Research Paper (APA STYLE)

INTRODUCTION Stress is a comple\f condition with emotional, cognitive, and biological factors. E\fcessive stress causes long\b and short\bterm disability in the various human systems, and activates the defense system of the central nervous system. The stress responses differ depending on the type of stress and the individual’s physiological responses. These latter responses consist of neuro\bendocrine and behavioral responses, and include the changes in the activity and immune function of the hypothalamo\bpituitary\badrenal (HPA) a\fis.

Sleep is an imp ortant comp onent of human homeostasis.

Sleep disorders are closely associated with significant medical, psychological and social disturbances. Chronic sleep restriction is an increasing problem in many countries. Since the body’s stress systems play a critical role in adapting to a continuously changing and challenging environment, it is an important question whether these systems are affected by sleep loss. The human body mobilizes defensive processes in an adaptive effort to maintain homeostasis.

If these defenses fail, insomnia may occur. Short\bterm insomnia is caused by a change in routine such as psychiatric illness, disability, and stress [1].

In the beginning of sleep, the activity of HPA a\fis is suppressed continually. In the latter part of sleep, the HPA secretory activity incre as es s o it is clos e to t he ma\fimum circ adi an rhyt hm immediately after waking up, and the prominent activity of the HPA a\fis and sympathetic nervous system influences the overall amount of rapid eye movement (REM) sleep [2]. Therefore, the rise of adrenocorticotrophic hormone (ACTH) in the morning is the decisive control factor regulating the end of sleep [3]. The Stress and Sleep Disorder K\bem S\bn Han 1, Lin Kim 2 and Insop S\fim 3* 1College of Nursing\f Korea University\f Seoul 136-705\f 2College of \bedicine\f Korea University\f Seoul 136-705\f 3College of Oriental \bedicine\f Kyung Hee University\f Seoul 130-701\f Korea http://d\f.doi.org/10.5607/en.2012.21.4.141E\fp Neurobiol. 2012 Dec;21(4):141\b150.pISSN 1226\b2560 • eISSN 2093\b8144 Review Article Received November 16, 2012, Accepted December 10, 2012 *To whom correspondence should be addressed.TEL: 82\b2\b961\b0698, FAX: 82\b2\b957\b0157e\bmail: [email protected] Copyrig\ft © Experimental Neurobiology 2\f12. www.enjo\brnal.org The purpose of this study was to review potential, physiological, hormonal and neuronal mechanisms that may mediate the sleep changes. This paper investigates the literatures regarding the activity of the hypothalamic\bpituitary\badrenal (HPA) a\fis, one of the main neuroendocrine stress systems during sleep in order to identify relations between stress and sleep disorder and the treatment of stress\binduced insomnia. Sleep and wakefulness are regulated by the aminergic, cholinergic brainstem and hypothalamic systems.

Activation of the HPA and/or the sympathetic nervous systems results in wakefulness and these hormones including corticotropin\b releasing hormone (CRH), adrenocorticotropic hormone (ACTH), cortisol or corticosterone, noradrenaline, and adrenaline, are associated with attention and arousal. Stress\brelated insomnia leads to a vicious circle by activating the HPA system. An awareness of the close interaction between sleep and stress systems is emerging and the hypothalamus is now recognized as a key center for sleep regulation, with hypothalamic neurontransmitter systems providing the framework for therapeutic advances. An updated understanding of these systems may allow researchers to elucidate neural mechanisms of sleep disorder and to develop effective intervention for sleep disorder.

Key words: stress, sleep disorders, psychological stress response This is an Open Access article distributed under the terms \ff the Creative C\fmm\fns Attributi\fn \b\fn-C\fmmercial License (http://creativec\fmm\fns.\frg/licenses/ by-nc /3.0) which permits unrestricted n\fn-c\fmmercial use, distributi\fn, and repr\fducti\fn in any medium, pr\fvided the \friginal w\frk is pr\fperly cited. 142 www.enjo\brnal.org \fttp://dx.doi.org/10.5607/en.2012.21.4.141 K\bem S\bn Han, et al.

fact that the beginning and end of sleep involve HPA a\fis activity and the close temporal relationship between the a\fis and sleep provides a clue to estimate the effects of the stress on sleep.

The immune system is also influential in the relationship bet\b ween stress and sleep. The most important link between the immune system and sleep is established by the cytokines which act as signaling molecules of the immune system such as interleukin\b1 beta (IL\b1β), tumor necrosis factor (TNF), and interferon. IL\b1β, TNF, and interferon are known to participate in the regulation of sleep [4]. If IL\b1β or TNF are injected, non\bREM (NREM) sleep will increase. But, in the absence of these substances, sleep is interrupted. IL\b1β is also involved with the immune regulating feedback chain, which activates the HPA a\fis, and may be one pathway involved in the relationship between stress and sleep [5].

Typically, stress\brelated insomnia is transient and persists for only a few days. But, in the clinic setting the real problem is chronic insomnia, which is also called physiological insomnia.

The stress\bdiathesis theory of the onset of chronic insomnia posits the involvement of a series of steps configured by the predisposing, precipitating, and perpetuating factors. A greater understanding is needed ab out the progress of insomnia caused by stress, particularly physiological insomnia.

In this study, the factors involved in sleep and alertness, their mechanisms of regulation, and the regulatory influences of the activation of HPA a\fis on stress\brelated physiological responses and changes in immune function on regulating sleep and alertness mechanisms were e\famined. As well, the mechanisms by which transient insomnia due to stress becomes chronically stabilized were investigated.

NEURONAL SYSTEMS AND CHEMICALS IN SLEEP AND WA\bING The arousal system of the brai\f stem The brain stem reticular formation has two dorsal pathways:

a pathway towards the thalamus and a pathway towards the basal forebrain. These pathways activate the cerebral corte\f [6].

Glutamate is the most common e\fcitatory neurotransmitter in the brain [7] and major function of the reticular formation neurons is to activate the sensory\bmotor, autonomic neuronal, and cerebral corte\f by the secretion of glutamate[8]. The pedunculopontine tegmental nuclei and the laterodorsal tegmental nuclei (PPT/LDT) which release acetylcholine play an important role on wakefulness by projecting through the thalamus, hypothalamus, and the basal forebrain [9]. Cholinergic neurons reciprocally enervate with the thalamus, the locus coeruleus (LC), and the raphe nuclei (DRN) [10]. E\fperimentally, acetylcholine in the cerebrum prompts was reported to be increased during alertness and, more abundantly, REM sleep [11]. Noradrenergic neurons of the LC spread out widely to the overall brain, and they activate alertness, followed by NREM, with activity being lowest during REM sleep [12]. When the LC is stimulated, the activity of the cerebral corte\f (i.e., EEG) is increased [13], and the changes in the LC activity are increased by new stimulation and various stressors. Stress may activate the LC activity by secretion of corticosteroid releasing hormone (CRH) in the paraventricular nucleus of the hypothalamus [14].

The nigrostriatal dopaminergic pathway promotes waking in motor activity, and inhibits sleep [15]. But, the mesocortical and mesolimbic dopaminergic neurons in the ventral tegmental area (VTA) of the midbrain affect the cerebral corte\f and the limbic systems, regulating alertness. Serotonergic neurons of the DRN are activated during waking state, and are inhibited in REM sleep [16]. Serotonergic neurons are involved in the generating of slow wave, but are not activated during sleep [17]. The collective data to data are consistent with the view that the serotonergic neurons are responsible for some of the activating systems, but seem to reduce the corte\f activation by e\ferting an inhibitory influence on other neurons responsible for alertness [7]. Serotonin 5\bHT1A receptors are e\fpressed in the gamma\baminobutyric acid (GABA) ergic neurons of the basal forebrain [18]. GABAergic neurons are hyperpolarized by secreting 5\bHT in the DRN. Therefore, i f G A BAe rg i c ne u rons are i n h i bite d by 5 \b H T 1 A re c e ptor agonist, then wakefulness can be indirectly caused by increasing acetylcholine in the corte\f.

Hypothalamic arousal systems When the hypothalamus is stimulated, a series of arousal reac\b tions including the activation of the HPA a\fis, the corte\f, and the autonomic nervous system are elicited [19]. The posterior hypothalamus, which is involved in alertness, uses glutamate as the primary neurotransmitter [20]. The tuberomammillary neurons (TM) located in the posterior hypothalamus are the only histamine neurons in the brain; they receive information from numerous activation\brelated regions of the brain stem and the ventrolateral preoptic area (VLPO) [21]. Histamine modulates to maintain cortical activity and wakefulness. Ore\fin, which is also called hypocretin, is secreted by neurons in the lateral and medial hypothalamus [22]. The ore\fin neurons project to the cerebral corte\f, and most of arousal regions including monoaminergic and cholinergic neurons and connect with the preoptic area (POA) and BF.

A lack of ore\fin causes narcolepsy. Ore\fin is activated in the alertness condition, and especially plays a role in motor activity.

The ore\fin neurons reciprocally project to VLPO neuron, but there are no ore\fin receptors in the VLPO [23]. Therefore, the 143 www.enjo\brnal.org \fttp://dx.doi.org/10.5607/en.2012.21.4.141 Stress and Sleep Disorder ore\fin neurons reinforce alertness, but do not directly suppress the VLPO, and the asymmetrical relationship seems to contribute to make the flip\bflop switch stable, which stops conduction to unwanted sleep. As a result, the activity of the LC, which is inactivated during REM, is predominated by ore\fin neurons, which led to conclusion that ore\fin is a target for regulating REM sleep [24].

POA The VLPO as a sleep center contains GABAergic/galaninergic neurons, which act as an inhibitory neurotransmitter. POA neu\b rons principally use histamine, and so assume to be involved in alertness and NREM [25, 26]. VLPO neurons send terminals to the DRN and LC, which have imp ortant roles for REM.

Conversely, GABAergic neurons in the VLPO are suppressed by noradrenalin and serotonin [27] and H2 receptors are suppressed by histamine. c\bFos\bimmunoreactive neurons (Fos\bIRNs) in the VLPO and median preoptic nucleus (MnPN) have been closely correlated with e\fisting sleep quantity. In particular, Fos\bIRNs were increased during sleep recovery after sleep deprivation [28].

These findings show that the VLPOA is a crucial neural substrate for sleep promotion. Adenosine promotes sleep by e\fciting the neural activity of the POA [27], while on the other hand it facilitates sleep by suppressing the alertness\bactivating neurons such as cholinergic neurons [29].

Cytokines including IL1\bβ and TNF influence homeostatic sleep control [30]. TNF\bα causes NREM via the POA and the LC. In e\fperiments with mice, the injection of TNF\bα in these regions resulted in increased NREM, and the LC suppressed noradrenaline alertness mechanisms. Prostaglandin D2 (PGD2) is another important endogenous sleep factor that also acts in the POA. Growth hormone\breleasing hormone (GHRH) also plays an important role in the regulation of NREM [30].

THE PROCESS OF SLEEP REGULATION Schema of a typical e\ftrai\fed 24-hour day Sleeping involves sufficient periods of wakefulness and decline of core temperature, which are merged to open the “gate” to sleep.

The beginning of sleep involves the first circadian verte\f of slow wave sleep. The pressure of slow wave sleep decreases with time.

Generally, the verte\f of circadian REM can be set between the half\bcycle of two slow wave sleep pressures. To minimize sleepiness in the early evening and to maintain proper alertness, three factors seem to be critical: low pressure of slow wave sleep, REM\b minimum pressure of sleep, and peak core temperature. Sleep and alertness are mutually competitive and necessarily e\fclusive; the development of alertness is the reverse of sleep pressure. In the late evening core temperature begins to decrease, and somnolence related to sustained alertness continuously increases. This cycle is repeated thereafter.

Homeostatic process of sleep Slow wave activity is a physio logical indicator of NREM sleep homeostasis. Slow wave activity can be considered an indicator of the depth or intensity of sleep. The stimulus reaction decreases depending on the increase of slow wave activity, and this activity is inversely correlated with alertness [31]. In addition, the process of comprehensive slow wave sleep is high in the beginning of sleep but decreases gradually thereafter [32]. Spectral analysis of brainwave activity revealed a change in density of average brainwave between 0.25\b2.0 Hz depending on the process of sleep [33]. A nap late in the afternoon includes increased slow wave sleep than a nap early in the afternoon [34]. Shorter duration of night\btime sleep produces increased slow wave activity in a nap the ne\ft morning [35]. Concerning the effects of sleep deprivation, recovery sleep includes increased slow wave sleep following the deprivation of partial or full sleep [32]. Especially, the increase of slow wave sleep is markedly enhanced in the first day of recovery sleep, as the e\ftension of alertness period [36].

The immune system is involved with the various stress responses, and homeostasis during sleep and generation of NREM. Levels of TNF and IL1\bβ in the brain change with time courses; a study conducted in a mouse model demonstrated high levels of TNF mRNA and protein in the corte\f and hypothalamus when sleep inclination was ma\fimal. In the study, sleep deprivation was linked with an increase in the brain density of cytokine. In addition, upregulation of cytokine and somnolence was also evident in mice challenged with infection. Bacterial cell wall muramyl peptides and viral double strand RNA [37] reinforce cytokine production, simil ar to comp ounds including IL1\bβ and TNF. If TNF is injected in the POA of the hypothalamus, it reinforces REM, while injections of TNF soluble receptor at the same site spur a spontaneous decrease in sleep. Injections of IL1\bβ receptors at the same site suppress alertness\bactivating neurons and stimulate sleep\bactivating neurons [30]. TNF or IL1\bβ reinforces sleep in these areas as well as in other regions of the brain, if TNF or IL1\bβ is injected directly into the cerebral corte\f; slow wave sleep is increased in the injected half of the brain sphere. Similarly, injection of TNF soluble receptor or IL1\bβ soluble receptor suppressed the increases of slow wave sleep after sleep deprivation in the injected half\bsphere [38].

Cytokines, especially TNF and IL1\bβ, act on the sleep control circuit and are involved with sleep\brelated morbidity. IL1\bβ, IL2, 144 www.enjo\brnal.org \fttp://dx.doi.org/10.5607/en.2012.21.4.141 K\bem S\bn Han, et al.

IL6, IL8, IL15, IL18, TNF, fibroblast growth factor, and nerve growth factor are some of the cytokines that have been shown to reinforce sleep. But, IL4, IL10, IL13, and insulin\blike growth factor as among the cytokines that suppress sleep. These sleep regulatory substances (SRS) are responsible for some regulatory mechanisms that maintain the ark of the cycle of long\blasting sleep/alertness, and so have been linked to sleep homeostatic mechanisms [30].

After sleep deprivation, the production of interferon (IFN), TNF, and IL1\bβ was increased [37]. Sleep apnea can accompany sleep deprivation and hypo\fia, and involves an increase of TNF [37].

IL1\bβ and TNF activate nuclear factor\bkappa B (NFκB) and c\bFos (AP\b1), transcription factors, and a myriad of short half\b life, small molecules such as activated nitric o\fide adenosine, and prostaglandins [39]. Adenosine causes NFκB nuclear translocation in the basal forebrain. NFκB is activated by sleep deprivation [40].

Summarizing the molecular connection related to homeostasis of sleep, SRS including TNF, IL1\bβ, and NGF are generated or secreted by neuron throughout the waking period, in a process that can be affected by stress. SRS production/secretion can be subject to positive or negative feedback regulation from transcription factors such as NFκB, cytokines, and hormones.

Cytokine production and activity includes transcription and deto\fification, and their direct actions on sleep were mediated by nitric o\fide and adenosine, whose short half\blives enable ready and swift response [5].

Circadia\f process of sleep The circadian cycle of physical function continues without outside temporal clues from the beginning, and it is natural and that the cycle is precisely 24 hours [35]. People naturally feel sleepy at night, due to the fatigue resulting from daily life rather than the screening of the internal clock, so sleep can be delayed by appropriate stimuli. As a result, the fact that determination of sleep time is changed by the circadian mechanisms in daily life can be overlooked. Control of circadian rhythm by REM is not related to sleep time, but the peak REM tendency is coincident with the peak nadir of body temperature in the early morning. Somnolence is regulated by homeostatic and behavioral results, and circadian rhythm. The tendency of sleep is consistently high when the rhythm of human body temperature is disrupted; the result is a need for sleep in early afternoon (i.e., nap, siesta). This distribution reflects the phase of the circadian cycle, which is determined endogenously.

The suprachiasmatic nucleus (SCN) is the “master clock” of the brain. SCN neurons are activated in a 24\bhour transcription and deto\fification cycle. Animal e\fperiments have demonstrated that SCN removal abrogates the circadian rhythm of behavioral and physiological processes, which can prevent sleep [41]. Under normal circumstances, melatonin in the SCN will be reset every day by being secreted by the light entering through the eyes in the morning and from the pineal at night [42]. The light is detected by series of ganglion cells equipped with the predisposing factor melanopsin, which is delivered to the SCN. Information from SCN neurons is amplified in the near sub\bparaventricular zone (SPZ) [43]. The neurons from the DMH deliver the information to neurons responsible for circadian secretion, which regulates hormones such as ore\fin neuron related to VLPO and alertness as central sleep, body temperature and corticosteroids, and thyrotropin\breleasing hormone. Therefore, sleep\bwake, activity, feeding, temperature and corticosteroid rhythms are changed equivalent to the DMH variable activity [44].

Core temperature is one of the physiological progresses regu\b lated by the circadian pacemaker. Sleep begins when the core temperature falls from its peak. Sleep ends following the nadir of core temperature. In addition to the circadian rhythm of core temperature, one of the important substances involved in the regulation of sleep\bwakefulness rhythm is melatonin. Dim light melatonin onset (DLMO) begins 2\b3 hours before the usual start time of sleep [45]. The DLMO is relatively less affected by e\fogenous factors, so it is recognized as reliable marker to measure the circadian rhythm of humans. In addition to melatonin, other substances involved in regulating the sleep\bwakefulness circadian rhythm are corticosteroids. Endogenous rhythm influences the circadian rhythm of HPA secretion through the multi\bsynaptic SCN\badrenal pathway [46]. Cortisol secretion is very rhythmic, and is maint ained at a low le vel during t he d ay and at t he beginning of night, but the secretion increases from the latter part of the night towards morning. The nadir of cortisol appears within 2 hours after the start of sleep. In other words, sleep begins when cortisol is lowest and finishes when cortisol is highest. Physical or physiological stress changes cortisol secretion by activating the HPA a\fis.

THEORETICAL MODELS OF INSOMNIA Stress as a precipitati\fg factor Post\btraumatic stress disorder (PTSD) is an e\ftreme case of stress\brelated insomnia, which occurs after traumatic e\fperiences.

According to Hefez et al. [47], individuals who have e\fperienced e\ftremely traumatic events shows more recollection of a dream with low sleep efficiency. Cartwright and Wood [48] reported that sleep can be easily disrupted in people undergoing divorce, with decreased delta sleep. Kageyama et al. [49] asserted the relevance of the subjective quality of reporting between career stress and 145 www.enjo\brnal.org \fttp://dx.doi.org/10.5607/en.2012.21.4.141 Stress and Sleep Disorder poor sleep, and Hall et al. [50] opined that stress\brelated thinking is connected with insomnia. Verlander et al. [51] reported that an emotional reaction is the best predictor for e\fplaining the factors such as depth and quality of sleep among three stress factors:

burden events, personality mediators, and emotion reactions.

Paulsen and Shaver [52] reported that the negative life events have indirect effects only, but do affect objective sleep. Cernovsky [53] demonstrated that the major stress and sleep obstacles are not closely correlated, and that the negative life\bcycle is somewhat connected with sleep obstacles among the various sleep factors.

Reynolds et al. [54] reported that REM is increased in the brain waves of the people who have e\fperienced bereavement, but it does not affect the rate of sleep efficiency, REM latency, and delta sleep.

In the 1980s, the interest in minor stress (i.e., “hassles”) was heightened by considering coping mechanism of individuals about stress or personality of characteristics separate from previous trends in major stress events such as death and divorce, which lead to significant changes in life. The daily worry and frustration that are a routine occurrence have been proposed as harmful for individual’s health [55]. Thus, minor stress is a more important factor than the major stress, can have bigger effects on the disease and psychological and physical symptoms, and can be a better predictor. Hick and Garcia [56] reported that the increasing stress lessens the length of sleep. The influence of stress as the trigger or influence of insomnia has been inconsistent. However, according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM\bIV), “Most of the insomnia occurs with acute for psychological, social and medical stress”; in one study, 78% insomnia patients reported a link between such stresses and insomnia [57].

In several prospective studies, the main predictors of insomnia were depression, health problems, physical inability, and mental and social state [58]. In addition, while stress is acknowledged as an important risk factor of insomnia, Morin et al. [59] opined that its’ significance differs between the insomnia patients and affected individuals concerning an individual’s reaction to the of frequency of stress.

Stress a\fd related sleep physiology Stress activates the sympatho\badreno\bmedullary (SAM) and HPA systems, influencing cardiovascular, catecholamine, cortisol, ACTH, and CRH hyperactivity [60]. The stress system interacts by endocrines, the gastrointestinal and immune systems, and positive/negative feedback pathways [61]. E\fcessive secretion of cor tis ol negatively af fe c ts ne ur a l str uc tures such as t he hippocampus, resulting in memory deficits [62] and, especially, negatively influences sleep by affecting the activity of the SAM and HPA systems [63]. The immune system is also affected by stress; the autonomic nervous system activates genes involved in production of immune substances such as cytokines [64].

Increased activity of the autonomic nervous system [65] and cortisol causes alertness. Increased ACT influences awakening.

Therefore, awakening from sleep after stress can be related to the early increase of ACTH [66]. It has been shown that the injection of ACTH increases sleep latency, decreases slow wave sleep, and fragments sleep [67]. For e\fample, the receptor activity of mineral corticosteroid increases NREM, and the receptor activity of glucocorticosteroid increases alertness and REM [66].

In e\fperiments where mice were immobilized or subjected to social stimulation, decreased slow wave sleep and REM were do cumented, and t heir incre as e during recover y sleep was revealed [68]. Acute and chronic stress decreases slow wave sleep and REM in mice e\fposed to stress, but a normal sleep pattern was re\bestablished upon recovery. In an acute stress situation, CRH (an ACTH secretion hormone) mediates the stress reaction in the central nervous system [69]. CRH acting as a neurotransmitter in the LC activates noradrenaline neurons in the LC. But, under chronic stress, distal corticosteroids increase and sleep is disrupted.

Therefore, in chronic stress, the reaction of slow wave sleep and REM is not significant.

The immune system is important in the relationship between stress and sleep. Acute or chronic stress in humans and animals considerably affects sleep through the immune system. Acute stress mainly activates the immune system related to natural killer (NK) cells mediated by catecholamine [70]. Meanwhile, chronic stress down\bregulates the immune system by decreasing B and T cells and reducing NK cell activity [71]. This occurs in depression and PTSD [71]. IL1\bβ is also involved in an immune regulated feedback that activates the HPA a\fis. This is involved in the relationship between stress and sleep. Blood IL\b1β levels change depending on the cycle of sleep\balertness, and blood TNF is related to the slow wave activity of brainwaves. Also, there is a strong correlation between the degree of the loss of sleep continuity and NK cell function obstacles [72].

Inversely, insomnia causes physiological responses like those in stress situations. Sleep increases growth hormone and testosterone [73], and reduces metabolism and blood flow, to fight against stress [74]. In a state of insomnia, cortisol, heart rate, central temperature, and o\fygen consumption are increased [2], as are glucose tolerance [75] and cytokines [76]. Sleep deprivation increases ghrelin and decreases leptin, which e\facerbates appetite [77]. Evidence to date indicates (bit has not confirmed) a close connection between stress and sleep. Stress causes pyscho\b 146 www.enjo\brnal.org \fttp://dx.doi.org/10.5607/en.2012.21.4.141 K\bem S\bn Han, et al.

physiological responses and activates the HPA system, which are incompatible with normal sleep. Also, insomnia causes a vicious circle of stress\binsomnia by further activating the HPA system.

Especially, chronic stress can cause continuous hippocampus\b related memory system fatigue by up\bregulating the HPA system.

The long\bterm impacts of chronic stress remain unclear.

Physiological model Patients with insomnia, despite lacking night sleep and day\b time fatigue, are at a higher state of alertness than those who have appropriate sleep, which has also been demonstrated by the fact that patients with insomnia have longer sleep latency than a control group consisting of ordinary people who sleep upon an e\fecution of latency repeat inspection. This suggests that insomnia is an over\balertness obstacle ranging for 24 hours, and not one limited only to nighttime [78]. As another piece of evidence of over\balertness, patients with insomnia have an increased metabolic rate for 24 hours, their sympathetic nervous system is relatively e\facerbated [78], and their adrenal corte\f hormone and cortisol density are markedly increased compared to ordinary people [2].

HPA a\fis activity\brelated cytokine hypersecretion or daily cycle fluctuation can e\fplain insomnia\brelated fatigue and poor sleep.

Also, patients with insomnia have an increased relative rate of beta\bpower in brainwaves while awake during the hypnagogic period in which the delta power declines, which suggests the alertness of the central nervous system [79]. The nervous system circuit interacting through brain imaging techniques plays an important role for the neuronal physiology of insomnia [80], in which general alertness system (upturn reticula formation and hypothalamus), the system that regulates emotions (hippocampu, tonsil, anterior cingulate corte\f) and cognitive system (prefrontal lobe), are involved.

Behavioral model According to a behavioral model proposed by Spielman et al.

[81], insomnia is presumed to be caused acutely by both consti\b tutional and causal factors. Acute insomnia is gradually and chro\b nically strengthened and stabilized by a nonadaptive reaction strategy. In other words, if an insomnia episode begins, patients choose various nonadaptive strategies intended to produce more sleep (e.g., spending e\fcessive time in bed and staying awake in bed for a long time). These behaviors reduce sleep efficiency, which results in conditioned alertness during usual sleep and the occurrence of chronic insomnia.

Cog\fitive model A cognitive model first proposed by Morin [82] notes that concern and reflection by early stress disrupts sleep and causes an acute episode of insomnia. The individual’s reactions to this transient sleep trouble (i.e., behaviors, beliefs, attitudes, and interpretations) contribute to sustaining or deteriorating the subsequent insomnia. Once sleep disturbance begins, concern and reflection changes from life stress to sleep itself, and with day\b time symptoms in the absence of sufficient sleep. This negative cognitive activity is further strengthened if one feels threatened related to sleep or perceives a lack of sleep [83]. Moreover, moni\b toring day\btime symptoms due to sleep and lack of sleep causes autonomic neuronal alertness and emotional distress, which causes selective attention to threatening clues associated with sleep to sustain insomnia [84]. Such a chain reaction causes a state of over\balertness, which conflicts with a state of rela\fation needed for inducing sleep. E\fcessive concern with sleep and fear for not having sleep generates bad sleep habits such as taking a nap or staying in bed for a long time, which collapses the sleep\b alertness cycle and homeostasis of sleep. In a nutshell, regardless of the causes of insomnia in an early phase, bad sleep habits and non\bfunctional recognition of sleep are almost always involved in perpetuating or deteriorating sleep obstacles over time [85].

Neurocog\fitive model Patients with insomnia tend to overestimate their sleep latency, while tending to underestimate their overall sleep time (i.e., they say it takes a long time to fall asleep and that they do not sleep in).

Polysomnogram data indicate wakefulness even if sleep begins, which prompts awakening. Also, for patients with insomnia, use of benzodiazepine\bbased sleeping pills does not normalize sleep, although patients report more benefits attributed to the medication than can be e\fplained by objective variables with improved sleep [86]. Cognitive neural perspective focusing on corte\f alertness measured by brainwave activity allows patients with insomnia to e\fplain diagnostically the parado\f in the patients [86]. The consistency of the behavioral model is that the neuronal cognitive model concerns the view that acute insomnia is stirred by living stress, while continuous insomnia is caused by maladjusted countermeasures, and that chronic insomnia results from conditioned alertness. The difference of the neuronal cognitive model on chronic insomnia focuses on cortical arousal, a form of conditioned alertness [86]. According to the neuronal cognitive model, hypnagogue or high frequenc y brainwave activity at that time is a primary feature of chronic insomnia, and conditioned alertness in this form prompts various sensory and cognitive phenomena that do not occur during quality sleep.

The theoretical model of insomnia is a stress\bconstitution model, which argues that pre\bonset predisposing factors, precipitating 147 www.enjo\brnal.org \fttp://dx.doi.org/10.5607/en.2012.21.4.141 Stress and Sleep Disorder factors like stress, and subsequent perpetuating factors causes the e\fpression of insomnia. In other words, people with insomnia have a characteristic of the predisposing factors of insomnia, the precipitating factors including cause an actual artwork, such acute insomnia is strengthened by nonadaptive reaction strategy to become chronically stabilized. Physiological, cognitive, and awakening of intellectual mind, maladjusted behavior, circadian rhythm, and sleep homeostatic obstacles can be the perpetuating factors that perpetuate transient insomnia caused by stress.

MANAGING INSOMNIA THROUGH DAILY LIFE STRESS MA- NAGEMENT Insomnia caused by various stress factors can be prevented and managed by managing everyday life habits. The management of day\bto\bday lifestyle can be divided into mental and physical aspects based on the comprehensive model of stress [87]. As the management of mental aspect, since the perception and evaluation of the factor rather than the event itself significantly affect stress, one should make efforts to change his/her cognitive evaluation to a more positive one and to reduce everyday life stress. This can be accomplished by maintaining the balance between work and rest by releasing stress at the moment to deal with the stress, e\fpressing concerns or problems with the e\fpression of emotional tension, maintaining an inner balance with reality by accepting what cannot be changed and accepting what is wrong, trying to plan and record a daily routine and form a habit of setting priorities, And seeking solutions by simplifying the pertinent issue when facing a complicated and difficult problem [88].

The management of day\bto\bday lifestyle in physical aspect includes regular and balanced meals, Balanced physical activity by regular moderate motion about for 30 min., 3\b4 times a week, (e.g., stretching, jogging, biking or hiking), and induced body rest and rela\fation, such as controlled respiration and muscle tension methods.

Most of all, goal\bsetting, continuing to make constant efforts toward the goals, accepting the fact that no one is perfect, and doing one’s best can help overcome insomnia caused by stress.

CONCLUSIONS E\fcessive stress is detrimental on many levels to humans, and it activates the defense system of the central ner vous system.

Stress\brelated physiological responses differ depending on each individual cognitive form, and these physiological responses cause the neuro\bendocrine responses and behavioral responses.

Sle e p is an ess enti a l biologic a l pro cess for humans. Many anatomical structures and biochemical substances are involved in the regulating mechanisms including the HPA a\fis, which is activated by the factors including stress and immune function. The regulation of sleep is configured with the circadian process that determines the beginning and ending of sleep, and the homeostatic process that maintains the depth and the amount of sleep. In the early stage of sleep, the activity of HPA a\fis is suppressed and ongoing, while in the latter part of sleep HPA secretion activity increases. The increased HPA a\fis and activity of the sympathetic nervous system influences rapid eye movement (REM) sleep.

Components of immune system including IL\b1β are involved in the homeostatic regulating mechanisms of sleep. In addition, IL\b1β participates in the immune regulating feedback chain that activates the HPA a\fis. Stress\brelated insomnia leads to a vicious circle by activating the HPA system. Chronic insomnia, which is termed physiological insomnia, is a clinical problem. The stress\b diathesis theory concerning the onset of chronic insomnia posits the involvement of a series of factors consisting of predisposing, precipitating, and perpetuating factors. Stress\binduced insomnia that becomes chronically stabilized is connected to the treatment, so that an understanding of the perpetuating factor is essential.

AC\bNOWLEDGEMENTS This study was supported by a KBSI grant (T31901) to SH.

REFERENCES 1. Partinen M (1994) Sleep disorders and stress. J Psychosom Res 38 Suppl 1:89\b91. 2. Vgontzas AN, Bi\fler EO, Lin HM, Prolo P, Mastorakos G, Vela\bBueno A, Kales A, Chrousos GP (2001) Chronic in \b somnia is associated with nyctohemeral activation of the hypothalamic\bpituitary\badrenal a\fis: clinical implications. J Clin Endocrinol Metab 86:3787\b3794. 3. Weibel L, Follenius M, Spiegel K, Ehrhart J, Brandenberger G (1995) Comparative effect of night and daytime sleep on the 24\bhour cortisol secretory profile. Sleep 18:549\b556. 4. Takahashi S, Kapás L, Fang J, Krueger JM (1999) Somnogenic relationships between tumor necrosis factor and interleu \b kin\b1. Am J Physiol 276:R1132\bR1140. 5. Krueger JM, R ector DM, Churchill L (2007) Sleep and cytokines. Sleep Med Clin 2:161\b169. 6. Steriade M, Oakson G, Ropert N (1982) Firing rates and patterns of midbrain reticular neurons during steady and transitional states of the sleep\bwaking cycle. E\fp Brain Res 46:37\b51. 148 www.enjo\brnal.org \fttp://dx.doi.org/10.5607/en.2012.21.4.141 K\bem S\bn Han, et al.

7. Jones BE (2005) From waking to sleeping: neuronal and chemical substrates. Trends Pharmacol Sci 26:578\b586. 8. Stenberg D (2007) Neuroanatomy and neurochemistry of sleep. Cell Mol Life Sci 64:1187\b1204. 9. McCormick DA (1989) Cholinergic and noradrenergic mo \b dulation of thalamocortical processing. Trends Neurosci 12:215\b221. 10. Ford B, Holmes CJ, Mainville L, Jones BE (1995) GABAergic n e u ro n s i n t h e r at p o nt o m e s e n c e p h a l i c t e g m e ntu m :

codistribution with cholinergic and other tegmental neurons projecting to the posterior lateral hypothalamus. J Comp Neurol 363:177\b196. 11. Vazquez J, Baghdoyan HA (2001) Basal forebrain acetylcho \b line release during REM sleep is significantly greater than during waking. Am J Physiol Regul Integr Comp Physiol 280:

R598\bR601. 12. Chu N, Bloom FE (1973) Norepinephrine\bcontaining neu \b rons: changes in spontaneous discharge patterns during sleeping and waking. Science 179:908\b910. 13. Berridge CW, Foote SL (1991) Effects of locus coeruleus activation on electroencephalographic activity in neocorte\f and hippocampus. J Neurosci 11:3135\b3145. 14. Valentino RJ, Fo ote SL (1988) C orticotropin\brele asing hormone increases tonic but not sensory\bevoked activity of noradrenergic locus coeruleus neurons in unanesthetized rats. J Neurosci 8:1016\b1025. 15. Trulson ME (1985) Activity of dopamine\bcontaining substa \b ntia nigra neurons in freely moving cats. Neurosci Biobehav Rev 9:283\b297. 16. McGinty DJ, Harper RM (1976) Dorsal raphe neurons:

depression of firing during sleep in cats. Brain Res 101:569\b 575. 17. Trulson ME, Jacobs BL (1979) Raphe unit activity in freely moving cats: correlation with level of behavioral arousal.

Brain Res 163:135\b150. 18. Lüttgen M, Ogren SO, Meister B (2005) 5\bHT1A receptor mRNA and immunoreactivity in the rat medial septum/ diagonal band of Broca\brelationships to GABAergic and cholinergic neurons. J Chem Neuroanat 29:93\b111. 19. Bailey TW, Dimicco JA (2001) Chemical stimulation of the dorsomedial hypothalamus elevates plasma ACTH in cons \b cious rats. Am J Physiol Regul Integr Comp Physiol 280:R8\b R15. 20. Ziegler DR, Cullinan WE, Herman JP (2002) Distribution of vesicular glutamate transporter mRNA in rat hypothalamus.

J Comp Neurol 448:217\b229. 21. Panula P, Pir vola U, Auvinen S, Airaksinen MS (1989) Histamine\bimmunoreactive nerve fibers in the rat brain.

Neuroscience 28:585\b610. 22. Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H, Williams SC, Richardson JA, Kozlowski GP, Wilson S, Arch JR, Buckingham RE, Haynes AC, Carr SA, Annan RS, McNulty DE, Liu WS, Terrett JA, Elshourbagy NA, Bergsma DJ, Yanagisawa M (1998) Ore\fins and ore\fin receptors: a family of hypothalamic neuropeptides and G protein\bcoupled receptors that regulate feeding behavior. Cell 92:573\b585. 23. Marcus JN, Aschkenasi CJ, Lee CE, Chemelli RM, Saper CB, Yanagisawa M, Elmquist JK (2001) Differential e\fpression of ore\fin receptors 1 and 2 in the rat brain. J Comp Neurol 435:6\b25. 24. Bourgin P, Huitrón\bRésendiz S, Spier AD, Fabre V, Morte B, Criado JR, Sutcliffe JG, Henriksen SJ, de Lecea L (2000) Hypocretin\b1 modulates rapid eye movement sleep through activation of locus coeruleus neurons. J Neurosci 20:7760\b 7765. 25. Lu J, Bjorkum AA, Xu M, Gaus SE, Shiromani PJ, Saper CB (2002) Selective activation of the e\ftended ventrolateral preoptic nucleus during rapid eye movement sleep. J Neurosci 22:4568\b4576. 26. Ko EM, Estabrooke IV, McCarthy M, Scammell TE (2003) Wake\brelated activity of tuberomammillary neurons in rats.

Brain Res 992:220\b226. 27. Gallopin T, Luppi PH, Cauli B, Urade Y, Rossier J, Hayaishi O, Lambolez B, Fort P (2005) The endogenous somnogen adenosine e\fcites a subset of sleep\bpromoting neurons via A2A receptors in the ventrolateral preoptic nucleus. Neuro \b science 134:1377\b1390. 28. Sherin JE, Shiromani PJ, McCarley RW, Saper CB (1996) Activation of ventrolateral preoptic neurons during sleep.

Science 271:216\b219. 29. Basheer R, Strecker RE, Thakkar MM, McCarley RW (2004) Adenosine and sleep\bwake regulation. Prog Neurobiol 73:379\b396. 30. Obal F Jr, Krueger JM (2003) Biochemical regulation of non\b rapid\beye\bmovement sleep. Front Biosci 8:d520\bd550. 31. Franken P, Dijk DJ, Tobler I, Borbély AA (1991) Sleep depri \b vation in rats: effects on EEG power spectra, vigilance states, and cortical temperature. Am J Physiol 261:R198\bR208. 32. Webb WB, Agnew HW Jr (1971) Stage 4 sleep: influence of time course variables. Science 174:1354\b1356. 33. Borbély AA, Baumann F, Brandeis D, Strauch I, Lehmann D (1981) Sleep deprivation: effect on sleep stages and EEG power density in man. Electroencephalogr Clin Neurophysiol 149 www.enjo\brnal.org \fttp://dx.doi.org/10.5607/en.2012.21.4.141 Stress and Sleep Disorder 51:483\b495. 34. Beersma DG, Daan S, Dijk DJ (1987) Sleep intensity and timing: a model for their circadian control. Lect Math Life Sci 19:39\b62. 35. Akerstedt T, Gillberg M (1986) Sleep duration and the power spectral density of the EEG. Electroencephalogr Clin Neurophysiol 64:119\b122. 36. Dijk DJ, Brunner DP, Borbély AA (1991) EEG power density during recovery sleep in the morning. Electroencephalogr Clin Neurophysiol 78:203\b214. 37. Majde JA, Krueger JM (2005) Links between the innate immune system and sleep. J Allergy Clin Immunol 116:1188\b 1198. 38. Yoshida H, Peterfi Z, García\bGarcía F, Kirkpatrick R, Yasuda T, Krueger JM (2004) State\bspecific asymmetries in EEG slow wave activity induced by local application of TNFα. Brain Res 1009:129\b136. 39. Luk WP, Zhang Y, White TD, Lue FA, Wu C, Jiang CG, Zhang L, Moldofsky H (1999) Adenosine: a mediator of interleukin\b 1beta\binduced hippocampal synaptic inhibition. J Neurosci 19:4238\b4244. 40. Brandt JA, Churchill L, Rehman A, Ellis G, Mémet S, Israël A, Krueger JM (2004) Sleep deprivation increases the activation of nuclear factor kappa B in lateral hypothalamic cells. Brain Res 1004:91\b97. 41. Moore RY, Eichler VB (1972) Loss of a circadian adrenal corticosterone rhythm following suprachiasmatic lesions in the rat. Brain Res 42:201\b206. 42. C a s s o n e V M , C h e s w o r t h M J, A r m s t ro ng SM ( 1 9 8 6 ) Entrainment of rat circadian rhythms by daily injection of melatonin depends upon the hypothalamic suprachiasmatic nuclei. Physiol Behav 36:1111\b1121. 43. Deurveilher S, Semba K (2005) Indirect projections from the suprachiasmatic nucleus to major arousal\bpromoting cell groups in rat: implications for the circadian control of behavioural state. Neuroscience 130:165\b183. 44. Saper CB, Lu J, Chou TC, Gooley J (2005) The hypothalamic integrator for circadian rhythms. Trends Neurosci 28:152\b 157. 45. L e w y AJ, Cut ler NL, Sack RL (1999) The endogenous melatonin profile as a marker for circadian phase position. J Biol Rhythms 14:227\b236. 46. Buijs RM, Wortel J, Van Heerikhuize JJ, Feenstra MG, Ter Horst GJ, Romijn HJ, Kalsbeek A (1999) Anatomical and functional demonstration of a multisynaptic suprachiasmatic nucleus adrenal (corte\f) pathway. Eur J Neurosci 11:1535\b 1544. 47. Hefez A, Metz L, Lavie P (1987) Long\bterm effects of e\ftreme situational stress on sleep and dreaming. Am J Psychiatry 144:344\b347. 48. Cartwright RD, Wood E (1991) Adjustment disorders of sleep: the sleep effects of a major stressful event and its resolution. Psychiatry Res 39:199\b209. 49. Kageyama T, Nishikido N, Kobayashi T, Kurokawa Y, Kaneko T, Kabuto M (1998) Self\breported sleep quality, job stress, and daytime autonomic activities assessed in terms of short\bterm heart rate variability among male white\bcollar workers. Ind Health 36:263\b272. 50. Hall M, Buysse DJ, Nowell PD, Nofzinger EA, Houck P, Reynolds CF 3rd, Kupfer DJ (2000) Symptoms of stress and depression as correlates of sleep in primary insomnia.

Psychosom Med 62:227\b230. 51. Verlander LA, Benedict JO, Hanson DP (1999) Stress and sleep patterns of college students. Percept Mot Skills 88:893\b 898. 52. Paulsen VM, Shaver JL (1991) Stress, support, psychological states and sleep. Soc Sci Med 32:1237\b1243. 53. Cernovsky ZZ (1984) Life stress measures and reported frequency of sleep disorders. Percept Mot Skills 58:39\b49. 54. Reynolds CF 3rd, Hoch CC, Buysse DJ, Houck PR, Schler \b nitzauer M, Pasternak RE, Frank E, Mazumdar S, Kupfer DJ (1993) Sleep after spousal bereavement: a study of recovery from stress. Biol Psychiatry 34:791\b797. 55. Weinberger M, Hiner SL, Tierney WM (1987) In support of hassles as a measure of stress in predicting health outcomes. J Behav Med 10:19\b31. 56. Hicks R A, G arci a ER (1987) L e vel of stress and sle e p duration. Percept Mot Skills 64:44\b46. 57. Bastien CH, Vallières A, Morin CM (2004) Precipitating factors of insomnia. Behav Sleep Med 2:50\b62. 58. Linton SJ (2004) Does work stress predict insomnia? A prospective study. Br J Health Psychol 9:127\b136. 59. Morin CM, Rodrigue S, Ivers H (2003) Role of stress, arousal, and coping skills in primar y insomnia. Psychosom Med 65:259\b267. 60. Dunn AJ, Berridge CW (1990) Physiological and behavioral responses to corticotropin\breleasing factor administration:

is CRF a mediator of an\fiety or stress responses? Brain Res Brain Res Rev 15:71\b100. 61. Chrousos GP, Gold PW (1992) The concepts of stress and stress system disorders. Overview of physical and behavioral homeostasis. JAMA 267:1244\b1252. 62. McEwen BS, Sap olsky RM (1995) Stress and cognitive function. Curr Opin Neurobiol 5:205\b216. 150 www.enjo\brnal.org \fttp://dx.doi.org/10.5607/en.2012.21.4.141 K\bem S\bn Han, et al.

63. Rock JP, Oldfield EH, Schulte HM, Gold PW, Kornblith PL, Loriau\f L, Chrousos GP (1984) Corticotropin releasing factor administered into the ventricular CSF stimulates the pituitary\badrenal a\fis. Brain Res 323:365\b368. 64. Bierhaus A, Wolf J, Andrassy M, Rohleder N, Humpert PM, Petrov D, Ferstl R, von Eynatten M, Wendt T, Rudofsky G, Jos wig M, Morcos M, S chwaninger M, McEwen B, Kirschbaum C, Nawroth PP (2003) A mechanism converting psychosocial stress into mononuclear cell activation. Proc Natl Acad Sci U S A 100:1920\b1925. 65. Kato T, Montplaisir JY, Lavigne GJ (2004) E\fperimentally induced arousals during sleep: a cross\bmodality matching paradigm. J Sleep Res 13:229\b238. 66. Born J, Fehm HL (1998) Hypothalamus\bpituitary\badrenal activity during human sleep: a coordinating role for the limbic hippocampal system. E\fp Clin Endocrinol Diabetes 106:153\b163. 67. Steiger A, Guldner J, Knisatschek H, Rothe B, Lauer C, Hols \b boer F (1991) Effects of an ACTH/MSH(4\b9) analog (HOE 427) on the sleep EEG and nocturnal hormonal secretion in humans. Peptides 12:1007\b1010. 68. Meerlo P, Pragt BJ, Daan S (1997) Social stress induces high intensity sleep in rats. Neurosci Lett 225:41\b44. 69. Marines co S, B onnet C, C espuglio R (1999) Inf luence o f s t r e s s d u r at i o n o n t h e s l e e p r e b o u n d i n d u c e d b y immobilization in the rat: a possible role for corticosterone.

Neuroscience 92:921\b933. 70. Benschop RJ, Godaert GL, Geenen R, Brosschot JF, De Smet MB, Olff M, Heijnen CJ, Ballieu\f RE (1995) Relationships between cardiovascular and immunological changes in an e\fperimental stress model. Psychol Med 25:323\b327. 71. Kiecolt\bGlaser JK, Glaser R (1995) Psychoneuroimmunology and health consequences: data and shared mechanisms.

Psychosom Med 57:269\b274. 72. Irwin M, Smith TL, Gillin JC (1992) Electroencephalographic sleep and natural killer activity in depressed patients and control subjects. Psychosom Med 54:10\b21. 73. A\felsson J, Ingre M, Akerstedt T, Holmbäck U (2005) Effects of acutely displaced sleep on testosterone. J Clin Endocrinol Metab 90:4530\b4535. 74. Braun AR , B al k in TJ, Wes enten NJ, C ars on RE, Varga M, Baldwin P, Selbie S, Belenky G, Herscovitch P (1997) Regional cerebral blood flow throughout the sleep\bwake cycle. An H2(15)O PET study. Brain 120:1173\b1197. 75. Renko AK, Hiltunen L, Laakso M, R ajala U, Keinänen\b Kiukaanniemi S (2005) The relationship of glucose tolerance to sleep disorders and daytime sleepiness. Diabetes Res Clin Pract 67:84\b91. 76. Vgontzas AN, Zoumakis E, Lin HM, Bi\fler EO, Trakada G, Chrousos GP (2004) Marked decrease in sleepiness in patients with sleep apnea by etanercept, a tumor necrosis factor\balpha antagonist. J Clin Endocrinol Metab 89:4409\b 4413. 77. Spiegel K, Tasali E, Penev P, Van Cauter E (2004) Brief communication: sleep curtailment in healthy young men is associated with decreased leptin levels, elevated ghrelin levels, and increased hunger and appetite. Ann Intern Med 141:846\b 850. 78. Bonnet MH, Arand DL (1995) 24\bHour metabolic rate in insomniacs and matched normal sleepers. Sleep 18:581\b588. 79. L amarche CH, Ogilvie RD (1997) Electrophysiological changes during the sleep onset period of psychophysiological insomniacs, psychiatric insomniacs, and normal sleepers.

Sleep 20:724\b733. 80. Nofzinger EA, Buysse DJ, Germain A, Price JC, Miewald JM, Kupfer DJ (2004) Functional neuroimaging evidence for hyperarousal in insomnia. Am J Psychiatry 161:2126\b2128. 81. Spielman AJ, Caruso LS, Glovinsky PB (1987) A behavioral perspective on insomnia treatment. Psychiatr Clin North Am 10:541\b553. 82. Morin CM (1993) A cognitive\bbehavioral conceptualization of insomnia. In: Insomnia: psychological assessment and management (Morin CM, ed), pp 46\b60. Guilford Press, New York. 83. Harvey AG (2002) A cognitive model of insomnia. Behav Res Ther 40:869\b893. 84. E s p i e C A ( 2 0 0 2 ) In s o m n i a : c o n c e p tu a l i s s u e s i n t h e development, persistence, and treatment of sleep disorder in adults. Annu Rev Psychol 53:215\b243. 85. Edinger JD, Fins AI, Glenn DM, Sullivan RJ Jr, Bastian LA, Marsh GR, Dailey D, Hope TV, Young M, Shaw E, Vasilas D (2000) Insomnia and the eye of the beholder: are there clinical markers of objective sleep disturbances among adults with and without insomnia complaints? J Consult Clin Psychol 68:586\b593. 86. Perlis ML, Giles DE, Mendelson WB, Bootzin RR, Wyatt JK (1997) Psychophysiological insomnia: the behavioural model and a neurocognitive perspective. J Sleep Res 6:179\b188. 87. Han KS (2007) Stress of the mid\blife stage. Korean J Stress Res 15:263\b270. 88. Seaward BL (2009) Managing stress: principles and strategies for health and well\bbeing, 6th ed. Jones and Bartlett Publi \b shers, Sudbury, MA.