“All of the sudden, I have this out of the blue urge to sleep.” – Scott

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The Neurobiology of Narcolepsy

In narcolepsy, the sleep-wake cycle is unpredictable and unstable.1-5

Insufficient activation of wake-promoting neurons as well as insufficient inhibition of non-REM sleep- and REM sleep-promoting neurons can lead to sleep-wake state instability.1-3,6 The transitions between wakefulness, non-REM sleep, and REM sleep become frequent and unpredictable, and the boundaries between them become unstable, allowing elements of one state to intrude into another.1-3,7,8 Watch to learn more about narcolepsy.

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Normal Sleep-Wake Cycle

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.4,6,9

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Narcolepsy Sleep-Wake Cycle

In narcolepsy, the sleep-wake cycle is unstable throughout a 24-hour period.1-5

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During wakefulness, insufficient activation of wake-promoting neurons causes…

  • Insufficient inhibition of non-REM sleep- and REM sleep-promoting neurons1,2,10
  • Intermittent activation of non-REM sleep- and REM sleep-promoting neurons1-3,6,10,11

Leading to…

  • Frequent and unpredictable transitions between states1,3,6
  • Unstable boundaries between states, allowing elements of one state to intrude into another2,6,7

What Causes Narcolepsy?

In people with narcolepsy who experience cataplexy, the disorder is usually caused by the selective loss of hypocretin neurons (hypocretin deficiency).2,12 Patients with hypocretin deficiency are usually diagnosed with narcolepsy with cataplexy (type 1 narcolepsy).12 The presence of cataplexy is generally thought to indicate more significant loss of hypocretin neurons.1,12,13 In people with narcolepsy without cataplexy, the cause is often not known.2,12

There's More to Know
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What happens to sleep-wake state stability in people living with narcolepsy?

Explore the elements »
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Signs and symptoms of narcolepsy are not always obvious.

Learn the manifestations »
  1. España RA, Scammell TE. Sleep neurobiology from a clinical perspective. Sleep. 2011;34(7):845-858.
  2. Scammell TE. Narcolepsy. N Engl J Med. 2015;373(27):2654-2662.
  3. Saper CB, Scammell TE, Lu J. Hypothalamic regulation of sleep and circadian rhythms. Nature. 2005;437(7063):1257-1263.
  4. Plazzi G, Serra L, Ferri R. Nocturnal aspects of narcolepsy with cataplexy. Sleep Med Rev. 2008;12(2):109-128.
  5. Rogers AE, Aldrich MS, Caruso CC. Patterns of sleep and wakefulness in treated narcoleptic subjects. Sleep. 1994;17(7):590-7.
  6. Scammell TE, Arrigoni E, Lipton JO. Neural circuitry of wakefulness and sleep. Neuron. 2017;93(4):747-765.
  7. 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.
  8. Schwartz JR, Roth T. Neurophysiology of sleep and wakefulness: basic science and clinical implications. Curr Neuropharmacol. 2008;6(4):367-378.
  9. Scammell TE. The neurobiology, diagnosis, and treatment of narcolepsy. Ann Neurol. 2003;53(2):154-166.
  10. Burgess CR, Oishi Y, Mochizuki T, Peever JH, Scammell TE. Amygdala lesions reduce cataplexy in orexin knock-out mice. J Neurosci. 2013;33(23):9734-42.
  11. Pillen S, Pizza F2, Dhondt K, Scammell TE, Overeem S. Cataplexy and its mimics: clinical recognition and management. Curr Treat Options Neurol. 2017;19(6):23.
  12. American Academy of Sleep Medicine. International Classification of Sleep Disorders. 3rd ed.; 2014.
  13. Drakatos P, Leschziner G. Cataplexy with normal sleep studies and normal CSF hypocretin: an explanation? J Clin Sleep Med. 2016;12(3):449-450.
  14. Singh AK, Mahlios J, Mignot E. Genetic association, seasonal infections and autoimmune basis of narcolepsy. J Autoimmun. 2013;43:26-31.
  15. Andlauer O, Moore H, Hong SC, et al. Predictors of hypocretin (orexin) deficiency in narcolepsy without cataplexy. Sleep. 2012;35(9):1247-1255F.
  16. Valko PO, Gavrilov YV, Yamamoto M, et al. Increase of histaminergic tuberomammillary neurons in narcolepsy. Ann Neurol. 2013;74(6):794-804.
  17. John J, Thannickal TC, McGregor R, et al. Greatly increased numbers of histamine cells in human narcolepsy with cataplexy. Ann Neurol. 2013 Dec;74(6):786-93.

Performance of routine tasks without awareness.

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

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 inappropriate transitions between states of sleep and wakefulness.

The inability to stay awake and alert during the day.

A neurotransmitter that supports wakefulness. The TMN is the only source of histamine in the brain.

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

A neuropeptide that supports wakefulness and helps control 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.

Brief, unintentional lapses into sleep or loss of awareness.

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

A state of sleep when muscle tone is decreased. Deep stages help to restore the body.

Overnight study used to diagnose sleep disorders by monitoring sleep stages and cycles to detect disruptions of a normal sleep pattern.

Normally occurs at night and includes vivid dreams. Also known as “paradoxical sleep.”

Daytime and evening habits and routines to help improve nighttime sleep.

Brief loss of control of voluntary muscles with retained awareness.

Sleep-onset REM period.

People with type 1 narcolepsy have low levels of hypocretin.

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