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

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Sleep-Wake State Instability

Narcolepsy is a disorder of sleep-wake state instability.1,2

Narcolepsy causes unstable boundaries and frequent and unpredictable transitions between wakefulness and sleep states.

In narcolepsy, insufficient activation of wake-promoting neurons leads to insufficient inhibition and intermittent activation of sleep-promoting neurons during the day.3-7 With unstable boundaries between sleep-wake states, non-REM sleep and elements of REM sleep can intrude into wakefulness (Non-REM and REM at the Wrong Time™).8,9 This instability between sleep-wake states can manifest as symptoms of narcolepsy, including excessive daytime sleepiness (EDS), cataplexy, hypnagogic hallucinations, and sleep paralysis.8,9

Narcolepsy is characterized by frequent transitions and unstable boundaries between sleep-wake states.

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How do histamine neurons help to promote and stabilize wakefulness?

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  1. Thorpy M, Morse AM. Reducing the clinical and socioeconomic burden of narcolepsy by earlier diagnosis and effective treatment. Sleep Med Clin. 2017;12(1):61-71.
  2. Ahmed I, Thorpy M. Clinical features, diagnosis and treatment of narcolepsy. Clin Chest Med. 2010;31(2):371-381.
  3. España RA, Scammell TE. Sleep neurobiology from a clinical perspective. Sleep. 2011;34(7):845-858.
  4. Saper CB, Scammell TE, Lu J. Hypothalamic regulation of sleep and circadian rhythms. Nature. 2005;437(7063):1257-1263.
  5. Scammell TE, Arrigoni E, Lipton JO. Neural Circuitry of Wakefulness and Sleep. Neuron. 2017;93(4):747-765.
  6. Pillen S, Pizza F, Dhondt K, Scammell TE, Overeem S. Cataplexy and its mimics: clinical recognition and management. Curr Treat Options Neurol. 2017;19(6):23.
  7. Burgess CR, Oishi Y, Mochizuki T, Peever JH, Scammell TE. Amygdala lesions reduce cataplexy in orexin knock-out mice. J Neurosci. 2013 Jun 5;33(23):9734-42.
  8. 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.
  9. Scammell TE. Narcolepsy. N Engl J Med. 2015;373(27):2654-2662.

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.