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."