Normal sleep mechanisms & why do we sleep?

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Merilyn Turner
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1 4 rd Congress of the European Academy of Neurology Lisbon, Portugal, June 16-19, 2018 Teaching Course 18 Basics of sleep medicine - Level 1 Normal sleep mechanisms & why do we sleep? Rolf Fronczek Leiden, The Netherlands r.fronczek@lumc.nl

2 Learning Objectives (1) Gain basic knowledge about sleep mechanisms (2) Gain insights in the current thought about why we sleep Conflict of interest: The author has no conflict of interest in relation to this manuscript 1

During our lives we are estimated to sleep around 27.000 nights. This amounts to around 200.000 hours. Sleep must thus be of great benefit to us.

3 During our lives we are estimated to sleep around nights. This amounts to around hours. Sleep must thus be of great benefit to us. Why else would we spend such a large part of our lives sleeping? But what is sleep exactly? And why do we sleep? It is difficult to find a good definition of sleep. This is one workable definition: Sleep is a quickly reversible state characterized by decreased reactivity, decreased motor activity and decreased metabolism. 2

Sleep is divided in different sleep stages: stage 1, 2, slow wave sleep (SWS) and Rapid Eye Movement (REM)-sleep. Stage 1, 2 and SWS are combined as NON-REM sleep (versus REMsleep).

4 Sleep is divided in different sleep stages: stage 1, 2, slow wave sleep (SWS) and Rapid Eye Movement (REM)-sleep. Stage 1, 2 and SWS are combined as NON-REM sleep (versus REMsleep). We are considered to have our lively, colorful dreams during REMsleep. However, there are also dream-like experiences reported during NON-REM sleep, often called sleep mentations, which are less colorful and feature less storylines than the dreams during REMsleep. During our lifetimes, we sleep less hours during each night. As you can see in the figure above, mainly the amount of SWS is decreased, but also the amount of REM-sleep, while there is more Wake after Sleep Onset (WASO). This could mean two things: (1) We just need less sleep when we age. (2) The neuronal systems responsible for sleep are degrading as we age, resulting in suboptimal sleep. Note, that sleep does not always have to be 100% recovered after sleep deprivation. In humans, only a 30% increase in recovery sleep is seen. 3

5 Most theories about the role of sleep are derived in an indirect way: from what happens when we don t sleep. Sleep deprivation can lead to decreased vigilance, the metabolic syndrome, mood disorders and decreased immune function. Sleep itself is considered to be important for learning, emotional processing and neurogenesis. However, these theories are difficult to prove directly. In order to form our thought regarding the role of sleep, we need to consider the following things: The fact that processes take place during nocturnal sleep, does not directly mean that these processes are directly linked to sleep itself. It might have been beneficial during evolution to have moved certain processes to the night. Most knowledge has been gathered by sleep deprivation experiments, never by directly influencing sleep itself. 4

6 Many things we know about sleep have been studied in animals in the wild and in experiments in zebrafish, nematodes and fruitflies. Many lifeforms show periods of inactivity, such as yeast, pine cones, trees, rotifers, moths and snails. Mammals and birds show periods with either high or low activity. This shows that the existence of these processes varies between species and is thus adaptive, a product of evolution. Low activity: Hibernation in the ground squirrel Torpor in hummingbirds Sleep as we know it High activity: Periods of sleeplessness in the walrus Reduced sleep during migration in birds Constant activity without sleep for days post-partum in killer whales 5

Phylogenetics is the study of the evolutionary history and relationships among individuals or groups of organisms (e.g. species, or populations).

7 Phylogenetics is the study of the evolutionary history and relationships among individuals or groups of organisms (e.g. species, or populations). One could think that species that share a place in the phylogenetic tree, would display similar sleep characteristic. However, this is not the case: Our house cats sleep 12.5 hours with 3.2 hours of REM-sleep, while a genet cat sleeps only 6.3 hours with 1.3 hours of REM-sleep. An owl monkey sleeps 17 hours with 1.9 hours of REM-sleep, while we humans sleep 8.0 hours with 1.9 hours of REM-sleep. Interestingly, we have a similar sleep pattern as the eastern American mole: 8.4 hours of sleep with 2.1 hours of REM-sleep. One could think that larger brains need more sleep. This is not the case. A small bushtail possum needs 18 hours of sleep, while a great elephant needs only 3.9 hours of sleep. 6

At first, there does not seem to be a relation between body weight and sleep duration. When only looking at carnivores, this relation is still absent.

8 At first, there does not seem to be a relation between body weight and sleep duration. When only looking at carnivores, this relation is still absent. However, in herbivores, there is a clear and significant relation between body weight and sleep duration: The heavier the herbivore, the less sleep. More time is needed to consume large amounts of food. Apparently, sleep adapted itself during evolution in these animals to allow for this. To conclude this part: Periods with inactivity exist in many organisms, also in organisms without a central nervous system. There is relation between sleep duration, phylogenetic order or brain size. Herbivores sleep less than carnivores and omnivores. In herbivoren there is a reverse relation between sleep duration and body weights. More wake time is needed to consume enough food. 7

9 More recent work points towards another reason why we might need sleep. Sleep might be useful for the removal of waste products after all. The glymphatic pathway is a recently described clearance system consisting of perivascular channels, formed by astroglial cells. During sleep, there is an increased flow of fluids in this system (the green line in figure C versus the orange line), thus an increased ability to remove waste from the brain, including amyloid-beta. After sleep, an increased amount of amyloid-beta was measured in the lumbar cerebrospinal fluid versus after a period of wakefulness. This might mean that more amyloid-beta is removed from the brain after sleep, through this glymphatic pathway. 8

10 There are several brain nuclei (red in the figure) that are active during wakefulness. These are called the mono-aminergic wake-active nuclei, for example: Tuberomammillary nucleus, which produces histamine Dorsal raphe nucleus, which produces serotonin Locus caeruleus, which produces norepinephrine There is one brain nucleus active during sleep (purple in the figure): The ventro-lateral pro-optic nucleus, a gaba-ergic nucleus In the lateral hypothalamus there is another neuronal cell group that is important in the regulation of sleep and wakefulness (green in the figure): The hypocretin-producing neurons These neurons can be seen as the conductor of the orchestra of sleep and wakefulness, since they play a major role in sleep-wake regulation. 9

11 The flip-flop model explains how the wake- and sleep-active brain nuclei interplay (top figure). The wake-active mono-aminergic nuclei (red) inhibit the activity of the sleep-active ventrolateral pre-optic (VLPO) nucleus (purple) The VLPO inhibits the activity of the wake-active nuclei So both the sleep and the wake nuclei reciprocally inhibit each other. In this way, intermediate states are avoided. The system is either awake of asleep. (down left figure) However, a small disturbance can tip the system towards the other side. When awake, one can quickly tip to the sleep side, or vice versa. The flip-flop system is thus inherently unstable. Hypocretin neurons are active during wakefulness and stabilize the flipflop at the wake-side (down right figure) Wakefulness is thus consolidated, and the system is less likely to tip to the other side because of his. When hypocretin neurons are lost (as is the case in the sleep disorder narcolepsy) the system becomes unstable with frequent transitions. 10

12 The flip-flop model explains transitions between sleep and wakefulness, but not homeostatic and circadian influences. These can be explained by the following two processes: Proces S the homeostatic process & Proces C the circadian process Proces S: During wakefulness, there is a constant build-up of sleep pressure. The longer we are awake, the greater becomes the need to sleep. This process is proposed to be partly mediated by adenosine as a result of neuronal metabolism. During sleep, there is rapid decrease in sleep pressure. Proces C: The biological clock is formed by a group of neurons in the hypothalamus, the suprachiasmatic nucleus (SCN). These neurons fire in a circadian pattern. The bottom graph shows the mathematical interaction of process S and C. When the SCN neurons are firing, sleep is suppressed. However, at the end of the day the firing rate decreases, while the homeostatic sleep pressure has steadily increased. When the gap between the to processes becomes to large, sleep is initiated. Sleep pressure quickly decreased and the processes start again the next day. 11

13 Electroencephalographic (EEG) patterns during sleep: Wake (eyes open): Mostly irregular and high frequency (beta, Hz) EEG activity Wake (eyes closed): 8-12 Hz alpha Waves occur, mostly in the occipital brain areas Stage 1 (non-rem sleep): The alpha waves disappear ( alpha drop-out ), slow oscillating eye movements Stage 2 (non-rem sleep): Higher voltage K-complexes occur, and 14 Hz sigma waves (sleep spindles). Stage 3 (non-rem, slow wave sleep): 1-4 Hz delta waves occur REM-Sleep: EEG patterns suddenly similar to wake, but with rapid eye movements and loss of muscle tone Sleep is scored in 30-second epochs according to the American Academy of Neurology (AASM) scoring rules (Iber et al, 2007), based upon the original scoring rules by Rechtschaffen & Kales (R&K). 12

14 A normal hypnogram 90-minute sleep cycles First one-third of the night: mainly slow-wave sleep Last part of the night: longest REM-sleep periods 13

Sleep, Dreaming and Circadian Rhythms

Sleep, Dreaming and Circadian Rhythms People typically sleep about 8 hours per day, and spend 16 hours awake. Most people sleep over 175,000 hours in their lifetime. The vast amount of time spent sleeping