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Thomas E. Scammell, MD
Published: May 27, 2015
Sleep problems are common in adults and should be treated to improve overall health and safety. To choose the best treatment for patients with sleep problems, clinicians should understand the sleep-wake cycle and the stages of rapid eye movement and non-rapid eye movement sleep as well as the neurologic pathways of sleep and wake systems. The sleep- and wake-promoting systems are mutually inhibitory, with the predominantly active system determining if a person is awake or asleep. The orexin system also plays an important role in the stabilization of the sleep-wake cycle.
From the Division of Sleep Medicine, Department of Neurology, Harvard Medical School, Boston, Massachusetts.
Supported by an educational grant from Merck & Co.
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Dr Scammell is a consultant for Eisai, Merck, Jazz, and Prexa; has received grant/research support from Eisai; and has served on the speakers/advisory boards for Merck.
The Chair for this activity, Andrew D. Krystal, MS, MD, is a consultant for Abbott, Astellas, AstraZeneca, Attentiv, Bristol-Myers Squibb, Teva, Eisai, Eli Lilly, GlaxoSmithKline, Jazz, Janssen, Merck, Neurocrine, Novartis, Otsuka, Lundbeck, Roche, Sanofi-Aventis, Somnus, Sunovion, Somaxon, Takeda, Transcept, and Vantia; and has received grant/research support from the National Institutes of Health, Teva, Sunovion, Astellas, Abbott, Neosync, Brainsway, Janssen, ANS St Jude, and Novartis.
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In spite of the high prevalence of insomnia and other sleep disorders, especially chronic sleep disorders, current treatments are imperfect. Many of the most commonly prescribed medications for insomnia, both benzodiazepines and nonbenzodiazepines, work to enhance sleep, but unfortunately, they can also cause a wide variety of side effects because of the widespread nature of the neurotransmitter system they target. In addition, some of these drugs have a risk of dependence and abuse. A more focused agent or one that regulates wakefulness might avoid these side effects and risks yet still effectively promote nighttime sleep and daytime wakefulness. Doctors, particularly psychiatrists, need more education on the new and emerging strategies for recognizing and treating sleep disorders so that they can make more informed, evidence-based treatment choices. This activity was designed to meet the needs of participants in CME activities provided by the CME Institute of Physicians Postgraduate Press, Inc., who have requested information on insomnia.
Dr Scammell has determined that, to the best of his knowledge, no investigational information about pharmaceutical agents that is outside US Food and Drug Administration–approved labeling has been presented in this activity.
The entire faculty of the series discussed the content at a peer-reviewed planning session, the Chair reviewed the activity for accuracy and fair balance, and a member of the External Advisory CME Board who is without conflict of interest reviewed the activity to determine whether the material is evidence-based and objective.
This Psychlopedia activity is derived from the planning teleconference series “New Strategies in Sleep,” which was held in October 2014, and is supported by an educational grant from Merck & Co. The opinions expressed herein are those of the faculty and do not necessarily reflect the opinions of the CME provider and publisher or the commercial supporter.
Too many people get insufficient sleep. A lack of sleep is associated with memory and concentration problems, mood disorders, decreased functioning, and driving accidents.1 In fact, about 25% of fatal car accidents in the United States are associated with drowsy driving, and 4% of adults reported falling asleep while driving in the previous month (AV 1).2 Because sleep disorders are common, clinicians are likely to treat patients with insomnia. About 15% of adults report chronic insomnia,1 which is disrupted sleep at least 3 nights a week, lasting for at least 3 months.3 Understanding the neurologic processes of the sleep-wake cycle can help clinicians implement appropriate treatments for patients with insomnia and other sleep problems.
Data from CDC2
Daily behavior can be divided into wakefulness, rapid eye movement (REM) sleep, and non-REM (NREM) sleep. Wakefulness is the state of awareness of self and the environment. Sleep begins with NREM sleep and cycles between NREM and REM sleep throughout the night in roughly 90-minute periods (AV 2).4 NREM sleep is typically divided into 3 stages ranging from lighter to deeper sleep. People rouse easily from the lightest stage of NREM sleep (N1), but they are harder to wake from the deepest stage (N3). REM sleep is characterized by quick eye movements and muscle paralysis. During REM sleep, the cortex is active, generating the vivid thoughts that accompany dreams, but brainstem circuits inhibit motor neurons, preventing people from acting out their dreams.5 Across the night, NREM sleep gets lighter while episodes of REM sleep get longer.
Based on National Sleep Foundation4
As people age, they spend less time in the deepest NREM sleep (N3), meaning that they are more easily roused by various stimuli, such as traffic noise or muscle aches. Nighttime awakenings may be associated with trouble returning to sleep, thereby decreasing total sleep time, which for adults should be an average of 7.5 to 8 hours per night.6 A survey7 of over 74,000 adults, however, showed that 35% averaged less than 7 hours of sleep during a 24-hour period. Some sleep problems are related to primary sleep disorders or medical or psychiatric conditions, while others are related to unhealthy behaviors.7
Two factors influence how much sleep people get and when they sleep.8 The homeostatic factor (also known as process S) reflects the drive to sleep; someone who has been awake for a long time will have high homeostatic pressure to sleep and will subsequently have prolonged, deep sleep. This homeostatic pressure accumulates during wakefulness and declines during sleep. The circadian factor (process C) causes alertness to vary with the time of day. Regulated by the suprachiasmatic nucleus, the circadian factor is a daily rhythm that helps promote arousal and wakefulness during the day.8,9 Processes C and S may counter each other. That is, if people stay awake all night, they may be especially tired around 3 or 4 am due to the high homeostatic pressure. But by 10 or 11 am, the circadian drive for wakefulness counters the high homeostatic drive for sleep, and people usually feel more alert, despite having been awake even longer.
Somnogens are sleep-promoting biochemicals, such as adenosine, prostaglandin D2, muramyl dipeptides, and tumor necrosis factor-α.8 Adenosine, which has received the most attention, is a simple biomolecule that rises during wakefulness and falls during sleep in specific brain regions. When injected into an animal’s brain, adenosine causes sleep. In fact, caffeine promotes wakefulness by blocking adenosine receptors.8 Less evidence is available on other somnogens, but some may promote sleep during inflammatory conditions.
Sleep-promoting systems. Until about 20 years ago, NREM sleep was thought to occur passively when wake-promoting systems somehow turned off on their own, but it is now clear that NREM sleep is a regulated phenomenon. One of the most important cell groups for producing NREM sleep is neurons of the ventrolateral preoptic area (VLPO). These neurons use GABA and galanin to send strong inhibitory signals to brain regions that promote wakefulness. Across the brain, most neurons are quiet or silent during NREM sleep, but the VLPO neurons are active during NREM sleep, and their activity helps shut down the activity of the wake-promoting systems.8
In REM sleep, a subset of cholinergic neurons in the pons (LDT/PPT) become active and help produce thalamic and cortical activation. These neurons are also involved with triggering a descending pathway that runs through the sublaterodorsal nucleus in the brainstem down to motor neurons in the spinal cord, which helps produce the paralysis of REM sleep. REM-promoting circuits are strongly inhibited by any of the monoamine neurotransmitters, which are released only during wakefulness.8
Wake-promoting systems. Wake-promoting pathways use 2 types of neurotransmitters: acetylcholine (ACh) and monoamine neurotransmitters, such as serotonin (5-HT), dopamine (DA), norepinephrine (NE), and histamine.8 The monoamine neurotransmitters are produced in various regions (eg, NE in the locus coeruleus, 5-HT in the dorsal raphe) and are released in the cortex and other regions where they produce excitatory effects and increase neuronal activity. The monoamine neurons are active during wakefulness but inactive during sleep, especially during REM sleep.
Other wake-promoting pathways use ACh to promote wakefulness and arousal. One group of ACh-producing neurons in the basal forebrain projects directly to the cortex, exciting cortical neurons. The basal forebrain also contains GABA-producing neurons, which create arousal by reducing activity in inhibitory neurons in the cortex, resulting in increased cortical activity. Cholinergic neurons are also located in the laterodorsal and pedunculopontine tegmental nuclei (LDT/PPT) in the pons. During wakefulness, the LDT/PPT neurons release ACh in the thalamus, enabling the thalamus to relay information to and from the cortex. During NREM sleep, these cholinergic neurons are less active, resulting in less signaling through the thalamus.8
Knowledge of these 2 mutually inhibitory groups of neurons, a wake-promoting group and a sleep-producing group, has led to a flip-flop circuit model of sleep-wake control.9 The monoamine neurotransmitters and ACh promote wakefulness while VLPO neurons use GABA and galanin to promote sleep. When one system inhibits the other, the result is a switch to wakefulness or sleep. A problem occurs when the circuit does not allow someone to remain awake or remain asleep. For example, a small amount of homeostatic sleep drive may turn on some VLPO neurons, which could cause the circuit’s switch to flip into sleep at the wrong time of day. Thus, another element is needed in this circuit to produce long periods of wake and sleep.
Orexin system. One stabilizing element is the orexin system, which was recently discovered. The orexin system is composed of neurotransmitters crucial for maintaining wakefulness.9 Two neurotransmitters, orexin-A and orexin-B, are neuropeptides that bind to and activate G-protein-coupled receptors, exciting target neurons. They appear to work in opposition to the accumulating sleep drive (process S) to maintain arousal during the day. Loss of orexin-producing neurons results in narcolepsy with cataplexy, a disorder characterized by difficulty maintaining long periods of wakefulness and rapid transitions into sleep.9 Orexins are produced by neurons in the lateral hypothalamus, and these cells project to brain regions that promote wakefulness, such as the tuberomammillary neurons that make histamine, the raphe neurons that make 5-HT, and the locus coeruleus neurons that make NE.8,10 Thus, the orexin system helps stabilize sleep-wake behavior, predominantly by promoting long, stable periods of wakefulness. During sleep, the VLPO neurons turn off the orexin neurons, just as they turn off the other wake-promoting systems.
Based on España and Scammell
Summary. The activity of regulatory neurons varies in each behavioral state (AV 3).8 For example, GABA neurons are active in both NREM and REM sleep but not during wakefulness. Monoamine neurons are mainly active during wakefulness, minimally active in NREM sleep, and silent in REM sleep. The ACh neurons are also very active during wakefulness, are not active during NREM sleep, and a minority of them are active again in REM sleep. The orexin neurons are active in wakefulness and inactive in sleep.8 Understanding how current and upcoming medications affect these systems will help clinicians gauge the associated therapeutic and adverse effects. As more research is done on these systems, new agents may provide better treatments for sleep disorders. For example, agents that inhibit orexin could make it easier for patients to fall asleep without the unsteadiness or confusion often associated with sleep-promoting agents. For more information on specific treatments and their effects on sleep- and wake-promoting systems, see “Current, Emerging, and Newly Available Insomnia Medications.”
Sleep problems are common in adults and must be treated to improve overall health and well-being. For clinicians to choose the best treatment for their patients with sleep problems, they should understand the sleep-wake cycle and the underlying neurobiology. REM sleep is characterized by an active cortex, muscle paralysis, and dreaming, while NREM sleep includes stages from lighter to deeper sleep with less vivid dreams. GABA and galanin promote NREM sleep while neural circuits in the pons regulate REM sleep. Monoamine neurotransmitters, including 5-HT, NE, DA, and histamine, as well as ACh neurons are active during wakefulness. The sleep- and wake-promoting systems are mutually inhibitory, with the predominantly active system determining if a person is awake or asleep. These systems are regulated by the orexin neurons, which help stabilize wakefulness. As more research is done on sleep- and wake-promoting systems, new medications may provide more specific and potent treatments for insomnia.
5-HT = serotonin, ACh = acetylcholine, BF = basal forebrain, DA = dopamine, GABA = γ-aminobutyric acid, LDT = laterodorsal tegmental, NE = norepinephrine, NREM = non-REM, PPT = pedunculopontine tegmental, REM = rapid eye movement, VLPO = ventrolateral preoptic area