Brain Circuitry Controlling Sleep and Wakefulness

Review Article

Address correspondence to Dr John H. Peever, Brain Circuitry Department of Cell and Systems Biology, University of Toronto, 25 Harbord St, Controlling Sleep and Toronto, ON M5S 3G5, Canada, [email protected]. Relationship Disclosure: Wakefulness Dr Horner has received personal compensation for serving as a consultant for Richard L. Horner, PhD; John H. Peever, PhD Dairy Farmers of Canada and Viord Inc and receives royalties from BookBaby for his book, The Universal ABSTRACT Pastime: Sleep and Rest Purpose of Review: This article outlines the fundamental brain mechanisms that Explained. Dr Horner has control sleep-wake patterns and reviews how pathologic changes in these control received grants from Canada Research Chair (950-229813), mechanisms contribute to common sleep disorders. the Canadian Institutes of Recent Findings: Discrete but interconnected clusters of cells located within the Health Research (MT-15563), brainstem and hypothalamus comprise the circuits that generate wakefulness, nonYrapid and the National Sanitarium Association Innovative eye movement (non-REM) sleep, and REM sleep. These clusters of cells use specific Research Program (00144051). neurotransmitters, or collections of neurotransmitters, to inhibitorexcitetheirrespective Dr Peever has received grant sleep- and wake-promoting target sites. These excitatory and inhibitory connections support from the Canadian Institutes of Health Research. modulate not only the presence of wakefulness or sleep, but also the levels of arousal Unlabeled Use of within those states, including the depth of sleep, degree of vigilance, and motor activity. Products/Investigational Dysfunction or degeneration of wake- and sleep-promoting circuits is associated with Use Disclosure: narcolepsy, REM sleep behavior disorder, and age-related sleep disturbances. Drs Horner and Peever report no disclosures. Summary: Research has made significant headway in identifying the brain circuits that * 2017 American Academy control wakefulness, non-REM, and REM sleep and has led to a deeper understanding of Neurology. of common sleep disorders and disturbances.

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INTRODUCTION sleep, the other being sleep intensity. From birth until death, the human Sleep intensity, or depth, is commonly brain spends one or more periods of measured as the difficulty in waking each 24-hour day in wakefulness and someone up from sleep in response to the remaining hours in sleep. Differ- a given stimulus, such as an auditory ent people sleep different amounts tone. Such an index of sleep depth is (typically 7 to 9 hours per day) to correlated with the prominence of equip them with optimal alertness, high-voltage slow waves in the EEG. attention, performance, and executive Based on the distribution of sleep function. Figure 1-1 summarizes the stages throughout the night, normal recommendations for sleep time du- sleep is typically characterized by: rations across the life span based on (1) deep nonYrapid eye movement an extensive literature review by a (non-REM) sleep predominating at panel of scientists and clinicians.1 the beginning of the night, (2) lighter The physiologic and neurobiological non-REM sleep and increasing in- mechanisms that influence the timing trusions of wakefulness toward the of sleep onset and offset are intro- end of the night, and (3) increasing duced in this article. REM sleep amounts and intensity Sleep duration is one of the two throughout the night. The brain mech- major components underlying optimal anisms that generate these states of

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FIGURE 1-1 Sleep amounts across the human life span. According to a report by the National Sleep Foundation, recommended amounts (hours) of sleep are shown for each age range and are arranged in the following categories: recommended, may be appropriate, and not recommended.

Data from Hirshkowitz M, et al, Sleep Health.1 sleephealthjournal.org/article/S2352-7218%252815%252900015-7/fulltext.

KEY POINTS wakefulness, non-REM, and REM sleep influence specific components of sleep h Different people sleep are the major focus of this article, behavior. Examples of such drugs and different amounts, but which serves as a key to understanding their mode of action on aspects of the normal healthy adults where the breakdown or pathophysio- sleep-wake circuitry will be discussed generally sleep between logic changes occur in the different in appropriate sections of this review. 7 and 9 hours per day. However, daily sleep sleep disorders. Individuals experience what would times vary among be classified as normal sleep behavior BRAIN MECHANISMS OF people and across their when the activity of these cell clusters life spans. WAKEFULNESS AND SLEEP andcircuitschangeinanormally h Cell groups located Several discrete clusters of cells exist coordinated sequence in time and primarily in the in distinct regions of the brain that place within the brain. However, sleep 2,3 brainstem and together comprise the interconnected disorders are common and varied. hypothalamus function circuits generating the states we recog- Suboptimal timing or quality of sleep to drive the individual nize as wakefulness, non-REM sleep, can occur as a result of two major behavioral states of and REM sleep. These interconnecting factors that are not mutually exclusive: sleep and wakefulness. clusters of brain cells use individual (1) a primary sleep disorder (eg, insom- These cell groups are neurotransmitters, or collections of nia, narcolepsy, restless legs syndrome, mutually connected neurotransmitters, to inhibit or excite sleep-related breathing problems, and and use specific their target sites. These excitatory and circadian rhythm sleep-wake disor- neurotransmitters to inhibitory connections modulate not ders) or (2) lifestyle influences (eg, promote each brain only the presence of wakefulness or phase shifts due to occupational or state by either inhibiting or activating their sleep per se, but also the levels of recreational activities such as shift work, respective target sites. arousal within those states, including lack of exposure to direct sunlight, or the depth of sleep, degree of vigilance, extended nocturnal exposure to artifi- and motor activity. Some commonly cial light). used drugs modulate these excitatory Each of these sleep disorders is intro- and inhibitory connections and thus duced and explained in subsequent exert alerting or sedating properties or articles in this issue. However, two

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINTS important overarching principles are cordingly, this article first introduces h Sleep is optimized when outlined in this introductory discussion the brain mechanisms that generate the sleep period is on sleep neurobiology and physiology the states of wakefulness and sleep. The aligned with an that relate to sleep disorders: article then focuses on sleep disorders individual’s circadian 1. Sleep is best optimized when the (narcolepsy and RBD) to highlight how body clock. sleep period is appropriately current research findings are identifying h Diffuse circuits located aligned with an individual’s the pathophysiologic underpinnings of in the brainstem, circadian body clock (ie, when the mechanisms and management of hypothalamus, and the sleep type is aligned with such disorders. basal forebrain chronotype). Misalignment or contain glutamate, mismanagement of this optimal Wakefulness-Generating norepinephrine, relationship can result in Circuits histamine, serotonin, experiences of poor sleep quality, Several neuronal groups contribute to dopamine, and orexin, inappropriate sleepiness, and the brain activation of wakefulness, which serve to promote wakefulness. sleep initiation or maintenance which is characterized by low-voltage insomnia. Such misalignment and fast-wave EEG activity and rest- occurs in shift work sleep ing postural motor tone in the EMG. disorder, advanced or delayed Lesions or degeneration of the ascend- sleep-wake phase disorders, ing projections of the arousal circuits and irregular sleep-wake can produce excessive sleepiness and phase disorder.2 are thought to underlie the outbreak of 2. Sleep parasomnias are best encephalitis lethargica in the 1920s.7,8 explained by the basic premise Drug-induced modulation of these that sleep and wakefulness are circuits facilitates sedation and sleep. not mutually exclusive states and Of significance to the initial discus- can dissociate. Such dissociation sion of wakefulness-generating systems can result in components of are the neuronal groups containing behaviors that are normally norepinephrine, histamine, serotonin, associated with wakefulness and dopamine (Figure 1-2A). Because temporarily overlapping with of commonalities in the chemical sleep.4,5 Such overlap causes a structure of these neuromodulators, class of sleep disorders that are they are collectively grouped under classified as the parasomnias the term monoamines.Othercell and defined as behaviors or groups also contribute to the activated experiences intruding into brain state of wakefulness. Accordingly, sleep.2,6 This overlap of waking orexin (hypocretin), acetylcholine, and and sleep behaviors/experiences glutamate-containing cell groups are produces identifiable and discrete also introduced in this section. clinical parasomnias (eg, REM Norepinephrine-containing neu- sleep behavior disorder [RBD], rons of the locus coeruleus in the hypnagogic hallucinations, dorsal pons have widespread projec- sleep paralysis, somnambulism, tions throughout the brain, includ- somniloquy, sleep terrors, ing the forebrain and cerebral cortex, 2 and bruxism). in addition to brainstem arousal and Overall, understanding how normal autonomic systems (Figure 1-2A). Their sleep-wake behavior is generated is activation contributes to attention, cor- a prerequisite to understanding the tical arousal, as well as autonomic pathophysiology underlying the spec- activation to support these processes. trum of clinical sleep disorders. Ac- Correspondingly, the activity of locus

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Y FIGURE 1-2 Hypothesized circuits underlying wakefulness, non rapid eye movement (non-REM) sleep, and REM sleep. A, Diffuse circuits located throughout the brainstem, hypothalamus, and basal forebrain promote wakefulness. Wakefulness-promoting cells located in the parabrachial nucleus (PBN; glutamate), locus coeruleus (LC; norepinephrine), laterodorsal tegmental nuclei (LDT), pedunculopontine tegmental nuclei (PPT; acetylcholine), tuberomammillary nucleus (TMN; histamine), dorsal raphe nucleus (serotonin), ventral tegmental area and periaqueductal gray (VTA/vPAG; dopamine), and lateral hypothalamus (LH; orexin [ORX]; melanin-concentrating hormone [MCH]) project to the thalamus, basal forebrain (BF), or cortex to support arousal. B, +-Aminobutyric acid (GABA) and galanin-containing cells in the ventrolateral preoptic (VLPO) area and GABA cells in the parafacial zone (PZ) of the brainstem function to promote non-REM sleep. VLPO neurons induce non-REM sleep by projecting to and inhibiting the cell circuits that promote wakefulness (A). GABA cells in the PZ also promote non-REM sleep by inhibiting wakefulness-promoting neurons in the parabrachial nucleus. C, Circuits that promote REM sleep and REM sleep paralysis are located in the brainstem. Glutamate cells in the subcoeruleus nucleus (SubC) project to and excite GABA and glycine (Gly) cells in the ventromedial medulla (VMM), which, in turn, project to somatic motor neurons to cause REM sleep paralysis (atonia). These same cells also participate in controlling the timing of REM sleep itself. They do this, in part, by projecting to the basal forebrain, which causes the cortical activation that defines the brain arousal state during REM sleep. Cholinergic cells in the PPT and LDT also communicate with the SubC to impact REM sleep timing and control. Importantly, REM sleep is suppressed by GABA cells in the ventrolateral periaqueductal gray (vlPAG) that project to and inhibit

uut2017 August the glutamate cells in the SubC that promote REM sleep.

Ach = acetylcholine; DA = dopamine; GABA = +-aminobutyric acid; Glut = glutamate; HIS = histamine; NE = norepinephrine; 5-HT = 5-hydroxytryptamine. coeruleus neurons is maximal in wake- neurons (ie, wakefulness greater than fulness, declines in non-REM sleep, and non-REM sleep, with minimal activity is minimal in REM sleep. Stimulant in REM sleep for noradrenergic, hista- medications (eg, methylphenidate, am- minergic, and serotonergic neurons). phetamines) facilitate noradrenergic The activity of dopaminergic neurons projections to promote alertness in has not been as well documented as patients with hypersomnia disorders. noradrenergic and serotonin systems, Histamine-containing neurons in the but recent photometry studies indi- tuberomammillary nucleus of the caudal cate that dopamine cells in the ventral hypothalamus contribute to brain arousal tegmental area are most active in via excitatory projections to the basal wakefulness and REM sleep and are forebrain, cerebral cortex, and brainstem. least active during non-REM sleep. The tuberomammillary nucleus is the one Activation of these neurons promotes major source of brain histamine and has wakefulness, whereas their inactiva- widespread projections throughout the tion promotes sleep.9 central nervous system (Figure 1-2A). Orexin-containing neurons located The activity of histaminergic neurons is in the lateral hypothalamus also have maximal in wakefulness, declines in widespread projections to the brain- non-REM sleep, and is minimal in REM stem, thalamus, hypothalamus, and sleep. Through this organization and cerebral cortex. The strongest projec- activity profile, antihistamines that pene- tions are to the locus coeruleus. The trate the blood-brain barrier promote activity of orexinergic neurons is maxi- drowsiness and sleep. mal in periods of wakefulness asso- Two major collections of serotonin- ciated with overt movements and containing neurons exist: (1) rostral motor activation and declines to minimal groups in the pons known as the dorsal levels in non-REM sleep and REM sleep raphe nuclei, and (2) caudal groups without muscle twitches (ie, periods in the medulla known as the caudal identified as tonic REM sleep). Loss of raphe nuclei. The pontine dorsal raphe orexin (hypocretin) neurons is involved serotonergic neurons project to the in the clinical signs and symptoms of cortex and contribute to brain arousal narcolepsy and cataplexy. Although (Figure 1-2A), whereas the medullary modafinil is a widely prescribed stimu- caudal raphe group primarily projects lant and is prescribed for patients with to the brainstem and spinal cord and narcolepsy, its mode of action is not well facilitates autonomic and motor func- understood. Studies in preclinical animal tions to support waking activities. models, however, have shown that Correspondingly, the activity of seroto- modafinil increases immediate early nergic neurons is maximal in wakeful- gene (c-Fos) expression in orexin (hypo- ness, declines in non-REM sleep, and is cretin) cells indicative of neuronal acti- minimal in REM sleep. vation and increases dopamine levels. Dopamine-containing neurons of The two major collections of the ventral tegmental areas and acetylcholine-containing neurons are periaqueductal gray project to the (1) a basal forebrain group, and (2) striatum and frontal cortex. Activation two pontine groups, which include the of these dopamine-containing neu- laterodorsal tegmental and pedunculo- rons is relevant to arousal and move- pontine tegmental nuclei (Figure 1-2A). ment, but recordings from these The basal forebrain cholinergic group neurons show that their activity profile projects to the cortex and promotes is unlike the other monoaminergic cortical arousal and attentive states,

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KEY POINT h The switch from whereas the pontine groups project to non-REM sleep and lowest in wakeful- wakefulness into the thalamus and also facilitate cortical ness, with maintained (or modestly nonYrapid eye arousal. Importantly, two subpopula- reduced) activity in REM sleep. These movement sleep is tions of pontine cholinergic neurons sleep-active cell groups synthesize facilitated and are identifiable from their activity pro- and secrete the inhibitory amino acid maintained by a group files. One group of cells has maximal +-aminobutyric acid (GABA) and the of neurons that inhibit activity in both wakefulness and REM neuropeptide galanin (Figure 1-2B). arousal-promoting sleep, facilitating low-voltage and fast- Overall, the high-voltage and slow- circuits. +-Aminobutyric wave EEG activity common to both wave EEG activity that occurs in Y acid containing cell states. The second group has minimal non-REM sleep is generated by a groups located in the activity in both wakefulness and non- combination of two factors: (1) inhibi- ventrolateral preoptic REM sleep and has maximal activity in tion of the ascending brain arousal area and medullary parafacial zone function REM sleep that is largely responsible for systems by the descending projec- to promote and stabilize the activated brain state of REM sleep; tions of these sleep-active GABA and nonYrapid eye the contribution of the monoaminergic galanin-containing inhibitory neurons movement sleep. and orexinergic neurons to the EEG and (2) activation of cortically projecting activation of REM sleep is minimal, as inhibitory neurons. those neuronal groups are effectively Importantly, these inhibitory sleep- silent in REM sleep. active +-aminobutyric acidYmediated The excitatory amino acid glutamate (GABA-ergic) cell groups receive in- is present in neuronal groups through- hibitory inputs from neurons of the out the pons and midbrain reticular ascending arousal system. Through formation. Glutamate is also present as this organization, they are minimally a cotransmitter in most of the neuronal active in wakefulness and states of groups projecting to the brainstem, heightened arousal. Likewise, these thalamus, hypothalamus, and cerebral inhibitory GABA-ergic sleep-active cell cortex. The activity of the pontine and groups project to, and inhibit, all the midbrain reticular neurons is typically neuronal groups involved in arousal. The maximal in wakefulness and minimal in inhibitory non-REM sleepYgenerating non-REM sleep, with similar (or in- system initiates and sustains sleep and creased) levels in REM sleep. Recently, inhibits arousal once these cell groups glutamatergic neurons in the pararachial are released from inhibition and be- nucleus have been shown to signifi- come active at sleep onset. This arrange- cantly contribute to behavioral respon- ment of reciprocal inhibition between siveness and activated cortical activity via arousal and non-REM sleepYgenerating a relay involving the basal forebrain and neuronal systems has been termed the lateral hypothalamus (Figure 1-2A).10,11 sleep-wake switch.8,12 However, the control of non-REM Non–Rapid Eye Movement sleep also appears to be modulated by Sleep-Generating Circuits circuits in the brainstem. Using opto- Non-REM sleep is facilitated and genetic and chemogenetic methods, maintained by a group of neurons that Anaclet and colleagues13 showed that inhibit the brain-arousal systems of direct activation of GABA-ergic neu- wakefulness (Figure 1-2B). The major rons in the medullary parafacial zone non-REM sleepYgenerating cell groups can rapidly induce non-REM sleep are located in the ventrolateral pre- (Figure 1-2B). Parafacial zone neurons optic area, anterior region of the hypo- monosynaptically innervate and re- thalamus, and the basal forebrain and lease GABA onto parabrachial neu- have activity levels that are maximal in rons, which, in turn, project to and

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. release glutamate onto magnocellular of the sleep-active GABA-ergic neurons, basal forebrain neurons. In addition to thus promoting sleepiness as well as GABA/galanin ventrolateral preoptic fragmentation of wakefulness and sleep cells, GABA-ergic parafacial zone neu- in patients with narcolepsy. rons also appear able to trigger non- Coordinating influence of the cir- REM and slow-wave activity. cadian timing system. A question that arises concerning the sleep-wake Organization of the Sleep-Wake switch is what causes the change in Switch balance and a sudden switch in brain The arrangement of reciprocal inhibi- state at night and in the morning? The tion between the arousal and non- answer relates to the first overarching REM sleepYgenerating circuits results principle of sleep-wake physiology: in sustained periods of sleep and Sleep is best optimized when the sleep wakefulness that are coordinated and period is appropriately aligned with an consolidated to appropriate periods individual’s circadian body clock. across the day. In short, the arousal In an average adult, a decline in neurons reinforce their own activation body temperature at night (usually by inhibiting sleep neurons, thus around 10:00 PM to 11:00 PM) pre- facilitating consolidated periods of cipitates optimal and typical sleep wakefulness appropriate for optimal onset, with most individuals reporting behaviors and cognition. Likewise, that they find it difficult to fall asleep sleep-active GABA neurons reinforce earlier than this time frame, and that it their own activation by inhibiting arousal is harder to stay awake after this time. neurons, thus facilitating consolidated Likewise, a rise in body temperature periods of sleep appropriate for op- in the morning (around 6:00 AM to timal behavior and cognition in subse- 7:00 AM) in an average individual quent wakefulness. triggers normal awakening and alert- This mutually inhibitory organiza- ness, with individuals commonly tion of the sleep-wake switch also reporting that they find it difficult to provides a degree of resistance to wake up earlier than this time and to changes in the sleep-wake state when stay asleep after this time. Other one side of the switch is active. This individuals who are early birds or steadiness and resistance to change night owls, or patients diagnosed with when one side of the switch is active advanced or delayed sleep-wake phase thus provides for consolidated periods disorder, have either advanced or de- of sleep at night and wakefulness layed sleep onset and offset times, as during the day (ie, the sleep-wake their circadian body temperature cycles switch is stable in either position). are further advanced or delayed com- Neurodegeneration or lesions impact- pared to that of the average person. ing some components of the sleep- A major reason that self-selected wake switch can destabilize it. For sleep phase is strongly linked to the example, loss of orexin (hypocretin) body temperature cycle is because neurons in patients with narcolepsy body temperature has significant ef- reduces excitation of the arousal neu- fects on the position of the sleep-wake rons, particularly of the locus coeruleus, switch. The circadian-mediated de- which receives the densest innervation. cline in body temperature at night This effectively unbalances the sleep- activates sleep-active GABA neurons, wake switch by both reducing levels of thus promoting sleep via a change in arousal, as well as removing inhibition position of the sleep-wake switch.

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KEY POINT Y h Commonly used drugs This body temperature mediated acti- In summary, when sleep phase is ap- can flip the sleep-wake vation of sleep-active GABA neurons propriately aligned with an individual’s switch toward alertness also leads to inhibition of the arousal body clock, then sleep timing, duration, or sedation. For example, circuits via the reciprocal inhibition, and consolidation are all optimized. In drugs that bind to resulting from the organization of the contrast, when the sleep phase is in- +-aminobutyric acid A sleep-wake switch. The decline in body appropriately aligned with an individ- receptors promote temperature at night therefore pro- ual’s body clock, then sleep timing, neuronal inhibition and motes sleep initiation and mainte- duration, and consolidation are sub- sleepiness, whereas nance by tipping the balance of the optimal. Under such conditions, sleep caffeine promotes sleep-wake switch simultaneously both initiation or maintenance insomnia and wakefulness by away from arousal and toward sleep. sleep fragmentation are typically reported. antagonizing adenosine Likewise, the circadian-mediated rise Effects of drugs on the sleep-wake receptors that suppress sleep induction circuitry. in body temperature in the morning in- switch. Commonly used drugs can also hibits sleep-active GABA neurons, thus flip the sleep-wake switch toward alert- promoting wakefulness via a reversal ness or sedation. For example, a variety of the position of the sleep-wake of drugs bind to the GABA-A receptor switch, and also leads to activation of and enhance the effects of GABA, the arousal circuits. The rise in body thereby promoting neuronal inhibition temperature in the morning therefore and sleepiness. Such drugs include the promotes the normal initiation of awak- benzodiazepines, imidazopyridines (ie, ening by tipping the balance of the the nonbenzodiazepine sedative hyp- sleep-wake switch simultaneously both notics), barbiturates, some IV and toward arousal and away from sleep. inhalational anesthetics (eg, propofol Self-selected sleep phase and opti- and isoflurane), and ethanol. Because mal timing of sleep are strongly linked of the anatomic arrangement of recip- to the circadian body temperature rocal inhibition between the arousal cycle. The relationship of optimal and sleep-generating circuits in the sleep phase to the body temperature sleep-wake switch, all of these GABA- cycle persists, regardless of an individ- ergic agents effectively flip the switch ual’s chronotype (ie, whether their toward sedation and, at the same time, chronotype fits with being an early away from arousal. However, because bird or a night owl, having an average of widespread inhibitory influences bedtime and waking schedule, or of GABA-A receptor stimulation also having advanced or delayed sleep- contained within the respiratory net- wake phase disorders). In each case, work, an attendant risk exists of re- sleep onset is facilitated when an indi- spiratory depression, hypoventilation, vidual’s body temperature declines and asphyxia following administration because of their circadian rhythm, of GABA-mimetic drugs, as well as a regardless of actual time of day, and, lack of compensatory respiratory and likewise, arousal is facilitated because arousal responses to that depression.14 of the circadian-mediated rise in body Development of antagonists for the temperature, again regardless of actual orexin (hypocretin) peptides also of- time of day. For example, despite a fers a promising avenue for drug night of shift work, people often development for insomnia, as well as report difficulty initiating and sustain- providing for brain sedation with re- ing sleep the next day because the duced risk of respiratory depression circadian variations in body tempera- due to the lack of direct effects of the ture are not fully adjusted to the orexinergic antagonists on the GABA- schedule (ie, similar to jet lag). ergic system.15

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. Caffeine is also widely used as a and arousal responses to acute respira- stimulant and acts as an adenosine tory distress can predispose infants to receptor antagonist. Adenosine is re- increased risk of life-threatening events leased from neurons and glia, and at night and sudden infant death adenosine levels increase as a function syndrome.19 Repeated exposure to of cellular metabolism and rise during intermittent hypoxia can also cause the day. Adenosine inhibits wake- degeneration of noradrenergic locus active neuronal groups, and blockade coeruleus neurons, thus predisposing of this inhibition with caffeine pro- individuals to the risks of deteriorating motes brain arousal and effectively respiratory and arousal responses to tipsthesleep-wakeswitchtoward asphyxia and of respiratory failure.20 arousal. Other central nervous system stimulants include amphetamines and Rapid Eye Movement cocaine, and these increase the syn- Sleep–Generating Circuits aptic concentrations of monoamines REM sleep is a state accompanied by by blocking reuptake and increasing dreaming, heightened brain neural ac- exocytosis. Administration of these tivity, paralysis of the skeletal muscula- drugs further tips the sleep-wake ture (although the diaphragm is spared switch toward heightened arousal. this inhibition), heightened respiratory Melatonin is a commonly used over- and cardiovascular variability, and de- the-counter sleep aid, but this drug pressed respiratory responses to hyp- may not exert direct influence on the oxia and hypercapnia.14,21 Disorders in sleep-wake circuitry. Instead, melato- discrete components of the REM sleep nin is a marker of, and is strongly circuitry can lead to distinct clinical aligned to, the circadian timing system. motor disorders and parasomnias.22,23 The appropriately timed administra- REM sleep is present in homeotherms tion of melatonin can be used to phase (ie, mammals and birds), but some shift the circadian timing system16 and, mammals (eg, the permanently aquatic by so doing, can entrain circadian cetaceans such as whales and dol- rhythms.15 This effect of melatonin phins) have no identifiable REM sleep can explain improved sleep observed to no apparent detriment. The under- in individuals with disrupted circadian standing of circuits generating REM rhythms.15 sleep, which has undergone major Effects of physiologic stressors on revisions in recent years, is introduced the sleep-wake switch. Sleep-related below before discussion of associated breathing disorders are common and clinical problems. lead to recurrent episodes of asphyxia Two major circuits are involved in and sleep disturbance. The hypercapnic REM sleep generation, and their es- and hypoxic stimuli lead to activation of sential elements include interactions respiratory neurons in an attempt to between (1) GABA and glutamatergic increase lung ventilation and correct neurons and (2) monoaminergic and the asphyxia, and these stimuli also lead cholinergic neurons (Figure 1-2C).24 to activation of brainstem arousal neu- The critical REM sleepYgenerating re- rons to trigger arousal from sleep.14 gion is located in the dorsal pons, and Noradrenergic locus coeruleus neu- activation of this region produces the rons and serotonergic raphe neurons defining signs of REM sleep, including have been strongly implicated in these low-voltage and fast-wave EEG activity responses.17,18 Developmental abnor- and muscle atonia due to active sup- malities in the integrated respiratory pression of postural motor tone.

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KEY POINTS h Rapid eye movement In the GABA and glutamatergic snoring, hypoventilation, and obstruc- sleep and its cardinal mechanism of REM sleep generation, tive sleep apnea. However, the pe- features (ie, cortical activation of pontine glutamatergic neu- riods of major suppression of upper activation and muscle rons of the subcoeruleus nucleus (also airway muscle activity that occur in atonia) are generated by known as the sublaterodorsal tegmental REM sleep do not seem to involve the +-aminobutyric acid, nucleus) leads to REM sleep. These same mechanism as for the suppres- glutamate, and glutamatergic cells become active to sion of spinal motor activity. For cholinergic neurons generate REM sleep when they are example, the tongue musculature is located in the released from inhibition by pontine suppressed through two additional brainstem. GABA-ergic neurons located in the ven- processes in REM sleep: first, with h Identification of the trolateral periaqueductal gray and lateral withdrawal of excitation (ie, a process brain circuits that pontine tegmentum (Figure 1-2C).25,26 of disfacilitation) mediated principally control wakefulness and In the monoaminergic and cho- by reduced monoaminergic and glu- sleep has led to a linergic explanation of REM sleep tamatergic inputs to the hypoglossal deeper understanding generation, decreased activity of the motor pool, and, second, with recruit- of several sleep monoaminergic cell groups preceding ment of REM sleep inhibition mediated disorders. and during REM sleep withdraws inhi- by a muscarinic receptor mechanism h Narcolepsy is caused by bition of pontine cholinergic neurons. linked to a G proteinYcoupled inwardly loss of hypothalamic This withdrawal leads to increased rectifying potassium channel. orexin cells and is acetylcholine release into the pontine characterized by DYSFUNCTION OF SLEEP-WAKE excessive sleepiness, reticular formation that promotes en- 27,28 CIRCUITRY UNDERLIES SLEEP disturbed rapid eye try into REM sleep. movement sleep, sleep The core circuit necessary for gen- DISORDERS paralysis (atonia), erating REM sleep involves the GABA- Investigation of the fundamental brain 22,24 and hypnagogic glutamate circuit. Cholinergic mechanisms underlying sleep-wake hallucinations. activity arising from interactions with- control has laid the foundation for in the monoaminergic-cholinergic cir- understanding the pathophysiology of cuit appears to serve an accessory role several sleep disorders. Breakdown in REM sleep generation, reinforcing in sleep-wake circuits and the commu- transitions into REM sleep from non- nication between them contributes REM sleep.24 Resolution of this REM to both narcolepsy and REM sleep sleepYgenerating circuitry and the pri- behavior disorder. Changes in the macy of one mechanism over another circuits controlling non-REM sleep is an active area of research.24,28 A lead to degeneration of normal sleep- recent study also identified GABA cells wake patterns that occur with age and in the medial medulla as potential in Alzheimer disease. players in REM sleep modulation.29 Spinal motor activity in REM sleep Narcolepsy is suppressed through recruitment Narcolepsy is a debilitating sleep dis- of descending neural circuits that order that can impair a person’s ability involve glycine (principally) and GABA to work, socialize, and drive safely. (Figure 1-2C). Disruption of this de- Narcolepsy is caused by loss of hypo- scending spinal motor inhibitory path- thalamic orexin cells and is character- way can lead to RBD. Suppression of ized by excessive sleepiness, disturbed motor activity in the muscles sur- REM sleep, sleep paralysis (atonia), rounding the upper airway during and hypnagogic and hypnopompic hal- physiologic atonia in REM sleep can lucinations. Another common symptom lead to periods of upper airway of narcolepsy is cataplexy, which is the narrowing and collapse, resulting in involuntary onset of skeletal muscle

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. 30Y32 KEY POINT paralysis or weakness during otherwise plexy and REM sleep. Muscle h Cataplexy may be normal wakefulness; these attacks are stretch and monosynaptic H reflexes caused by inappropriate debilitating for patients because they are absent during both cataplexy and recruitment of circuits 33,34 leave the affected individual conscious REM sleep. Neuroimaging studies that generate rapid but unable to move and create risk for in patients with narcolepsy and elec- eye movement sleep falls and injury. The neural mechanisms trophysiologic recordings from iso- paralysis. that trigger cataplexy are unclear, but it lated neurons in narcoleptic dogs show is hypothesized that it results from that the brainstem circuitry involved in intrusion of normal REM sleep paralysis REM sleep has similar activity during into wakefulness (Case 1-1). both REM sleep and cataplexy.35Y38 For Our understanding of the mecha- example, in narcoleptic dogs, cells in nisms of REM sleep is helping to the locus coeruleus (a brainstem re- identify some of the potential causes gion involved in REM sleep control) of cataplexy. Converging lines of evi- abruptly cease firing during both REM dence suggest that cataplexy and REM sleep and cataplexy,39 and cells in the sleep share a common neural mecha- medullary gigantocellular nucleus (a nism. For example, tricyclic antide- region critical for promoting REM pressants, which are used to alleviate sleep paralysis) increase their activity cataplexy, also suppress REM sleep, during both REM sleep and cataplexy.40 and rapid withdrawal of these drugs In addition, serotonin cells in the dorsal causes large rebounds in both cata- raphe nucleus, which are associated

Case 1-1 A 17-year-old boy, who had been highly motivated and had excellent grades in school, suddenly began experiencing relentless sleepiness. No matter how much he slept, he continued to struggle to stay awake during the day, although he felt refreshed immediately after awaking in the morning or after a daytime nap. He also reported that his sleep was restless, and he often experienced frequent nighttime awakenings. His persistent daytime sleepiness and lack of vigilance began to impact his ability to study for school, and his grades declined. He also reported that he would awaken from vivid dreams but was unable to move for several seconds afterward despite being awake and conscious. He also reported apparent vivid, dreamlike hallucinations while dozing off to sleep on several occasions. About a month after developing sleepiness, he experienced two episodes of bilateral muscle weakness that caused him to suddenly slump down in his chair despite remaining fully conscious. These attacks lasted about a minute each and occurred while he was laughing heartily. Comment. This is a typical account of narcolepsy. Many patients are diagnosed in their teenage years, often after developing sleepiness and restless nighttime sleep. Sleepiness persists despite increasing amounts of nighttime sleep or after adding daytime naps to their sleep schedules. Daytime sleepiness typically has a major impact on their daytime functioning. Sleep paralysis (inability to move after waking from a dream) and hypnagogic hallucinations (vivid dreamlike experiences while falling asleep) are also common symptoms in narcolepsy. However, the tell-tale sign of narcolepsy is cataplexy (the sudden onset of muscle weakness or paralysis following a very humorous or emotionally charged situation). Narcolepsy results from death of orexin (hypocretin) cells in the lateral hypothalamus.

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KEY POINTS 41 45 h Cataplexy attacks are with modulating behavioral arousal, lacking orexin. Furthermore, GABA- usually triggered by also influence cataplexy. Restoration of ergic neurons in the amygdala send strong positive emotions orexin receptors onto dorsal raphe descending projections to critical ele- such as excited neurons in mice that lack these re- ments of sleep-wake circuitry, includ- laughter, elation, or ceptors decreases cataplectic attacks in ing the locus coeruleus, the lateral surprise, but they are this model of narcolepsy.42 pontine tegmentum, the ventrolateral also associated with Some patients with narcolepsy re- periaqueductal gray, as well as the negative emotions port hypnagogic hallucinations during subcoeruleus, which is a critical part such as fear. cataplectic attacks, and some patients of the REM sleepYgenerating circuit.45 h The amygdala regulates enter REM sleep during cataplexy, However, one of the strongest asso- emotions and is suggesting that such attacks result ciations between narcolepsy and the activated during from inappropriate recruitment of REM dysfunction of sleep-wake circuits arises cataplexy; therefore, it sleep circuits. Recent data show that from the fact that arousal-promoting may play a central role cataplexylike attacks can be triggered in orexin neurons are lost in human nar- in triggering cataplexy orexin knockout mice (ie, narcoleptic colepsy and that loss of orexin and attacks that occur in mice) by activating the brainstem circuit orexin cells and mutation of orexin response to strong positive emotions. (ie, the subcoeruleus nucleus) that receptors can trigger symptoms of nar- controls REM sleep.43 This observa- colepsy in dogs and mice, which could h Rapid eye movement tion suggests that cataplexy may result explain the profound sleepiness that sleep behavior disorder from pathologic recruitment of the defines narcolepsy.23 This concept is is a parasomnia that is characterized by circuits that cause REM sleep paralysis, supported by multiple lines of experi- excessive and elaborate and that muscle paralysis in REM sleep mental data showing that orexin cells movements during rapid and cataplexy stem from a common are most active during wakefulness, eye movement sleep. neural mechanism. and that their direct activation or It is important to recognize that inactivation promotes arousal and cataplexy attacks are usually triggered sleep, respectively.46 Another link be- by strong positive emotions such as tween the orexin system and narcolepsy excited laughter, elation, or surprise, stems from the fact that orexin neurons but they are also associated with are highly responsive to strong positive negative emotions such as fear. The emotions; therefore, the loss of these association between emotion and cat- neurons in patients with narcolepsy aplexy suggests that circuits regulating may destabilize the natural muscle emotion may also play a role in regulation system within the brainstem cataplexy control. The amygdala is a and allow positive emotions to trigger brain structure that not only underlies motor paralysis.47,48 the processing of emotions, but is one that has been associated with REM Rapid Eye Movement Sleep sleep regulation44 and could therefore Behavior Disorder be involved in controlling emotionally RBD is a parasomnia that is character- triggered cataplexy. The link between ized by excessive and elaborate move- the amygdala and cataplexy is sup- ments during REM sleep. Movements ported by imaging studies showing in RBD range from simple motor that the amygdala is activated during activity such as talking, shouting, and cataplexy.36 In narcoleptic dogs, neu- limb jerking, to more complex move- rons of the amygdala increase firing ments such as gesturing, punching, or during cataplectic attacks.35 A recent kicking. Movements in RBD are often study indicates that bilateral lesions of so violent that they cause injury to the the amygdala significantly reduce the patient or their bed partner and can frequency of cataplectic attacks in mice cause severe injuries (eg, lacerations or

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINTS broken bones) that may require med- Studies indicate that RBD could h Rapid eye movement ical treatment. RBD is a serious health be caused by degeneration of the sleep behavior disorder problem because most patients even- circuits that control healthy REM sleep is the strongest 53 tually develop a neurodegenerative (Figure 1-2C). For example, experi- predictor of the onset disease that is characterized by !- mentally induced lesions of the core of neurodegenerative synuclein deposition.49 RBD is cur- REM sleep circuits, including the diseases, with more rently the strongest predictor of the subcoeruleus nucleus and ventral me- than 80% of patients onset of neurodegenerative diseases, dial medulla, cause RBD-like motor developing Parkinson with more than 80% of patients devel- behaviors in cats, rats, and mice.54,55 disease, dementia with oping Parkinson disease (PD), dementia This observation is in line with clinical Lewy bodies, or multiple with Lewy bodies, or multiple system neuroimaging studies and postmor- system atrophy. atrophy. Therefore, identification of tem tissue analysis showing damage h Degeneration of rapid prodromal neurodegeneration before or defects of the brainstem regions eye movement sleep actual disease onset has major clinical that house REM sleep circuits in circuits in the brainstem implications. Scientifically, RBD pre- patients with RBD.49,56,57 However, underlies the motor symptoms of rapid eye sents a unique opportunity to study and perhaps most importantly, recent movement sleep the development of a neurodege- studies show that some patients with behavior disorder. nerative syndrome from its prodromal RBD have Lewy bodies, neuronal loss, stages and may be the ideal way to depigmentation, or gliosis within (or develop neuroprotective therapies for near) the circuits that control normal the prevention of ensuing degenerative REM sleep (eg, subcoeruleus, ventral disorders.50 medial medulla, and pedunculopontine The close association between RBD tegmental nucleus).49,58Y64 These find- and the subsequent development of ings not only support the neuroimag- synucleinopathies suggests that RBD ing findings of neuronal cell loss in itself could result from a neurodegen- these areas associated with RBD path- erative process. One possibility is that ogenesis,56,57 but they also substantiate RBD arises from neurodegeneration of basic neuroscience data showing that the circuits that control healthy REM lesions within the REM sleep circuits sleep, and subsequent pathologies trigger RBD-like behaviors in animals.65Y68 develop as degeneration spreads ros- Therefore, one possibility is that RBD trally. Although this idea remains is caused by degeneration of the core speculative, it fits well with the classic circuits that control healthy REM sleep. model of PD pathogenesis by Braak However, some forms of RBD prob- and colleagues,51 which proposes that ably do not stem from neurodegenera- neurodegeneration starts in the tive processes. For example, RBD also brainstem before ascending rostrally can be triggered by brainstem tumors, into the central nervous system struc- infarcts, and lesions.69,70 The location tures associated with the classic motor of these lesions is typically confined and cognitive features of PD. Clinical to brainstem regions associated with data support this idea. For example, REM sleep control. RBD is also associ- patients with RBD often exhibit PD- ated with alcohol withdrawal and is like symptoms (eg, bradykinesia) be- common in long-term antidepressant fore they are clinically diagnosed with users.71 RBD in these situations could PD,52 suggesting that RBD and PD stem from a drug-induced imbalance in symptoms stem from a common neuro- the normal biochemical mechanisms degenerative process that potentially that control REM sleep. Data suggest affects the caudal brainstem areas asso- that RBD could also result from distur- ciated with REM sleep and movement. bances in the normal biochemical

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KEY POINT h Loss of nonYrapid mechanisms that control REM sleep. trol, then a link should exist between eye movement For example, pharmacologic blockade these disorders. In fact, RBD is com- sleepYgenerating cells of either GABA/glycine or cholinergic mon in patients with narcolepsy. Ap- in the ventrolateral inhibition results in enhanced motor proximately 45% to 61% of patients 54,72,73 preoptic area is activity during REM sleep, sug- who have narcolepsy with cataplexy associated with sleep gesting that imbalances in the release (narcolepsy type 1) experience RBD.74 fragmentation during of these transmitters could facilitate Interestingly, patients with narcolepsy aging, and more severe RBD-like movements. In addition, with cataplexy are more frequently loss of ventrolateral overactivation of the red nucleus (a affected by RBD than those who have preoptic cells is region that controls muscle twitches narcolepsy without cataplexy (narco- associated with greater during REM sleep) triggers excessive lepsy type 2). Also, RBD can be trig- nonYrapid eye movements during REM sleep in mice gered or aggravated by antidepressant movement sleep disturbance in patients and rats. Together, these observations treatment in patients with narcolepsy with neurodegenerative suggest that the exaggerated motor with cataplexy. In addition, many pa- disorders. activity in patients with RBD can result tients with narcolepsy exhibit marked from overexcitation of circuits gen- increases in overall levels of motor erating twitches or breakdown of bio- activity during REM sleep, even if they chemical mechanisms that normally do not experience frank RBD. There- suppress motor activity in REM sleep. fore, one major commonality between Another line of evidence sup- RBD and narcolepsy is abnormal motor porting the claim that RBD could stem activity, with RBD resulting from loss of from a biochemical imbalance in REM normal REM sleep paralysis, and cata- control mechanisms comes from a plexy resulting from intrusion of REM genetic study in mice.54 This study sleep paralysis into wakefulness. These showed that RBD-like behaviors can clinical observations suggest that RBD be triggered in transgenic mice with and narcolepsy may result from abnor- deficient glycine and GABA transmis- mal control of the circuits that underlie sion, which are not only key players in REM sleep, and particularly those that promoting REM sleep paralysis, but are regulate REM sleep paralysis. also important in controlling REM sleep timing. Brooks and Peever54 Age-Related Sleep found that impaired inhibitory trans- Disturbances mission not only induced overt RBD- Investigation of the brain mechanisms like motor behaviors (eg, chewing, face underlying non-REM sleep control has grooming,running),butitalsocaused also improved our understanding of mild sleep disturbances and cortical age-related changes in sleep. Dis- EEG slowing, which are both findings turbed sleep is a common and trou- in RBD. However, Brooks and Peever54 bling symptom associated with both also found that RBD symptoms could normal aging and certain degenerative be mitigated by treating mice with disorders such as Alzheimer disease. either clonazepam or melatonin (two Multiple lines of data suggest that effective treatments for RBD). These GABA- and galanin-containing cells in findings suggest that impairments or the ventrolateral preoptic area play a imbalances in central nervous system role in controlling non-REM sleep8 neurotransmission, particularly, in GABA (Figure 1-2B). For example, targeted and glycine transmission, could con- lesions of ventrolateral preoptic cells tribute to RBD pathogenesis. cause fragmented sleep in rodents, If both RBD and narcolepsy arise and optogenetic activation of ventro- from disturbances in REM sleep con- lateral preoptic cells induces non-REM

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. sleep in mice. Recently, Lim and generated by GABA, glutamate, and colleagues75 found that cell loss within cholinergic neurons located in the the intermediate nucleus (the ven- brainstem (Figure 1-2C). However, it trolateral preoptic homologue in remains unclear how these brainstem humans) was correlated with sleep circuits communicate with the cell fragmentation in elderly (approximately groups that initiate wakefulness and 89 years of age) individuals and those non-REM sleep. Identification of the with Alzheimer disease.75 Specifi- brain circuits that control wakefulness cally, they found that individuals with and sleep has led to a deeper under- more galanin-containing ventrolateral standing of several sleep disorders. preoptic neurons had better sleep, Loss of orexin cells underlies the whereas those with fewer ventrolateral sleepiness of narcolepsy, and pathologic preoptic neurons had more fragmented recruitment of REM sleep-promoting sleep patterns. This work suggests circuits is associated with cataplexy that the ventrolateral preoptic area in in narcolepsy. Degeneration of REM humans promotes non-REM sleep, and sleep circuits underlies motor symp- that degeneration or neuronal loss in toms in RBD, whereas loss of non-REM this critical area is associated with sleepYgenerating cells is associated age-related changes in normal sleep with sleep fragmentation during aging patterns in older adults, and that and neurodegenerative disorders. greater ventrolateral preoptic cell loss in neurodegenerative disorders may REFERENCES result in more deranged non-REM 1. Hirshkowitz M, Whiton K, Albert SM, et al. National Sleep Foundation sleep sleep architecture. time duration recommendations: methodology and results summary. Sleep CONCLUSION Health 2015;1(1):40Y43. doi:10.1016/ Cell groups located primarily in the j.sleh.2014.12.010. brainstem and hypothalamus function 2. American Academy of Sleep Medicine. International classification of sleep disorders. to drive the individual behavioral states 3rd ed. Darien, IL: American Academy of Sleep of sleep and wakefulness. These cell Medicine, 2014. groups are mutually connected and 3. Colten H, Altevogt B. Sleep disorders use specific neurotransmitters to pro- and sleep deprivation: an unmet public mote each brain state by either in- health problem. Washington, DC: Institute of Medicine. Committee on Sleep hibiting or activating their respective Medicine and Research, Board on Health target sites. Diffuse circuits that contain Sciences Policy, The National Academies glutamate, norepinephrine, histamine, Press, 2006. serotonin, dopamine, and orexin pro- 4. Avidan A. Non-rapid eye movement mote wakefulness (Figure 1-2A). The parasomnias; clinical spectrum, diagnostic features, and management. In: Kryger MH, switch from wakefulness into non- Roth T, Dement WC, eds. Principles and REM sleep is facilitated and main- practice of sleep medicine. St. Louis, MO: tained by a group of neurons that Elsevier, Saunders, 2017:981Y992. inhibit arousal-promoting circuits 5. Silber M, St. Louis E, Boeve B. Rapid eye movement sleep parasomnias. In: Kryger M, (Figure 1-2B). GABA-containing cell Roth T, Dement W, eds. Principles and groups located in the ventrolateral Practice of Sleep Medicine. St. Louis, MO: preoptic area and medullary parafacial Elsevier, Saunders, 2017:993Y1001. zone function to promote and stabilize 6. Sateia M, Thorpy M. Classification of sleep non-REM sleep. REM sleep and its disorders. In: Kryger M, Roth T, Dement W, eds. Principles and Practice of Sleep cardinal features (ie, cortical activa- Medicine. St. Louis, MO: Elsevier, Saunders, tion and muscle atonia) are primarily 2017:618Y626.

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