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The Neurobiology of Sleep, Wakefulness, and Narcolepsy

The Normal Neurobiology of Sleep and Wakefulness

Optimal health and cognitive function require the coordinated activity of several neuronal systems that regulate the timing and stability of three distinct states: wakefulness, non-REM sleep, and REM sleep.1-5 Wakefulness usually occurs during the day, while non-REM sleep and REM sleep generally occur at night.2,3 Learn about these states and how the brain regulates them to ensure that elements of one state do not intrude into another.

There’s more to know about how the brain regulates sleep and wakefulness

The Neurobiology of Normal Sleep and Wakefulness
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The Pathophysiology of Narcolepsy

Narcolepsy is most often caused by the loss of hypocretin.6,7 This loss can lead to insufficient activation of wake-promoting neurons and insufficient inhibition of non-REM sleep-promoting neurons and REM sleep-promoting neurons, leading to sleep-wake state instability.3,6,8,9 The boundaries between wakefulness, non-REM sleep, and REM sleep become unstable, allowing elements of one state to intrude into another, and the transitions between states to become frequent and unpredictable.4,6,8-10

There’s more to know about how narcolepsy affects sleep and wakefulness

The Pathophysiology of Narcolepsy
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The Role of Histamine in Sleep and Wakefulness

In the central nervous system, histamine neurons originate only in the hypothalamus and are thought to play an important role in the regulation of sleep-wake state stability.3,11 Learn how histamine has been shown to help promote and stabilize wakefulness.3,11,12

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

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  1. Schwartz MD, Kilduff TS. The neurobiology of sleep and wakefulness. Psychiatr Clin North Am. 2015;38(4):615-644
  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. España RA, Scammell TE. Sleep neurobiology from a clinical perspective. Sleep. 2011;34(7):845-858.
  7. Silber MH, Krahn LE, Olson EJ, Pankratz VS. The epidemiology of narcolepsy in Olmsted County, Minnesota: a population-based study. Sleep. 2002;25(2):197-202.
  8. Saper CB, Scammell TE, Lu J. Hypothalamic regulation of sleep and circadian rhythms. Nature. 2005;437(7063):1257-1263.
  9. Scammell TE. Narcolepsy. N Engl J Med. 2015;373(27):2654-2662.
  10. 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.
  11. Haas HL, Sergeeva OA, Selbach O. Histamine in the nervous system. Physiol Rev. 2008;88(3):1183-1241.
  12. 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.

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.

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 at sleep-wake transitions.

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.