stress-induced hyperthermia and hypothermia

TAKAKAZU OKA*
Department of Psychosomatic Medicine, International University of Health and Welfare Hospital, Tochigi-ken, Japan

Abstract
Stress affects core body temperature (Tc). Many kinds of stress induce transient, monophasic hyperthermia,
which diminishes gradually if the stressor is terminated. Stronger stressors produce a longer-lasting effect.
Repeated/chronic stress induces anticipatory hyperthermia, reduces diurnal changes in Tc, or slightly
increases Tc throughout the day. Animals that are exposed to chronic stress or a cold environment exhibit
an enhanced hyperthermic response to a novel stress. These changes persist for several days after cessation
of stress exposure. In contrast, long-lasting inescapable stress sometimes induces hypothermia. In healthy
humans, psychologic stress induces slight increases in Tc, which are within the normal range of Tc or just
above it. Some individuals, however, develop extremely high Tc (up to 41°C) when they are exposed to
emotional events or show persistent low-grade high Tc (37–38°C) during or after chronic stress situations.
In addition to the nature of the stressor itself, such stress-induced thermal responses are modulated by
sex, age, ambient temperature, cage mates, past stressful experiences and cold exposure, and coping.
Stress-induced hyperthermia is driven by mechanisms distinct from infectious fever, which requires
inflammatory mediators. However, both stress and infection activate the dorsomedial hypothalamus–
rostral medullary raphe region–sympathetic nerve axis to increase Tc.

INTRODUCTION these will only be referred to minimally as these topics

are described more precisely in Chapters 20 and 21.
In homeotherms, core body temperature (Tc) is main- Stress affects human body temperature as well.
tained around 37°C. However, there are several factors
Consequently, the effects of psychologic stress on Tc in
that affect Tc: immune insults such as infection and
healthy humans and its possible mechanisms will be
inflammation, the sleep/wake cycle, the menstrual cycle
described, especially focusing on the role of brown adi-
in females, diet, and stress.
pose tissue (BAT). I will also refer to “psychogenic
This chapter presents an overview of the effects of
fever,” pathologic manifestations of the effects of
single, repeated, or chronic stress on Tc and its modulat-
psychologic stress on Tc in humans.
ing factors in laboratory animals. I will also describe the
current understanding of the mechanisms of stress-
MANY KINDS OF SINGLE STRESS
induced hyperthermia/hypothermia and discuss the char-
INDUCE TRANSIENT, MONOPHASIC
acteristics of stress-induced hyperthermia/hypothermia
HYPERTHERMIA
by comparing these features with systemic inflammation-
induced fever/hypothermia (see Chapter 34). Neural In laboratory animals, many kinds of stress induce tran-
mechanisms responsible for stress-induced thermal sient increases in Tc. Figure 35.1 shows the time course of
responses are shared, at least partly, with those responsi- Tc (i.e., the temperature of the intraperitoneal cavity)
ble for arousal and sleep because many kinds of stress changes when an experimental rat is exposed to social
increase arousal levels and promote insomnia. However, defeat stress (where a rat is placed into the cage of a

*Correspondence to: Takakazu Oka, Department of Psychosomatic Medicine, International University of Health and Welfare
Hospital, Iguchi 537-3, Nasushiobara-shi, Tochigi-ken 329-2763, Japan. Tel: +81-287-37-2221, Fax: +81-287-39-3001, E-mail:
oka-t@iuhw.ac.jp
600 T. OKA

Fig. 35.1. Effects of indomethacin on social defeat stress-induced hyperthermia (A) and lipopolysaccharide (LPS)-induced fever
(B). Effects of diazepam and SR59230A on social defeat stress-induced hyperthermia (C and D). Rats received an intraperitoneal
injection of indomethacin, a cyclooxygenase inhibitor (5 mg/kg) (A), diazepam, an anxiolytic drug (4 mg/kg) (C), SR59230A,
a b3-adrenoceptor antagonist (5 mg/kg) (D), or their respective vehicles at the time point indicated by arrows and were subse-
quently exposed to social defeat stress (stress) or left undisturbed (control) during the period indicated by the horizontal
bars. LPS, a pyrogen (10 mg/kg), or a mixture of LPS and indomethacin (5 mg/kg) was injected into rats at time zero (B). Data
represent mean  SEM. (Modified from Lkhagvasuren B, Nakamura Y, Oka T, et al. (2011a) Social defeat stress induces hyperthermia
through activation of thermoregulatory sympathetic premotor neurons in the medullary raphe region. Eur J Neurosci 34: 1442–1452.)

dominant rat but is separated by wire mesh) for 1 hour
and then returned to its home cage. Social defeat stress
induces an abrupt increase in Tc up to 1.5–2.0°C within
25 minutes before gradually returning to baseline levels
within hours (Fig. 35.1A) (Hayashida et al., 2010;
Lkhagvasuren et al., 2011a, 2014a).
A similar stress response, i.e., transient, monophasic
hyperthermia, can be induced by either physical stressors,
such as insertion of a thermometer probe into the rectum
(Pae et al., 1985; Cabanac and Briese, 1992; Olivier
et al., 2003), tail pinch (Romanovsky et al., 1997), abdom-
inal prick with a needle (Romanovsky et al., 1998), foot
shock (Millan et al., 1981), and restraint/immobilization
(Parrott and Lloyd, 1995; Gray et al., 2008), or by psycho-
logic stressors, such as changing home cages (Morimoto
et al., 1991, 1993; Nakamori et al., 1993a, b; Oka et al.,
2003), placing into an open field or a novel environment
(known as open-field stress or novelty stress) (Singer
et al., 1986; Kluger et al., 1987; LeMay et al., 1990;
Soszynski et al., 1998), confrontation with an intruder
(known as social threat stress) (Brodkin et al., 2002;
Conley and Hutson, 2007; Mohammed et al., 2014), and
social isolation (Dallmann et al., 2006).
Basic researchers have labeled this single stress-induced
transient increase in Tc stress-induced hyperthermia
(Olivier et al., 2003; Adriaan Bouwknecht et al., 2007)
or stress-induced fever (Sanches et al., 2003). They have
also termed it psychologic stress-induced hyperthermia
(Kataoka et al., 2014) or emotional hyperthermia (Hajos
and Engberg, 1986)/fever (Soszynski, 2006) when the
increased Tc is associated with psychologic stress.
Such stress-induced hyperthermia is observed not only
in rats and mice but also in rabbits (Yokoi, 1966; Snow
and Horita, 1982), tree shrews (Kohlhause et al., 2011;
Schmelting et al., 2014), sheep (Pedernera-Romano et al.,
2010), squirrels (Muchlinski et al., 1998; Lee et al., 2000),
chimpanzees (Parr and Hopkins, 2000), impalas (Meyer
et al., 2008), chickens (Cabanac and Aizawa, 2000), ducks
(Maloney and Gray, 1998; Cabanac and Guillemette, 2001;
Gray et al., 2005, 2008), pigeons (Nomoto, 1996, 2003;
Bittencourt Mde et al., 2015), great tits (Carere and van
Oers, 2004), and humans (Falcon-Lesses and Proger,
1930; Hiramoto et al., 2009; Oka et al., 2013).
In any case, as shown in Figure 35.1, most single
stress-induced hyperthermic responses are transient
and monophasic, and diminish within several hours if
the stressor is terminated. However, strong psychologic
stressors such as social defeat stress sometimes affect
Tc for longer periods (Meerlo et al., 1996, Nakashima
et al., 2004). For example, when rats are subjected to a
single social defeat by placing them in the home cage
of an aggressive animal for 1 hour in the dark period,
some, but not all, rats display elevated Tc in the light
period for as long as 10 days (Meerlo et al., 1996).
 STRESS-INDUCED HYPERTHERMIA AND HYPOTHERMIA 601

Fig. 35.2. Effects of repeated social defeat stress on core temperature (Tc) in rats. Diurnal Tc changes in rats after exposure to
repeated social defeat (▪) or control rats () on a stress-free day after 21 defeats (A) and on a stress-free day 8 days after cessation
of 28 defeats (B). Data represent mean  SEM. *p < 0.05 compared with control. (Modified with permission from Hayashida S,
Oka T, Mera T, et al. (2010) Repeated social defeat stress induces chronic hyperthermia in rats. Physiol Behav 101: 124–131.)

EFFECTS OF REPEATED AND CHRONIC

STRESS ON BODY TEMPERATURE
Generally, repeated exposure to the same stressor leads to
a habituation of stress-induced physiologic responses.
However, this is not necessarily the case with stress-
induced hyperthermia. For example, daily handling
(Cabanac and Briese, 1992; Thompson et al., 2003) or
restraint/immobilization (Kuroshima and Yahata, 1985;
Barnum et al., 2007) is reported to decrease the magni-
tude of stress-induced hyperthermia gradually. However,
repeated exposure to other kinds of stress, such as
novel cage exposure (Pardon et al., 2004) or manipula-
tive handling (Bouwknecht et al., 2004), exhibits little
habituation.
Interestingly, repeated exposure to stronger and
uncontrollable stressors has complex effects on Tc. First,
repeated exposure to stressors such as daily confronta-
tion with a dominant conspecific at fixed time intervals
induces anticipatory or learned hyperthermia, i.e., Tc
becomes higher during the hour preceding the scheduled
time of stress application or during the hour when ani-
mals have been exposed to dominant animals even if they
are kept in their home cages without stress exposure
(Fig. 35.2A) (Eikelboom, 1986; Pardon et al., 2004;
Hayashida et al., 2010).
Second, repeated application of stressors (over
several weeks) either reduces diurnal changes in Tc,
mostly by increasing Tc in the light (inactive) period
602 T. OKA

Fig. 35.3. Mechanisms of acute psychologic stress-induced hyperthermia in comparison with infectious fever. Both infection and
acute stress activate the hypothalamic–medullary–sympathetic axis to increase core temperature (Tc). However, infectious fever is
associated with elevated acute-phase proteins such as C-reactive protein (CRP) and sickness behavior. By contrast, psychologic
stress increases Tc without accompanying sickness-related symptoms or inflammatory signs. So far, it is not known how psycho-
logic stress activates the dorsomedial hypothalamic nucleus (DMH) neurons to increase Tc or how the preoptic area (POA) and
other brain regions are involved in acute psychologic stress-induced hyperthermia. Possible brain regions that are involved in
stress-induced hyperthermia (? in the rectangle) include the prefrontal cortex, the medial amygdala, the lateral habenula, and
orexin-containing neurons. BAT, brown adipose tissue; IML, intermediolateral cell column; M’, macrophage; PG, prostaglandin;
rRPa, rostral raphe pallidus nucleus.

(Kant et al., 1991; Ushijima et al., 2006; Natarajan et al.,
2015), or slightly increases Tc (around 0.2–0.3°C)
throughout the day (Fig. 35.2B) (Endo and Shiraki,
2000; Hayashida et al., 2010).
Third, when compared with naïve subjects, animals
that have been exposed to repeated or chronic stress come
to exhibit enhanced hyperthermic responses to a novel
stressor (Bhatnagar et al., 2006), whereas ability to increase
Tc becomes impaired when animals are exposed to a
cold environment (Natarajan et al., 2015). Of note, these
changes persist even several days (or months) after cessa-
tion of the final stress exposure (Kant et al., 1991; Endo
and Shiraki, 2000; Hayashida et al., 2010; Natarajan
et al., 2015). Furthermore, these rats display depressive-
like behavior, such as decreased sucrose preference and
increased immobility in the forced swim test, rather than
increased anxiety-like behavior (Ushijima et al., 2006;
Rygula et al., 2008; Hayashida et al., 2010). This stands
in contrast to the observation that acute single stress-
induced hyperthermia is associated with increased anxiety
(Zethof et al., 1995).
LONG-LASTING INESCAPABLE STRESS
INDUCES HYPOTHERMIA
Stress-induced thermal responses are not always hyper-
thermic. In some cases, long-lasting inescapable stress
causes hypothermia. For example, Tc is decreased when
rabbits are subjected to restraint (Grant, 1950). This
restraint- or immobilization stress-induced hypothermic
response is observed not only in rabbits (Grant, 1950;
Morimoto et al., 1987) but also in rats (Tanaka et al.,
1974, 1981; Amar and Sanyal, 1981) and has been
termed “emotional hypothermia” (Grant, 1950).
MECHANISM OF ACUTE STRESS-
INDUCED HYPERTHERMIA
Acute and single psychologic stressors induce transient,
monophasic increases in Tc via mechanisms distinct from
infectious fever (Fig. 35.3) (Oka et al., 2001, 2003;
Vinkers et al., 2009).
When animals suffer from infectious diseases, they
frequently develop polyphasic increases in Tc, i.e., fever
 STRESS-INDUCED HYPERTHERMIA AND HYPOTHERMIA
(Romanovsky et al., 2005). Infectious fever is induced
when brain-permeable prostaglandin E2 (PGE2) acts on
neurons in the preoptic area of the hypothalamus
(POA), a thermoregulatory and febrile center within
the brain (Ushikubi et al., 1998; Oka et al., 2000; Saha
et al., 2005; Lazarus et al., 2007). The first phase of fever
is induced by PGE2 released from hepatic and pulmonary
macrophages (Romanovsky et al., 2006; Steiner et al.,
2006). Macrophages also release proinflammatory cyto-
kines, including interleukin (IL)-1b and IL-6, and
stimulate synthesis and release of acute-phase proteins,
including C-reactive protein, from hepatocytes. These
proinflammatory cytokines also stimulate synthesis of
PGE2 from endothelial cells of the brain vasculature
(Yamagata et al., 2001; Engblom et al., 2003) or perivas-
cular cells (Schiltz and Sawchenko, 2003) to induce later
phases of fever (Kluger, 1991; Leon, 2002). Therefore,
infectious fever is associated with elevated inflammatory
markers and attenuated by nonsteroidal anti-inflammatory
drugs (NSAIDs), such as cyclooxygenase inhibitors,
by blocking PGE2 synthesis (Fig. 35.1B).
POA neurons directly project to the dorsomedial hypo-
thalamus (DMH) and the rostral medullary raphe region,
including the rostral raphe pallidus nucleus and the raphe
magnus, which receives monosynaptic excitatory inputs
from the DMH (Nakamura et al., 2002, 2005; Madden
and Morrison, 2003; Yoshida et al., 2003; Cao et al.,
2004; Dimicco and Zaretsky, 2007). Stimulation of both
nuclei activates sympathetic preganglionic neurons in
the spinal cord, resulting in activation of b3-adrenoceptor
(AR)-mediated nonshivering thermogenesis in BAT
and a-AR-mediated cutaneous vasoconstriction to inhibit
heat loss (Nakamura et al., 2004; Rathner et al., 2008).
It also activates shivering thermogenesis in skeletal mus-
cles (Kerman et al., 2003; Tanaka et al., 2006; Nakamura
and Morrison, 2011). Both sympathetic nerve activation
and shivering combine to increase Tc. In this chapter,
I would like to term the DMH–rostral medullary raphe
region–sympathetic nervous system the DMH–medul-
lary–sympathetic axis. In most cases, as the POA sends
tonic inhibitory input to the DMH–medullary–sympathetic
axis, PGE2 induces fever by inhibiting the POA neurons,
i.e., by disinhibiting this axis (Nakamura, 2011).
In contrast to fever, psychologic stress increases Tc
via proinflammatory cytokine- and PGE2-independent
mechanisms (Long et al., 1990b; Watkins et al., 1995;
Takaki etal., 1999; Oka et al., 2003; Saha et al., 2005;
Kataoka et al., 2014), although several studies suggest a
partial involvement of PGE2 (Singer et al., 1986; Kluger
et al., 1987; Morimoto et al., 1991; Parrott and Lloyd,
1995; Cabanac and Dardashti, 1999). Therefore, systemic
administration of NSAIDs, such as indomethacin, fails
603
to inhibit many kinds of stress-induced hyperthermia,
including cage-mate removal stress (Zethof et al., 1995),
novelty stress (Vinkers et al., 2009), or social defeat
stress (Lkhagvasuren et al., 2011a) (Fig. 35.1A). Rather,
drugs that possess anxiolytic properties, such as benzodi-
azepines (e.g., diazepam, alprazolam, chlordiazepoxide)
and serotonin (5-HT)1A receptor agonists (e.g., buspir-
one, flesinoxan) (Borsini et al., 1989; Lecci et al.,
1990; Zethof et al., 1995; Van der Heyden et al.,
1997; Bouwknecht et al., 2000; Olivier et al., 2002;
Lkhagvasuren et al., 2014a), as well as b3-AR antagonists
(e.g., SR59230A) (Zhang et al., 2010; Lkhagvasuren
et al., 2011a), diminish the magnitude of stress-induced
hyperthermia (Fig. 35.1C and D). These findings suggest
that anxiety-induced sympathetic activation plays an
important role in the development of stress-induced
hyperthermia.
Stress activates sympathetic effector responses, includ-
ing nonshivering thermogenesis in BAT and constriction
of skin blood vessels (Nagasaka et al., 1979; Shibata
and Nagasaka, 1982, 1984; Nakamori et al., 1993a;
Ootsuka et al., 2008; Kataoka et al., 2014, Wanner
et al., 2017). In contrast, the involvement of shivering is
less studied.
Furthermore, corticotropin-releasing hormone
(Morimoto et al., 1993; Nakamori et al., 1993b), opioid
peptides (Blasig et al., 1978; Millan et al., 1983; Pae
et al., 1985), noradrenergic systems (Nakamori et al.,
1993a; Soszynski et al., 1996; Mayfield et al., 1999),
and serotonergic systems (Ootsuka et al., 2008; Beig
et al., 2009) within the central nervous system, all of
which are released or activated by stress, may also con-
tribute to single stress-induced hyperthermia. 5-HT may
contribute further by inhibiting 5-HT1A receptors in
the rostral medullary raphe region (Brown et al., 2008;
Nakamura and Morrison, 2011) or by activating 5-HT1A
(Madden and Morrison, 2010), 5-HT2A (Ootsuka et al.,
2004, 2008; Beig et al., 2009), and 5-HT7 receptors
(Madden and Morrison, 2010) in the intermediolateral
cell column of the spinal cord. In contrast, the dopaminer-
gic system does not appear to play an important role in
single stress-induced hyperthermia because neuroleptics
(haloperidol, chlorpromazine, clozapine, pimozide, sulpir-
ide) have little effect on the magnitude of stress-induced
hyperthermia (Borsini et al., 1989; Lecci et al., 1990).
Recent studies have demonstrated that, like infectious
fever, psychologic stress also activates the DMH–
medullary–sympathetic axis to increase Tc (DiMicco
et al., 2006; Dimicco and Zaretsky, 2007; Kataoka
et al., 2014) (Fig. 35.3). Several studies have suggested
that the POA is also involved in stress-induced hyper-
thermia (Pae et al., 1985; Cao and Morrison, 2005). Other
604 T. OKA
possible brain regions and neurons include the prefrontal
cortex (Pecoraro et al., 2008), the medial (Vinkers et al.,
2010) but not basolateral (Wellman et al., 2016) amygdala,
the lateral habenula (Ootsuka et al., 2017), and orexin neu-
rons (Zhang et al., 2010). As motivated arousal-induced
hyperthermia is associated with activation of the infralim-
bic cortex and the tuberomammillary nucleus (Valdes
et al., 2010; Riveros et al., 2014, 2015), these nuclei
and the histaminergic system (Lkhagvasuren and Oka,
2017) might also be involved in the stress-induced hyper-
thermia. So far, however, these findings are fragmented
and it is not fully understood whether the POA is really
involved in stress-induced hyperthermia, how psycho-
logic stress activates DMH neurons, or how other brain
regions affect the DMH–medullary–sympathetic axis dur-
ing psychologic stress.
Another interesting contribution could come from the
role of the vagus nerve in stress-induced hyperthermia.
Numerous studies have suggested that the vagal afferent
fibers, specifically the hepatic vagal fibers, are involved
in the development of systemic inflammation-induced
fever since subdiaphragmatic vagotomy (especially
transection of the hepatic branch), capsaicin treatment,
or chemical vagotomy attenuates several phases of
lipopolysaccharide(endotoxin)-induced fever (for review,
see Romanovsky (2000)). The vagal afferent fibers are also
involved in diet-induced thermogenesis (Liu et al., 2014)
and cooling-induced thermogenesis (Madden and
Morrison, 2016). However, the role of the vagus in stress-
induced hyperthermia is still inconclusive and in dispute.
An early study observed that subdiaphragmatic vagot-
omy attenuated handling stress-induced hyperthermia as
well as intraperitoneally injected IL-1b-induced fever
(Watkins et al., 1995). However, the following studies
failed to reproduce this finding because subdiaphrag-
matic vagotomy did not affect stress-induced hyperther-
mia evoked by tail pinch (Romanovsky et al., 1997) or
handling (Cabanac and Dardashti, 1999). In contrast,
another study demonstrated that methyl scopolamine, a
peripheral muscarinic antagonist, suppressed hyperther-
mia evoked by handling and cage-switch stress while pyr-
idostigmine, an acetylcholinesterase inhibitor, enhanced
it, without affecting basal core body temperature in rats
(Johnson Rowsey et al., 2002). This finding suggests
the involvement of the vagal efferent nerve in the develop-
ment of stress-induced hyperthermia. However, its precise
mechanisms remain unknown.
Figure 35.3 briefly summarizes the differences and
shared mechanisms between infectious fever and acute
stress-induced hyperthermia. Infectious fever is induced
by proinflammatory cytokines, which increase inflam-
matory markers such as C-reactive protein, and cause
behavioral changes termed the sickness response or sick-
ness behavior as well as fever. Therefore, infectious fever
is associated with sickness behaviors, such as decreased
vigilance, hypersomnia, and/or decreased activity. In
contrast, acute stress-induced hyperthermia is associated
with the systemic stress response, including increased
arousal and anxiety, insomnia, and/or increased activity,
especially when subjects are exposed to an unfamiliar
environment during the light period. Both infection and
acute stress activate the DMH–medullary–sympathetic
axis to increase Tc.
MECHANISMS OF HYPERTHERMIA
DURING REPEATED/CHRONIC STRESS
Conditioned hyperthermia
After exposure to initial stressors, the associated fearful
memories also increase Tc. For example, once animals
have received an electric shock in an unfamiliar cage,
they display behavioral and autonomic responses that
are characteristic of fear when they are re-exposed to
the same cage (conditioned fear to the paired context)
(Godsil et al., 2000; Vianna and Carrive, 2005, 2010;
Marks et al., 2009; Thompson et al., 2012; Wellman
et al., 2016). The sympathetic nervous system plays an
important role in the development of contextual
condition-induced hyperthermia because responses are
abolished via systemic administration of propranolol
(Marks et al., 2009). However, conditioned hyperthermia
does not seem to be induced by exactly the same mech-
anisms as acute stress-induced hyperthermia, particu-
larly with regard to hypothalamic signaling.
Conditioned fear-induced vasoconstriction in the tail
was abolished by microinjection of muscimol, a
g-aminobutyric acid (GABA)A receptor agonist, into the
rostral medullary raphe region (Vianna et al., 2008), sug-
gesting that conditioned fear-induced hyperthermia, acute
stress-induced hyperthermia (Lkhagvasuren et al., 2011a),
and infectious fever (Korsak and Gilbey, 2004) all share a
common medullary-sympathetic mechanism leading to
hyperthermia. However, contextual conditioned fear does
not induce the expression of Fos, a marker of neuronal
activation, in the DMH, but does increase Fos in spinally
projecting neurons in the perifornical area of the hypothal-
amus (Carrive and Gorissen, 2008). Furthermore, inter-
scapular BAT does not seem to contribute to conditioned
fear-induced hyperthermia (Marks et al., 2009), while it
is a primary mediator of infectious fever and stress-induced
hyperthermia.
Enhanced hyperthermic response
to a novel stress
Another characteristic of the effects of chronic stress
is that it facilitates hyperthermic responses to a novel
stressor (Bhatnagar et al., 2006). It also enhances
 STRESS-INDUCED HYPERTHERMIA AND HYPOTHERMIA
norepinephrine- (Nozu et al., 1992) and 5-HT2A/C
receptor- (Matuszewich and Yamamoto, 2003) mediated
hyperthermic effects, both of which are mediators of
acute stress-induced hyperthermia. Previous studies have
demonstrated that, after repeated immobilization, the
magnitude of the intravenous norepinephrine-induced
increase in Tc, interscapular BAT temperature, and oxygen
consumption becomes greater in stressed rats versus con-
trols (Nozu et al., 1992). As repeated immobilization stress
induces interscapular BAT hyperplasia (Kuroshima et al.,
1984) and increases uncoupling protein 1, a protein that
generates heat according to its expression and function
in BAT (Gao et al., 2003), these functional and morpho-
logic changes may lead to prominent stress-induced
hyperthermia (Fig. 35.4) (Kuroshima et al., 1984;
Kuroshima and Yahata, 1985).
Another study has demonstrated that 5-HT2A/C
receptor-mediated enhancement of hyperthermic effects
can be observed even 60 days after cessation of the stress
procedure (Matuszewich and Yamamoto, 2003). Thus,
animals that have been exposed to chronic stress become
prone to the induction of an enhanced hyperthermic
response to stressors that can cause acute stress-induced
hyperthermia.
Persistent low-grade hyperthermia and
flattened diurnal Tc rhythm
Chronically stressed rats show a persistent low-grade
hyperthermia or flattened diurnal rhythm of Tc. They
Fig. 35.4. Mechanisms for enhanced stress-induced hyper-
thermic responses in chronically stressed rats. In addition to
repeated psychologic stress, repeated exposure to a cold
environment also enhances stress-induced hyperthermia. BAT,
brown adipose tissue; SNS, sympathetic nervous system; Tc, core
body temperature, UCP1, uncoupling protein 1. (Modified
from Oka T (2015) Psychogenic fever: how psychological stress
affects body temperature in the clinical population. Temperature
2: 368–378.)
605
also display depression-like behavior (Rygula et al.,
2008; Hayashida et al., 2010). So far, it is not fully
understood if these changes are solely caused by the
sympathetic nervous system in the absence of any
involvement of pyrogenic cytokines. Furthermore, it is
not known if anxiolytic drugs can attenuate chronic
stress-induced changes in Tc.
Previous studies have demonstrated that diazepam fails
to affect these behavioral changes in chronically stressed
rats (Rygula et al., 2008), whereas chronic administration
of antidepressants such as citalopram (Rygula et al.,
2006b) and fluoxetine (Rygula et al., 2006a) was effective.
One study demonstrated that, in rats, metyrapone, a corti-
costerone synthesis inhibitor, did not normalize low-grade
hyperthermia (Natarajan et al., 2015). In humans, chronic
administration of tandospirone, a 5-HT1A receptor agonist
(Kura et al., 2004; Oka et al., 2006a), and paroxetine, a
selective serotonin reuptake inhibitor (Oka et al., 2006b),
attenuated low-grade hyperthermia that developed during
chronic stress situations. These findings suggest that dys-
function of the 5-HT system within the brain is, at least
in part, involved in persistent low-grade hyperthermia.
In comparison, repeated/chronic stress is known to
induce microglial activation (Hinwood et al., 2012,
2013) and subsequent proinflammatory cytokine produc-
tion (Johnson et al., 2013) via norepinephrine-mediated
mechanisms in the central nervous system. As brain-
derived cytokines also increase Tc (Oka et al., 1993,
1995) and induce depressive-like behavior (Raison
et al., 2006; Miller et al., 2009; Song and Wang, 2011),
there is a possibility that persistent hyperthermia and
depressive-like behaviors in rats exposed to chronic
stress are mediated, at least partly, by activated microglia
and subsequent proinflammatory cytokines within the
brain. However, further studies are needed to clarify
these mechanisms.
MECHANISM OF LONG-LASTING,
INESCAPABLE STRESS-INDUCED
HYPOTHERMIA
In rats, immobilization stress-induced hypothermia is
associated with a significant increase in the brain content
of 5-hydroxyindoleacetic acid, a principal metabolite of
5-HT, without alteration of 5-HT content in the whole
brain (Tanaka et al., 1974), and was completely abolished
by pretreatment with an intraperitoneal injection of
p-chlorophenylalanine, a 5-HT synthesis inhibitor
(Tanaka et al., 1981).
Another study demonstrated that 2-hour-immobilization
stress-induced hypothermia has two phases: a initial
phase characterized by a rapid fall in Tc (0–45 minutes)
followed by a late phase characterized by a slow gradual
fall in Tc (45–120 minutes) (Amar and Sanyal, 1981).
606
Fig. 35.5. Modulating factors of stress-induced hyperthermia and hypothermia.
Intracerebroventricular administration of either 5,6-
dihydroxytryptamine, a specific tryptaminergic neuron
degenerator, or methyl ester of parachlorophenylalanine,
a synthesis blocker of 5-HT, reduced the late phase of
hypothermia but not the initial phase. Pretreatment with
6-hydroxydopamine, an adrenergic neuron degenerator,
did not alter the course of immobilization-induced
hypothermia.
When benztropine was administered before
6-hydroxydopamine to produce a more selective degen-
eration of noradrenergic neurons, again there was no
significant change in the pattern and extent of the hypo-
thermia. However, when animals were pretreated with
desmethylimipramine and 6-hydroxydopamine to cause
more selective degeneration of dopaminergic neurons,
the early phase of hypothermia was attenuated (Amar
and Sanyal, 1981). These findings suggest that immobi-
lization stress-induced hypothermia is mediated by
5-HT within the brain, whereas its early phase is medi-
ated by dopamine.
The neural mechanisms responsible for stress-
induced hypothermia have not been well studied. There-
fore, it is not known if the POA or the DMH is involved
in this response. According to studies on systemic
inflammation-induced fever and hypothermia, the para-
ventricular nucleus of the hypothalamus and the DMH
and its adjacent dorsal hypothalamic area have been
proposed as key hypothalamic areas that mediate the
switch from fever to hypothermia (Wanner et al., 2013).
If this is the case for stress-induced thermoregulatory
responses, the paraventricular nucleus of the hypothala-
mus and the DMH/dorsal area might be involved in
stress-induced hypothermia.
T. OKA
MODULATING FACTORS OF
STRESS-INDUCED HYPERTHERMIA
AND HYPOTHERMIA
Numerous factors are known to affect the development of
stress-induced thermal responses (hyperthermia, hypo-
thermia, or no effect) and their magnitude and recovery.
Such factors include individual factors (e.g., sex and
age), environmental factors (e.g., ambient temperature),
and social factors (e.g., presence or absence of cage
mate), as well as the nature of the stressor itself. Further-
more, past experiences of stressful events and coping
strategies combating stress also modulate stress-induced
thermal responses (Fig. 35.5).
Nature and severity of stressors
In rodents, stress-induced hyperthermia is a very sensi-
tive physiologic response. As a consequence, even
changing their home cages or inserting a thermal probe
into their rectum increases their Tc. However, the magni-
tude of stress-induced hyperthermia is different depend-
ing on the severity of stress. For example, the change
resulting from social defeat stress is larger than that gen-
erated from mild stress, such as cage confinement or
restraint (Barnum et al., 2007). Furthermore, although
repeated mild stress exposure decreases the magnitude
of stress-induced hyperthermia, little habituation is
observed after repeated bouts of social defeat (Barnum
et al., 2007). Rather, repeated social defeat induces antic-
ipatory hyperthermia (Pardon et al., 2004; Hayashida
et al., 2010). In contrast, long-lasting inescapable stress
induces hypothermia.
 STRESS-INDUCED HYPERTHERMIA AND HYPOTHERMIA
Individual factors
SPECIES
Open-field stress induces hyperthermia in rats and mice.
However, female guinea pigs decreased their Tc during
exposure to an open field (Dymond and Fewell, 1999).
STRAIN
Hyperthermic responses of spontaneously hypertensive
rats (SHR), a genetic model of hypertension, are greater
than those of normotensive Wistar Kyoto rats when the ani-
mals are loosely restrained (Hajos and Engberg, 1986) or
exposed to an open field (Morley et al., 1990). As immobi-
lization stress-induced increases in plasma norepinephrine
are greater in SHR than Wistar Kyoto rats (Kvetnansky
et al., 1979; Saiki et al., 1997), greater sympathetic nervous
system activation in SHR may account for this difference.
SEX
Several, but not all (Wachulec et al., 1997), studies have
demonstrated that acute stress-induced hyperthermia is
greater in female than male rats (Thompson et al.,
2003; McGivern et al., 2009). This may be due to a dif-
ferential responsiveness of the hypothalamic–pituitary–
adrenocortical axis to stressors, with females reacting
more robustly than males, possibly because estrogen
can enhance hypothalamic–pituitary–adrenocortical axis
function and corticotropin-releasing hormone has a ther-
mogenic action (Handa et al., 1994). In contrast, in
guinea pigs, females decreased their Tc during exposure
to an open field whereas males did not change their Tc
(Dymond and Fewell, 1999).
AGE
In rats, the magnitude of acute stress-induced hyperthermia
becomes blunted with age (Foster et al., 1992; Wachulec
et al., 1997), as some old rats showed no change in Tc or
even became hypothermic after exposure to a novel envi-
ronment (Wachulec et al., 1997). This may be due to
decreased sympathetic nerve-mediated interscapular BAT
nonshivering thermogenesis with aging (Balmagiya and
Rozovski, 1983; McDonald et al., 1988; Scarpace
et al., 1992).
PREGNANCY
Pregnancy may attenuate stress-induced hyperthermia in
a gestational stage-dependent fashion (Fewell and Tang,
1997; Smith et al., 1997). For example, open-field stress-
induced hyperthermia was not attenuated on gestation
day-10 rats, but was abolished on gestation day-15 and
day-20 rats (Fewell and Tang, 1997).
607
TRAIT ANXIETY
The magnitude of acute stress-induced hyperthermia
differs between animals with high anxiety-related behav-
ior versus low anxiety-related behavior. Following
a 5-minute exposure to the elevated plus-maze, Tc in
rats with low anxiety-related behavior showed a greater
increase and faster return to baseline levels compared to
rats with high anxiety-related behavior (Liebsch
et al., 1998).
Environmental factors
TIME OF DAY
In rats, the magnitude of stress-induced hyperthermia
becomes slightly greater in the dark (active) phase than
in the light (inactive) phase (Briese and Cabanac, 1991).
AMBIENT TEMPERATURE
Ambient temperature affects the magnitude of stress-
induced hyperthermia. It also affects the appearance of
stress-induced hypothermia. One study showed that the
magnitude of stress-induced hyperthermia was not dif-
ferent between rats housed at 11°C and 25°C (Long
et al., 1990a). However, another study demonstrated that
rats kept at 8°C displayed a higher stress-induced hyper-
thermia than those kept at room temperature (23°C),
while rats kept at 30°C exhibited a lower stress-induced
hyperthermia than those kept at room 23°C (Briese,
1992). In a cool environment (15°C), restraint stress
produced hypothermia in rats and rabbits (Grant, 1950;
Yokoi, 1966; Amar and Sanyal, 1981). In contrast, at
ambient temperatures above 30°C, it did not cause hypo-
thermia. Rather, restraint stress caused hyperthermia
(Yokoi, 1966; Amar and Sanyal, 1981).
These findings suggest that cold environments
increase the magnitude of stress-induced hyperthermia,
whereas warm environments decrease it. Warm temper-
atures may mask the appearance of stress-induced
hypothermia even though the same stress induces hypo-
thermia at room temperature or lower.
COLD ACCLIMATION
Chronic or intermittent exposure to cold environment
also exaggerates the magnitude of stress-induced hyper-
thermia (Kuroshima and Yahata, 1985; Miyamoto et al.,
2017) and prevents stress-induced hypothermia (Grant,
1950). For example, after rats were housed at 5°C
(cold-acclimated) or 25°C (controls) for about 4 weeks,
the magnitude of immobilization-induced hyperthermia
was greater in the cold-acclimated rats than in control rats
(Kuroshima and Yahata, 1985). In contrast, prior expo-
sure to a cold environment (5°C) inhibited restraint
608 T. OKA
stress-induced hypothermia in rabbits (Grant, 1950).
This is likely because cold exposure leads to browning
of white adipose tissue (Bai et al., 2015; Kiefer, 2016),
increased thermogenesis in BAT (Rowland et al.,
2015; Saito et al., 2016; Miyamoto et al., 2017), and
increased nonshivering thermogenesis in skeletal muscle
(Bal et al., 2012; Pant et al., 2015; Rowland et al., 2015).
Social factors
The presence of a conspecific also modifies the magni-
tudes of stress-induced hyperthermia and conditioned
hyperthermia. For example, restraint stress-induced
hyperthermia becomes smaller when a mouse receives
restraint stress in the presence of cage mates, compared
to when alone. In contrast, hyperthermia is greater when
a mouse receives restraint stress beside freely moving
cage mates (Watanabe, 2015). Conditioned fear-induced
hyperthermia is also diminished when animals are
pair-housed with a conspecific after a stressful event
(Kiyokawa et al., 2004, 2007).
Early-life experiences
EARLY-LIFE STRESS
Early-life stress affects both stress-induced hyperthermia
(Ito et al., 2006) and stress-induced hypothermia (Mrdalj
et al., 2014) in adulthood. One study assessed the effects
of exposure to a novel environment on Tc in adult rats that
were weaned early (weaned at 16 days of age) or weaned
normally (weaned at 30 days). Early-weaned male rats
(but not female rats) showed a higher Tc response to nov-
elty stress compared to rats weaned at a normal time.
Early-weaned male rats also showed higher levels of
anxiety-like behavior as assessed by the elevated plus-
maze test (Ito et al., 2006).
Another study assessed the effects of maternal separa-
tion in rats during postnatal days 2–14 on chronic
mild stress-induced hypothermic effects in adulthood.
Exposure to chronic mild stress provoked a stronger
and longer-lasting hypothermia in a long-maternal sepa-
ration group (180 minutes, daily) compared to a brief-
maternal separation group (10 minutes, daily) (Mrdalj
et al., 2014).
JUVENILE STRESS
Juvenile stress also affects stress-induced thermal responses
in adulthood. For example, one study demonstrated that,
although social defeat stress-induced hyperthermia was
not different between adult rats (around the age of 48 days)
that had been subjected to juvenile stress (around 28 days
of age) and control rats, juvenile stress rats displayed an
elevated anticipatory hyperthermia versus controls when
animals were re-exposed to the social defeat environment
(Yee et al., 2011).
Coping
As described, many kinds of stress that lead to fight-or-
flight responses increase Tc, whereas long-lasting, ines-
capable stress that leads to passive coping decreases it.
Furthermore, differences in coping strategies affect the
recovery from stress (Kant et al., 1991; Meerlo et al.,
1999). For example, after introducing experimental rats
to an aggressive conspecific for 1 hour, circadian body
temperature rhythms were disrupted for several days.
Rats that did not counterattack took a longer time to
recover than animals that fought back (Meerlo
et al., 1999).
Another example was demonstrated where two rats
received the same around-the-clock intermittent signaled
foot shock for 2 weeks. One rat could control and termi-
nate the shock (stress-controlled); however, another rat
was yoked to the controlling rat (stress-uncontrolled)
such that the controlling rat and the yoked rat received
shocks of the same duration, but only the controlling
rat could terminate shock. Both stress groups had
decreased amplitude of Tc rhythms compared to control
animals, while the yoked animals were more severely
disrupted and remained disrupted for a longer period than
the stress-controlled animals (Kant et al., 1991).
Systemic inflammation can induce either fever or
hypothermia. Both thermoregulatory responses are pro-
posed to have adaptive values and are assumed to be
complementary strategies of survival in systemic inflam-
mation (Romanovsky and Szekely, 1998). Likewise,
stress-induced hyperthermia, which is associated with
active coping and energy utilization to survive fight-or-
flight situations, and hypothermia, which is associated
with passive coping to save energy to survive long-
lasting difficult situations, may also be two adaptive
strategies to survive stressful situations.
EFFECTS OF PSYCHOLOGIC STRESS ON
TC IN HEALTHY HUMANS
Hyperthermia
As observed in laboratory animals, psychologic stress
also increases Tc in healthy humans (Table 35.1). Previ-
ous studies have observed that Tc just before psycholog-
ically stressful events in daily life is higher than Tc after
these events or at the same hour of the day under non-
stressful conditions (Wynn, 1919; Kleitman, 1945;
Gotsev and Ivanov, 1950; Renbourn, 1960; Aschoff
et al., 1974; Marazziti et al., 1992; Briese, 1995; Shah
 STRESS-INDUCED HYPERTHERMIA AND HYPOTHERMIA 609
Table 35.1
Effects of psychologic stress on core body temperature (Tc) in healthy human subjects

Stressor Age Number Changes in Tc (°C) Reference

Exam 40 subjects Oral, Wynn (1919)

36.8 ➔ 37.2 (0.4)
Watching 10s, 20s 2 females Oral, Kleitman (1945)
movie 37.0 ➔ 37.5 (0.5)
37.2 ➔ 37.5 (0.3)
Boxing 12–14 years old 12 boys Oral, Renbourn (1960)
contest 36.8 ➔ 37.6 (0.8)
Exam 26–33 years old 22 residents Axillary, Marazziti et al. (1992)
36.4 ➔ 37.0 (0.6)
Exam 18–27 years old 108 medical Oral, Briese (1995)
students 37.2 ➔ 37.4 (0.2)
Exam 17–19 years old 30 medical Oral, Shah and Patel (2014)
students 36.7 ➔ 36.9 (0.2)
Trier Social 18–26 years old 24 subjects Temporal arteery Vinkers et al. (2013)
Stress Test temperature: no change
Intestinal temperature
decreased

and Patel, 2014). For example, the mean oral temperature
before boxing contests (37.55°C) in schoolboys (12–14
years old) was 0.8°C higher than that taken at home at the
same hour of the day (36.75°C) (Renbourn, 1960).
Academic stress-induced hyperthermia has also been
observed repeatedly, and the findings are consistent.
Examination stress induces small but significant
increases (0.2–0.6°C) in oral or axillary temperature,
which rarely exceeds Tc above the normal range or just
slightly above the normal range of Tc (in most cases,
lower than 37.5°C) (Wynn, 1919; Marazziti et al.,
1992; Briese, 1995; Shah and Patel, 2014).
There is one study that investigated the effect of lab-
oratory testing on Tc. However, exposing healthy sub-
jects to a standardized laboratory stress task (the Trier
Social Stress Test) did not change temporal artery tem-
perature, and decreased intestinal temperature, both of
which are assumed to reflect Tc (Vinkers et al., 2013).
In any case, humans are capable of increasing Tc via
neurocognitive mechanisms since practicing g-tummo
meditation increases axillary temperatures from 36.8°C
to 38.3°C in expert meditators (Kozhevnikov et al., 2013).
Hypothermia
On the contrary, to my knowledge, stress-induced hypo-
thermic responses have not been documented in human
subjects, although it is theoretically possible (e.g., when
an individual is lost in the mountains). One reason for the
lack of evidence might be that hypothermia has been
investigated from the viewpoint of stress reduction but
not as another kind of stress response. In clinical settings,
sympathetic suppression-associated physical responses,
such as increases in fingertip temperature, have been
used as a parameter of stress reduction and relaxation.
It is well known that relaxation-inducing therapeutic
techniques increase peripheral temperature, such as fin-
gertip temperature (which increases heat loss), and
reduce metabolic rate (which reduces heat generation),
both of which contribute to decrease Tc, even though
the magnitude is small (for review, see Oka (2012) and
Benson (1975).
MODULATION OF BROWN
ADIPOSE TISSUE ACTIVITY BY
STRESS, STRESS HORMONES, AND
STRESS REDUCTION IN HEALTHY
HUMAN SUBJECTS
In rodents, BAT is a major source of nonshivering ther-
mogenesis and plays a crucial role in the development
of stress-induced hyperthermia (Shibata and Nagasaka,
1982, 1984; Lkhagvasuren et al., 2011a; Kataoka et al.,
2014). However, in humans, until recently, the presence
of BAT had been believed to be relevant only in infants.
As in rodents, BAT is found in the interscapular region in
human infants, with negligible physiologic relevance in
adults. Therefore, it remained questionable whether
findings obtained in animal studies explain the mecha-
nisms of psychologic stress-induced hyperthermia in
human subjects.
610 T. OKA
Recent studies have demonstrated that BAT is distrib-
uted in paracervical, supraclavicular, and parathoracic
regions in adults (Cypess et al., 2009; van Marken
Lichtenbelt et al., 2009; Saito et al., 2009; Virtanen
et al., 2009; Enerback, 2010) and plays an important role
in cold-induced thermogenesis (Cypess et al., 2009;
Saito et al., 2009; van Marken Lichtenbelt et al., 2009;
Ouellet et al., 2012) and diet-induced thermogenesis
(Hibi et al., 2016), although the incidence of BAT
and cold-induced thermogenic activity of BAT decline
with age (Cypess et al., 2009; Yoneshiro et al., 2011;
Symonds et al., 2012).
Currently, human BAT activity is measured by two
means, i.e., 18F-fluorodeoxyglucose-positron emission
tomography combined with computed tomography
(18F-FDG-PET/CT) (Cypess et al., 2009; Saito et al.,
2009; van Marken Lichtenbelt et al., 2009; Virtanen
et al., 2009; Enerback, 2010) and infrared thermal Fig. 35.6. Possible mechanisms of stress-induced brown adi-
pose tissue (BAT) thermogenesis and hyperthermia in healthy
imaging of the suprascapular region (Lee et al., 2011;
human subjects. AR, adrenoceptor; SNS, sympathetic nervous
Symonds et al., 2012). Recent studies have demonstrated
system.
that anticipatory psychologic stress increases supraclavi-
cular temperature in lean healthy female subjects, reflect-
ing BAT thermogenesis (Robinson et al., 2016), whereas
PSYCHOGENIC FEVER: PATHOLOGIC
experience of an anxiety-reducing atmosphere reduces
MANIFESTATION OF THE
18
F-FDG uptake in BAT (Vogel et al., 2012). These
PSYCHOLOGIC STRESS-INDUCED
studies suggest that psychologic stress increases BAT
HYPERTHERMIC EFFECT IN HUMANS
activation and that stress-reducing interventions decrease In contrast to stress-induced transient, slight increases in
BAT activity in healthy humans. Tc in healthy subjects, some individuals exhibit extremely
Stimulation of sympathetic nerve activity by ephed- high Tc (up to 41°C) when they are exposed to emotional
rine (Carey et al., 2013) and mirabegron, a b3-AR ago- events, while some show a persistent low-grade high Tc
nist, increases BAT activity (Cypess et al., 2015), (37–38°C) lasting months and even years either during
while propranolol, a b-AR blocker, attenuates it or after situations of chronic stress (for review, see Oka
(Soderlund et al., 2007). Daily 2-hour cold exposure at and Oka (2012) and Oka (2015). The existence of such
17°C for 6 weeks results in a parallel increase in BAT patients was recognized as far back as the early 1900s
activity and cold-induced thermogenesis (Yoneshiro (Friedmann and Kohnstmann, 1914), and their high Tc
et al., 2013). These findings are in agreement with those was termed “psychogenic fever” (Falcon-Lesses and
in rodents. However, the role of glucocorticoids may dif- Proger, 1930; Bakwin, 1944; White and Long, 1958) or
fer between humans and rodents. In rodents, glucocorti- “neurogenic fever” (Kintner and Rowntree, 1934; Wolf
coids have been demonstrated to have an inhibitory and Wolf, 1942), long before the precise mechanisms of
effect on BAT thermogenesis (Hardwick et al., 1989; fever were known (Williams et al., 1977).
van den Beukel et al., 2014). However, in lean healthy Psychogenic fever is especially seen during adoles-
men, prednisolone increases BAT activity during cold cence and in young adults (Oka and Oka, 2007;
exposure (Ramage et al., 2016). Furthermore, in healthy Kaneda et al., 2009). Patients with psychogenic fever
subjects, infusion of hydrocortisone enhances sympa- develop “fever” without any inflammatory signs (Kura
thetically activated BAT thermogenesis (Scotney et al., 2004; Hiramoto et al., 2009) and NSAIDs do not
et al., 2017). reduce the “fever” (McNeil et al., 1984; Timmerman
Therefore, in healthy humans, it is possible to suggest et al., 1992; Kura et al., 2004), which is in agreement
that psychologic stress increases BAT thermogenesis, with characteristics of stress-induced hyperthermia in
leading to hyperthermia via activating sympathetic animals. Some patients develop extremely high Tc via
b3-ARs. The stress hormone cortisol may act in a syner- emotional events that provoke negative affect such as
gistic way with this mechanism to increase Tc (Fig. 35.6). arguments (Falcon-Lesses and Proger, 1930), separation
It is also possible that repeated cold exposures enhance from nurturing persons (Bakwin, 1944, 1949), or
stress-induced BAT thermogenesis similar to rodents. extreme tension (Hiramoto et al., 2009). In the case of
 STRESS-INDUCED HYPERTHERMIA AND HYPOTHERMIA 611
patients who do not seem to have any psychologic
problems, suppression of negative emotion (e.g., anger)
is associated with high Tc (Meyer and Beck, 1976;
O’Toole and Dyck, 1977). In these patients, not only
actual exposure to stressful events but also stress-
associated interviews (i.e., recalling and talking about
stressful events) increase Tc (Hiramoto et al., 2009).
Patients with persistent low-grade fever often com-
plain of numerous stress-related symptoms such as
fatigue, headache, or insomnia. For some patients,
increases in Tc are associated with worsening of these
symptoms, especially fatigue. Therefore, they experi-
ence the low-grade fever, even slight increases in Tc just
above 37.0°C, as disabling (Oka et al., 2006a). Some of
them have overadapted to social needs, i.e., they com-
pensate too well to be exhausted (Araki et al., 2004;
Kura et al., 2004), whereas others are neurotic and suffer
from high anxiety (Kintner and Rowntree, 1934).
Psychogenic fever is also observed in patients who
have had traumatic experiences in their early lives
(Duras, 1942) and those who have psychiatric disorders
such as anxiety (panic and posttraumatic stress) disorders
(Timmerman et al., 1992), mood (depressive and bipolar)
disorders (Weinstein, 1985; Timmerman et al., 1992), Fig. 35.7. Effects of a stress interview on core and periph-
somatoform (conversion) disorders (Duras, 1942), cata- eral temperatures in a 26-year-old patient with myalgic
tonia (Bohorfoush et al., 1965; O’Toole and Dyck, encephalomyelitis/chronic fatigue syndrome. Changes in axil-
1977), or borderline personality disorders (McNeil lary (armpit) and tympanic membrane (tym.) temperatures (A)
et al., 1984). For these reasons, they worry about their and fingertip temperature (B) during and after a 60-minute stress
high Tc and may consult with their physician, asking interview. Her subjective level of fatigue is also shown. The stress
for the fever to be treated. interview was conducted for 1 hour (0–60 minutes). (Modified
with permission from Oka T, Kanemitsu Y, Sudo N, et al.
(2013) Psychological stress contributed to the development of
Psychogenic fever in patients with physical low-grade fever in a patient with chronic fatigue syndrome: a
diseases case report. Biopsychosoc Med 7, 7.)
Psychogenic fever is stress-related hyperthermia without
any inflammatory causes. However, psychogenic fever afternoon. Antipyretic medications such as acetamino-
can also be found in patients with inflammatory or malig- phen failed to reduce this low-grade fever. She noticed
nant diseases (e.g., a patient with lung cancer) who have that she felt hotter and her axillary temperature reached
somatic symptom-associated anxiety (Xu et al., 2015). 38.5°C at work, especially when she was in a situation
Furthermore, psychogenic fever is also observed in of psychologic stress, such as being in a meeting with
patients with myalgic encephalomyelitis/chronic fatigue her head nurse. After hospitalization, her axillary temper-
syndrome or fibromyalgia syndrome (Oka, 2013b). ature decreased to 37.0–37.5°C in the afternoon.
Patients with myalgic encephalomyelitis/chronic fatigue To investigate the mechanisms for her low-grade
syndrome and fibromyalgia syndrome frequently exhibit fever, we conducted a 60-minute stress interview at 2
low-grade fever of unknown cause (Buchwald et al., p.m., in which we asked her to recall and talk about
1987; Oka, 2013a). Psychologic stress exacerbates their her difficult life. Her axillary temperature at baseline
symptoms, including low-grade fever. One example is was 37.2°C, and increased to 38.2°C (a 1.0°C increase)
presented below (Oka et al., 2013). by the end of the interview, whereas her fingertip tem-
A 26-year-old female nurse with myalgic encephalo- perature decreased during the interview (31.3°C at base-
myelitis/chronic fatigue syndrome was hospitalized line, 28.7–29.2°C during the interview) (Fig. 35.7). The
due to an exacerbation of fatigue. She had been checking severity of her fatigue on a numeric rating scale was 6 at
her own temperature and noted that, before hospitaliza- 1.30 p.m., and increased to a level of 9 by the end of the
tion, her axillary temperature was 37.5–38.0°C in the interview, decreasing back to 6 at 5 p.m.
612 T. OKA
Table 35.2
Changes in cardiovascular parameters and blood levels of cytokines and catecholamines during and after a 60-minute stress
interview (pre-60 minutes)

9 a.m. Pre 30 minutes 60 minutes 120 minutes 180 minutes

Ta (°C) 37.1 37.7 38.1 38.2 36.7 37

IL-1b (pg/mL) 0.39 0.29 0.3 0.33 0.28 0.37
IL-6 (pg/mL) 2.9 3.1 1.8 1.9 3.6 3.3
TNF-a (pg/mL) 1.5 1.3 1.4 1.1 1 1.5
IL-10 (pg/mL) <2 <2 <2 <2 <2 <2
A (pg/mL) 36 65 59 36
NA (pg/mL) 298 409 431 285
DA (pg/mL) 9 10 14 <5
SBP (mmHg) 100 116 126 121 122 106
DBP (mmHg) 66 79 97 93 77 75
HR (mmHg) 72 92 103 102 83 86

A, adrenaline (epinephrine); DA, dopamine; DBP, diastolic blood pressure; HR, heart rate; IL-1b, interleukin-1b; IL-6, interleukin-6; IL-10,
interleukin-10; NA, noradrenaline (norepinephrine); SBP, systolic blood pressure; Ta, axillary temperature; TNF-a, tumor necrosis factor-a.

In spite of the increase in axillary temperature, serum
levels of pyretic cytokines, such as IL-1b and IL-6, or
antipyretic cytokines, such as tumor necrosis factor-a
and IL-10, did not change. Rather, IL-6 and tumor necro-
sis factor-a were slightly suppressed during the interview
and 1 hour afterwards, and returned to pre-interview
levels 2 hours after the interview (180 minutes). During
the interview, heart rate, systolic and diastolic blood pres-
sure, and plasma levels of norepinephrine and epineph-
rine increased (Table 35.2). These results suggest that
stress interview-induced hyperthermia is not mediated
by pyretic cytokine production in the periphery but by
emotional expression-associated sympathetic activation,
which is in agreement with the findings on the mecha-
nisms of stress-induced hyperthermia in animal studies.
Treatment of psychogenic fever
The author treats psychogenic fever patients with: (1)
psychoeducation; (2) psychotherapy with environmental
adjustment; (3) relaxation training; (4) pharmacotherapy;
and/or (5) treatment for comorbid physical and/or psy-
chiatric disorders.
Psychotherapy is aimed to facilitate awareness of mind/
body interaction, change patients’ coping skills and life-
style, and reduce anxiety and stress. In the case of patients
who suppress their negative emotions and conflicts, the
author facilitates their ability to ventilate them verbally
(Duras, 1942; McNeil et al., 1984) or nonverbally (Araki
et al., 2004), since suppressed anger increases b-AR sensi-
tivity and enhances the stress response (Mills and Dimsdale,
1993). Relaxation training (such as autogenic training) is
also useful (Timmerman et al., 1992; Kura et al., 2004)
because it reduces anxiety and inhibits sympathetic tone.
Pharmacotherapy should consider the patient’s age,
blood pressure, psychologic symptoms, and comorbid
psychiatric and sleep disorders. Candidate drugs include
benzodiazepines (Xu et al., 2015), 5-HT1A receptor
agonists such as tandospirone (Kura et al., 2004; Oka
et al., 2006a), and antidepressants, especially serotoner-
gic tricyclic antidepressants such as amitriptyline and
clomipramine (Timmerman et al., 1992; Oka, 2005)
and selective serotonin reuptake inhibitors such as parox-
etine (Oka et al., 2006b). Serotonin/norepinephrine
reuptake inhibitors should be prescribed with caution
since they activate norepinephrine systems within the
brain, leading to activation of the sympathetic nervous
system and, in some patients, increased Tc.
In contrast to findings in animal studies, a consider-
able number of patients are reluctant to continue taking
b-blockers such as propranolol due to adverse events,
e.g., decreased blood pressure and worsened fatigue.
Patients with psychogenic fever often have comorbid
psychiatric disorders, as described above, as well as
physical diseases, such as primary headache, functional
gastrointestinal disorders, and orthostatic intolerance
(Lkhagvasuren et al., 2011b, 2013, 2014b). Therefore,
treatment should not only be focused on their high Tc,
but should also target comorbid psychiatric and physical
diseases.
PHYSIOLOGIC SIGNIFICANCE OF
STRESS-INDUCED HYPERTHERMIA
AND HYPOTHERMIA
In anxiety-provoking or fight-or-flight situations, animals
increase their Tc. Interestingly, not only homeotherms
but also poikilotherms, such as lizards (Cabanac and
 STRESS-INDUCED HYPERTHERMIA AND HYPOTHERMIA
Gosselin, 1993) and fish (Rey et al., 2015), increase Tc
via behavioral means, e.g., moving to warmer environ-
ments in stressful situations. Such stress-induced hyper-
thermia may have an adaptive value for animals to
survive “fight-or-flight” situations because it helps to
warm up muscular and central nervous systems, leading
to increased physical and cognitive performances
(Wright et al., 2002; Bishop, 2003; Bishop et al., 2003;
Koshinaka et al., 2013). For example, elevation of muscle
temperature within a physiologic range stimulates glucose
uptake in rat skeletal muscle (Koshinaka et al., 2013). In
humans, a slight increase in Tc around 0.15°C can improve
cognitive performance such as working memory, subjec-
tive alertness, and visual attention (Wright et al., 2002).
In contrast, when animals are exposed to inescapable sit-
uations for a long period, they sometimes show hypother-
mia, which may help to save energy to survive in a difficult
situation.
However, psychogenic fever could be a maladaptive
manifestation of many kinds of hyperthermic responses
modeled in animals since patients with psychogenic
fever report the elevated Tc to be disabling and ask for
treatment (Oka et al., 2006a). Their long-lasting persis-
tent hyperthermia may lead to physical exhaustion, while
exaggerated hyperthermia up to 42°C might cause path-
ologic changes in the central nervous system (Sharma
and Hoopes, 2003; Haveman et al., 2005).
SUMMARY
● Stress affects Tc in laboratory animals and humans.
● Many kinds of acute stress induce transient, mono-
phasic hyperthermia, whereas long-lasting inescap-
able stress induces hypothermia.
●
Repeated stress induces anticipatory hyperthermia. It
either reduces diurnal changes in Tc or slightly
increases Tc throughout the day. These changes per-
sist even several days or weeks after cessation of the
final stress exposure. Furthermore, animals that have
been exposed to repeated or chronic stress exhibit
enhanced hyperthermic responses to a novel stressor.
● Stress-induced hyperthermia is induced by mecha-
nisms distinct from systemic inflammation-induced
fever, which require proinflammatory mediators
such as PGE2 and pyrogenic cytokines.
● The sympathetic nervous system, particularly b3-
AR-mediated nonshivering thermogenesis in BAT,
plays a crucial role in the development of stress-
induced hyperthermia.
● Not only the kinds of stressors but also past stressful
experiential, individual, environmental, and social
factors and coping strategies modulate stress-
induced hyperthermia/hypothermia.
613
● In humans, stress-induced hyperthermia can be
observed in healthy subjects. Emotional event-
related extreme high Tc or persistent low-grade high
Tc during chronic stress has been documented as
“psychogenic fever.” In contrast, stress-induced
hypothermia is less observed in human subjects.
ACKNOWLEDGMENTS
This study was supported in part by a Grant-in-Aid for
Scientific Research from the Japan Society for the Pro-
motion of Science (number 23390189).
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