Biological Rhythms and Sleep Ch 10

CHAPTER 10 Biological Rhythms and Sleep Neil V. Watson Simon Fraser University S. Marc Breedlove Michigan State University Don’t Make Me Laugh Adrian first became aware of his problem as an adult when he sneaked up on his mother working in the garden, thinking that surprising her would be funny. As Adrian expected, she was indeed startled; she, Adrian, and the rest of his family laughed. But then Adrian suddenly felt progressively weaker in his knees and back, slowly slumping until he was lying down, totally paralyzed, for 15–20 seconds. Several more instances of paralysis occurred in the following months, always when Adrian was doing something he thought would be funny. He would laugh and then slowly collapse to the floor, fully conscious but unable to move. During a visit to the zoo, a joke that he thought would amuse his daughters left Adrian slumped over the fence in front of the monkey enclosure, helpless. According to Adrian, the trigger is not laughing but doing something that he thinks is funny and would make others laugh. “I can sit and watch a comedian, I can laugh myself inside out without any effect at all. But if I were to say something that I felt was very funny to you, there’s a good chance that I would end up on the floor” (Leschziner, 2019, p. 113). What was happening to Adrian? By the end of this chapter, we’ll know a lot more about sleep and what happened in Adrian’s brain to cause these symptoms. All living systems show repeating, predictable changes over time. Some rhythms, like brain potentials, are rapid; other rhythms, like annual hibernations, are slow. Daily rhythms, the topic of the start of this chapter, have an intriguing clocklike regularity and are seen in virtually every physiological measure, including body temperature and hormone secretion. The rest of the chapter concerns that familiar daily rhythm known as the sleep-waking cycle. By age 60, most humans have spent 20 years asleep (some, alas, on one side or the other of the classroom podium). We’ll find that sleep is not a passive state of “nonwaking,” but rather the interlocking of several different brain states. We’ll conclude with a consideration of sleep disorders, as well as some tips on how to get the sleep you need. 10.1 Biological Rhythms Organize Behavior The Road Ahead The start of the chapter reviews the evidence that the brain contains a biological clock to synchronize our behavior to the world around us. After reading this section, you should be able to: 10.1.1 Discuss the evidence that a tiny brain structure imposes a daily rhythm on behavior. 10.1.2 Describe the neural pathway by which daylight synchronizes that structure. 10.1.3 Understand how a molecular clock in brain neurons generates that daily rhythm. 10.1.4 Evaluate the evidence that later start times benefit high school students. Biological rhythms are regular fluctuations in any living process. Almost all physiological measures—hormone levels, body temperature, drug sensitivity—change over the course of the day in a repeating pattern. Because such rhythms last about a day, they are called circadian rhythms (from the Latin circa, “about,” and dies, “day”). Circadian rhythms are by far the most studied of the biological rhythms, and they will be our major concern here. Still, you should know that some biological rhythms are shorter than a day. Such rhythms are referred to as ultradian (because they repeat more than once per day; the Latin ultra means “beyond”), and they vary from several minutes to hours long. Ultradian rhythms are seen in such behaviors as bouts of activity, feeding, and hormone release. Biological rhythms that take more than a day are called infradian rhythms because they repeat less than once per day (the Latin infra means “below”). A familiar infradian rhythm is the human menstrual cycle, typically about 28 days in length. Many animal behaviors vary across the year; for example, most animals breed only during a particular season. (By the way, the widespread belief that depression and suicide peak during the winter holiday season is an urban myth —in fact they peak in the spring.) You might think that breeding seasons in animals would be triggered by changes in temperatures or food availability, but experiments indicate that the duration of light each day is the real trigger: in the laboratory, animals exposed to short days and long nights (mimicking wintertime conditions) reliably change to the nonbreeding condition (FIGURE 10.1). FIGU R E 1 0 . 1 Winter Is Coming View larger image Circadian rhythms are generated by an endogenous clock Many mammals, including humans, are diurnal—active during the day—but a majority of mammalian species, including most rodents, are nocturnal—active during dark periods. These circadian rhythms are extraordinarily precise: the beginning of activity may vary only a few minutes from one day to another. For humans equipped with watches and clocks, this regularity may seem uninteresting, but other animals achieve such remarkable regularity using only a built-in biological clock. A favorite way to study circadian rhythms exploits rodents’ love of running wheels. A switch attached to the wheel connects to a computer that registers each turn, revealing an activity rhythm as in FIGURE 10.2A. A hamster placed in a dimly lit room continues to show a daily rhythm in wheel running despite the absence of day versus night, suggesting that the animal has an internal clock. But even when the light is constantly dim, it is always possible that the animal detects other external cues (e.g., outside noises, temperature, cosmic rays—who knows?) signaling the time of day. Arguing for a biological clock, however, is the fact that in constant light or dark the circadian cycle is not exactly 24 hours: activity starts a few minutes later each day, so eventually the nocturnal hamster is active while it is daytime outside (FIGURE 10.2B, bottom). The animal is said to be free-running, maintaining its own personal cycle, which, in the absence of external cues, is a bit more than 24 hours long. FIGU R E 1 0 . 2 How Activity Rhythms Are Measured View larger image The free-running period, the time between two similar points of successive cycles (such as sunset to sunset), differs from one hamster to another. If two hamsters are placed in constant dim light next door to each other, eventually one may be active when the other is asleep—further evidence that they are not detecting some mysterious external cue. Rather, every animal has its own endogenous clock; periods vary from one individual to another. Normally this internal clock is reset by light. If we expose a freerunning nocturnal animal to periods of light and dark, the animal soon adjusts its wheel running to start just before the dark period. The shift of activity produced by a synchronizing stimulus is referred to as a phase shift (see Figure 10.2B middle), and the process of shifting the rhythm is called entrainment. Any cue that an animal uses to synchronize its activity with the environment is called a zeitgeber (German for “time giver”). Light is a powerful zeitgeber, and we can easily manipulate it in the lab. Because light stimuli can entrain circadian rhythms, the endogenous clock must receive information about light and dark, as we’ll confirm shortly. We humans experience a mismatch of internal and external time when we fly from one time zone to another. Flying three time zones east (say, from California to New York) means that sunlight arrives 3 hours sooner than our brain expects. The next morning we’ll probably have a hard time waking up at 7:00 am New York time, because it’s 4:00 am California time. We need about one day per time zone to entrain after such travel, and in the meantime we experience jet lag, with symptoms such as insomnia and daytime fatigue. The major value of circadian rhythms is obvious: they enable us to anticipate an event, such as sunrise or sunset, and to begin physiological and behavioral preparations before that event. Let’s talk about how this circadian clock works. The hypothalamus houses a circadian clock Where is the biological clock that drives circadian rhythms, and how does it work? Classic research showed that while removing various endocrine glands had little effect on the free-running rhythm of rats, large lesions of the hypothalamus interfered with circadian rhythms (Richter, 1967). It was subsequently discovered that lesions of a tiny subregion of the hypothalamus—the suprachiasmatic nucleus (SCN), named for its location above the optic chiasm—eliminate circadian rhythms of drinking and locomotor behavior (FIGURE 10.3) (Stephan and Zucker, 1972) and of hormone secretion (R. Y. Moore and Eichler, 1972). FIGU R E 1 0 . 3 The Effects of Lesions in the SCN View larger image The clocklike nature of the SCN is also evident in its metabolic activity. If we take SCN cells out of the brain and put them in a dish (Pavan et al., 2022), their electrical activity continues to show a circadian rhythm for days or weeks. This striking evidence supports the idea that the SCN contains an endogenous clock. But even stronger proof that the SCN generates a circadian rhythm comes from transplanting the SCN from one animal to another, as we’ll see next. RESEARCHERS AT WORK Transplants Prove That the SCN Produces a Circadian Rhythm Ralph and Menaker (1988) found a male hamster that exhibited an unusually short free-running activity rhythm in constant conditions. Normally, hamsters free-run at a period slightly longer than 24 hours, but this male showed a free-running period of 22 hours. Half of his offspring also had a shorter circadian rhythm, indicating that he had a genetic mutation affecting the endogenous clock. Grandchildren inheriting two copies of this mutation had an even shorter period: 20 hours. The mutation was named tau, after the Greek symbol used by scientists to represent the period (duration) of cyclical processes. These hamsters entrained to a normal 24-hour lightdark cycle just fine; their abnormal endogenous circadian rhythm was revealed only in constant conditions. Dramatic evidence that the SCN is a master clock was provided by transplant experiments (Ralph et al., 1990), as detailed in FIGURE 10.4. FIGU R E 1 0 . 4 Brain Transplants Prove That the SCN Contains a Clock View larger image Reciprocal transplants gave comparable results: the endogenous rhythm following the transplant was always that of the donor SCN, not the recipient, so the SCN must be driving the circadian rhythms. This remains the only known case of transplanting brain tissue from one individual to another in which the recipient subsequently displayed the donor’s behavior! In mammals, light information from the eyes reaches the SCN directly Most vertebrates have photoreceptors outside the eye that entrain their circadian rhythms (Ben-Moshe et al., 2014). For example, the pineal gland of some birds and amphibians is itself sensitive to light (Bertolesi et al., 2022) and helps entrain circadian rhythms to light. Because the skull over the pineal is especially thin in some species, we can think of those species as having a primitive “third eye” in the back of the head. (Some elementary school teachers also seem to have an eye in the back of the head, but this has not been proven to be the pineal gland.) At night, the pineal gland secretes a hormone, melatonin, that informs the brain about day length. In mammals, however, cells in the eye tell the SCN when it is light out. Certain retinal ganglion cells send their axons along the retinohypothalamic pathway, veering out of the optic chiasm to synapse directly within the SCN. This short pathway carries information about light to the hypothalamus to entrain rhythms (FIGURE 10.5). Most of the retinal ganglion cells that extend their axons to the SCN do not rely on the traditional photoreceptors—rods and cones—to learn about light. Rather, these retinal ganglion cells themselves contain a special photopigment, called melanopsin, that makes them sensitive to light (Do, 2019). Transgenic mice that lack rods and cones, and so are blind in every other respect, will still entrain their behavior to light (Hatori and Panda, 2010) if the specialized melanopsin-containing ganglion cells are present. FIGU R E 1 0 . 5 Components of a Circadian System View larger image Unfortunately, those melanopsin-containing retinal ganglion cells appear to be absent or dysfunctional in most totally blind humans, because people who are blind often show a free-running circadian rhythm, with difficulties getting to sleep at night and staying awake during the day (Bridge et al., 2021). Taking melatonin at bedtime, thus mimicking the normal nightly release of the hormone from the pineal gland, helps sighted people to get to sleep (Burgess and Emens, 2018), and it also helps blind people to entrain to daylight. This result suggests that while humans rely primarily on light stimulation of the retinohypothalamic tract to the SCN in order to entrain to light, our brains have retained enough sensitivity to melatonin that we can use that cue in the absence of information about light. Deprived of light cues, people free-run just like hamsters. Spending weeks in a cave with all cues to external time removed, they display a circadian rhythm of the sleep-waking cycle that slowly shifts from 24 to 25 hours (FIGURE 10.6), just as a hamster does (see Figure 10.2). Because the free-running period is greater than 24 hours, some people in these studies are surprised when they’re told that the experiment has ended. They may have experienced only 74 sleepwaking cycles during a 77-day study. FIGU R E 1 0 . 6 Humans Free-Run Too View larger image Another way to detect the effect of daylight on human circadian rhythms is to examine when people go to sleep within a given time zone. Even though everyone’s clocks/watches/phones report the same time, people in the western part of a time zone go to bed a bit later than those in the eastern part, presumably because the sun sets later in their half (FIGURE 10.7). FIGU R E 1 0 . 7 Humans Are Still Entrained by Light View larger image Circadian rhythms have been genetically dissected in flies and mice Genes that were found to affect circadian rhythms in the fruit fly Drosophila melanogaster (Belle and Allen, 2018) were later discovered to have differently named but similar-acting counterparts in mammals. This paved the way for understanding the molecular basis of the circadian clock. Neurons in the mammalian SCN make the proteins Clock and Cycle, which bind together to form a dimer (a pair of proteins attached to each other). The Clock/Cycle dimer then binds to the cell’s DNA to promote the transcription of other genes, including one called period (per). The proteins made from these other genes go back to inhibit the action of Clock and Cycle, which started the whole process. Because those inhibitory proteins degrade with time, eventually the inhibition is lifted, starting the whole cycle over again (FIGURE 10.8). The entire cycle takes about 24 hours to complete, and it is this 24-hour molecular cycle that drives the 24- hour activity cycle of SCN cells. FIGU R E 1 0 . 8 A Molecular Clock in Flies and Mice View larger image One indication of the importance of the molecular clock in controlling circadian behavior is the effect of differences in the genes involved in the clock. We’ve already seen that hamsters with a mutation in tau have a free-running rhythm that is shorter than normal. Mice in which both copies of the Clock gene are disrupted show severe arrhythmicity under constant conditions (FIGURE 10.9). People who feel energetic in the morning (“larks”) are likely to carry a different version of the Clock gene than “night owls” have (S. E. Jones et al., 2019). Different versions of other genes in the molecular clock are also associated with being a lark versus an owl in both humans (Blum et al., 2018) and mice (Pfeffer et al., 2015). Human night owls are at greater risk than larks for depression (R. G. Foster et al., 2013) and obesity (Roenneberg et al., 2012), perhaps because they are forced to adapt their natural sleep rhythm to fit into an early-bird society. FIGU R E 1 0 . 9 When the Endogenous Clock Goes Kaput View larger image At puberty, most people shift their circadian rhythm of sleep, so they get up later in the day (FIGURE 10.10), basically acting more like night owls. Unfortunately, many school systems require students to come to school earlier in the day when they hit adolescence. When high schools shifted their morning start to after 8:30 am, students showed improved academic performance, including (big surprise!) less sleeping in class, and a reduced incidence of depression (J. C. Lo et al., 2018). Plus, the student drivers had 70 percent fewer car crashes (Wahlstrom et al., 2014)! FIGU R E 1 0 . 1 0 How I Hate to Get Out of Bed in the Morning! View larger image Having covered some of the mechanisms that enforce our daily rhythms, we’ll spend the rest of the chapter exploring that mysterious circadian behavior called sleep. How’s It Going? 1. Give some examples of ultradian and infradian rhythms. 2. What are circadian rhythms, and how can they be studied and manipulated in lab animals? 3. Describe experiments that established which parts of the brain control circadian rhythms. 4. How does information about day and night reach the mammalian brain? 5. Describe in general terms how a molecular process in the brain cycles about every 24 hours. FOOD FOR THOUGHT Western culture is mostly scheduled in a way that is easier for early birds than night owls, presumably because they are in the majority. Why might night owls be less common in humans? 10.2 Sleep Is an Active Process The Road Ahead The next section concerns our most prominent circadian behavior: sleep. Studying this material should allow you to: 10.2.1 Describe the various stages of sleep and how they are distributed across the night. 10.2.2 Distinguish the types of mental activity typical of the two major classes of sleep. Human sleep exhibits different stages In the 1930s, experimenters found that brain potentials recorded from electrodes on the scalp by electroencephalography (EEG; see Figure 2.16A) provide a way to define, describe, and classify levels of arousal and states of sleep. In sleep studies, eye movements and muscle tension are monitored in addition to the EEG. Together, these measures led to the groundbreaking discovery that there are two distinct classes of sleep: rapid-eye-movement (REM) sleep (Aserinsky and Kleitman, 1953) and non-REM sleep. What are the electrophysiological distinctions that define different sleep states? Let’s begin with the pattern of EEG activity in the brain of a fully awake, alert person. It is a mixture of low-amplitude waves with many relatively fast frequencies (greater than 15–20 cycles per second, or hertz [Hz]). This pattern is sometimes referred to as beta activity or a desynchronized EEG (FIGURE 10.11A). FIGU R E 1 0 . 11 Electrophysiological Correlates of Sleep and Waking View larger image When you relax and close your eyes, a distinctive rhythm appears in the EEG, consisting of a regular oscillation at a frequency of 8–12 Hz, known as the alpha rhythm. As drowsiness sets in, the time spent in the alpha rhythm decreases, and the EEG shows waves of smaller amplitude and irregular frequency, as well as sharp waves called vertex spikes. This is the beginning of non-REM sleep, called stage 1 sleep (FIGURE 10.11B), which is accompanied by slowing of the heart rate and relaxation of the muscles; in addition, under the closed eyelids the eyes may roll about slowly. Stage 1 sleep usually lasts several minutes and gives way to stage 2 sleep (FIGURE 10.11C), which is defined by waves of 12–14 Hz called sleep spindles that occur in periodic bursts, and by K complexes. If awakened during these first two stages of sleep, people may deny that they have been asleep, even though they failed to respond to signals while in those stages. Stage 2 sleep leads to (can you guess?) stage 3 sleep (FIGURE 10.11D), which is defined by the appearance of large-amplitude, very slow waves called delta waves (about one per second). These waves give stage 3 sleep its other name—slow-wave sleep (SWS). As the night progresses, the delta waves become even more prominent. The slow waves of electrical potential that give SWS its name represent a widespread synchronization of cortical neuron activity (Guo et al., 2022) that has been likened to a room of people who are all chanting the same phrase over and over. From a distance, you would be able to hear the rise and fall of the cadence of speech in a slow rhythm. Contrast this with a room full of people each saying something different. You would hear only a buzz—the rapid frequencies of many desynchronized speakers. This is like the desynchronized EEG of wakefulness, when many parts of the cortex are communicating different things and fulfilling different functions. After about an hour, the typical time to progress through the SWS stage, with a brief return to stage 2—something totally different occurs: REM sleep. Quite abruptly, the EEG displays a pattern of small-amplitude, high-frequency activity similar in many ways to the pattern of an awake individual (FIGURE 10.11E), except the eyes are darting rapidly about under their lids (the rapid eye movements that give REM sleep its name). Aside from those muscles moving the eyes, all other skeletal muscles not only are relaxed, but show a complete absence of muscle tone, called atonia. The active-looking EEG coupled with deeply relaxed muscles is typical of REM sleep. If you see a cat sleeping in the sitting, sphinx position, it cannot be in REM sleep; in REM, it will be sprawled limply on the floor. For the same reason, a student sleeping while sitting upright in class (you know who you are) cannot be in REM sleep. This flaccid muscle state appears, despite intense brain activity, because during REM sleep, brainstem regions are profoundly inhibiting motor neurons. This seeming contradiction—the brain waves look awake, but the muscles are flaccid and unresponsive—is what gives REM sleep its other name: paradoxical sleep. Unlike SWS, REM sleep is accompanied by irregular breathing and pulse rate, as in wakefulness. During REM sleep we experience vivid dreams, as we’ll discuss shortly. Wired for Sleep Machines measure electrical activity across the various electrodes to monitor EEG, eye movements, and muscle tension across sleep stages. View larger image The EEG portrait shows that sleep consists of a complex series of brain states, not just an “inactive” period. The total sleep time of young adults usually ranges from 7 to 8 hours, about half of it in stage 2 sleep. REM sleep accounts for about 20 percent of total sleep. A typical night of adult human sleep shows repeating cycles approximately 90–110 minutes long, recurring four or five times in a night, reflecting a basic ultradian rest-activity cycle (Kaiser, 2013). These cycles change in a subtle but regular manner through the night. Stage 3 SWS, when we are most deeply asleep and the pituitary releases growth hormone, is more prominent early in the night (FIGURE 10.12), and then it tapers off as the night progresses. In contrast, REM sleep is more prominent in the later cycles of sleep. The first REM period is the shortest, while the last REM period, just before waking, may last up to 40 minutes. Brief arousals (yellow bars in Figure 10.12) occasionally occur immediately after a REM period, and the sleeper may shift posture at this time (Amici et al., 2014). TABLE 10.1 compares the properties of REM and non-REM sleep. FIGU R E 1 0 . 1 2 A Typical Night of Sleep in a Young Adult View larger image TA B LE 1 0 . 1 Properties of REM Sleep and Non-REM Sleep Property REM sleep Non-REM sleep AUTONOMIC ACTIVITIES Property REM sleep Non-REM sleep Heart rate Variable, with high burst Slow decline Respiration Variable, with high burst Slow decline Brain temperature Increased Decreased Cerebral blood flow High Reduced SKELETAL MUSCULAR SYSTEM Postural tension Eliminated Progressively reduced Knee-jerk reflex Suppressed Normal Twitches Increased Reduced Eye movements Rapid, coordinated Infrequent, slow, uncoordinated COGNITIVE STATE Dream state Vivid dreams, well organized Vague thoughts HORMONE SECRETION Growth hormone secretion Low High in SWS NEURAL FIRING RATES Cerebral cortex activity Increased firing rates Many cells reduced We do our most vivid dreaming during REM sleep We can record the EEGs of participants to monitor their sleep stages, awaken them at a particular stage (1, 2, 3, or REM), and ask them about thoughts or perceptions they were having. Early studies of this sort suggested that dreams happen only during REM sleep, but we now know that dreams also occur in other sleep stages. What is distinctive about dreams during REM sleep is that they are characterized by visual imagery, whereas dreams during non-REM sleep are of a more “thinking” type. REM dreams are apt to include a story that involves odd perceptions and the sense that the dreamer “is there” experiencing sights, sounds, smells, and emotions (McNamara et al., 2010). People awakened from non-REM sleep report thinking about problems rather than seeing themselves in a mental movie. The dreams of these two states are so different that people can be trained to predict accurately whether a described dream occurred during REM sleep or SWS (Siclari et al., 2017). Almost everyone has terrifying dreams on occasion (Llewellyn and Hobson, 2015). Nightmares are defined as long, frightening dreams that awaken the sleeper. They are occasionally confused with night terror, which is a sudden arousal from stage 3 SWS marked by intense fear and autonomic activation. In night terror, the sleeper does not recall a vivid dream but may remember a sense of a crushing feeling on the chest, as though being suffocated. Night terrors are common in children during the early part of an evening’s sleep. Many medications, including antidepressants and drugs that control blood pressure, make nightmares more frequent (J. F. Pagel, 2012), but nightmares are quite prevalent even without such influences. At least 25 percent of college students report having one or more nightmares per month. Have you had the common one, which Sigmund Freud had, of suddenly remembering that you’re supposed to be taking a final exam that is already in progress? As fascinating as they are, we still do not know what function, if any, is fulfilled by dreams. The activation-synthesis theory suggests our experiences in REM sleep are the more or less random results of which neurons happen to get activated (Hobson and Friston, 2012). The brain strings together these disparate activated elements into a more or less coherent story, a narrative. Next we’ll discuss evidence that at least some other animals experience dreaming, which suggests that dreaming either fulfills an important purpose or is an unavoidable consequence of some other function of REM sleep. Night Terror This 1781 painting by Henry Fuseli is called The Nightmare. It also aptly illustrates night terror, or even sleep paralysis, discussed later in the chapter, as the demon crushes the breath from his victim as the dreamer feels unable to breathe. View larger image Different species provide clues about the evolution of sleep With the aid of behavioral and EEG techniques, sleep has been studied in a wide assortment of mammals and, to a lesser extent, in reptiles, birds, and amphibians (Lesku et al., 2009; Hartse, 2011). Nearly all mammalian species that have been investigated thus far, including our most distant mammalian relatives, such as the platypus (Manger et al., 2002), display both REM sleep and SWS. Among the other vertebrates, birds display clear signs of both SWS and REM sleep, which indicates that REM sleep was present in an ancestor common to birds and mammals. The report of REM sleep in a reptile (Shein-Idelson et al., 2016) suggests that maybe it arose even earlier. The absence of REM sleep in dolphins is probably a later adaptation that evolved when their land-dwelling ancestors took to the water, because they must come to the surface of the water to breathe. That requirement may be incompatible with the deep relaxation of muscles during REM sleep. Another dolphin adaptation to living in water is that only one side of the dolphin brain engages in SWS at a time (Mascetti, 2016). It’s as if one whole hemisphere is asleep while the other is awake (FIGURE 10.13). During these periods of “unilateral sleep,” the animals continue to come up to the surface occasionally to breathe. Birds can also display unilateral sleep—one hemisphere sleeping while the other hemisphere watches for predators (Rattenborg, 2006). Unilateral sleep while gliding may also enable birds to fly long distances without stopping; for example, a bar-tailed godwit flew nonstop more than 10,000 miles, from Alaska to Australia, in a week (Gill et al., 2009). FIGU R E 1 0 . 1 3 Sleep in Marine Mammals View larger image Like Sleeping on Air A female bar-tailed godwit flew over 10,000 miles, nonstop, from Alaska to Australia in a week. Were both sides of its brain awake the entire time? View larger image How’s It Going? 1. What are the different stages of sleep, and what measures define them? 2. What happens to our muscles during the sleep stage characterized by the most vivid dreams? 3. Contrast the mental activity present in REM sleep versus SWS. 4. Describe ways that certain species manage to sleep despite obstacles like living in water and nonstop flying. FOOD FOR THOUGHT From ancient times, people have examined dreams as sources of information or even prophecy. Why? 10.3 Our Sleep Patterns Change across the Life-Span The Road Ahead The next section covers what we know about why we sleep, and how the brain switches from one stage to another. Studying this material should allow you to: 10.3.1 Describe the changes in sleep as we grow up and grow old. 10.3.2 Critically discuss the effects of partial versus total sleep deprivation. 10.3.3 Discuss various theories about the function of sleep. 10.3.4 Describe four brain systems that influence the sleep-waking cycle. How much sleep and what kind of sleep we get changes across our lifetime. As infants, we sleep a lot; as we grow, we sleep less and less until we hit adolescence, when once again sleep seems precious. After that, we sleep less as we age, sometimes to our disappointment. These changes as we grow up and grow old suggest that the function(s) of sleep are more important during some stages of life than others. Human infants sleep a lot, but a clear cycle of sleeping and waking takes several weeks (that feel like years to parents) to settle in (FIGURE 10.14). A 24-hour rhythm is generally evident by 16 weeks of age. Infant sleep is characterized by shorter sleep cycles than those of adults, probably reflecting the relative immaturity of the brain, since sleep cycles in prematurely born infants are even shorter than in full-term newborns. FIGU R E 1 0 . 1 4 The Trouble with Babies This classic study may represent an extreme example of a baby slow to entrain to the day-night rhythm. View larger image Infant mammals also show a large percentage of REM sleep. In humans, for example, half of sleep in the first 2 weeks of life is REM sleep. The prominence of REM sleep is even greater in premature infants. Unlike most adults, human infants can move directly from an awake state to REM sleep. The REM sleep of infants is quite active, accompanied by muscle twitching, smiles, grimaces, and vocalizations. The preponderance of REM sleep early in life (FIGURE 10.15) suggests that this state provides stimulation that is essential to maturation of the nervous system. By contrast, orcas and bottlenose dolphins appear to spend little or no time in REM sleep (or any other sleep stage) for the first month of life (Lyamin and Siegel, 2019), presumably because they have to surface often to breathe. So, either REM sleep does not fill a crucial need in all mammalian infants, or dolphin and whale infants have evolved an alternative way to fill that need. FIGU R E 1 0 . 1 5 Human Sleep Patterns Change with Age View larger image Most people sleep appreciably less as they age The character of sleep changes in old age, though more slowly than in early development. FIGURE 10.16 shows the sleep pattern typical of an elderly person. The total amount of sleep declines, while the number of awakenings increases (compare with Figure 10.12). Lack of sleep, or insomnia (which we discuss at the end of this chapter), is a common complaint of the elderly and is associated with a variety of physical and cognitive impairments (Winer et al., 2021). FIGU R E 1 0 . 1 6 The Typical Pattern of Sleep in an Elderly Person Compare this recording with the young adult sleep pattern shown in Figure 10.12. View larger image I Need Sleep! Doing without sleep has one clear effect: you feel sleepy. View larger image In humans and other mammals, the most dramatic decline is in stage 3 sleep; 60-year-old people spend only about half as much time in stage 3 as they did at age 20 (Mander et al., 2017). By 90 years of age, stage 3 sleep has disappeared. This decline in stage 3 sleep may be related to diminished cognitive functioning, since an especially marked reduction of stage 3 SWS characterizes the sleep of people with senile dementia. Growth hormone is secreted primarily during stage 3 SWS (see Table 10.1), so perhaps the loss of growth hormone due to disrupted sleep in the elderly leads to the cognitive deficits (Stitch et al., 2022). Loss of SWS probably also impairs memory processes (discussed below) in older people and people with dementia (Winer et al., 2021). Most elderly people fall asleep easily enough, but then they may have a hard time staying asleep, which causes sleep “dissatisfaction.” As in so many things, attitude may be important for how you experience sleep loss as you age. Objective measures of sleep suggest that elderly people who complain of poor sleep may actually sleep more than those who are satisfied with their sleep (McCrae et al., 2005). Perhaps if, as you grow older, you can regard waking up at 3:00 am as a “bonus” (a little more time awake before you die), you will be more satisfied with the sleep you get. Manipulating sleep reveals an underlying structure Another persuasive clue that sleep is important is revealed when we go without it. First of all, our mental function is impaired. This is bad news for college students, who rarely get enough sleep, just when they’re supposed to be learning how to make their way in the world. In addition, after sleep deprivation we tend to sleep more than we would have, as though catching up on something we need, as we’ll see. Most of us at one time or another have been willing or not-so-willing participants in informal sleep deprivation experiments. Thus, most of us are aware of the primary effect of partial or total sleep deprivation: it makes us sleepy. It has other effects as well. Early reports from sleep deprivation studies emphasized a similarity between schizophrenia and “bizarre” behavior provoked by sleep deprivation. But examination of people with schizophrenia does not fit this view. For example, many people with schizophrenia show sleep-waking cycles similar to those of typical adults, and sleep deprivation does not exacerbate their symptoms. The behavioral effects of prolonged, total sleep deprivation vary appreciably and may depend on some general personality factors and on age. In studies employing prolonged total deprivation—205 hours (8.5 days!)—a few participants showed occasional episodes of hallucinations. But the most common behavior changes were increases in irritability, difficulty in concentrating, and episodes of disorientation. You don’t need to resort to total sleep deprivation to see effects. Moderate effects of sleep debt can accumulate with successive nights of little sleep. In one study, research participants who got 6 or 4 hours of sleep per night for 2 weeks showed ever-mounting deficits in attention tasks and in speed of reaction, compared with those sleeping 8 hours per night (Van Dongen et al., 2003). By the end of the study, the people getting less than 8 hours of sleep per night had cognitive deficits equivalent to those of participants who had been totally sleep-deprived for 3 days! If that doesn’t persuade you about the importance of sleep for cognition, note that the GPAs of first-year college students are positively correlated with how much they sleep at night (Creswell et al., 2023)! Sleep recovery may take time One of the most famous cases of sleep deprivation began as a high school student’s science project. Researchers became involved only after Randy Gardner had started his deprivation schedule, which is why we have no data about his sleep before he decided to stay awake for, believe it or not, 11 days! As in other studies, Randy’s performance on some tests was impaired, but he could still hold a conversation and was articulate and clear in a press conference at the end of his experiment. In other words, he showed no signs of insanity—he just acted really, really sleepy. Skipping Sleep for Science As a young man, Randy Gardner decided to see how long he could stay awake as a science fair project. The answer? Just over 11 days. Is that a record for the most demanding science fair project? View larger image Randy’s sleep recovery after 11 days of sleep deprivation, depicted in FIGURE 10.17, shows the same pattern of sleep recovery as in controlled studies with shorter periods of deprivation. In the first night of sleep recovery, stage 3 sleep shows the greatest relative difference from normal. This increase in stage 3 sleep is usually at the expense of stage 2 sleep. However, the added stage 3 sleep during recovery never completely makes up for the deficit accumulated over the deprivation period. In fact, Randy had no more additional stage 3 sleep than do people deprived of sleep for half as long. REM sleep in recovery nights is more “intense” than normal, with a greater number of rapid eye movements per period of time. So you never recover all the sleep time you lost, but you may make up for the loss by having more intense sleep for a few nights. The sooner you get to sleep, the sooner you recover. FIGU R E 1 0 . 1 7 Sleep Recovery after 11 Days Awake View larger image Finally, it is clear that prolonged, total sleep deprivation in mammals compromises the immune system and leads to death, as we’ll see in Signs & Symptoms, next. SIGNS & SYMPTOMS Total Sleep Deprivation Can Be Fatal Sustained sleep deprivation in rats causes them to increase their metabolic rate, lose weight, and, within an average of 19 days, die (Everson et al., 1989). Allowing them to sleep prevents their death. After the fatal effect of sleep deprivation had been shown, researchers undertook studies in which they terminated the sleep deprivation before the fatal end point and looked for pathological changes in different organ systems. No single organ system seems affected in chronically sleepdeprived animals, but early in the deprivation they develop sores on their bodies. These sores mark the beginning of the end; shortly thereafter, blood tests reveal infections from a host of bacteria, which probably enter through the sores (Rechtschaffen and Bergmann, 2002). These bacteria are not normally fatal, because the rat’s immune system and body defenses keep the bacteria in check, but severely sleep-deprived rats fail to develop a fever in response to these infections. (Fever helps the body fight infection.) In fact, the sleep-deprived animals show a drop in body temperature, which probably speeds bacterial infections that in turn cause diffuse organ damage. The decline of these severely sleep-deprived rats is complicated, but it seems clear that getting sleep improves immune system function (Bryant et al., 2004). So perhaps Shakespeare’s theory of the function of sleep, “Sleep that knits up the ravell’d sleave of care,” isn’t so far from the truth. Even fruit flies will die without sleep (Vaccaro et al., 2020). Some unfortunate humans inherit a defect in the gene for the prion protein, which can transmit mad cow disease, and although they sleep normally at the beginning of life, in midlife they simply stop sleeping—with fatal effect. People with this disease, called fatal familial insomnia, die 7–24 months after the insomnia begins (Zhang et al., 2022). Autopsy reveals degeneration in the cerebral cortex (FIGURE 10.18) and thalamus, which may cause the insomnia. Like sleep-deprived rats, sleep-deprived humans with this disorder don’t have obvious damage to any single organ system, but they have diffuse bacterial infections. Apparently, these people die because they are chronically sleep-deprived, and these results, combined with research on rats, certainly support the idea that prolonged insomnia is fatal. The effects of sleep deprivation suggest that sleep plays an important function, or even several functions, that we’ll consider next. FIGU R E 1 0 . 1 8 Fatal Sleeplessness Note the large holes (arrows) that have developed in this section of frontal cortex from a person with fatal familial insomnia. View larger image How’s It Going? 1. Describe how sleep changes as we grow up and grow old. 2. What happens when we are deprived of sleep? 3. Describe the outcome of Randy Gardner’s famous selfstudy. What are the biological functions of sleep? Doesn’t it seem like a big waste of time to spend one-third of our lifetime asleep? Most of us have fantasized about how great it would be if we could stay awake and chipper all the time, but we’ve seen that it’s just not possible. What is so important about sleep that we can’t seem to live without it? Let’s consider the four functions that are most often ascribed to sleep: 1. Energy conservation 2. Niche adaptation 3. Body and brain restoration 4. Memory consolidation Conservation of energy We use up less energy when we sleep than when we’re awake. For example, SWS is marked by reduced muscular tension, lowered heart rate, reduced blood pressure, reduced body temperature, and slower respiration. This diminished metabolic activity during sleep suggests that one role of sleep is to conserve energy. We can see the importance of this function by considering small animals. Small mammals and birds have very high metabolic rates (see Chapter 9). In general, the smaller the mammal, the higher its metabolic rate and the more time it spends asleep. Larger mammals, like elephants, have low metabolic rates and sleep only a few hours per day (Gravett et al., 2017). That correlation supports the idea that sleep helps conserve energy. But energy savings from sleep seem modest at best (Lesku et al., 2009). Finding Your Niche in Life Species that can sleep in secure circumstances tend to sleep more than other species. View larger image Niche adaptation Almost all animals are either nocturnal or diurnal. This specialization for either nighttime or daytime activity is part of each species’ ecological niche, that unique assortment of environmental opportunities and challenges to which each organism is adapted. Thanks to these adaptations, each species is better at gathering food either at night or in the daytime, and it is also better at avoiding predators either during the day or at night. If you’re a nocturnal mammal, like a mouse, you are adept at sneaking around in the dark, using your acute senses of hearing and smell to navigate and find food. The rest of the time, during daylight, you should spend holed up somewhere safe to stay away from keen-eyed diurnal predators. Sleep debt and the unpleasant feelings of sleepiness have the effect of enforcing the circadian rhythm characteristic of your species. So, one important function of sleep, or of the results of sleep deprivation, is to force the individual to conform to the particular ecological niche for which it is well adapted (Meddis, 1975), and natural selection must have played an important role in its evolution. Physical restoration If someone asked you why you wanted to go to sleep, you might answer that you “feel worn out.” Indeed, one of the proposed functions of sleep is simply the rebuilding or restoration of materials used during waking, such as proteins (Pulak and Jensen, 2014). Maybe this is why most growth hormone release happens during slow-wave sleep. We’ve seen that prolonged and total sleep deprivation—either forced on rats or, in humans, as a result of inherited pathology—interferes with the immune system and leads to death. Even relatively mild deprivation, having sleep shortened or disrupted (e.g., by a nurse taking vital signs every hour), makes people more sensitive to pain the following day (Edwards et al., 2009). A study of over a million Americans found that those sleeping less than 6 hours per night were more likely to die over the next 6 years, although interestingly, people who slept more than 8 hours per night were also at greater risk (Kripke et al., 2002). People who sleep less than 5 hours per night are more likely to develop diabetes (Gangwisch et al., 2007). Perhaps the most alarming link between sleep and health is the finding that people who work at night and sleep in the daytime are more likely to die of cardiovascular disease or cancer (Su et al., 2021). So the widespread belief that sleep helps the body ward off illness is well supported by research. There’s also evidence that sleep may help “clean out” the brain. Glia control the flow of cerebrospinal fluid through a network of microscopic channels throughout the brain, the glymphatic system we described in Chapter 1 (see Figure 1.17), collecting and disposing of toxins that build up. This flow is much faster during sleep and pulses with each delta wave in stage 3 (L. D. Lewis, 2021), flushing out brain waste products as we snooze, including proteins—betaamyloid and Tau—that are implicated in Alzheimer’s disease (Holth et al., 2019). Memory consolidation A peculiar property of dreams is that, unless we describe them to someone or write them down soon after waking, we tend to forget them, as though the brain refuses to store anything that we experience during REM sleep. This seems like a good idea—why waste memory storage space on something that never happened? Similarly, and despite ads you might read in the backs of magazines, you cannot learn significant amounts of new material while you’re sleeping. Putting a speaker under your pillow to recite material for a final exam will not help you, unless you stay awake to listen. A Nonsleeper When Ray Meddis brought this 70-year-old nurse into the lab for sleep recording, he confirmed that she slept only about an hour per night. Yet she was a healthy and energetic person. Here she’s touring a garden with Meddis’s son. View larger image Sleep seems important for learning in another way, however. In 1924 an experiment suggested that sleep helps you learn or remember material or events experienced before you went to bed (Jenkins and Dallenbach, 1924). Some participants were trained in a verbal learning task at bedtime and tested 8 hours later on rising from sleep; other people were trained early in the day and tested 8 hours later (with no intervening sleep). The results showed better retention when a period of sleep intervened between a learning period and tests of recall. A surge of supporting evidence has shown that sleep helps with memory formation in many domains, not just verbal memory (Cherdieu et al., 2018; Navarro-Lobato and Genzel, 2018; Uji and Tamaki, 2022). Despite early assumptions that REM sleep would play a bigger role in learning and memory, most research suggested that it is SWS that helps memory consolidation (Nishida and Walker, 2007). In fact, consolidation of a declarative memory task was even better if the person’s cortical slow-wave oscillations during SWS were boosted by electrically stimulating electrodes over the skull (Marshall et al., 2006). (Don’t try this at home.) What’s more, one man who had brainstem injuries that seemed to eliminate REM sleep could still learn, and he earned a law school degree (P. Lavie, 1996). So even if REM sleep aids learning, clearly it is not absolutely necessary for learning (Ackermann and Rasch, 2018). Don’t rule out a role for REM sleep in learning entirely, however, because synapses are being rearranged during that state (W. Li et al., 2017), and some memory consolidation seems dependent on REM (Boyce et al., 2016). Some humans sleep remarkably little, yet function normally One challenge to all the theories about the function of sleep is the existence of a few people who seem perfectly healthy, yet sleep hardly at all. These cases are more than just folktales. A Stanford University professor slept only 3–4 hours a night and lived to be 80 (Dement, 1974). Sleep researcher Ray Meddis (1977) found a cheerful 70-yearold retired nurse who said she had slept little since childhood. She was a busy person who easily filled up her 23 hours of daily wakefulness. During the night, she sat in bed reading or writing, and at about 2:00 am she fell asleep for an hour or so, after which she readily awakened. For her first two nights in Meddis’s laboratory, she did not sleep at all, because it was all so interesting to her. On the third night, she slept a total of 99 minutes, and her sleep contained both SWS and REM sleep periods. In a later session, her sleep was recorded for 5 days. She didn’t sleep the first night, but on subsequent nights she slept an average of 67 minutes. She never complained about not sleeping more, and she did not feel drowsy during either the day or the night. Several genes have been associated with different people who sleep only an hour or two per night (Dong et al., 2022). Whatever the function of sleep is, some people (and elephants) have a way of fulfilling it in just a few hours per night. Why aren’t their immune systems compromised? We don’t know, but perhaps their immune systems don’t need much sleep either. Or perhaps the small amount of sleep they have almost every night is more efficient at doing whatever sleep does. The important point, though, is that no healthy person has ever been found who does not sleep at all. How’s It Going? 1. Describe the four most prominent theories about the function of sleep and the evidence to support them. 2. What can we conclude about the function of sleep when we consider people who sleep very little? 3. What happens when we stop sleeping altogether? RESEARCHERS AT WORK The Forebrain Generates Slow-Wave Sleep Some of the earliest studies of sleep found a system in the forebrain that promotes SWS. These are experiments in which an animal’s brain is transected—literally cut into two parts: an upper part and a lower part. The entire brain can be isolated from the body by an incision between the medulla and the spinal cord. This preparation was first studied by the Belgian physiologist Frédéric Bremer (1892–1982), who called it the isolated brain (Bremer, 1938). The EEGs of such animals showed signs of waking alternating with sleep (FIGURE 10.19A). During EEG-defined wakeful periods, the pupils were dilated and the eyes followed moving objects. During EEG-defined sleep, the pupils were small, as in normal sleep. REM sleep can also be detected in the isolated brain. These results demonstrated that wakefulness, SWS, and REM sleep are all mediated by networks within the brain. FIGU R E 1 0 . 1 9 Transecting the Brain at Different Levels View larger image When Bremer made the transection higher along the brainstem —in the midbrain—a very different result was seen. Bremer referred to such a preparation as an isolated forebrain, and he found that the EEG from the brain in front of the cut displayed constant SWS (FIGURE 10.19B), with no indications of wakefulness or REM sleep. This result demonstrates that the forebrain alone can generate SWS, without contributions from the lower brain regions. The constant SWS seen in the cortex of the isolated forebrain appears to be generated by the basal forebrain in the ventral frontal lobe and anterior hypothalamus (FIGURE 10.20A). Electrical stimulation of the basal forebrain can induce SWS activity, while lesions there suppress sleep (McGinty and Sterman, 1968). Neurons in this region become active at sleep onset and release gamma-aminobutyric acid (GABA) (Gallopin et al., 2000) to stimulate GABA receptors in the nearby tuberomammillary nucleus in the posterior hypothalamus. These same GABA receptors are stimulated by general anesthetics—drugs such as barbiturates and anesthetic gases that render people unconscious during surgery. Thus, general anesthetics produce slow waves in the EEG that resemble those seen in SWS (Franks, 2008). A A FIGU R E 1 0 . 2 0 Brain Mechanisms Underlying Sleep View larger image So the basal forebrain promotes SWS by releasing GABA into the nearby tuberomammillary nucleus, and if left alone, this system would keep the cortex asleep forever. But as we’ll see next, the brainstem contains a system that arouses the forebrain from slumber. At least four interacting neural systems underlie sleep At one time sleep was regarded as a passive state, as though most of the brain simply stopped working while we slept, leaving us unaware of events around us. We now know that sleep is an active state mediated by at least four interacting neural systems: 1. A forebrain system that generates SWS 2. A brainstem system that activates the sleeping forebrain into wakefulness 3. A pontine system that triggers REM sleep 4. A hypothalamic system that coordinates the other three brain regions to determine which state we’re in Let’s examine each of these systems in some detail. The reticular formation wakes up the forebrain In the late 1940s, scientists found that they could wake sleeping animals by electrically stimulating an extensive region of the brainstem known as the reticular formation (FIGURE 10.20B) (Moruzzi and Magoun, 1949). The reticular formation is a diffuse group of cells whose axons and dendrites course in many directions, extending from the medulla through the thalamus. Because electrical stimulation anywhere along this region activates the forebrain, the reticular formation is sometimes called the reticular activating system of the brainstem. Conversely, lesions of these regions produced persistent sleep in the animals. So the basal forebrain region actively imposes SWS on the brain, and the brainstem reticular formation seems to push the brain from SWS to wakefulness. What system imposes REM sleep? The pons triggers REM sleep Several experiments indicated that a region of the pons is important for REM sleep. Lesions of the region just ventral to the locus coeruleus abolish REM sleep (FIGURE 10.20C) (B. E. Jones, 2020). Electrical stimulation of the same region, or pharmacological stimulation of this region with cholinergic agonists, can induce or prolong REM sleep. Finally, some neurons in this region seem to be active only during REM sleep. So the pons has a REM sleep center near the locus coeruleus. One important job of the pontine REM sleep center is to prevent motor neurons from firing. During REM sleep, the inhibitory transmitters GABA and glycine produce powerful inhibitory postsynaptic potentials (discussed in Chapter 3) in spinal motor neurons, preventing them from reaching threshold to produce an action potential (Seifinejad et al., 2021). Thus, the dreamer’s muscles are not just relaxed, but flaccid. This loss of muscle tone during REM sleep can be abolished by small lesions that damage only a part of the REM center, suggesting that this subregion is what normally disables the motor system during REM. Cats with such lesions seem to act out their dreams. They enter SWS as they normally would, but when they begin to display the EEG signs of REM sleep, instead of becoming completely limp as normal cats do, these cats stagger to their feet (A. R. Morrison, 2013). Are they awake or in REM sleep? They move their heads as though visually tracking moving objects (that aren’t there), bat with their forepaws at nothing, and ignore objects that are present (FIGURE 10.21). In addition, the cats’ inner eyelids, the translucent nictitating membranes, partially cover the eyes. Thus, the cats appear to be in REM sleep, but motor activity is not being inhibited by the brain. These results strongly suggest that animals dream too. What do cats dream of? If their actions while sleeping are any indication, they dream of stalking prey, perhaps a mouse or a ball of yarn. FIGU R E 1 0 . 2 1 Acting Out a Dream View larger image So far, we’ve described three interacting brain systems controlling sleep: an SWS-promoting region in the forebrain, an arousing reticular formation in the brainstem, and a system in the pons that triggers REM sleep, including paralysis of the body during that state. There is a fourth important system, which seems to act as a “coordinating center” among these three centers, in the hypothalamus (FIGURE 10.20D). To understand how we learned about this fourth system, we need to consider sleep disorders because a rare but fascinating condition taught us about a specific neurotransmitter that is crucial in the control of sleep. How’s It Going? 1. Describe the brain systems that control different stages of the sleep-waking cycle, discussing the experiments that revealed each. 2. What receptor systems do anesthetics act upon to render people unconscious? 3. What happens when brainstem systems to inhibit movement during REM sleep are damaged? FOOD FOR THOUGHT Imagine that you inherited a gene that meant you only needed to sleep an hour or two per night to feel great and perform well. Would there be any downsides to that life? 10.4 Sleep Disorders Can Be Serious, Even Life-Threatening The Road Ahead We close the chapter by considering disorders of sleep and wakefulness. Studying this material will enable you to: 10.4.1 Discuss narcolepsy and how the study of this disorder revealed a neural system controlling sleep. 10.4.2 Describe several different sleep disorders associated with particular sleep stages or partial arousals. 10.4.3 Distinguish between different types of insomnia, and offer advice for good sleep hygiene. For some people, the peace and comfort of regular, uninterrupted sleep is routinely disturbed by the inability to fall asleep, by prolonged sleep, or by unusual awakenings. Other people experience episodes where they cannot move, despite remaining conscious. Study of this disruptive disorder, first in dogs and then in people, revealed an important system for coordinating sleep states. A hypothalamic sleep center was revealed by the study of narcolepsy You might not consider getting lots of sleep an affliction, but some people are either drowsy all the time or experience sudden attacks of sleep. At the extreme of such tendencies is narcolepsy, an unusual disorder in which the person is afflicted by frequent, intense attacks of sleep that last 5–30 minutes and can occur at any time during usual waking hours. These sleep attacks occur several times a day. Most people display SWS for an hour or more before entering REM; individuals who have narcolepsy, however, tend to enter REM in the first few minutes of sleep. People with this disorder exhibit an otherwise normal sleep pattern at night, but they experience abrupt, overwhelming sleepiness during the day. Some people with narcolepsy also show cataplexy, a sudden loss of muscle tone, leading to collapse of the body without loss of consciousness. Cataplexy can be triggered by sudden, intense emotional stimuli. Narcolepsy usually manifests itself between the ages of 15 and 25 years and continues throughout life. Remember Adrian from the start of this chapter? His narcolepsy was unusual in several ways: his only symptom was cataplexy, and that began unusually late in life, in his thirties. However, the trigger for Adrian’s cataplexy, humor, is typical of others with narcolepsy; they become literally weak with laughter. Several strains of dogs exhibit narcolepsy (Mignot, 2014), complete with sudden collapse, usually triggered by being excited, and very rapid sleep onset (FIGURE 10.22). Just like humans with narcolepsy, these dogs often show REM immediately upon falling asleep. Abrupt collapse in these dogs is suppressed by the same drugs (discussed shortly) that are used to treat human cataplexy. FIGU R E 1 0 . 2 2 Canine Narcolepsy View larger image Finding the mutant gene responsible for narcoleptic dogs revealed a hypothalamic system that is responsible for narcolepsy in people too. This was the gene for a neuropeptide called orexin (also known as hypocretin; see Chapter 9) (Shan et al., 2015). Mice with the orexin gene knocked out also display narcolepsy (M. Liu et al., 2017). Genetically normal rats can be made narcoleptic if injected with a toxin that destroys neurons possessing orexin receptors (Gerashchenko et al., 2001). The narcoleptic dogs start losing orexin neurons at about the age when symptoms of narcolepsy appear (John et al., 2004). Similarly, postmortem examination of humans with narcolepsy reveals they have lost about 90 percent of their orexin neurons (FIGURE 10.23) (Mahoney et al., 2019). This degeneration of orexin neurons seems to cause inappropriate activation of the cataplexy pathway that normally happens only during REM sleep. So, orexin normally keeps sleep at bay and prevents the transition from wakefulness directly into REM sleep. FIGU R E 1 0 . 2 3 Neural Degeneration in Humans with Narcolepsy View larger image The neurons that produce orexin are found almost exclusively in the hypothalamus. Where do these neurons send their axons to release the orexin? Not so coincidentally, the axons go to each of the three brain centers that we mentioned before: basal forebrain, reticular formation, and locus coeruleus (Mahoney et al., 2019). The orexin neurons also project axons to the hypothalamic tuberomammillary nucleus—the same structure that is inhibited by the basal forebrain to induce SWS. So, it looks as if the hypothalamus contains an orexin-based “switching station” (see Figure 10.20D) that switches the brain between states, from wakefulness to non-REM sleep to REM sleep (Saper et al., 2010). This system normally triggers paralysis only during REM, so loss of the system in narcolepsy leads to paralysis while awake (cataplexy). The traditional treatment for narcolepsy was the use of amphetamines in the daytime. The drug GHB (gammahydroxybutyrate, trade name Xyrem, also called sodium oxybate) helps some narcoleptics (although there are concerns about potential abuse of this drug [Fuller and Hornfeldt, 2012]). A newer drug, modafinil (Provigil), is sometimes effective for preventing narcoleptic attacks and has been proposed as an “alertness drug” for people with attention deficit hyperactivity disorder (Chien et al., 2022; Thorpy and Bogan, 2020). There is also debate about whether modafinil should be available to anyone who feels sleepy or needs to stay awake (Battleday and Brem, 2015), but at least one study found the drug no more effective than caffeine in this regard (Wesensten et al., 2004). Our friend Adrian, from the chapter opener, eventually found a combination of drugs that worked for him and continued a very successful career in the financial sector. Still, he finds he has to avoid trying to say or do anything amusing. “You just start to back away from the things that you know will almost without fail push you over the edge, which is a shame actually” (Leschziner, 2019, p. 131). Typical of people with narcolepsy, Adrian has low levels of orexin in CSF sampled through a spinal tap. Now that narcolepsy is known to be caused by a loss of orexin signaling, there is hope of developing synthetic drugs to stimulate orexin receptors, both for the relief of symptoms in narcolepsy and to combat sleepiness in people without narcolepsy. Many people who do not have narcolepsy nevertheless occasionally experience the cataplexy that accompanies narcolepsy (Denis, 2018). Sleep paralysis is the temporary inability to move or talk either just before dropping off to sleep or, more often, just after waking. In this state, people may experience sudden sensory hallucinations (Ghibellini and Meier, 2023), including the belief that something is crushing their chest. Sleep paralysis never lasts more than a few minutes, so it’s best to relax and avoid panic. One hypothesis is that sleep paralysis results when the pontine center (see Figure 10.20C) continues to impose paralysis for a short while after a person awakes from a REM episode. Some minor dysfunctions are associated with non-REM sleep Some dysfunctions associated with sleep are much more common in children than in adults. Two sleep disorders in children—night terrors (described earlier) and sleep enuresis (bed-wetting)—are associated with SWS. Most people grow out of these conditions without intervention, but pharmacological approaches can be used to reduce the amount of stage 3 sleep (as well as REM time) while increasing stage 2 sleep. For sleep enuresis, some doctors prescribe a nasal spray of the hormone vasopressin (see Chapter 9) before bedtime (Van Herzeele et al., 2017), which decreases urine production. Somnambulism (sleepwalking) consists of getting out of bed, walking around the room, and appearing awake. Although more common in childhood, it sometimes persists into adulthood. These episodes last a few seconds to minutes, and the person usually does not remember the experience. Because such episodes occur during stage 3 SWS, they are more common in the first half of the night when that stage predominates. Likewise, episodes of “sexsomnia,” when adults have sex but afterward have no memory of it (Idir et al., 2022), happen during non-REM sleep, early in the night. Narcolepsy and other sleep disorders (TABLE 10.2) have made sleep disorder clinics common in major medical centers. TA B LE 1 0 . 2 Classification of Sleep Disorders with Some Examples INSOMNIAS PARASOMNIAS Chronic insomnia (more than 3 months) NREM-related parasomnias Paradoxical insomnia (sleep state misperception) Night terrors Inadequate sleep hygiene Sleepwalking (somnambulism) Drug-related insomnia REM-related parasomnias Insomnia associated with psychiatric disorders Nightmares Short-term insomnia (less than 3 months) Recurrent sleep paralysis SLEEP-RELATED BREATHING DISORDERS REM behavior disorder (RBD) Obstructive sleep apnea Sleep enuresis (bed-wetting) Central sleep apnea SLEEP-RELATED MOVEMENT DISORDERS CENTRAL DISORDERS OF HYPERSOMNOLENCE Restless legs syndrome Narcolepsy Bruxism (teeth grinding) Hypersomnolence associated with psychiatric disorder Sleep-related myoclonus (sleep starts) Hypersomnolence due to medication or substance SLEEP-RELATED MEDICAL AND NEUROLOGICAL DISORDERS CIRCADIAN RHYTHM SLEEP-WAKE DISORDERS Fatal familial insomnia Shift work disorder Sleep epilepsy Jet lag disorder Sleep headaches Source: American Academy of Sleep Medicine, 2014. International Classification of Sleep Disorders, 3rd ed. American Academy of Sleep Medicine: Darien, IL. Some people appear to be acting out their nightmares While most sleepwalkers are not acting out a dream, there is a disorder where people appear to be acting out a dream. REM behavior disorder (RBD) is characterized by organized behavior —such as fighting an imaginary foe, eating a meal, or acting like a wild animal—by a person who appears to be asleep. Sometimes the person remembers a dream that fits well with their behavior (Fasiello et al., 2022), like the man in the low-light video on our website (FIGURE 10.24). This disorder usually begins after the age of 50 and is more common in men than in women. Individuals with RBD are reminiscent of the cats with a lesion near the locus coeruleus, mentioned earlier, that were no longer paralyzed during REM and so acted out their dreams. In both cases, they no longer benefit from brainstem inhibition of motor neurons that would normally prevent them from moving (Figorilli et al., 2021). Unfortunately, the onset of RBD is often followed by symptoms of Parkinson’s disease and dementia (Abbott and Videnovic, 2014), suggesting that the disorder marks the beginning of widespread neurodegeneration. The breakdown appears to begin in the brainstem region that imposes muscle atonia (see Figure 10.19) (Peever et al., 2014). RBD may be controlled by antianxiety drugs (benzodiazepines like Valium) taken at bedtime. FIGU R E 1 0 . 2 4 Battling in Your Dreams View larger image People with insomnia have trouble falling asleep or staying asleep Almost all of us have trouble falling asleep on occasion, but many people persistently find it difficult to get as much sleep as they would like. Depending on the definition used for insomnia, its prevalence ranges from 10 percent to 40 percent of the adult population (Mai and Buysse, 2008), and it became even more prevalent during the COVID pandemic (AlRasheed et al., 2022). Insomnia is more commonly reported by older people, females, and users of drugs like tobacco, caffeine, and alcohol. It is not a trivial disorder; recall that adults who regularly sleep for short periods show a higher mortality rate than those who regularly sleep 7–8 hours each night (Vgontzas et al., 2010). Insomnia seems to be the final common outcome for various conditions. Situational factors such as shift work, time zone changes, and changes in the daily routine (that hard motel bed) can lead to insomnia. Usually these conditions produce transient sleep-onset insomnia, a difficulty in falling asleep. Drugs, as well as neurological and psychological factors, seem to cause sleepmaintenance insomnia, a difficulty in remaining asleep. In this type of insomnia, sleep is punctuated by frequent nighttime arousals. People with sleep state misperception (Lichstein, 2017; Rezaie et al., 2018) report that they didn’t sleep even when the EEG showed signs of sleep and they failed to respond to stimuli. They are sleeping without knowing it. Sometimes these people, upon learning that they really are sleeping, are more satisfied with the sleep they get. In some people, respiration becomes unreliable during sleep. Breathing may cease for a minute or so, or it may slow alarmingly; blood levels of oxygen drop markedly. This syndrome, called sleep apnea, arises either from the progressive relaxation of muscles of the chest, diaphragm, and throat cavity or from changes in the pacemaker respiratory neurons of the brainstem. In the former instance, relaxation of the throat obstructs the airway—a kind of selfchoking. This mode of sleep apnea is common in very obese people, but it also occurs, often undiagnosed, in non-obese people. Sleep apnea is frequently accompanied by loud, interrupted snoring, so loud snorers should consult a physician about the possibility that they have sleep apnea. Investigators have speculated that sudden infant death syndrome (SIDS, or crib death) arises from sleep apnea as a result of immature systems that normally control respiration. Autopsies of SIDS victims reveal abnormalities in brainstem serotonin systems (Kinney and Haynes, 2019); interfering with this system in mice renders them unable to regulate respiration effectively (Audero et al., 2008). Since the start of the Safe to Sleep campaign, which urges parents to place infants on their backs to sleep rather than on their stomachs, the incidence of SIDS is less than a third what it was before (FIGURE 10.25). Placing the baby face down may lead to suffocation if the baby cannot regulate breathing or arouse properly. Exposure to cigarette smoke also increases the risk of crib death. FIGU R E 1 0 . 2 5 Back to Sleep View larger image Although many drugs affect sleep, there is no perfect sleeping pill Throughout recorded history, humans have reached for substances to enhance sleep. Ancient Greeks used opium from the juice of the poppy, as well as products of the mandrake plant, to aid sleep. The preparation of barbituric acid in the mid-nineteenth century started the development of many drugs—barbiturates—that were widely used to combat insomnia. Most modern sleeping pills—including benzodiazepines (see Chapter 4), like triazolam (Halcion), and nonbenzodiazepine sedatives, the “Z drugs” like zolpidem (Ambien) and eszopiclone (Lunesta)—bind to GABA receptors, inhibiting broad regions of the brain. But reliance on sleeping pills poses many problems (Carr, 2018). Viewed solely as a way to deal with sleep problems, current drugs fall far short of being a suitable remedy, for several reasons. First, even the newest class of sleeping pills produce little more sleep than placebos (Huedo-Medina et al., 2012). Second, continued use of sleeping pills causes them to lose effectiveness (Walker, 2017), and this declining ability to induce sleep often leads to increased self-prescribed dosages that can be dangerous. Another major drawback is that sleeping pills produce marked changes in the pattern of sleep, both while the drug is being used and for days afterward. Use of sleeping pills may lead to a persistent “sleep drunkenness,” coupled with drowsiness, that impairs waking activity, or to memory gaps about daily activity. Police have reported cases of “Ambien drivers,” people who have taken a sleeping pill and then got up a few hours later to go for a spin, with sometimes disastrous results, while apparently asleep (Farkas et al., 2013). In other cases, people taking such medicines eat snacks, shop over the internet, or even have sex, with no memory of these events the next day (Poceta, 2011). Everyone should practice good sleep hygiene Certainly, the treatment for insomnia that has the fewest side effects, and that is very effective for most people, is not to use any drug, but to practice good sleep hygiene. One strategy is to develop a regular routine to exploit the body’s circadian clock. The best advice for people with insomnia is to use an alarm clock to wake up faithfully at the same time each day (weekends included, FIGURE 10.26) and then simply go to bed once they feel sleepy. They should also avoid daytime naps and having caffeine at night. Going through a bedtime routine in a quiet, dark environment can also help to condition sleep onset. Melanopsin, the retinal photopigment that tells the SCN about light and dark, is especially sensitive to bluish light (Gooley et al., 2010), such as the light that comes from LCD screens. So avoiding the use of smartphones and laptops at bedtime (or at least dimming their light) can thus improve sleep (Bedrosian et al., 2013). These steps will let you get the sleep you need (TABLE 10.3), and sleeping pills will not (no matter what the millions of dollars in annual pharmaceutical advertising might say). FIGU R E 1 0 . 2 6 Sleeping In on the Weekend View larger image TA B LE 1 0 . 3 Sleep Hygiene Tips Keep your internal clock set with a consistent sleep schedule (get up at the same time each day). Seek sunlight in the daytime, avoid lights at night. Turn your bedroom into a sleep-inducing environment. Avoid caffeine, alcohol, and nicotine before bedtime. Establish a soothing presleep routine. Only go to sleep when you’re truly tired. If you’re going to nap, do it early in the day. Lighten up on evening meals. Balance fluid intake to avoid night trips to the bathroom. Avoid using computer screens before bedtime. Don’t exercise late in the day. Source: Healthy Sleep, http://healthysleep.med.harvard.edu/healthy/getting/overcoming/tips Unfortunately, many college students adopt schedules that virtually guarantee they won’t get enough sleep. Waking up early on Monday and Wednesday to attend one class, sleeping a bit later on Tuesday and Thursday, and then sleeping a lot later on weekends disrupts your circadian sleep cycle, making it hard to fall asleep when you should on the nights before an early class. It’s unpopular advice, but if you want enough sleep, get up at the same time every day, not just the days you have that early class, and go to bed about the same time each night. True, you’ll miss out on some late-night activities with your friends, but you’ll get to feel so self-righteous being awake and working while they are sleeping in. Plus you’ll stay awake in lectures (we hope). How’s It Going? 1. What is narcolepsy, and what brain system seems to be responsible for this disorder? 2. During what stage of sleep does sleepwalking tend to happen? During what time of night? 3. What are the different types of insomnia, and why are sleeping pills an imperfect long-term solution? 4. Describe REM behavior disorder. FOOD FOR THOUGHT As people age, many find themselves awake for an hour or two in the middle of the night. Can you think of any adaptive function this might have fulfilled in the past? RECOMMENDED READING Aserinsky, E., and Kleitman, N. (1955). Regularly occurring periods of eye motility, and concomitant phenomena, during sleep. Science, 118, 273–274. Forger, D. B. (2017). Biological Clocks, Rhythms, and Oscillations: The Theory of Biological Timekeeping. Cambridge, MA: MIT Press. Kryger, M. K., Roth, T., and Goldstein, C. A. (Eds.). (2022). Principles and Practice of Sleep Medicine (7th ed.). Philadelphia, PA: Saunders/Elsevier. Leschziner, G. (2019). The Nocturnal Brain: Nightmares, Neuroscience, and the Secret World of Sleep. New York, NY: St. Martin’s Press. McNamara, P. (2019). The Neuroscience of Sleep and Dreams. Cambridge, UK: Cambridge University Press. Walker, M. (2017). Why We Sleep: Unlocking the Power of Sleep and Dreams. New York, NY: Scribner. Zadra, A., and Stickgold, R. (2021). When Brains Dream: Exploring the Science and Mystery of Sleep. New York, NY: W. W. Norton. VISUAL SUMMARY You should be able to relate each summary to the adjacent illustration, including structures and processes. The online version of this Visual Summary includes links to figures, animations, and activities that will help you consolidate the material. Visual Summary Chapter 10 View larger image LIST OF KEY TERMS alpha rhythm basal forebrain Biological rhythms cataplexy circadian rhythms delta waves desynchronized EEG ecological niche electroencephalography (EEG entrainment fatal familial insomnia free-running general anesthetics infradian isolated brain isolated forebrain K complexes locus coeruleus melanopsin melatonin narcolepsy Nightmares night terror non-REM sleep orexin period phase shift rapid-eye-movement (REM) sleep REM behavior disorder (RBD) reticular formation retinohypothalamic pathway sleep apnea sleep deprivation sleep enuresis sleep-maintenance insomnia sleep-onset insomnia Sleep paralysis sleep recovery sleep spindles sleep state misperception Somnambulism stage 1 sleep stage 2 sleep stage 3 sleep sudden infant death syndrome (SIDS suprachiasmatic nucleus (SCN) tuberomammillary nucleus ultradian vertex spikes zeitgeber