Overview of mechanisms of normal sleep and wakefulness

A basic understanding of mechanisms of sleep and wakefulness is essential to understanding potential mechanisms of insomnia and how insomnia medications affect these pathways to promote sleep.

Both animal and human studies support a model of 2 processes that regulate sleep and wakefulness: homeostatic and circadian. The homeostatic process is the drive to sleep that is influenced by the duration of wakefulness. The circadian process transmits stimulatory signals to arousal networks to promote wakefulness in opposition to the homeostatic drive to sleep.

Sleep-wake cycle.

The suprachiasmatic nucleus (SCN) is entrained to the external environment by the cycle of light and darkness. The retinal ganglion cells transmit light signals via the retinohypothalamic tract to stimulate the SCN. A multisynaptic pathway from the SCN projects to the pineal gland, which produces melatonin. Melatonin synthesis is inhibited by light and stimulated by darkness. The nocturnal rise in melatonin increases between 8 and 10 am and peaks between 2 and 4 am, then declines gradually over the morning. Melatonin acts via specific melatonin receptors MT1 which attenuates the alerting signal and MT2 which phase shifts the SCN clock. The novel sleep-promoting drug ramelteon acts specifically at the MT1 and MT2 receptors to promote sleep.

Brain areas critical for wakefulness include the tuberomammillary nucleus (TMN) in the posterior hypothalamus that contains histamine neurons, which project stimulatory inputs to brainstem arousal centers such as the locus coeruleus (LC) (norepinephrine), the dorsal raphe nuclei (DRN) (serotonin), the ventral tegmental area (VTA) (dopamine), and the basal forebrain (acetylcholine), which project diffusely to cortical areas to promote arousal.

The TMN also inhibits sleep-promoting areas, such as the anterior hypothalamus. Similarly, the brainstem arousal regions inhibit sleep-promoting regions in the anterior hypothalamus. Adenosine, a neurotransmitter, accumulates in the brain during prolonged wakefulness and inhibits wake-promoting regions in the posterior hypothalamus and the basal forebrain. Acetylcholine in the basal forebrain also projects diffusely to cortical areas and the TMN to promote wakefulness.

The ascending arousal system. Adapted from Saper et al. Hypothalamic Regulation of Sleep and Circadian Rhythms. Nature 2005;437:1257-1263.

The anterior hypothalamus, which includes the ventrolateral preoptic nucleus (VLPO) contains GABA and the peptide galanin, which are inhibitory and promote sleep. They project to the TMN and the brainstem arousal regions to inhibit wakefulness. GABA is the predominant inhibitory neurotransmitter in the central nervous system.

Ventrolateral pre-optic nucleus inhibitory projections to main components of the arousal system to promote sleep.

Saper and colleagues proposed the flip-flop switch model of sleep-wake regulation.¹ This flip-flop circuit consists of 2 sets of mutually inhibitory components. The sleep side is the VLPO and the arousal side includes TMN histaminergic neurons and brainstem arousal regions (the DRN serotonergic neurons, VTA dopaminergic neurons, and LC noradrenergic neurons). Each side of the switch inhibits the other. For example, when activation of one side is slightly stronger, the weaker side has increased inhibition, thus further tipping the balance toward the stronger side. This flip-flop switch allows for rapid state transitions.

Schematic flip-flop switch model. Adapted from Saper C et al. Hypothalamic regulation of sleep and circadian rhythms. Nature 2005;437:1257-1263.

Hypocretin neurons in the posterolateral hypothalamus are active during wakefulness and project to all of the wakefulness arousal systems described above. Hypocretin neurons interact with both the sleep-active and the sleep-promoting systems and act as stabilizers between wakefulness-maintaining and sleep-promoting systems to prevent sudden and inappropriate transitions between the 2 systems.² For example, patients with narcolepsy with cataplexy have a greater than 90% loss of hypocretin neurons, and they have sleep-wake state instability with bouts of NREM/REM sleep intruding into wakefulness.

Benzodiazepine receptor agonists (BZRAs) and nonbenzodiazepine receptor agonists (NBZRAs), for example, work through GABA_A receptors to promote sleep by inhibiting brainstem monoaminergic arousal pathways, through facilitation of VLPO inhibitory GABAergic projections to arousal centers such as the anterior hypothalamus TMN, the posterolateral hypothalamic hypocretin neurons, and the brainstem arousal regions (see Medication for further information about BZRAs and NBZRAs).

In summary, sleep and wakefulness is a tightly regulated process with reciprocal connections that produce consolidated periods of wakefulness and sleep that are entrained by environmental light to occur at specific times of the 24-hour cycle.

Frequency

United States

In a 1991 survey, 30-35% of American adults reported difficulty sleeping in the past year and 10% reported the insomnia to be chronic and/or severe. Despite the high prevalence, only 5% of persons with chronic insomnia visited their physician specifically to discuss their insomnia. Only 26% discussed their insomnia during a visit made for another problem.

International

A study from Quebec indicated an overall prevalence of insomnia of approximately 20% of French Canadians. A study of young adults in Switzerland indicated a 9% prevalence of chronic insomnia. A World Health Organization (WHO) study conducted in 15 centers found a prevalence of approximately 27% for the complaint "difficulty sleeping."

Pathophysiology

In the late 1980s, Spielman created a model of insomnia in terms of predisposing, precipitating, and perpetuating factors.

Predisposing factors

Genetic and neurobiologic factors likely determine a person’s risk of developing insomnia in the context of a precipitating factor (psychosocial, medical, or psychiatric). Many of these have not been identified. Sleep and wakefulness is an active, tightly regulated process that may differ between individuals who have different susceptibilities to exogenous influences.

Recent studies indicate differential genetic susceptibility to exogenous influences such as caffeine, light, and stress. For example, one study found that differences in the adenosine 2A receptor gene (ADORA2) determine differential sensitivity to caffeine’s effect on sleep. The ADORA2A 1083T>C genotype determined how closely the caffeine-induced changes in brain electrical activity (increased beta activity) during sleep resembled the alterations observed in patients with insomnia.

In addition, circadian clock genes (Clock, Per2) have been identified that regulate the circadian rhythm. For example, a mutation or functional polymorphism in the clock gene (Per2) can lead to circadian rhythm disorders such as advance sleep phase syndrome (sleep and morning awakening occur earlier than normal), and delayed sleep phase syndrome (sleep and morning awakening are delayed). Furthermore, a study examining the association between Clock gene polymorphisms and insomnia revealed a higher recurrence of initial, middle, and terminal insomnia in patients homozygous for the Clock genotype.

A missense mutation has been found in the gene encoding the GABA_A beta 3 subunit in a patient with chronic insomnia. Polymorphisms in the serotonin receptor transporter gene may modulate the ability of an individual to handle stress or may confer susceptibility to depression. In depression, serotonin is an important neurotransmitter for arousal mechanisms. Furthermore, antagonism of the 5-HT2 receptor promotes slow wave sleep. Therefore, preliminary basic science evidence indicates a possible genetic predisposition to hyperarousal and insomnia.

Clinical research has also shown that patients with chronic insomnia show evidence of increased brain arousal. For example, studies have indicated that patients with chronic primary insomnia demonstrate increased fast frequency activity during NREM sleep, an EEG sign of hyperarousal, and evidence of reduced deactivation in key sleep/wake regions during NREM sleep when compared with controls. Furthermore, patients with insomnia have higher day and night body temperatures, urinary cortisol and adrenaline secretion, and ACTH than patients with normal sleep. A study of normal sleepers demonstrated that these changes were not due to sleep deprivation. Only a fraction of patients with medical and psychiatric conditions develop insomnia, which suggests that some patients have an inherent susceptibility (whether psychosocial, medical, or psychiatric) to develop insomnia in the context of a stressful event.

Precipitating factors

In retrospective studies, a large proportion of patients with insomnia (78%) can identify a precipitating trigger for their insomnia. Morin and colleagues showed that these patients demonstrate an increased response to stress as compared with controls. A number of factors can trigger insomnia in vulnerable individuals. These factors include depression, anxiety, sleep-wake schedule changes, medications, other sleep disorders, and medical conditions. In addition, positive or negative family, work-related, and health events are common insomnia precipitants.

Perpetuating factors

Insomnia, regardless of how it is triggered, is generally accepted to be perpetuated by cognitive and behavioral mechanisms. Cognitive mechanisms include misconceptions about normal sleep requirements and excessive worry about the ramifications of the daytime effects of inadequate sleep. As a result, these patients often become obsessive about their sleep or try too hard to fall asleep. These dysfunctional beliefs often produce sleep disruptive behaviors such as trying to catch up on lost sleep with daytime naps or sleeping in late, which in turn reduces their natural homeostatic drive to sleep at their habitual bedtime. Learned sleep-preventing associations are characterized by overconcern about inability to fall asleep.

Consequently, these patients develop conditioned arousal to stimuli that would normally be associated with sleep (ie, heightened anxiety and ruminations about going to sleep in their bedroom). A cycle then develops in which the more the patients strive to sleep, the more agitated they become, and the less they are able to fall asleep. They also have ruminative thoughts or clock watching as they are trying to fall asleep in their bedroom. Thus, conditioned environmental cues causing insomnia develop from the continued association of sleeplessness with situations and behaviors that are typically related to sleep.

Theoretical model of the factors causing chronic insomnia. Chronic insomnia is believed to primarily occur in patients with predisposing or constitutional factors. These factors may cause the occasional night of poor sleep but not chronic insomnia. A precipitating factor, such as a major life event, causes the patient to have acute insomnia. If poor sleep habits or other perpetuating factors occur in the following weeks to months, chronic insomnia develops despite the removal of the precipitating factor. Adapted from Spielman AJ, Caruso LS, Glovinsky PB: A behavioral perspective on insomnia treatment. Psychiatr Clin North Am. 1987 Dec;10(4):541-53.

Background Of Insomnia

Insomnia is defined as repeated difficulty with the initiation, duration, maintenance, or quality of sleep that occurs despite adequate time and opportunity for sleep that results in some form of daytime impairment. Approximately one third of adults report some difficulty falling asleep and/or staying asleep during the past 12 months, with 17% reporting this problem as a significant one. Insomnia can be acute or chronic. Acute adjustment insomnia occurs in the context of an identifiable stressor (eg, personal loss, change in interpersonal relationships, bereavement, occupational stress, job loss) that acts as a precipitating factor. It typically lasts 3 months or less, and resolves as the stressor is no longer present or as the individual adapts to the stressor. The 1-year prevalence of adjustment insomnia in adults is approximately 10-15%.

Despite inadequate sleep, many patients with insomnia do not complain of excessive daytime sleepiness, such as involuntary episodes of drowsiness in boring, monotonous, nonstimulating situations. However, they do complain of feeling tired and fatigued with poor concentration. This may be related to a physiological state of hyperarousal (seePathophysiology). In fact, despite not getting adequate sleep, patients with insomnia oftentimes have difficulty falling asleep even during daytime naps.

Chronic insomnia also has numerous health consequences. For example, patients with chronic insomnia report reduced quality of life comparable to other conditions such as diabetes, arthritis, and heart disease. Quality of life improves with treatment but still does not reach the level seen in the general population. In addition, chronic insomnia is associated with impaired occupational and social performance and an elevated absenteeism rate that is 10-fold greater than controls. Furthermore, insomnia is associated with higher healthcare use, including a 2-fold increase in hospitalizations and office visits.

Insomnia can also be a risk factor for depression and a symptom of a number of medical, psychiatric, and sleep disorders. In fact, insomnia appears to be predictive of a number of disorders, including depression, anxiety, alcohol dependence, drug dependence, and suicide. The annual cost of insomnia is not inconsequential with the estimated annual costs for insomnia at $12 billion dollars for healthcare and $2 billion dollars for sleep promoting agents.

In 2005, the National Institutes of Health held a State of the Science Conference on the Manifestations of Chronic Insomnia in Adults. This conference focused on the definition, classification, etiology, prevalence, risk factors, consequences, comorbidities, public health consequences and the available treatments and evidence for their efficacy. A summary of this conference can be obtained at the NIH Consensus Development Program home page. Prior to this conference, most cases of chronic insomnia were widely believed to be secondary to another medical or psychiatric condition and effective treatment of the primary condition was believed to effectively address secondary insomnia. However, at this 2005 conference, based on the review of the literature and the panel experts, the following was concluded:

Most causes of insomnia are co-morbid with other conditions. Historically, this has been termed secondary insomnia. However, the limited understanding of the mechanistic pathways precludes drawing firm conclusions about the nature of these associations or directions of causality. Furthermore, there is concern that the term secondary insomnia may promote under treatment. Therefore, we propose the term comorbid insomnia.

This is an important point since insomnia is often only a secondary symptom that will resolve once the primary cause, whether it be medical or psychiatric, is treated. Consequently, this results in the underrecognition and undertreatment of insomnia. Furthermore, oftentimes if sleep difficulties are not the presenting complaint, there is too little time to address them at an office visit. There is also very little training in medical school on sleep disorders and their impact on patient overall health and quality of life. In fact, most providers rate their knowledge of sleep medicine as only fair. Finally, many providers are not aware of the safety issues, efficacy of cognitive behavioral and pharmacologic therapies, or when to refer a patient to a sleep medicine specialist.

Insomnia often persists despite treatment of the underlying medical or psychiatric condition and the persistence of insomnia can increase the risk of relapse of the primary condition in certain cases. In this regard, the clinician needs to understand that insomnia is a condition in its own right that requires prompt recognition and treatment to prevent morbidity and improve quality of life for their patients.