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Normal Sleep and Wakefulness

Optimal health and cognitive function require the coordinated timing and stability of three distinct states: wakefulness, non-REM sleep, and REM sleep.1-5

Three Sleep-Wake States Are Defined by Distinct Neurophysiologic Characteristics3,5

H11 Wakefulness

Normally, wakefulness is promoted during the day by multiple interconnected neuronal systems, including acetylcholine, dopamine, histamine, norepinephrine, and serotonin neurons.1,2 Wakefulness is characterized by high muscle tone and fast-frequency neuronal activity that is necessary for alertness and higher-order neurocognitive functioning.3,5


H11 Non Rem Sleep
Non-REM Sleep

Non-REM sleep is a sleep state with slower-frequency neuronal activity and light to deep stages of non-REM sleep. Skeletal muscle tone is lower than during wakefulness.3,5 Nighttime sleep normally begins with an episode of non-REM sleep.3


H11 Rem Sleep
REM Sleep

During REM sleep, which is associated with dreaming and skeletal muscle atonia, neuronal activity is faster and desynchronized, with distinct wave patterns (e.g., sawtooth waves) on electroencephalogram (EEG).3,5,7 Episodes of REM sleep typically occur at night after non-REM sleep and become longer over the course of the night.3


Circadian Timekeeping Coordinates Sleep and Wakefulness With the Daily Light/Dark Cycle3

A normal sleep-wake cycle is generally characterized by consolidated wakefulness during the day and predictable, alternating periods of non-REM and REM sleep at night, with generally infrequent awakenings.2,3,7

Circadian timekeeping Circadian timekeeping

The Hypothalamus Is a Critical “Control Center” for Sleep-Wake State Stability3,8-10,

Coordinated systems in the brain help to maintain stability between states of sleep and wakefulness.1,3,4,8

Like hypocretin neurons, histamine neurons play an important role in promoting and stabilizing wakefulness1,11-13 by:

  • Activating the cortex and wake-promoting neurons outside of the hypothalamus11
  • Inhibiting non-REM sleep–promoting neurons15
  • Inhibiting REM sleep–promoting neurons3,11,16

*Based on animal and human studies.

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In most patients, narcolepsy is caused by loss of hypocretin.

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Histamine neurons help to promote and stabilize wakefullness.

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  1. España RA, Scammell TE. Sleep neurobiology from a clinical perspective. Sleep. 2011;34(7):845-858.
  2. Scammell TE. The neurobiology, diagnosis, and treatment of narcolepsy. Ann Neurol. 2003;53(2):154-166.
  3. Scammell TE, Arrigoni E, Lipton JO. Neural circuitry of wakefulness and sleep. Neuron. 2017;93(4):747-765.
  4. Schwartz JR, Roth T. Neurophysiology of sleep and wakefulness: basic science and clinical implications. Curr Neuropharmacol. 2008;6(4):367-378.
  5. Brown RE, Basheer R, McKenna JT, Strecker RE, McCarley RW. Control of sleep and wakefulness. Physiol Rev. 2012;92(3):1087-1187.
  6. Broughton R, Valley V, Aguirre M, Roberts J, Suwalski W, Dunham W. Excessive daytime sleepiness and the pathophysiology of narcolepsy-cataplexy: a laboratory perspective. Sleep. 1986;9:205-215.
  7. Plazzi G, Serra L, Ferri R. Nocturnal aspects of narcolepsy with cataplexy. Sleep Med Rev. 2008;12(2):109-128.
  8. van der Heide A, Lammers GJ. Narcolepsy. In: Thorpy MJ, Billiard M, eds. Sleepiness: Causes, Consequences and Treatment. Cambridge, UK: Cambridge University Press; 2011:111-125.
  9. Shan L, Dauvilliers Y, Siegel JM. Interactions of the histamine and hypocretin systems in CNS disorders. Nat Rev Neurol. 2015;11:401-13.
  10. Saper CB, Scammell TE, Lu J. Hypothalamic regulation of sleep and circadian rhythms. Nature. 2005;437(7063):1257-1263.
  11. Haas HL, Sergeeva OA, Selbach O. Histamine in the nervous system. Physiol Rev. 2008;88(3):1183-1241.
  12. Schwartz MD, Kilduff TS. The neurobiology of sleep and wakefulness. Psychiatr Clin North Am. 2015;38(4):615-644.
  13. Scammell TE, Jackson AC, Franks NP, Wisden W, Dauvilliers Y. Histamine: neural circuits and new medications. Sleep. 2019;42(1): doi: 10.1093/sleep/zsy183.
  14. Scammell TE. Narcolepsy. N Engl J Med. 2015;373(27):2654-2662.
  15. Williams RH, Chee MJ, Kroeger D. Optogenetic-mediated release of histamine reveals distal and autoregulatory mechanisms for controlling arousal. J Neurosci. 2014;34(17):6023-6029.
  16. Crochet S, Onoe H, Sakai K. A potent non-monoaminergic paradoxical sleep inhibitory system: a reverse microdialysis and single-unit recording study. Eur J Neurosci. 2006;24(5):1404-1412.

Performance of routine tasks without awareness.

Sudden and brief loss of muscle tone, often triggered by strong emotions or certain situations. Narcolepsy with cataplexy is known as narcolepsy type 1.

Complete collapse to the ground; all skeletal muscles are involved.

Only certain muscle groups are involved.

Biological clock mechanism that regulates the 24-hour cycle in the physiological processes of living beings. It is controlled in part by the SCN in the hypothalamus and is affected by the daily light-dark cycle.

Frequent awakenings and inappropriate transitions between states of sleep and wakefulness during nighttime sleep.

The inability to stay awake and alert during the day.

A neurotransmitter in the brain that supports wakefulness.

Vivid, realistic, and frightening dream-like events that occur when falling asleep.

A neuropeptide that supports wakefulness and helps suppress non-REM sleep and REM sleep.

Primary brain region for regulating the timing of sleep-wake states.

Unintentionally falling asleep due to excessive daytime sleepiness. Also known as “sleep attacks.”

Brief, unintentional lapses into sleep, or loss of awareness.

A validated objective measure of the tendency to fall asleep in quiet situations.

People with narcolepsy type 1 have low levels of hypocretin.

Narcolepsy without cataplexy; the cause of narcolepsy type 2 is unknown.

A state of sleep characterized by slower-frequency, more synchronized neuronal activity and decreased muscle tone. Deep stages help to restore the body.

A multiparameter test that monitors physiologic signals during sleep; used as a diagnostic tool in sleep medicine.

A state of sleep characterized by low-amplitude, fast-frequency EEG, vivid dreams, and loss of muscle tone. Normally occurs 60-90 minutes after sleep onset. Also known as “paradoxical sleep.”

Brief loss of control of voluntary muscles with retained awareness at sleep-wake transitions.

Sleep-onset REM period.