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Sleep-Wake State Instability in Narcolepsy

Loss of hypocretin neurons in narcolepsy leads to sleep-wake state instability.¹

During the day, lack of hypocretin in narcolepsy leads to:

Insufficient activation of histamine neurons and wake-promoting neurons outside the hypothalamus^2,3
Insufficient inhibition and intermittent activation of non-REM sleep–promoting neurons (Non-REM at the Wrong Time™)^2,4
Insufficient inhibition and intermittent activation of REM sleep–promoting neurons (REM at the Wrong Time™)^2,5,6

This process causes sleep-wake state instability, which manifests as:

Frequent and unpredictable transitions between sleep-wake states^7,8
Unstable boundaries between sleep-wake states, which allows elements of one state to intrude into another^7,9

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The Pathophysiology of Cataplexy

Cataplexy occurs when the muscle atonia associated with REM sleep intrudes into wakefulness during the day.^3,11 Learn about the neuronal processes that allow strong emotions to trigger a loss of muscle tone in people living with narcolepsy.^3,10

Manifestations

Understand signs and symptoms that reflect underlying sleep-wake state instability.

Make the connection »

Histamine

There’s more to know about the role of histamine in regulating wakefulness.

Discover »

References

España RA, Scammell TE. Sleep neurobiology from a clinical perspective. Sleep. 2011;34(7):845-858.
Saper CB, Fuller PM, Pedersen NP, Lu J, Scammell TE. Sleep state switching. Neuron. 2010;68(6):1023-1042.
Scammell TE. Narcolepsy. N Engl J Med. 2015;373(27):2654-2662.
Mochizuki T, Crocker A, McCormack S, Yanagisawa M, Sakurai T, Scammell TE. Behavioral state instability in orexin knock-out mice. J Neurosci. 2004;24(28):6291-6300.
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.
Bassetti C, Aldrich MS. Narcolepsy, idiopathic hypersomnia, and periodic hypersomnias. In: Culebras A, ed. Sleep Disorders and Neurological Disease. New York, NY: Marcel Dekker; 2000:323-354.
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.
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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.
Szabo S, Thorpy M, Mayer G, Peever J, Kilduff T. Neurobiological and immunogenetic aspects of narcolepsy: implications of pharmacotherapy. Sleep Med Rev. 2019;43:23-36.
Dauvilliers Y, Siegel J, Lopez R, Torontali Z, Peever J. Cataplexy – clinical aspects, pathophysiology and management strategy. Nat Rev Neurol. 2014;10(7):386-395.
Meletti S, Vaudano AE, Pizza F, et al. The brain correlates of laugh and cataplexy in childhood narcolepsy. J Neurosci. 2015;35(33):11583-11594.
Burgess C, Oishi Y, Mochizuki T, Peever J, Scammell T. Amygdala lesions reduce cataplexy in orexin knock-out mice. J Neurosci. 2013;33(23):9734-9742.
Juvodden HT, Alnæs D, Lund MJ, et al. Hypocretin-deficient narcolepsy patients have abnormal brain activation during humor processing. Sleep. 2019;42(7):zsz082.