The Neuroscience of Narcolepsy

March 2, 2021

Written by: Greer Prettyman

Maybe you fall asleep as soon as your head hits the pillow at night, or maybe you lie awake for what feels like hours before you can drift off. Many things affect our transitions from wake to sleep and back to wake again, like environmental cues, caffeine consumption, daily habits, and genetics. For some people who have a chronic sleep disorder called narcolepsy, sleep transitions become dysregulated, causing sleep-related difficulties during the day and at night.

The most common symptom of narcolepsy is excessive daytime sleepiness that often leads to falling asleep throughout the day. Meanwhile, sleep at night is also affected by narcolepsy. A night of sleep for a healthy adult involves cycling between two states of sleep: rapid eye movement (REM) and non-REM sleep. For a person with narcolepsy, a night of sleep does not follow this typical pattern. There are two subtypes of narcolepsy. In addition to shared symptoms of daytime sleepiness and disrupted nighttime sleep, narcolepsy type 1 includes a symptom called cataplexy¹. Cataplexy is a loss of muscle tone, leading to temporary paralysis that often begins in the face and neck, but sometimes travels throughout the body and causes a person to slump over. An individual experiencing cataplexy is not asleep, however. They are conscious but simply unable to move for a brief period of time. Individuals with narcolepsy type 2 have sleep symptoms but do not experience cataplexy¹. 

What happens in the brains of people with narcolepsy to produce these symptoms? The transition from being awake to being asleep is primarily regulated by part of the brain called the hypothalamus. Within the hypothalamus, some neurons produce a neuropeptide, or chemical signal, called orexin (you may also hear this signal referred to as hypocretin). Orexin promotes wakefulness by sending excitatory signals to many different parts of the brain. These excitatory communications act to suppress REM sleep, keeping the brain awake throughout the day². When it’s time to sleep, other brain regions can inhibit orexin neurons, allowing the brain to transition from wake to sleep².

Scientists discovered that individuals with narcolepsy have a selective reduction in orexin-producing neurons in the lateral hypothalamus, the region within the hypothalamus where these neurons are found². Without orexin, these individuals are not able to suppress sleep normally, and often enter REM sleep while taking naps several times a day. During the night, adults typically enter a state of non-REM sleep for about an hour prior to the first bout of REM sleep. For people with narcolepsy, on the other hand, REM sleep usually begins shortly after falling asleep and normal sleep bouts are disrupted throughout the night². 

Why do people with type 1 narcolepsy lose muscle tone spontaneously while they are awake? Narcolepsy causes dysregulation of transitions between wake and sleep that can also include entering intermediate states, like paralysis without sleep. Usually when we enter REM sleep, our muscles are paralyzed so we do not move. In some sleep disorders such as REM sleep behavior disorder, the body is not properly paralyzed during sleep, leading to sleepwalking and even physically acting out dreams. Individuals with narcolepsy type 1 experience the opposite phenomenon during cataplexy; they are paralyzed as if they were sleeping, but they remain conscious. Orexin neurons prevent muscle paralysis during the day by suppressing activity in regions that produce REM sleep and related behaviors. During sleep, this activity is no longer suppressed, causing a region called the sublaterodorsal nucleus (SLD) to transmit signals to the muscles, preventing them from moving². Since narcolepsy patients have reduced orexin signaling, they are unable to properly inhibit muscle paralysis during the day, leading to cataplexy. 

Interestingly, cataplexy is often triggered by strong positive emotions like joy and excitement¹. Mouse models of narcolepsy entered a state of cataplexy after receiving rewards like chocolate and toys². In addition to regulating sleep and wake states, orexin neurons send and receive information about rewards from a brain region called the medial prefrontal cortex. It is believed that orexin might help to produce the high arousal state involved in reward seeking and motivation². With narcolepsy, the disruption in orexin signaling removes the intermediary inhibition between activation in the medial prefrontal cortex and the SLD, causing positive emotions to trigger the type of muscle paralysis that usually occurs during sleep. 

The selective loss of orexin-producing neurons explains why the symptoms of narcolepsy occur. But what causes these neurons to be lost? Some research indicates that narcolepsy is actually an autoimmune disorder². Autoimmune disorders arise when the body’s immune system attacks its own cells. In a typical immune system response, immune cells called CD4+ T cells help to attack pathogens by releasing cytokines to clear infection. Activated T cells can then “remember” the specific pathogens and attack them if they return in the future. Orexin peptides can contain a similar marker as some pathogens, leading activated CD4+ T cells to release cytokines that destroy this specific type of neuron as if they were an invading threat².

Additionally, there is a strong genetic risk for developing narcolepsy type 1. People who carry a specific copy of the human leukocyte antigen (HLA) class II gene are much more likely to develop narcolepsy, and 90% of narcolepsy type 1 patients carry this genetic risk factor². Other genetic variants involved in regulating the immune system may also increase risk for narcolepsy.

Environmental factors can increase the risk of narcolepsy, particularly in individuals who are already at high genetic risk. Common infections that trigger an immune response, such as influenza and streptococcus, can kickstart the autoimmune attack of orexin neurons that leads to narcolepsy². Infection with COVID-19 might also lead to an increased risk for narcolepsy following an immune response needed to fight off the virus³. Over a year into the global pandemic, scientists are still learning about potential long-term effects of the COVID-19 virus and will be monitoring for an increase in rates of narcolepsy in people who have recovered from COVID. The changes to daily life during quarantine and lockdowns, including loss of normal sleep schedules, can also exacerbate narcolepsy symptoms. In a recent survey, patients with narcolepsy reported changes in sleep routines and increases in narcolepsy symptoms during the pandemic, unrelated to infection with COVID-19⁴. More research will be needed to better understand the effects of the pandemic on development and severity of narcolepsy. 

If you are prone to dozing off during movies or falling asleep in class and wondering if you have narcolepsy, you can talk to your doctor. Diagnosing narcolepsy involves monitoring a patient’s sleep behavior and using EEG to record brain activity during transitions to and from sleep. Treatment for narcolepsy usually involves taking stimulants to reduce daytime sleepiness as well as other medications to improve sleep quality¹. Now that scientists understand more about how and why narcolepsy occurs, future research may be able to leverage our knowledge about autoimmune mechanisms to improve treatment for this chronic and disruptive disorder. 

Cover Image Photo by Mert Kahveci on Unsplash

References:

1. Narcolepsy. (2017). Nat Rev Dis Primers 3, 16101.
2. Mahoney, C.E., Cogswell, A., Koralnik, I.J. et al. (2019) The neurobiological basis of narcolepsy.Nat Rev Neurosci 20, 83–93.
3. Schirinzi, T., Landi, D., & Liguori, C. (2020). COVID-19: dealing with a potential risk factor for chronic neurological disorders. Journal of neurology, 1–8. Advance online publication. 
4. Rodrigues Aguilar AC, Frange C, Huebra L, Dias Gomes AC, Tufik S, Santos Coelho FM. (2020) The effects of the COVID-19 pandemic on patients with narcolepsy. J Clin Sleep Med. Epub ahead of print.