Interactions between stress and sleep: from basic research to clinical situations

Full text

Sleep Medicine Reviews, Vol. 4, No. 2, pp 201–219, 2000
doi:10.1053/smrv.1999.0097,
available online at http://www.idealibrary.com on
SLEEP
MEDICINE
reviews
PHYSIOLOGY OF SLEEP (REVIEW)
Interactions between stress and sleep: from basic
research to clinical situations
O. Van Reeth
1
, L. Weibel
1
, K. Spiegel
1
, R. Leproult
1
, C. Dugovic
2
and
S. Maccari
3
1
Centre d’Etudes des Rythmes Biologiques, School of Medicine, Ho
ˆpital Erasme,
Universite
´Libre de Bruxelles, Brussels;
2
Janssen Research Foundation, Beerse, Belgium;
3
Laboratoire de Neurosciences du Comportement, Universite
´de Lille 1, Villeneuve d’Ascq,
France
Acute stress is a fundamental adaptive response which enables an organism to cope with daily threatening
environmental stimuli. If prolonged and uncontrollable, the stress response may become inadequate and
ultimately result in health damage. Animal models of stress in rodents indicate that both acute and
chronic stressors have pronounced effects on sleep architecture and circadian rhythms. One major
physiological response elicited by stress is activation of the hypothalamo-pituitary-adrenal axis. In both
animals and humans, the hypothalamo-pituitary-adrenal axis plays an important role in sleep–wake
regulation and in alterations of the sleep–wake cycle secondary to exposure to acute or chronic stressors.
In humans, dysfunction of the neuroendocrine regulation of sleep can lead to severe sleep disturbances.
The progressive decay of the hypothalamo-pituitary-adrenal axis in elderly people, which mimics chronic
exposure to stress, may contribute to fragmented and unstable sleep in ageing. Shift workers, chronic
insomniacs or patients suffering from mental disorders show abnormal hypothalamo-pituitary-adrenal
secretory activity and concomitant sleep disturbances. Those sleep disorders and possible underlying
mechanisms are briefly reviewed. 2000 Harcourt Publishers Ltd
Key words: stress, sleep, circadian, insomnia, depression, shift work, rhythm, PTSD, ageing,
hypothalamo-pituitary-adrenal axis, catecholamines
Introduction
Walter Bradford Cannon was the first to study the various physiological responses to
directly threatening environmental influences [1]. Although Cannon can be considered
as the father of “stress”, this term was coined for the first time by Hans Selye in 1935
[2]. Everyone has their own understanding of stress and finding a definition is difficult.
Stress is a “multidimensional concept” built around at least three components: (i) the
Correspondence should be addressed to: Dr Olivier Van Reeth, Centre d’Etudes des Rythmes
Biologiques, School of Medicine-Universite
´Libre de Bruxelles, Ho
ˆpital Erasme, Route de Lennik,
808, 1070 Brussels, Belgium.
1087–0792/00/020201+19 $35.00/0 2000 Harcourt Publishers Ltd

O. Van Reeth et al.202
stimulus, or stressor, which can be positive or negative; (ii) the cognitive evaluation of
the stressor, which depends on the previous life experience of the individual and on his/
her ability to predict the stressful experience; (iii) the resulting physiological response(s)
of the individual. This third component refers to Selye’s characterization of the stress
response as a “general adaptation syndrome”, organized into three stages [3]. The first
stage is the general alarm reaction, during which numerous biological systems (including
the neuroendocrine axis) are activated in response to the stressor. The second stage
would lead to resistance, with the activated biological systems returning to normal. If
the stressful stimulus is maintained, the organism loses its resistance and enters a phase
of exhaustion, regarded as the third stage of the syndrome (Fig. 1).
The consequences of physiological activation are many (Fig. 1): mobilization of energy
(such as free fatty acids, glycerol, glucose, amino acids) from storage nutrients (tri-
glycerides, glycogene, proteins) and ceasing further energy storage, increase in cardio-
vascular/pulmonary tone to facilitate tissue delivery of oxygen and glucose, slowing
down of anabolic processes until the acute emergency has passed, and suppression of
digestion, growth, reproduction, inflammatory responses and immunity [4]. Cognition
is simultaneously altered, with a tendency towards sharpened sensory thresholds, a
logical adaptation for coping with an emergency situation. At the same time, negative
feedback mechanisms are activated to counteract the physiological activation and reinstate
a new equilibrium. If these feedback mechanisms succeed, the organism will be able to
deal with the stressful situation, eliminate its source and initiate appropriate behaviours:
stress is then an adaptive response which enables the organism to cope with daily
threatening environmental stimuli. If the source(s) of stress are prolonged and/or
uncontrollable, feedback mechanisms fail in restoring the equilibrium; then the stress
response becomes inadequate and may ultimately result in various pathological states
(e.g. hypertension, cardiomyopathy, G.I. ulcerations) including sleep and mood disorders.
Although many individuals experiencing stressful events do not develop such pathologies,
stress seems to be a provoking factor in those individuals with particular vulnerability,
determined by genetic factors or earlier experience [5].
Indirect evidence for the deleterious effects of stress on sleep comes from various
studies showing sleep changes immediately after disturbing life events (e.g. death,
divorce, job loss, financial loss), in chronic insomniacs [6], in shift workers [7], in stress-
related disorders (such as depression [8] or post-traumatic stress disorders [9, 10]), or in
elderly subjects [11]. These clinical situations will be reviewed in the second part of this
article.
Through the development of various animal models of stress (see below) and human
laboratory studies, progress has recently been made in the understanding of the
neuroendocrine regulation of sleep, and the effects of sleep or sleep loss back on those
regulating systems. This should yield new insights in the aetiology and physiopathology
of human sleep and mood disorders, and lead to a better understanding of the long-
term consequences of sleep deprivation.
Neuroendocrine substrates of the stress response
Major physiological responses elicited by stress are the activation of the hypothalamo-
pituitary-adrenal (HPA) axis and sympatho-adrenomedullary systems. Those two
systems are not separate entities, but exert mutual control on each other. Their responses
are under the control of stimulatory and inhibitory inputs to the hypothalamic

Interactions between stress and sleep 203
Stimulus–stressor
Cognitive evaluation
Physiological response
Neuroendocrine activation Behavioural response
Consequences: + Energy mobilization
+ Cardiovascular tonus
– Growth hormone
– Reproduction
– Immune system
Homeostatic state of the organism
Successful
Adaptation
Unsuccessful
Maladaptation
Disease: Ulcer
Amenorrhoea
Anorexia
Major depression
Drug addiction
Figure 1 Schematic representation of a multidimensional concept of stress build around
three important concepts: the stimulus-stressor, its cognitive evaluation by the organism
and resulting physiological response(s). Activation of various biological systems (in-
cluding neuroendocrine and behavioural components) leads to resistance of the organ-
ism, resulting in activated biological systems returning to normal. If the source(s) of
stress are prolonged and/or uncontrollable, feedback mechanisms fail in restoring the
equilibrium, the stress response becomes inadequate and may ultimately result in
various pathological states, including sleep and mood disorders.
paraventricular nuclei (PVN), which control the secretion of corticotropin-releasing-
hormone (CRH) and vasopressin (VP) into the pituitary portal circulation as well
as other neuropeptides [12]. CRH and VP secretion leads to pituitary release of
adrenocorticotropin (ACTH) and adrenal gland activation, with release of glu-
cocorticoids. Inhibitory inputs to the PVN mainly involve the feedback action of
glucocorticoids on their receptors located in the PVN and the limbic system. Cortico-
steroids that bind preferentially to hippocampal type I (mineralocorticoid) receptors

O. Van Reeth et al.204
appear to be involved in maintaining basal activity of the HPA axis, while glucocorticoid
receptors mediate the effects of corticoids aimed at restoring the homeostasis in the
reactive mode [12]. Those feedback mechanisms play a crucial role in the second stage
of Selye’s general adaptation syndrome.
The circadian timing system is another major physiological system involved in the
adaptation of the organism to environmental changes. In contrast to the stress system,
whose adaptive value is “reactive” to unexpected environmental changes, the circadian
system has a “predictive” adaptive role, as it prepares the organism to anticipate the
daily changes in the environment. Recent animal [13–15] and human [16–18] data have
revealed the existence of strong interactions between the circadian system and the
stress system. Those data indicate, first, that the response of an organism to an acute
stressor varies as a function of the time of day of stressor presentation. They also
indicate that the functioning of the circadian system is affected by stress, in such a
way that its response to stress is a function of the time of day at which the stressor is
applied. A better understanding of those interactions could be of high therapeutic
value, especially in improving preventive strategies in some of the stress-related
diseases (e.g. cardiac and neurological ischaemic diseases) whose onset demonstrate
a marked circadian variation with an increased risk during the morning hours [19].
Practice Point
Reaction to unexpected environmental changes involves the stress system, with
activation of the HPA axis and sympatho-adrenomedullary systems. Anticipation
to daily changes in the environment involves the circadian system. A better under-
standing of the interactions between those two adaptive systems may have important
therapeutic implications
Sleep and circadian rhythms in animal models of stress
Both acute and chronic stressors have pronounced effects on sleep architecture and
circadian rhythmicity in rodents. Recovery from acute stress usually involves a
reparative sleep rebound, characterized by an increase deep in slow wave sleep (SWS)
and in rapid eye movement (REM) sleep. In rats, for instance, an acute “immobilization
stress” procedure decreases SWS and suppresses REM sleep as long as the animal is
immobilized. After release, there is a significant increase in REM sleep and SWS [20,
21], and altered circadian rhythm of corticosterone secretion [22]. “Social defeat” in
rats, a natural stressor causing strong neuroendocrine and behavioural stress responses,
also induces changes in sleep and circadian rhythmicity. The major sleep change
consists of a sharp increase in EEG slow-wave activity (SWA) during deep SWS. SWA
has been identified as an indicator of sleep intensity [23], which suggests that acute
stressors may accelerate the build-up of a sleep debt [24]. In hamsters, acute induction of
arousal/locomotor activity at a time of usual inactivity/sleep, or acute immobilization at
a time of usual intense activity, are both powerful stressful stimuli for the animal and
behavioural resetting stimuli for the circadian clock [13, 14]. These data emphasize the
interactions between “stress-based” and “circadian time-based” adaptive physiological
systems.
In rats, hypothalamic CRH has been implicated in the regulation of physiological

Interactions between stress and sleep 205
waking [25] and in sleep-wake modifications induced by acute stress exposure,
primarily manifested by changes in REM sleep [21]. Stress-induced elevation of plasma
ACTH is associated with an increase in REM sleep and to a lesser extent in SWS sleep
[26]. Effects of acute stress on sleep seem primarily to involve central mechanisms
(rather than the HPA axis), since adrenalectomy does not modify those effects [27].
Both the noradrenergic and serotonergic systems are thought to play a permissive role
in REM sleep regulation [28]. Under stress conditions, CRH acting as a neurotransmitter
in the locus coeruleus, induces an increase in activity of noradrenergic neurons, which
leads to an increase in REM sleep [21, 29]. Serotonergic neurons in the raphe, activated
by acute immobilization stress, are important in the mediation of the restraint stress-
induced ACTH response [30].
Various paradigms involving chronic stress can also affect sleep architecture in
rodents, mainly through a sleep-disrupting effect [27]. For example, rats exposed to
chronic “intermittent foot shock” or “learned helplessness” exhibit an increase in REM
sleep during the first day of recovery [31]. Chronic “unpredictable mild stress” in rats
induces a decrease in latency to REM sleep onset, an increase in REM sleep and a
decrease in deep SWS [32]. In prolonged exposure to immobilization stress, reparative
SWS and REM sleep rebounds are eliminated [27]. Interestingly, the immobilization-
induced corticosterone secretion appears to play a role in this suppression of sleep
rebound, since adrenalectomized rats show an increased sleep rebound after im-
mobilization compared to controls [27], and treatment with the glucocorticoid receptor
agonist, dexamethasone, can mimic the effects of prolonged immobilization stress on
sleep [27]. Exposure of rats to chronic stressors also alters their behavioural, endocrine
and autonomic circadian rhythms [33]. Similarly, manipulations used to induce sleep
deprivation (total [34] or selective REM [35] sleep) in rats activate the HPA axis,
indicating the stressful nature of the methods used to induce sleep deprivation in
rodents.
Interestingly, the effects of chronic stressors on sleep seem dependent on the nature,
the timing and the duration of applied stressors. For instance, all the above-described
stress-induced changes in sleep and circadian rhythms in rats are transient and
disappear in the days following the end of the stressor. In contrast, exposure of rats
to stress in utero can lead to profound endocrine [15] and behavioural [36] abnormalities
that are persistent and stable over time [36].
Pre-natally-stressed (PNS) rats tested during adulthood exhibit abnormally pro-
longed stress-induced corticosterone secretion [37]. Under baseline conditions, those
rats show an increase in REM sleep and light SWS, higher sleep fragmentation, and a
slight decrease in deep SWS (Fig. 2). During recovery sleep from acute immobilization
stress, all those baseline sleep changes persist and are correlated with abnormal stress-
induced corticosterone secretion in PNS rats [36]. Those PNS rats also show disturbances
in circadian rhythms (locomotor activity, corticosterone secretion) that are consistent
with those observed in depressed patients [15, 38]. Those sleep abnormalities in rats
are consistent with reports of abnormal “sleep-like behaviours” in pre-natally-stressed
humans [39].
We have recently observed sleep abnormalities in Wistar Kyoto (WKY) rats, a strain
of rats with depressive and anxiety-like behaviours, abnormal circadian rhythms of
corticosterone and thyroid-stimulating hormones and hyper-response to stress [40].
Under baseline conditions, WKY rats show a 50% increase in REM sleep during the
light phase and an increase in sleep fragmentation during both the light and dark
phase. After a 6-h sleep deprivation, REM sleep rebound is more pronounced during

O. Van Reeth et al.206
10
70
% W
20
30
40
50
60 *
0
30
% Light SWS
5
10
15
20
25
*
10
70
% Deep SWS
20
30
40
50
60
0
30
% REM sleep
5
10
15
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25
*
*
*
**
*
*
*
*
*
*
*
**
0–4 4–8 8–12 12–16 16–20 20–24
Time intervals (h)
0–4 4–8 8–12 12–16 16–20 20–24
Time intervals (h)
Figure 2 Distribution per 4-h intervals of vigilance states in eight control (CONT: Φ)
and eight pre-natally-stressed (PNS: ΕΦ) rats under baseline conditions. Animals were
subjected to a 12:12 light–dark cycle (lights on, 00:00–12:00 h; lights off, 12:00–24:00 h).
Mean (±SEM) values of wake (W), light slow-wave sleep (SWS1), deep slow-wave
sleep (SWS2) and REM sleep are expressed as percentage of recording time. PNS rats
showed an increased time in REM, during both the light and dark phases. Those
changes result from an increase in the number of REM episodes, while their mean
duration remained the same. Pre-natal stress also induced an increase in total SWS1
time, restricted to the dark phase. ∗P<0.05, ∗∗ P<0.01, ∗∗∗ P<0.001 (two-tailed unpaired
Student’s t-test) for between-groups comparisons (adapted from [36]).
the dark phase in WKY rats. As the WKY rat represents a genetic model for depression
with altered EEG sleep patterns and abnormal responses to stress, this strain may be
particularly useful for investigating the relationship between depression, stress and
sleep abnormalities.
Practice Point
Both acute and chronic stressors have pronounced effects on sleep architecture in
rodents. Recovery from acute stress usually involves a reparative sleep rebound
characterized by an increase in REM sleep and SWS, driven by central mechanisms.
Exposure to chronic stress leads to fragmented sleep, probably driven by a stress-
induced increase in corticosteroids.
Mechanisms involved in the interactions between stress and human
sleep
In humans, there is a close and robust temporal association between sleep structure
and HPA axis activity. The early phase of nocturnal sleep, dominated by extended
epochs of SWS, is the only time of day during which secretory activity of the HPA
axis is subject to a pronounced and persistent inhibition, resulting in minimum
concentrations of ACTH and cortisol, with concomitant high levels of growth hormone

Interactions between stress and sleep 207
(GH) [41]. In contrast, during late sleep, predominated by REM sleep, HPA secretory
activity increases to reach a diurnal maximum shortly after sleep awakening. Also,
while arousals during light SWS are associated with bursts of sympathetic-nerve
activity, during deep SWS sympathetic-nerve activity is reduced compared to wake-
fulness [42]. Activities of the HPA axis and sympathetic system are positively correlated
to the overall amount of REM sleep [43]. The implication of the daily fluctuations of
ACTH in sleep regulation has been recently outlined in a study showing that a morning
rise in ACTH seems to play a critical role in timing the end of nocturnal sleep [44].
On the other hand, sleep–wake transitions (i.e. from wakefulness to sleep or from
sleep to wakefulness) affects the functioning of the HPA axis. Sleep onset is reliably
associated with decreasing or low cortisol levels [45, 46]. This might be related either
to the high amount of SWS during the first hours of sleep [47], or to preparatory
mechanisms facilitating sleep onset since cortisol secretion has been shown to have an
inverse relationship to SWA, with cortisol secretions preceding SWA variations by
about 10 min [45, 48]. Conversely, awakenings during or at the end of the sleep period
are consistently followed by a pulse of cortisol [49]. The recent demonstration of
temporal coupling between cortisol secretion and EEG bactivity (i.e. an index of
central alertness) during wakefulness is consistent with this observation [50].
Exogenous administration of each of the major mediators of the HPA axis (i.e. CRH,
ACTH and cortisol) has shown effects on sleep architecture. Pulsatile administration
of CRH produces several hormonal and sleep changes (reduced SWS, reduced REM
sleep during the second part of the night) that resemble those found in depression
[51]. Intravenous administration of ACTH was found to delay sleep onset, reduce SWS
and induce fragmented sleep [52]. Single dosed, continuous or pulsatile cortisol
infusions increase SWS and decrease REM sleep [51]. The effects of different corticoids
on sleep may involve the activation of different corticosteroid receptor types. Activation
of mineralocorticoid receptors increases the time spent in NREM sleep, while binding
to glucocorticoid receptors increases time spent awake or in REM sleep [41].
In considering possible mechanisms underlying the interactions between stress and
sleep, one cannot ignore the role of the immune system and its response to stress [53].
Acute or chronic stressors have a strong impact on immune function in both animals
and humans. Acute stressors have an activating impact on immune function which
concerns mainly the number of natural killer (NK) cells and may be mediated by
catecholamines [54]. In contrast, chronic stress can lead to a downregulation of the
immune response, with fewer B and T lymphocytes cells and decreased natural killer
cell activity [55]. A number of stressful life events have been associated with decreases
in immune function, such as bereavement [56], divorce or marital difficulties [57].
Similarly, affective states associated with stress, such as depression [58] or post-
traumatic stress disorder [59], have been associated with reduced immune defences.
Various studies on the role of cytokines have pointed out the important roles of
interleukin-1b(IL-1b), tumour necrosis factor (TNF) and interferon in sleep regulation
[60]. Administration of exogenous IL-1bor TNF induces increased NREM sleep,
while their inhibition reduces spontaneous sleep [61]. IL-1balso participates in an
immunoregulatory feedback loop leading to the activation of the HPA axis; this
represents one of the links between stress and sleep regulation. Available data in
humans show that plasma IL-1blevels vary in phase with the sleep-wake cycle, and
plasma TNF levels in phase with EEG slow-wave activity, and that both IL-1b
and TNF increase during sleep deprivation [62]. Also, strong associations between
disruptions of sleep continuity and impaired NK cell function have been reported [58].

O. Van Reeth et al.208
Practice Point
In humans, there is a close and robust temporal association between sleep–wake
states and activity of the HPA axis and the sympathetic system. Exogenous ad-
ministration of each of the major mediators of the HPA axis has effects on sleep
architecture. Various components of the immune system also have an impact on
sleep structure. Immune function, which in turn can be altered by acute or chronic
stressors, may thus play an important role in mediating some of the interactions
between stress and sleep
Sleep deprivation and stress
An important step in responding to a stressor is the subjective evaluation of the stress
by the subject. The perception of short-term sleep deprivation does not correspond to
the usual perception of an acute stress. Indeed, in human laboratory studies, during
and after a night of total sleep deprivation, subjects do not report being more “tense”
or less “calm” on visual analog scales (Leproult et al., unpublished data), suggesting
that in these experimental conditions sleep deprivation is not perceived as a stressor.
This could be due to the fact that in such studies subjects are aware of the modification
and the experimental procedure. They know the exact duration of the sleep deprivation
and that they will be able to recover their sleep need immediately after the study.
However, there are arguments to consider sleep deprivation as a stressor. One comes
from the immediate effects of sleep loss on the HPA axis at the usual time of sleep
onset. Since the modulatory effects of sleep–wake transitions on cortisol release are
absent under sleep deprivation, the cortisol profile shows mild alterations resulting in
reduced amplitude. The absence of sleep onset is indeed associated with higher cortisol
levels at the quiescent period of the rhythm [63]. A more robust argument in favour
of the stressful nature of sleep deprivation arises when we consider its effects on the
HPA axis on the following day. Under regular sleep–wake conditions, the 24-h profile
of plasma cortisol in young adults show an early morning maximum and declining
levels throughout the day, with a quiescent period centred around midnight and a
rapid elevation in late sleep. In contrast, a state of sleep loss induced in healthy young
men either by partial or total sleep deprivation or by semi-chronic curtailment of the
sleep period, results in an elevation of evening cortisol levels the following day and
in a delayed onset of the quiescent period of cortisol secretion (Fig. 3) [64, 65]. The
normal day-long decline of cortisol levels partially reflects the recovery of the HPA
axis from the early morning circadian stimulation that occurs in response to increased
CRH drive during the second part of the night. Elevation of evening cortisol levels
might thus reflect an alteration of the rate of recovery of the HPA axis from this
endogenous challenge which is likely to involve an impairment of the feedback
regulation of the HPA axis mediated by the hippocampus.
Since sleep loss seems to affect this HPA resiliency in young subjects, the ability of
the HPA axis to recover from exogenous stimulation by stressors may also be affected
by sleep loss. The superimposed effect of stress and sleep loss experienced in a chronic
manner is likely to be associated with long-term exposure to cortisol, yet prolonged
exposure to cortisol increases the natural vulnerability of neurons and is supposed to

Interactions between stress and sleep 209
0
7
2
3
4
5
6
8 h
in bed
8 h
in bed
1
(a)
n.s.
8 h
in bed
4 h
in bed
(b)
P < 0.03
8 h
in bed
No
sleep
(c)
P = 0.003
12 h
in bed
over 6
nights
4 h
in bed
over 6
nights
P = 0.003
Cortisol
g/dl
µ
Figure 3 Evening cortisol levels observed in three groups of young healthy subjects
before and after they were studied in three different conditions. (a) A normal bedtime
condition in which sleep was allowed from 23:00 to 07:00 h. (b) An acute sleep loss
condition, either partial with a 4-h bedtime period from 04:00 to 08:00 h (left part of
the middle panel) or total (right part of the middle panel). Acute sleep loss was
associated with 30–50% higher cortisol levels in the later part of the day. (c) A semi-
chronic sleep loss condition during which subjects were allowed only 4 h in bed for 6
days. This condition was also associated with higher cortisol levels in the later part of
the day. Cortisol levels were measured in each subject on two separate occasions:
under baseline conditions (left column in each bar graph) and after sleep manipulation
(right column in each bar graph) (adapted from [64, 65]).
accelerate hippocampal deterioration [66]. As the hippocampus is the main structure
involved in the feed back regulation of cortisol release, a situation of stress and chronic
sleep loss would further promote alterations in the feedback mechanisms involved in
the control of the HPA axis. Chronic sleep loss may therefore accelerate the development
of metabolic and cognitive consequences of glucocorticoid excess, such as cognitive
deficits and decreased carbohydrate tolerance [67, 68]. Recent studies indicate that
populations of developed countries chronically sleep deprive themselves because of
their socioeconomic and cultural environments. In addition to the adverse consequences
on mood and alertness, the possible central and peripheral disturbances associated
with glucocorticoid excess in chronic sleep loss may lead to long-term adverse health
effects.
Such an elevation of evening cortisol levels also occurs in a variety of conditions
including depression [69] and ageing [70]. It is possible that the sleep fragmentation
which characterizes both depression and ageing play a role in this abnormality of
HPA function. Interestingly, the functional component of HPA regulation that is most
affected by ageing is the rate of recovery from a challenge, i.e. the resiliency of the
response, rather than the unstimulated levels or the magnitude of the response [71].
Practice Point
Experimental evidence is in favour of the stressful nature of sleep deprivation in
humans. Chronic sleep loss may therefore accelerate the development of metabolic
and cognitive consequences of glucocorticoid excess, such as cognitive deficits and
decreased carbohydrate tolerance.

O. Van Reeth et al.210
023
20
Clock time
(a)
Cortisol ( g/dl)
19
15
10
5
23 3 7 11 15 19
Sleep time
0 8
20
Sleep time (h)
(b)
Cortisol ( g/dl)
15
10
5
135642 7
0 8
20
Work time (h)
Cortisol ( g/dl)
15
10
5
135642 7
µ
µµ
Figure 4 (a) 24-h cortisol rhythm in permanent night workers. Their sleep schedule
(07:00-15:00 h) is shown at the bottom of the panel. There is a clear distortion of the
cortisol rhythm: the acrophase shows good adaptation, whereas the quiescent period,
abruptly interrupted by a large peak, underwent only a partial shift of about 3 h,
leading to its dissociation from the sleep episode. (b) Plasma cortisol levels during the
usual sleep period (top) and the usual work period (bottom) in night workers (–––)
compared to day-active workers (– – –). In night workers, the sleep period coincides
with high cortisol levels, whereas the work period coincides with the quiescent period
of cortisol secretion (adapted from [73, 112]).
Shift work and stress
More and more businesses provide their full range of services 24 h per day, 7 days a
week. To meet these demanding challenges, more than 20% of the working force in
industrialized countries work permanently at night, or on schedules requiring a rotation
of day, evening and night work. Around the clock operations are associated with major
changes in light–dark cycles and the behavioural control of sleep–wake cycles, leading
to desynchrony between circadian rhythms and environmental periodicities. Workers
on permanent or rotating night shifts do not adapt to these schedules, even after several
years on the job [72, 111]. Figure 4 shows that the temporal profile of cortisol shows only
partial adaptation to the work schedule [73]. Therefore, workers are required to work
during the “wrong” phase of their circadian rhythms, when they are mostly sleepy,
inefficient and prone to accidents and to try to sleep at an unadapted circadian time,
leading to chronic behavioural and physiological maladaptation.
Shift work is a major health hazard, involving an increased risk of stress-related dis-
eases: ischaemic heart disease, gastrointestinal disorders, psychosocial complaints, sub-
stance abuse, sleep disturbances, reduced immune function and infertility (see [74] for
review). Sleep problems are certainly the most sensitive index of health dysfunction in
shift workers [75]. About 60–70% of shift workers complain of their sleep: most of them
report difficulties falling and staying asleep, poor quality of sleep, and difficulties staying

Interactions between stress and sleep 211
awake at work. Dislocation of circadian rhythms affect most shift workers, but only
20–30% of them tolerate it poorly, suggesting that additional coping factors might be
important. Indeed, many of the unspecific complaints of night workers, such as fatigue,
malaise, difficulty concentrating and irritability, can result from sleep loss [76]. Sleep
after night work is usually shorter and more fragmented than sleep after day work [7].
Shortening of daytime sleep after a night shift mainly affects REM sleep and stage 2 of
NREM sleep. Reduced effects on SWS were attributed to the sleep pressure due to the
extended duration of prior wakefulness. In a recent study investigating daysleep quality
in night shift nurses (alternating between day and evening schedules) a reduction in SWS
was reported, whether or not the nurses had subjective sleep complaints [77]. Sleep
during the daytime may be altered by both endogenous and exogenous factors. Endo-
genous factors include high and rising body temperature, high circulating levels of
hormones associated with wakefulness (such as cortisol, see Fig. 4), and low levels of
hormones associated with sleepiness (such as melatonin). Exogenous factors include,
among others, stress, traffic, children playing and household noise.
Over time, various models have been proposed to explain the relationship between
shift work and health. Those models have evolved from a linear relationship of shift work,
circadian disturbances and health to modelling a dynamic relationship characterized by
multidirectional pathways, incorporating the important roles of psychological variables
such as coping and cognitive appraisal (for review see [78]). The stress component is
thought to play a major role in linking shift work and health consequences. Stress can be
viewed in terms of “circadian rhythm disturbance”; stress is then the temporal disorder
of physiological performance, caused by the discrepancy between the time structure of
behaviour and the normal phases of circadian rhythms [78]. However, characteristics of
shifts (i.e. length, direction, rotation speed), biological disturbances and stable individual
differences are not enough to explain fully individual variations in adaptation to shift
work. Indeed, shift work is only one of several job stressors (which include lack of
autonomy, time pressures, monotony) encountered by those workers. In addition they
are also exposed to non-occupational stressors. Indeed, part of the stress of shift work is
due to social factors, such as frequent absence from the family with disruption of its
organization, insufficient recreation, parenting and the sexual role, resulting in family
tension and pre-occupation.
Practice Point
The stress component is thought to play a major role in linking shift work and health
consequences, including sleep disturbances. Sleep in shift workers can be altered by
both endogenous (i.e. circadian, metabolic, hormonal) and exogenous (traffic, children
playing, household noise) stress-related factors. Social stress factors (disruption of
family organization, parenting role) also contribute to sleep fragility in shift workers.
Sleep in selected stress-related disorders
Dysfunction of the above described neuroendocrine regulation of sleep can lead to
severe sleep disturbances. For instance, elderly subjects [11] or depressed patients [8]
all show insufficient inhibition of HPA secretory activity (particularly prominent during
early sleep) and concomitant reduced SWS. Patients with chronic fatigue syndrome

O. Van Reeth et al.212
[79] or fibromyalgia [80] show features of secondary adrenocortical deficiency of central
origin. The “burnout” syndrome is characterized by lower cortisol secretion and higher
cortisol suppression with dexamethasone [81]. A recent study in chronic insomniacs
without major psychiatric disorder shows that activity of both limbs of the stress
system (i.e. the HPA axis and the sympathetic system) relates positively to the degree
of sleep disturbances, as objectively measured by polysomnographic indices [6]. These
data in chronic insomniacs fit with results of previous studies showing a higher urinary
excretion of 17-hydroxysteroids in poor sleepers than in good sleepers [82]. Selected
clinical situations characterized by stress-related sleep disturbances will be briefly
described.
Ageing
The greater prevalence of disturbed sleep with increasing age has been found both in
surveys and in laboratory studies. In contrast to young adults, the elderly show a
reduction of SWS and a decrease in GH secretion at the beginning of the night, a
shortened REM latency and a flattened night-time rise of cortisol secretion, which also
occurs prematurely during the night [70]. Additional sleep characteristics in elderly
subjects include shortening of total sleep time and increased number of nocturnal
awakenings. Insomnia in the elderly is often the product of multiple factors that can
be difficult to separate [83].
The decay of the HPA axis may contribute to fragmented and unstable sleep in the
elderly. Diurnal rhythmicity of cortisol secretion is preserved in old age, but its relative
amplitude is dampened, and timing of the circadian elevation is advanced [84]. Also,
the level of the nocturnal nadir of cortisol increases progressively with age. Those
changes in the levels and diurnal variation of adrenocorticotropic activity are consistent
with the hypothesis of the “wear and tear” of lifelong exposure to stress [4]. Cumulative
exposure to glucocorticoids causes hippocampal defects, resulting in an impairment
of the ability to terminate glucocorticoid secretion at the end of stress and, therefore,
in increased exposure to glucocorticoids, which in turn further decreases the ability
of the HPA axis to recover from stress. Such changes in circadian amplitude and phase
could be involved in the aetiology of sleep disorders in the elderly [84].
Many other factors are contributory to disturbed sleep in older people, possibly
through HPA disturbances, e.g. sleep disordered breathing, periodic leg movement,
medication, physical illness, mood disorder, socioeconomic problems and life stress.
Even in the healthy elderly, those experiencing the death of a spouse are much more
likely to have complaints of chronic insomnia. Indeed, late life sleep disturbances have
been associated with specific stressful events such as bereavement [85], retirement, or
divorce [86]. In those cases, the insomnia is likely to be due to both the functional
(change in lifestyle) and the emotional consequences of those events. Interestingly,
good and poor elderly sleepers have different susceptibilities to similar stressful life
events, suggesting that ongoing life stress may play a role in the perpetuation of
chronic insomnia in older poor sleepers [11].
Adjustment sleep disorder
Also called transient psychophysiological insomnia or acute stress insomnia, this
disorder represents sleep disturbance temporally related to acute stress, conflict and

Interactions between stress and sleep 213
environmental changes causing emotional arousal [87]. Symptoms usually develop in
association with the identified stressor (death of a loved one, divorce, financial
problems, exams, unfamiliar sleep environment) and revert if the stressor is removed
or the level of adaptation is increased. Such patients may experience interference with
sleep onset and early morning awakenings.
Depression
Almost every depressed patient complains of insomnia. Recent studies also show that
chronic insomnia is indicative of a greater long-term risk for subsequent clinical
depression and psychiatric distress [88]. Subjective complaints of depressed patients
include prolonged latency to sleep, frequent and prolonged awakenings at night and
early morning awakening, vivid dreams, unrefreshed sleep and daytime tiredness [89].
Objective polysomnographic measurements in depressive patients show decreased
SWS, reduced REM sleep latency, increased REM sleep amount and density during
the first sleep cycle [90].
Stress is often a predisposing factor in the development of insomnia [91] and
depression [92, 93]. Studies aimed at establishing a causal relationship between stress,
hypercortisolism and vulnerability to depression have often pointed out to previous
or early life experience, both in animals (see section on animal models of stress)
and humans. Vulnerability factors named in studies documenting neuroendocrine
abnormalities and depressive states include traumatic life events, work or marital
problems, maternal separation or childhood abuse. Hyperactivity of the sympathetic
nervous system and the HPA axis with hypercortisolism are seen in about 50% of
depressed patients, and can be reversed by successful antidepressant therapy [94, 95].
In these depressed patients, CRH and VP expression in the PVN is enhanced, adrenals
show hypertrophy and basal corticosteroid levels are increased [96]. When challenged
with cortisol, dexamethasone, CRH or the combined dexamethasone-CRH test, those
patients show feedback resistance at the level of the PVN and pituitary [12]. Current
hypotheses hold that mechanisms underlying abnormal HPA function are causal factors
in the development and course of depression. Studies in depressed patients have
shown that HPA axis abnormalities are positively correlated with amounts of night-
time waking or light SWS during sleep, and negatively with amounts of deep SWS
[97]. After adequate treatment of depression, normalization of initially disturbed HPA
axis indicates a good prognosis, and persistent HPA dysregulation is associated with
a greater likelihood of relapse or chronicity [98].
It has been proposed that HPA hyperactivity in depression is probably initiated
and/or maintained by the combination of enhanced central production of CRH and
desensitization of glucocorticoid receptor binding system in the hippocampus, the
central regulator of HPA activity. Evidence has emerged that corticosteroid receptor
function is impaired in many depressed patients and in healthy individuals at increased
genetic risk for a depressive disorder [99]. If this is true, then secretion of CRH would
be enhanced in various brain areas, accounting for a variety of depressive symptoms.
Feedback resistance and basal hypercortisolism, which characterize depressed patients,
are already present in healthy subjects at high risk for affective disorders [99]. Those
individuals already have an imbalance in drive and feedback inhibition of their
HPA axis which precedes clinical manifestations and becomes harmful only during
conditions of chronic exposure to stress.

O. Van Reeth et al.214
As shown in animals with impaired glucocorticoid receptor function, antidepressants
enhance the signalling through corticosteroid receptors [100]. This mechanism of action
can be amplified through blocking central mechanisms that drive the HPA system,
suggesting that depressive patients with HPA hyperactivity may profit from treatments
with agents blocking excessive corticoid signalling, such as metyrapone [101], cortico-
steroid antagonists [102], or the promising CRH receptor antagonists [103, 104].
Recent work has revealed a putative important role for neuroactive steroids in the
maintenance of homeostasis during hormonal response to stress by counteracting the
activity of the HPA axis [105]. Interestingly, some of those compounds have an agonistic
modulator effect at the level of GABAa receptors. Fluctuation in the concentrations of
neuroactive steroids could in part be responsible for the increased vulnerability
to develop certain psychiatric diseases. Moreover, rats receiving the antidepressant
fluoxetine show an increase in brain synthesis and content of neuroactive steroids (e.g.
allopregnanolone), suggesting a possible anxiolytic and antidysphoric actions of this
drug via neural steroids [106]. Indeed, the imbalance of these steroids in patients can
be corrected by treatment with antidepressant drugs [107].
Post-traumatic stress disorder
Victims of disasters or people trying to adapt to traumatic events typically experience
recurring and distressing thoughts about the stressful event, and attempt to avoid
behaviours associated with the event. Those intrusive and uncontrollable images may
play a role in maintaining the stress and its deleterious effects long after the stressor
is gone. Sleep disturbances are cardinal symptoms in patients suffering from post-
traumatic stress disorder (PTSD). Fragmented sleep caused by frequent nightmares,
re-experiencing the trauma, is the primary sleep disturbance in such patients. The
frequency of nightmares has a strong relationship to the level of exposure to the
traumatic event [108]. To a lesser extent, those patients experience sleep onset and/or
maintenance insomnia. Polysomnographic findings in PTSD patients vary from one
study to another but usually include reduced sleep efficiency, longer time awake,
elevated awakening and movement time and paradoxical elevated waking thresholds
during sleep [10, 109]. Many patients with PTSD often meet clinical criteria for major
depression. However, HPA axis sensitivity in PTSD is different from what is found in
depression. PTSD is characterized by enhanced negative feedback of HPA axis, which
results in a lowered setpoint of HPA activity, with higher CRH levels [17] and
reduced daily production of cortisol [110]. Differences in sleep characteristics and HPA
abnormalities between PTSD and depression may help differentiating the conditions.
Practice Point
Severe sleep disturbances associated with dysfunctions of neuroendocrine regulation
are observed in elderly subjects and in patients suffering from various mental or
physical disorders, such as depression, chronic fatigue, fibromyalgia, PTSD, burnout
syndrome or various forms of insomnia.
Conclusions
The HPA axis, central catecholamine systems and sympathetic system play an important
role in the regulation of the sleep–wake cycle. Research findings also suggest that

Interactions between stress and sleep 215
circadian rhythms, sleep and wakefulness states can influence the functioning of those
regulatory systems. The set point of the HPA axis is genetically determined but can
be modulated and reset to other levels by early or later stressful experiences. In
animal models of stress and in various clinical situations, there is good evidence that
dysregulation of the neural and neuroendocrine mediators of the stress response can
lead to sleep and/or mood disturbances. Depending on the type of dysregulation and
the individual’s genetic factors or earlier experience, vulnerability may develop to
different sleep or mood disorders.
Research Agenda
Further development of animal models involving early life environmental mani-
pulations or genetic modifications (such as inbred strains and mutations) responsible
for differences in sleep phenotypes should allow the testing of various hypotheses
regarding the importance of physiological state or genetic background in the
regulation of sleep and its disturbances. These strategies will help in clarifying the
question of individual differences in the impact of stress on sleep, and elucidate
the mechanisms that link sleep, the circadian clock and stress systems to each other
and to mood alterations. This approach will lead to new experimental paradigms
in humans aimed at a better characterization of sleep disorders, and the relative
contribution of genetic and environmental factors in their symptomatology. It should
open the way to the development of more specific therapeutic tools in sleep medicine,
leading to a better integration between pharmacological and non-pharmacological
approaches in the treatment of sleep disorders.
Acknowledgements
This work was supported in part by the Belgian FNRS and FRSM, a NATO collaborative
research grant (ref: #960771), a CGRI-INSERM grant and a CEE research training
program.
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