Sleep Disorders


Insomnia

Insomnia is the most common sleep disorder and is one of the most common medical complaints.  Someone with insomnia may have trouble falling asleep (increased sleep latency) or may wake frequently during the night and have difficulty getting back to sleep (decreased sleep efficiency).  The lack of sleep or poor quality of sleep may cause problems with daytime function, such as drowsiness, lack of energy, or an inability to focus attention.

Various factors can cause insomnia.  Insomnia frequently arises as a consequence of behavioral stress, or some other factor which is thought to create a situation of hyperarousal.  In hyperarousal, there is increased activation of the arousal-promoting nuclei, which can overcome the inhibition from the sleep-promoting nucleus, the VLPO.

Insomnia can be successfully treated with behavioral therapy, which involves techniques designed to overcome poor sleep habits and to address issues that may be contributing to stress and hyperarousal.  Behavioral treatments for insomnia may be more effective over the long-term than drug treatments.

Drug therapy for insomnia usually involves the use of benzodiazepines or Z-drugs, which work as GABA potentiators.  The GABA potentiators vary mainly in terms of their half-life, which reflects how long the drug will be effective.  For instance, Zaleplon (Sonata®) has a very short half-life, and is used to treat insomnia in which the main problem is with increased sleep latency.  Drugs with a longer half-life are used to increase sleep efficiency, although these drugs may cause daytime sleepiness and incoordination. Benzodiazepines and Z-drugs are also generally not intended for long-term use.

Suvorexant (Belsomra®) is an orexin antagonist that was approved by the FDA in August 2014.  Orexin is a peptide neurotransmitter that is released by a relatively restricted set of neurons located in the LHA nucleus of the hypothalamus (see below under "Narcolepsy").  Orexin-releasing neurons are active during waking and thought to help maintain the awake state.  It remains to be seen whether these drugs will be safe and effective treatments for insomnia.

The melatonin agonist ramelteon (Rozerem®) is a drug that has been approved for long-term use in the treatment of insomnia.  Ramelteon may also be better for treating insomnia in the elderly, because it is less likely to cause next-day drowsiness and incoordination.  Insomnia tends to be more common in the elderly population, and may be related to decreased melatonin secretion.  


Sleep Apnea

Sleep apnea is another common disorder that may lead to excessive daytime sleepiness. Sleep apnea is really a respiratory disorder: “apnea” means lack of breathing. The most common form of sleep apnea is obstructive sleep apnea, which results because physical factors lead to obstruction of the airways during sleeping. The lack of ventilation triggers an increase in respiratory effort that causes the person to wake. These constant disruptions cause inadequate sleep and lead to daytime sleepiness. Obstructive sleep apnea is treated with a device attached to a mask that provides higher pressure to keep the airways open (continuous positive airway pressure or CPAP).


Narcolepsy

Narcolepsy is a sleep disorder in which there is a loss of stability in the maintenance of the awake and sleep states, so that aspects of sleep intrude into wakefulness and vice versa.

Narcolepsy is characterized by excessive daytime sleepiness.  This excessive sleepiness may cause a narcoleptic individual to fall asleep at inappropriate times ("sleep attacks").  Note that although there is daytime sleepiness, someone with narcolepsy does not sleep more than normal.  Narcolepsy also often causes disturbed sleep at night, with frequent wakings.  As well, about half of the people with narcolepsy experience the following symptoms, in which aspects of REM sleep are seen during waking.

LHA activityIn the late 1990's researchers in several labs determined that narcolepsy is caused by a deficiency of orexin signaling.  Orexin (also called hypocretin) is a peptide neurotransmitter released by neurons found in the LHA.  The activity of the LHA is thought to stabilize the awake state through excitation of the arousal-promoting nuclei (see figure).  In the absence of activity from the orexin-releasing neurons of the LHA, unwanted transitions are made between sleeping and waking.  The frequent transitions result in a lack of consolidation of both the arousal and sleep states.

Cataplexy is thought to occur through dysregulation of the system responsible for REM atonia (the lack of skeletal muscle activity during REM sleep).  During REM sleep, a nucleus in the pons activates inhibitory neurons that turn off activity of somatic efferent neurons in the spinal cord.  In the absence of orexin release from the LHA, this nucleus is turned on inappropriately causing cataplexy.

REM atonia

Narcolepsy is treated using a variety of drugs.  Daytime sleepiness is treated with stimulants such as modafinil.  Cataplexy is treated with antidepressants, drugs that increase norepinephrine and serotonin.  These neurotransmitters are thought to prevent activation of the nucleus that turns on REM atonia.  GHB (Xyrem®) is a hypnotic that is taken at night to promote sleep consolidation.  Treatment with GHB also reduces cataplexy, although the mechanism is unclear. 


REM Sleep Behavior Disorder

REM sleep behavior disorder (RBD) is a disorder in which there is strong and disturbing motor behavior during REM sleep. Individuals with this disorder often have violent and disturbing dreams in which they scream or swear, and which are accompanied by movements that are related to dream content.  This disorder predominantly affects men, usually in late middle age.

RBD is diagnosed using polysomnography, where EEG recording is combined with EMG recording to look at skeletal muscle activity during sleep.  Polysomnography reveals that REM atonia fails to occur.  A hypothesis is that RBD is caused by dysregulation of the pathway controlling REM atonia.

One intriguing aspect of RBD is that a large proportion of individuals diagnosed with the disorder subsequently go on to develop neurodegenerative diseases in which there is an abnormal accumulation of the protein alpha-synuclein.  Parkinson's disease is the most well-known example. 

RBD can be effectively treated with the benzodiazepine drug clonazepam. The mechanism of action in reducing muscle movements during REM sleep is not known. 



Quick Quiz


Fill in Answer Correct False Correct Answer
1. Which sleep disorder is associated with hyperarousal?
2. Name a specific brain nucleus that would be activated in hyperarousal.  (Use the abbreviations we have been using in class).
3. Name a drug that has been approved for long-term use in the treatment of insomnia.
4. Name the neurotransmitter that is deficient in narcolepsy.
5. Which of the following occurs during cataplexy? [loss of consciousness; loss of skeletal muscle tone; hallucinations]
6. Name the sleep disorder in which the REM atonia controller is inappropriately turned on.
7. Name the type of physiological recording that is used to diagnose REM sleep behavior disorder (RBD).
8. Which sleep disorder is associated with an increased risk of developing Parkinson's disease?
9. Name the disorder for which the drug suvorexant (an orexin antagonist) is an approved treatment.


(Spelling must be correct)