- Research has revealed that narcolepsy with cataplexy is caused by a lack of orexins (hypocretins), brain chemicals that help sustain alertness and prevent REM sleep from occurring at the wrong times.
- Genetics, age, and triggering infections or inflammation play important roles in the development of narcolepsy.
- Ongoing research is shedding light on many aspects of the disorder; as more is learned about the biology of narcolepsy, the door widens for more effective treatments.
Orexins are neurotransmitters, chemicals that transmit signals from a neuron to a target neuron. Orexins are only produced by a small cluster of neurons in the hypothalamus, a brain region located roughly behind the eyes and between the ears. Of the billions of neurons in the brain, only about 100,000–200,000 produce orexins. Orexins are released from these neurons during wakefulness and bind to specific orexin receptors on target neurons, which increases the activity of these neurons.
Orexins were first discovered in 1998 when two research groups independently identified them in the brain. 1, 2 One group named them hypocretin-1 and -2, and the other group named them orexin-A and -B. (This website uses the term “orexins,” as this name is preferred by clinicians.)
Orexins and brain function
In individuals without narcolepsy and whose sleep is well regulated, orexins are released during wakefulness and increase activity in target neurons that promote wakefulness and suppress rapid-eye-movement (REM) sleep. In people who have narcolepsy with cataplexy, most of the orexin-producing neurons die off. The consequent lack of orexins results in lasting sleepiness and poor control of REM sleep. In fact, REM sleep can become so poorly regulated that the paralysis or dreaming that normally occurs only in REM sleep can mix into wakefulness, causing cataplexy and dreamlike hallucinations.
Dr. Thomas Scammell recalls the discovery of hypocretin and how it is lost in narcolepsy.
Though much has been learned about narcolepsy with cataplexy, considerably less is known about the cause of narcolepsy without cataplexy. Most likely, it is caused by less severe injury to the orexin neurons, resulting in fewer and less severe symptoms. (See Key discoveries below for more on some of the studies that have shed light on the role of orexins in narcolepsy.)
How orexin loss affects the brain
In addition to revealing the normal role of orexin neurons in the brain, research has provided many insights into how a loss of orexin signaling causes sleepiness and cataplexy.
Many researchers theorize that the sleepiness of narcolepsy is a consequence of “sleep state instability,” a condition in which the thresholds between wake and sleep are easily crossed, resulting in both fragmented wakefulness during the daytime and fragmented sleep at night.
During normal wakefulness, orexin neurons send signals that produce long-lasting increases in the activity of many other neurons essential for sustaining alertness and wakefulness. These neurons include those that produce key neurotransmitters such as norepinephrine, serotonin, and dopamine. In narcolepsy, the loss of orexins may result in reduced or inconsistent activity in these target neurons. As a consequence, people with narcolepsy can be fully alert at times, but have great difficulty sustaining this alertness for long periods of time.
Cataplexy and sleep paralysis are unusual states in which the brain circuits that produce paralysis during REM sleep become active during wakefulness. During REM sleep, most muscles are paralyzed by circuits in the lower brainstem and spinal cord. These paralysis circuits are normally blocked by norepinephrine and serotonin during wakefulness. With loss of orexins, levels of these two neurotransmitters may be lower, permitting paralysis to occur even during wakefulness. This observation provides the main rationale for treating cataplexy with antidepressants that increase brain levels of norepinephrine and serotonin.
Ongoing research is also beginning to reveal how cataplexy may be triggered by positive e