Shining Evolutionary Light on Human Sleep and Sleep Disorders Downloaded from Charles L

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review Evolution, Medicine, and Public Health [2016] pp. 227–243 doi:10.1093/emph/eow018

Shining evolutionary light on human sleep and sleep disorders Downloaded from Charles L. Nunn*,1,2,3, David R. Samson1 and Andrew D. Krystal4

1Department of Evolutionary Anthropology, Duke University, Durham, North Carolina 27708, USA; 2Duke Global Health Institute, Durham, North Carolina 27710, USA; 3Triangle Center for Evolutionary Medicine, Durham, NC 27708, USA and 4Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, NC 27710 http://emph.oxfordjournals.org/ *Correspondence address. Department of Evolutionary Anthropology, Duke University, Durham, North Carolina 27708, USA; Tel: 919 660 7281; E-mail:[email protected] Received 25 March 2016; revised version accepted 15 June 2016

ABSTRACT Sleep is essential to cognitive function and health in humans, yet the ultimate reasons for sleep—i.e. ‘why’ sleep evolved—remain mysterious. We integrate findings from human sleep studies, the ethno- at Duke University Law School on August 4, 2016 graphic record, and the ecology and evolution of mammalian sleep to better understand sleep along the human lineage and in the modern world. Compared to other primates, sleep in great apes has undergone substantial evolutionary change, with all great apes building a sleeping platform or ‘nest’. Further evolutionary change characterizes human sleep, with humans having the shortest sleep duration, yet the highest proportion of rapid eye movement sleep among primates. These changes likely reflect that our ancestors experienced fitness benefits from being active for a greater portion of the 24-h cycle than other primates, potentially related to advantages arising from learning, socializing and de- fending against predators and hostile conspecifics. Perspectives from evolutionary medicine have implications for understanding sleep disorders; we consider these perspectives in the context of insomnia, narcolepsy, seasonal affective disorder, circadian rhythm disorders and sleep apnea. We also identify how human sleep today differs from sleep through most of human evolution, and the implications of these changes for global health and health disparities. More generally, our review highlights the importance of phylogenetic comparisons in understanding human health, including well-known links between sleep, cognitive performance and health in humans.

KEYWORDS: sleep disorder; evolutionary mismatch; comparative study; phylogeny; human health; human evolution.

INTRODUCTION decision-making, and visual-motor performance [1– Sleep is essential to cognitive function and health in 3]. Chronic sleep deprivation and alterations in cir- humans. For example, experiments have shown that cadian rhythms, such as shift work, also increase the sleep is important for working memory, attention, risks for obesity, hypertension, heart disease and

ß The Author(s) 2016. Published by Oxford University Press on behalf of the Foundation for Evolution, Medicine, and Public Health. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. 228 | Nunn et al. Evolution, Medicine, and Public Health

immune system dysfunction, which may increase concepts, such as tradeoffs, are important for under- the risks for infection, inﬂammation, and some types standing human sleep. of cancer [4–8]. In the USA, 50–70 million Americans We begin by considering patterns of human sleep suffer from chronic sleep disorders, and 20% of ser- in relation to other primates, including the ways that ious automobile accidents are attributable to sleep human sleep differs from our close evolutionary rela- deprivation [9]. Although less is known about global tives. We also review recent hypotheses involving variation in sleep patterns [10], rates of sleep prob- sleep and infants [23, 24]. In an effort to understand lems and chronic sleep deprivation are probably the reasons why human sleep differs from other pri- increasing in developing countries, where aging mates, we review our knowledge of sleep patterns populations, transitions to market economies, and across mammals, focusing on the correlates of that adoption of Western lifestyles are altering sleep pat- variation. We also provide evolutionary perspectives terns [11–13]. on several major sleep disorders, and on links be- Despite growing appreciation of the importance tween poor or disrupted sleep and health disparities.

of sleep, the ultimate reasons for sleep remain mys- We suggest that sleep deprivation is a largely unrec- Downloaded from terious. Sleep appears to help rejuvenate the brain, ognized global health problem that may contribute including purging byproducts of metabolism that to both infectious and non-infectious disease risks accumulate during the day [14]. The growing realiza- in developing countries, and to health disparities in tion that sleep interconnects deeply with many other developed countries. physiological and cognitive mechanisms suggests http://emph.oxfordjournals.org/ that sleep has many functions, including growth HUMAN SLEEP IN PRIMATE and repair of the body (e.g. release of growth hor- PERSPECTIVE mone, 15), immune function [16, 17], and even adaptive stillness to avoid predation [18, 19]. These Most primate species are arboreal, and this appears functions are likely to vary in importance across spe- to be the ancestral state for primates [25]. Kappeler cies, including in humans compared to other pri- [26] used primate life history traits to reconstruct the mates. In addition, evolutionary perspectives evolutionary history of sleep site usage. His analysis at Duke University Law School on August 4, 2016 involving tradeoffs are important for understanding revealed that the ancestral primate probably sleep, including tradeoffs between sleep and other resembled extant galagos: they were likely to be noc- fitness relevant activities such as foraging or caring turnal, solitary and producing a single offspring that for offspring, and also pleiotropic effects of genes on was provisioned in a tree-hole nest, or ‘fixed-point’ sleep and related physiological processes. sleep site. A primary advantage of these fixed-point We need to understand why humans sleep the way sleep sites may have been increased safety from we do, why sleep deprivation is so detrimental to our predators [27], along with improved thermoregula- health through various neurological and physio- tion [28]. logical mechanisms, and how we can sleep better. Like many other mammals, the primate lineages Here, we integrate recent findings from human sleep emanating from the Paleocene evolved increased studies and the ecology and evolution of sleep, with body size [29, 30]. This increase in body size led pri- the goal to deepen our understanding of human mates on many of these lineages to abandon fixed- sleep, including sleep disorders and the global point sleep sites, as naturally occurring enclosed health implications of sleep deficiency. A central sites would be challenging for larger animals to find. premise of our article is that human sleep has Similarly, the evolution of diurnal activity patterns— undergone changes from our primate ancestors and associated shifts to living in larger groups [31]— [20, 21]. These derived characteristics (and their cor- would have made it even more difficult for larger relates) may hold important clues to understanding groups of animals to locate fixed point sleep sites. the links between sleep, cognitive performance and These factors led early primates to abandon the ad- human health. Another premise is that humans in vantages of enclosed and sturdy sleep sites, and to the developed world sleep differently than our ances- instead sleep on tree branches. Sleeping on tors did [21, 22]. These changes partly arise through branches would have exposed these animals to increased access to electrical lighting in the de- increased risks from predation and to falling, espe- veloped world, but also through our use of separate cially because wind speeds, with punctuated gusts, bedrooms, soft beds and cultural norms against day- are greater in the canopy [32]. Indeed, the primat- time napping. A final premise is that evolutionary ology literature provides multiple accounts of Shining evolutionary light on human sleep Nunn et al. | 229 primates falling from arboreal sleeping sites, result- of interfering (i.e. distracting) activities, sleep plays ing in injuries and death [33, 34]. a role in memory consolidation in chimpanzees, bonobos and orangutans. Increased body mass likely also played a role in the Great ape sleep origins of great ape sleeping platforms [21]. In par- A major evolutionary transition in sleep likely ticular, larger-bodied great apes would find it more occurred in the ancestor of the great apes: humans, difficult to sleep on tree branches. This effect would orangutans, gorillas, chimpanzees and bonobos all have favored individuals that built more resilient build platforms (or ‘nests’) upon which to sleep sleeping platforms to reduce the probability of lethal [35–37]. Great ape sleeping platforms show a falls, and to reduce physical stressors on the bodies conserved pattern of construction and function, of sleeping individuals. A distinct mass threshold and phylogenetic reconstruction points to emer- (30 kg) has been proposed that separates the great gence of this sleeping behavior sometime between apes that use sleeping platforms from the lesser

18 and 14 million years ago [38]. Typically, these apes and monkeys that do not [21, 45]. Once the Downloaded from platforms are built in trees that are selected for their use of sleeping platforms evolved, this could have firm, stable and resilient biomechanical properties enabled higher quality sleep within great apes, with [39–41]. Platforms are rebuilt each night, with each emergent cognitive benefits. individual (except dependent young) building a separate sleeping nest. In sharp contrast, the lesser http://emph.oxfordjournals.org/ Human sleep apes—the gibbons—do not build nests for sleeping. Instead, gibbons follow the pattern found in most Human sleep has undergone additional changes monkeys: they typically sleep on branches in a lying from other great apes in several key features. An or sitting position, with no environmental alter- obvious feature is where we sleep, namely on the ations [42, 43]. ground; among other apes, terrestrial sleep is rare, Why do great apes build sleeping platforms? occurring only when predation risk is low, and typic- Based on evidence showing a link between sleep ally only by very large bodied males [48–51]. In con- at Duke University Law School on August 4, 2016 and cognition in humans and great apes, the ‘sleep trast, humans of both sexes habitually sleep on the quality hypothesis’ proposes that more stable ground, which could plausibly provide even more sleeping sites provide physical support needed for stable sleeping locations to achieve even deeper large bodied hominoids to maintain deep, sustained sleep. Predation represents a major tradeoff in this sleep to enable enhanced cognitive function [37, 44, context, with risk of predator attack thought to in- 45]. An alternative ‘engineering hypothesis’ states crease for terrestrial primates [52, 53]. that great ape platform building simply reflects In relation to human ground sleep, Coolidge and greater cognitive ability, which enables the great Wynn [54] proposed the ‘tree-to-ground hypothesis’. apes to build nests [44]. This is a simple reversal of They suggested that when hominins became fully cause and effect, where the cause is greater cognitive terrestrial they gained the advantage of greater sta- facility providing the opportunity to build effective bility than was possible in arboreal sleep. Freed from sleep platforms, rather than use of platforms to en- the disadvantages of arboreal sleep they could have able greater cognitive performance. achieved longer duration and higher quality sleep, Recent captive research on apes has tested two which would have improved waking cognition. crucial elements of the sleep quality hypothesis for Without terrestrial sleeping sites, they argue, fully the use of sleeping platforms in great apes. In a zoo human procedural memory consolidation for vis- study, Samson and Shumaker [46]provided ual-motor skills and visual-spatial locations could orangutans with varied sleep materials, and then not have evolved. In addition, under the assumption scored the quality of sleeping platforms the that sleep plays a role in problem solving in social orangutans produced with different materials. and other domains involving ‘threat simulation’ [55], They found that sleeping platform quality was posi- they proposed that hominins would have been less tively correlated with reduced arousability and primed for daily activity due to less sleep the previ- lower sleep fragmentation (i.e. metrics of better ous night [20, 54]. quality sleep). In another study of zoo animals, The controlled use of fire may have been an essen- Martin-Ordas and Call [47] found that, by making tial precursor to secure ground sleep [20]. Arboreal memory more resistance to the detrimental effects sleeping platforms reduce predation risk [56] and 230 | Nunn et al. Evolution, Medicine, and Public Health

minimize insect biting rates by masking host attract- in developed countries [65] suggest that humans ants or actually repelling insects [57, 58]. Sleeping show flexibility in their sleep. In a review of human platforms also provide some insulation for warmth sleep across cultures, Worthman [22] noted that, [57], and give a stable and secure environment to ‘Human nights are filled with activity and signifi- enable higher quality sleep [39, 40]. A fire probably cance, and nowhere do people typically sleep from also reduces risk of predation and provides evening to dawn’ (p. 301). Similarly, reflecting on his opportunities for thermoregulation, while smoke re- study of the Piraha˜ hunter-gatherers in South duces insect activity [59, 60]. Control of fire in early America, Everett (66) noted, ‘Piraha˜s take naps (fif- Homo erectus may therefore have enabled the night- teen minutes to two hours at the extremes) during time transition from trees to the ground [20, 61]. the day and night. There is loud talking in the village Quantitative characteristics of human sleep have all night long’ (p. 79). Similar patterns appeared to also evolved along the human lineage. We consider occur in European and equatorial societies prior to here two major aspects: reduced total sleep and a the advent of cheap and effective lighting, with a

higher percentage of rapid eye movement (REM) historical analysis documenting extensive use of Downloaded from sleep [21]. Humans are empirically the shortest the concept of ‘first sleep’ and ‘second sleep’, con- sleeping primates and have the highest percentage sistent with a biphasic sleep pattern that differs rad- of REM (Fig. 1). New phylogenetic methods can ically from what we consider ‘normal’ in Western rigorously investigate evolutionary change on a sin- societies today [64, 67]. Flexibility can also occur in gle branch, allowing a comparative biologist to in- the context of daytime sleep, i.e. the occurrence of http://emph.oxfordjournals.org/ vestigate whether an exceptional amount of napping or siestas. For example, Pennsylvanian Old evolutionary change has occurred [62, 63]. More spe- Order Amish, a conservative Christian sect that cifically, these methods compare actual sleep char- avoids modern electrical conveniences, have been acteristics in humans to the predicted outcomes characterized as ‘common’ nap-takers, with 58% from a statistical model that includes both phyl- of the population recording a nap a least once per ogeny and a set of predictor variables that influence week [68]. sleep characteristics. One can then test whether Counter to these findings and suggestions, how- at Duke University Law School on August 4, 2016 humans are a typical primate (our observed sleep ever, a recent study of sleep in three hunter-gatherer duration falls within the predicted 95% credible populations [69] interpreted their actigraphy data as interval) or a ‘phylogenetic outlier’ (our sleep dur- indicating consolidated sleep at night and with little ation falls outside the predicted 95% credible napping during the day, and thus arguing against the interval). flexibility of sleep. This presents a challenge, and Using this approach, Samson and Nunn [21] dis- calls for better methods of assessing sleep phasing covered that human sleep duration is extremely dif- using actigraphy, including through use of new al- ferent from phylogenetic predictions: our actual gorithms, validation with reported episodes of sleep sleep duration falls outside the 95% credible inter- and wakefulness, and development of new methods val, suggesting that we can be more than 95% cer- to better assess sleep without reliance on actigraphy. tain that human sleep differs from other primates. It should be noted, however, that this study also re- As we discuss below when considering the potential vealed considerable heterogeneity in sleep onset evolutionary drivers of shorter sleep along the time (but less in awakening), consistent with flexi- human lineage, tradeoffs between sleep and other bility in the timing of sleep. activities are likely to be important factors. When Given the global distribution of humans, adaptation this same approach was applied to study the propor- to local conditions may be expected for sleep, as seen tion of REM sleep in humans, the analyses revealed for other human phenotypes. One obvious aspect of that humans pack a higher proportion of REM into this involves latitude, and the effects of large changes their sleep than any other primate. It is worth noting, in day-length throughout the year. Unfortunately, how- however, that some other primates have a longer ever, sleep research in circumpolar environments has absolute duration of REM sleep (see Fig. 1). primarily focused on European populations [70, 71] As a last point of comparison to other primates, and the effects of latitude on the physiology of military humans may be more flexible in the timing of sleep personnel [72]. Thus, little is known regarding the than our closest living relatives. Evidence from effects of seasonally variable day–night cycles on the small-scale societies and subtropical hunter-gath- sleep-wake patterns of nonindustrial indigenous erers [22], the historical record [64] and experiments populations [12]. Moreover, reports of sleep in Shining evolutionary light on human sleep Nunn et al. | 231 Downloaded from http://emph.oxfordjournals.org/ Figure 1. Duration of REM, NREM and total sleep in primates. Humans sleep the least compared to all other primates, yet have the greatest proportion of total sleep time dedicated to REM at Duke University Law School on August 4, 2016

Figure 2. Infant versus adult sleep. A sleep comparison between polyphasic human infant and consolidated sleep in an adult living in a post-industrial society (adapted from reference [75])

post-industrial societies have shown conflicting into a polyphasic sleep schedule consisting of at first evidence and small effects with respect to sleep two naps and one bout of night-time sleep, and even- duration across seasons [73, 74]. Several factors tually one and then no naps (with longer may influence the outcome of such studies, consolidated sleep at night). Furthermore, infant including lack of direct exposure to changes in sleep is characterized by larger amounts of REM light and temperature among participants in la- sleep, suggesting that REM sleep may have import- boratory environments, or the environmental buf- ant consequences for the developing brain [76]. fer provided by modern work and residential Infant sleep is important to the evolutionary story facilities. In contrast, evidence supports the idea of sleep in two other ways: one involves the role of that sleep is modulated by season in traditional, infant-parent co-sleeping, and the other involves in- equatorial societies; e.g. longer total sleep times fant crying. (53–56 min increase) were associated with the ‘win- Infant-parent co-sleeping has attracted much at- ter’ season in the San and Tsimane [69]. tention in recent decades, with parents faced with the dilemma of sleeping with the baby versus putting the baby in a separate room. All discussions of co- Sleep and human development sleeping should begin by appreciating how radically Ontogeny can also shed light on human sleep. As all novel it is for dependent children to even have the parents know, babies sleep a lot, yet they are born option to sleep separately from their caregivers. without a regular sleeping rhythm (Fig. 2). The chaos Throughout evolutionary history, families slept to- of sleep phasing in the first days of life consolidates gether, possibly with extended family members, 232 | Nunn et al. Evolution, Medicine, and Public Health

and the same is true in many traditional societies As noted by Haig [23], the explicit inter-gener- today [59, 77]. It is only in modern living condi- ational and intra-genomic conflicts in his proposal tions—with increased safety and availability of sep- challenge the assumption of mother–infant co- arate bedrooms for parents and children—that the sleeping as a highly co-evolved and harmonious sys- dilemma of infant–parent co-sleeping arises. tem that was suggested above in some of the re- James McKenna was among the first anthropolo- search on co-sleeping. Instead, Haig’s [23] gists to investigate mother–infant night-time inter- research suggests a need to appreciate that substan- actions empirically, often injecting an evolutionary tial parent-offspring conflict likely exists even in the perspective [78, 79]. In some of this research, the context of sleep. investigators found that bed-sharing resulted in less deep sleep for mothers and infants, but more sim- MAMMALIAN SLEEP IN COMPARATIVE ultaneous awakenings by mothers and infants that AND THEORETICAL PERSPECTIVE were associated with more breastfeeding [24]. Thus,

mothers would tend to awaken or transition between To understand the reasons for short human sleep Downloaded from sleep states at times when babies were also likely to discussed above (Fig. 1), we can turn to comparative awaken, resulting in less disruption to the mothers’ variation in mammalian sleep to ask, ‘what are the sleep cycles and a higher feeding frequency for in- factors that influence sleep durations across spe- fants [80]. Overall, these studies demonstrate a mu- cies?’ Are these factors related to the function of tually reinforcing relationship between mother– sleep, for example involving the brain, or circadian http://emph.oxfordjournals.org/ infant co-sleeping and feeding, probably reflecting release of growth hormone? Or are ecological factors correlated evolution among these behaviors. more informative of sleep durations, perhaps be- This research has been used to inform the poten- cause they constrain how much time is available tial risks associated with solitary sleep practices; e.g. for sleep? This comparative perspective can help un- the lack of breastfeeding and solitary sleeping has cover the factors that have led humans to sleep so been identified as a risk factor for sudden infant differently from other primates (and perhaps more death syndrome (SIDS), suggesting that less deep similarly to other mammals). Although many earlier at Duke University Law School on August 4, 2016 sleep in infants who were co-sleeping and breast- studies have investigated comparative patterns of feeding more regularly were at lower risk of SIDS sleep [86–88], here we focus on more recent studies [81, 82]. However, other studies have found that that made use of larger sample sizes and improved bed sharing also increases risk of SIDS, which may statistical-phylogenetic methods [63]. be amplified by factors such as infant age or use of Two independent research groups [89, 90] have alcohol or drugs [83]. investigated the phylogenetic, ecological and life his- The other insight to infant sleep comes in the con- tory drivers of sleep architecture, which is defined as text of infant crying, a feature not observed in chim- the quantitative structure and pattern of sleep. Sleep panzees [84]. Haig [23] revived and extended a architecture includes variables related to total sleep hypothesis [85] that night-time arousal and crying time, duration of REM and NREM sleep, duration of by infants is an adaptive behavior to extend inter- the NREM–REM cycle, and distribution of sleep birth intervals, benefiting the crying infant at the po- through the 24-h period into one or many bouts tential cost to parental reproductive success. (i.e. monophasic vs polyphasic, respectively). We Reviewing the literature, Haig [23] notes that shorter consider the major hypotheses for sleep duration inter-birth intervals lead to greater offspring mortal- that have been investigated comparatively, which fall ity, and that more night-time breastfeeding episodes into two broad categories: those in which ecological results in longer postpartum amenorrhea. Thus, factors, such as diet, influence sleep durations; and ‘natural selection will have preserved suckling and other hypotheses proposing that specific functional sleeping behaviors of infants that suppress ovarian benefits of sleep, such as memory consolidation, function in mothers because infants have benefited influence sleep architecture. Among the ecological from delay of the next birth’ (p. 34). Additionally, factors, several variables are considered to be im- Haig [23] incorporated modern perspectives of gen- portant: (i) predation risk, with longer sleep times omic conflict by considering how imprinted genes of expected when animals have access to a safe and maternal origin might favor more consolidated stable sleep site; (ii) metabolism, with higher metab- sleep, whereas genes of paternal origin promote olism either favoring more sleep to conserve energy, greater wakefulness. or less sleep to enable animals to better meet Shining evolutionary light on human sleep Nunn et al. | 233 nutritional needs; and (iii) body mass (or its correl- sleep stages [95]. This tradeoff perspective is highly ates), with larger bodied animals needing more re- relevant to understanding the short duration of sources and thus having less time for sleep. In terms human sleep: it suggests that if an animal has some- of functional benefits of sleep, one major hypothesis thing better to do than sleep (such as forage, court involves memory consolidation, with larger brained potential mates or watch for predators), natural se- animals proposed to need more sleep [91]. Another lection will favor shorter sleep durations. functional benefit involves immune function, with Based on these findings across mammals, we animals exposed to more parasites and pathogens argue that activities that are crucial for success in allocating more time to sleep and use of that “down- humans—such as learning new knowledge or skills, time” to reallocate energy to increase the standing and building and cementing social bonds through crops of disease-fighting leukocytes (and other po- social activity—are so important for reproductive tential mechanisms of improved immune defenses). success that natural selection has favored the expan- Lesku et al. [89, 92] and Capellini et al. [90] applied sion of these activities beyond daylight hours [21], new phylogenetic methods to investigate the evolu- despite the probable costs for cognitive, metabolic Downloaded from tionofmammaliansleep,workingindependentlyand and immune function. Sleeping on the ground likely with somewhat different methods and approaches. also increased risk of predation and potential for at- Fromthesestudies,wecandrawseveralconclusions. tacks by hostile conspecifics, favoring less sleep. First,predationriskappearstobeamajorpredictorof Although we hear many sleep scientists and doctors sleeparchitectureinmammals,withsaferoptionsfor lament the temptations of digital media as counter http://emph.oxfordjournals.org/ sleep leading to more sleep. Similarly, animals at to healthy sleep, the phylogenetic comparative re- lower trophic levels (e.g. herbivores) sleep less than sults from above suggest that natural selection has those at higher trophic levels (e.g. carnivores). been hard at work eroding human sleep for many Second, relative brain mass shows no association millennia. We therefore expect to find that across with sleep durations, but does covary positively with societies, humans run sleep debts, even among the percentage of REM sleep across mammals; spe- hunter-gatherers and traditional agriculturalists. In cific brain regions were also generally unrelated to support of this, recent work with actigraphy devices at Duke University Law School on August 4, 2016 sleeparchitecture,withtheexceptionoftheamygdala in three pre-industrial populations revealed that and NREM sleep [91]. Third, basal metabolic rate hunter-gatherers do not sleep more than ‘modern’ (with and without control for body mass) showed a humans, with average sleep durations of only 6.5 h negative association with sleep durations, suggest- per night [69]. Similarly, research on rural Haitian ing that greater metabolic needs in a lineage favors [95] and Malagasy agriculturalists [96] without ac- less sleep. Fourth, animals with longer gestation cess to electricity found that they also sleep only lengths sleep less, even after controlling for body 6.5–7 h per night on average. mass. Fifth, species with more sleep have higher white blood cell counts and possibly fewer parasites EVOLUTIONARY PERSPECTIVES ON [93]. Finally, the durations of REM and NREM sleep SLEEP DISORDERS covary positively [94]. This finding suggests that the total amount of time spent in different sleep stages Evolutionary perspectives can shine new light on does not strictly reflect specific functional benefits human health, in many cases providing new treat- associated with those states; instead, animals add ment options while also enhancing our understand- both REM and NREM when ecological conditions ing of the underlying causes of these disorders [97, provide opportunity for more sleep. 98]. Sleep biologists have engaged with evolutionary Overall, results from these studies suggest that perspectives for decades [86, 87, 99, 100], and some ecology is the primary driver of sleep durations, with studies from within and outside sleep medicine have evolution adjusting sleep durations across species applied an evolutionary perspective to investigate based on the benefits and costs of being awake for human sleep disorders [22, 59, 64, 101]. We consider predation, foraging and social interactions. In other some of these attempts. words, tradeoffs between sleep and other activities are more central to understanding comparative vari- Insomnia ation in sleep, and more so than functional benefits of sleep. Functional benefits may instead be Insomnia is defined as persistent difficulty falling or acquired through deeper sleep during particular staying asleep despite the adequate opportunity to 234 | Nunn et al. Evolution, Medicine, and Public Health

do so, and is associated with significant impairment Middle of night insomnia may represent a differ- in function or reduced quality of life; it has a popu- ent situation. As noted earlier, the historical record lation prevalence of 10% [102, 103]. Multiple lines in Europe indicates that many populations exhibited of evidence suggest that insomnia is generally a biphasic sleep pattern: a ‘first sleep’ that was inter- associated with a state of hyper-arousal, which in- rupted by middle-of-the night activity, followed by a cludes multiple alterations involving activation of ‘second sleep’ [64]. From this, it is reasonable to the sympathetic nervous system and diminished hypothesize that middle of night insomnia is a relic homeostatic drive for sleep [104, 105]. of a long-term, evolutionarily adaptive sleeping pat- Consistent with this framework, McNamara and tern. If biphasic sleep patterns were under selection Auerbach [101] considered insomnia to result from in populations that have experienced highly sea- stress and hyper-vigilance associated with some ex- sonal fluctuations in day length (i.e. at high lati- ternal threat. In essence, they viewed insomnia as an tudes), one would expect that middle-of-the night adaptive trait under circumstances of perceived insomnia characterizes individuals with ancestors

threat. In support of the view that sleep need can from these regions, perhaps for adaptive reasons Downloaded from be adjusted based on perceived threats, research such as ensuring one’s family is warm and well fed on insomniacs has revealed relatively less daytime during long winter nights. sleepiness and lower cognitive costs of sleep depriv- An alternative viewpoint should also be con- ation, when compared with the adverse conse- sidered. Middle of the night ‘awakening’ should be quences of depriving those without insomnia of differentiated from middle of the night ‘insomnia’; http://emph.oxfordjournals.org/ sleep [104, 106]. This suggests that individuals the former may be normal, while the latter patho- may sacrifice a small decline in cognitive function logical and representative of underlying problems for overall broader vigilance against a perceived with maintaining sleep. The hallmark of the non- threat. People diagnosed with insomnia may com- pathological phenomenon is the absence of daytime plain of daytime impairment (indeed, it is included impairment. Those with middle of the night in diagnosis), yet natural selection operates on the awakening and difficulty returning to sleep have reproductive benefits conferred by facilitating sur- greater tendency towards impairment and com- at Duke University Law School on August 4, 2016 vival of self and kin. plaint than those with sleep onset problems [108, Taking an evolutionary perspective, it makes good 109]. Some experts have proposed that sleep onset sense for mechanisms to evolve that suppress the problems reflect different underlying causes than need to sleep when threats exist, such as the pres- middle of the night insomnia; for example, sleep ence of predators or conspecific competitors. In onset problems may reflect stress, effects of light today’s society, however, these threats are substan- at night or delays of circadian phase, whereas mid- tially less common (although they may persist in dle-of-night insomnia may reflect maintenance dangerous neighborhoods in developed countries problems and a true inability to sleep given an ad- or in the growing urban populations of developing equate opportunity to do so [108–110]. countries, see below and reference 106). Loss of sleep due to anxiety before an examination or other Narcolepsy stressful event is hardly as useful as it might have been when vigilance was needed for physical threats. Narcolepsy presents another interesting situation Thus, we have a mismatch situation in which poten- from an evolutionary perspective, again with a mis- tially adaptive solutions from our ancestral past are match or ‘novel environment’ component to its eti- no longer beneficial to many people living today in ology. Narcolepsy afflicts about 0.02–0.03% of the safe environments (which is an evolutionary nov- US population [111]. This low prevalence suggests elty). From a clinical perspective, this strongly sug- that narcolepsy itself is not adaptive, and that in- gests that doctors need to alleviate the sources of stead, we need to consider how evolution has made the anxiety and stress to effectively treat insomnia humans susceptible to this disease. Individuals with [101], or to teach effective coping strategies when the this condition experience excessive daytime sleepi- perceived threats are unresolvable. For patients, ness; a majority suffer from cataplexy (i.e. where an understanding evolutionary drivers of this dis- emotionally salient event can trigger an intrusion of order—at least when dysfunction is associated with paralysis), such as occurs typically during REM some stressor—may also help individuals overcome sleep, while the affected individual remains con- insomnia. scious. Narcolepsy often first appears in Shining evolutionary light on human sleep Nunn et al. | 235 adolescence. Evidence suggests that the condition environmental triggers are important in narcolepsy. likely involves an autoimmune process, with symp- Evidence for this view includes discordance between toms of the disorder arising as a consequence of genetic variants and disease across populations autoimmune destruction of the hypocretin (orexin) [116], and low concordance of narcolepsy among neurons in the hypothalamus [111]. monozygotic twins and other family members [117]. In this context, narcolepsy presents two evolution- In addition, narcolepsy is best documented in ary angles to explore. First, what accounts for the humans and in domesticated animals that have close genetic variants that lead to this condition, espe- and regular contact with humans, such as dogs, cially involving potentially adaptive consequences horses and sheep [see 118]. This concordance is con- of narcolepsy-related genetic variants in past or pre- sistent with all these animals and humans sent environments? Second, does modern life in- experiencing a common environmental factor in volve new environmental factors that trigger the modern environments. Hence, the search has been onset of narcolepsy in those with genetic variants on for environmental factors that might cause narco- associated with narcolepsy? We proceed to each of lepsy in those with genetic backgrounds that make Downloaded from these in turn. them susceptible. Several studies have identified genetic variants Infectious agents have been among the factors associated with narcolepsy, including variants in thought to act as an environmental trigger for nar- the human leukocyte antigen loci that are involved colepsy [111]. Potential links to H1N1 influenza have http://emph.oxfordjournals.org/ in immune responses [112]. For example, one recent received the most attention, including potential trig- genome-wide association study identified a genetic gers by influenza vaccines. Following the vaccin- variant in the purinergic receptor subtype P2Y11 ation campaign against the H1N1 epidemic in gene that is associated with narcolepsy [113]. This 2009–10, increased cases of narcolepsy were re- variant is involved in substantially reduced expres- ported in Europe [116]. Similarly, increased inci- sion of the gene in natural killer cells and CD8+ T- dence of narcolepsy was reported in China after cells, and reduced resistance to apoptosis in these the H1N1 epidemic, and onset was found to be sea- cells. sonal in other years, occurring at higher rates after at Duke University Law School on August 4, 2016 Although these genetic studies may explain the the cold-and-flu season [119]. However, the findings link to narcolepsy and potentially other autoimmune in China are unlikely to be linked to vaccinations. In diseases, it is unclear whether the alleles were addition to influenza, high levels of antibodies (anti- favored by natural selection. If some genetic variants streptolysin O) to Streptococcus pyrogenes—causal show tradeoffs arising from antagonistic pleiotropy, agent of strep throat—have been linked to narco- for example, we might expect some other phenotypic lepsy [117]. benefits that outweigh the potential costs of narco- Overall, we propose that narcolepsy represents a lepsy in a subset of individuals. Alternatively, it could disorder that has ancient genetic roots, with some be that narcolepsy and the associated genes reflect genetic variants having insufficient environmental ancient adaptations that are no longer relevant, and have been carried along due to low selective pres- triggers to express themselves until the present. sure against them. One such explanation views When these genetic variants were expressed genes associated with narcolepsy as evolutionary throughout our evolutionary history, they may have hangovers (atavisms) that originally had a role in been under low levels of selection for their removal predator defense. In particular, the genes may have from the population, and that is even truer today. been adaptive in the context of feigning death as a Whether these genetic variants have fitness benefits last resort to predator attacks (i.e. tonic immobility, remains unknown, but it seems unlikely given the a widespread response to predators among verte- extremely low prevalence. The well-documented brates and invertebrates). According to one recent cases of narcolepsy in domesticated animals, such hypothesis, REM sleep—with its associated paraly- as sheep and dogs, also exemplifies the benefits of sis—may have its roots in tonic immobility [114]. investigating this question in a One Health frame- Researchers have identified neurological similarities work [120], which considers how the health of between the paralysis in narcolepsy and tonic immo- humans, animals and the environment are intercon- bility in animals [115]. nected. Future research may find, for example, that a A second perspective invokes evolutionary mis- common environmental trigger influences disease match. In addition to genes, it appears that in all these species. 236 | Nunn et al. Evolution, Medicine, and Public Health

Circadian rhythm disorders degree and to diminish the symptoms associated with circadian rhythm disorders. For most individ- Disorders of circadian rhythm are defined by a mis- uals, however, the best strategy may be to guide them match of an individual’s natural sleep period and the towards lifestyles that best match their natural circa- desired sleep period based on the social environ- dian proclivities. For those in school, this may include ment [121]. Circadian rhythm disorders are a late start to the school day or permission to nap. characterized by various types of sleep period mis- Individuals with delayed sleep phase syndrome will match, such as: ‘delayed sleep phase syndrome’, in generally function best in jobs that can start in the which affected individuals tend to go to bed later and afternoon. Those with irregular sleep/wake schedules sleep later than ideal for optimal function in their often do best in self-employment situations or loosely environment; ‘advanced sleep phase syndrome’, in structured jobs. Finally, patients may take solace in which affected individuals tend to fall asleep earlier understanding that phenotypic variation in sleep and wake up earlier than preferred; and ‘irregular phasing may reflect adaptive strategies in ancestral sleep wake schedule’, where a shifting mismatch environments. Downloaded from occurs between the period in which an individual is able to sleep and their preferred sleep period. The population prevalence of these conditions varies, Seasonal affective disorder with the most prevalent being delayed sleep phase Seasonal affective disorder (SAD) is characterized syndrome, which has a prevalence of 7–16% among by the presence of symptoms of depression that http://emph.oxfordjournals.org/ adolescents [121]. recur every winter and remit every summer [124]. These conditions have a genetic basis that is Many affected individuals also report a mild hypo- modulated by developmental and environmental mania during the spring and summer. The patho- factors [121]. They actually only represent disorders physiology of this condition appears to lie in a in the sense that society demands a particular sleep– deviant response to decreased exposure to light in wake schedule that cannot be met without the devel- the winter. As would be expected on this basis, SAD opment of symptoms by individuals who deviate is more common in extreme latitudes with very short at Duke University Law School on August 4, 2016 from the norm, but who are really ‘normal variants’ day lengths during the winter. For example, the in that they are asymptomatic if allowed to sleep on prevalence of SAD is <1% in the USA, but 2–3% in their preferred schedule. Yet, it could be argued that Canada [124]. The prevalence is higher in women variant sleep–wake patterns are actually beneficial than men, and tends to occur during childbearing for many individuals and societies, allowing years in women [125]. them to serve necessary roles for society. This in- Some evidence suggests that SAD is actually a cludes night workers, shift workers, and those who circadian rhythm disorder because melatonin pro- need to work for extended shifts before sleep is duction, which is normally suppressed by light ex- possible. posure, is increased in extent and duration in From an evolutionary perspective, benefits may those suffering from SAD compared with their have accrued to those with slightly different circa- neighbors without SAD [124]. On this basis, it is dian cycles—or different ‘chronotypes’—with bene- hypothesized that individuals with SAD experience fits for their communities, too. Just as there exist a shift in their circadian sleep–wake schedules multiple roles in today’s society to meet demands that makes them more lethargic during the day, par- of economic growth and around-the-clock safety, ticularly on winter mornings. This explanation having individuals in a social group on different is also consistent with the phenotype of SAD, sleep schedules may have been beneficial in our evo- which in contrast to unipolar major depression, is lutionary past, even in hunter-gatherer populations. more likely to be associated with reports of daytime Indeed, a hunter-gatherer community in which at sleepiness and lethargy. Given the presumed patho- least one person is always vigilant would presumably physiology, it is not surprising that the treatment of be better protected from hostile conspecifics or choice for this condition is light exposure therapy predators. Variability in chronotype is heritable in [124]. humans and has been shown to differentially affect It has been hypothesized that SAD is adaptive reproductive output [122, 123]. in highly seasonal environments, where Treatments exist to help affected individuals nor- increasing sleep during thewinterwouldconserve malize their sleep–wake schedules to a modest energy and maintain thermoregulation, while Shining evolutionary light on human sleep Nunn et al. | 237 increased energy and capacity for work would be GLOBAL HEALTH, SLEEP AND beneficial during warmer, more productive EVOLUTIONARY MEDICINE months, coupled with potential advantages of Many factors are changing sleep patterns and sleep SAD symptoms for pregnant women during the quality globally, including expanded use of artificial winter months [126, 127]. It is easy to appreciate lighting, shift-work, use of screen-based digital the adaptive value of such a trait prior to electrical media and excessive environmental stimuli in urban lighting and in agrarian societies, and in areas environments. Sleep is a critically important aspect with long, dark winters and food production of health; as noted earlier, it is intimately connected concentrated in a subset of the year. If future re- with almost every aspect of human health, including search finds support for this hypothesis, SAD immune function, metabolism, and cardiovascular would be adaptive for a relatively small (and disease. Sleep is also critical for effective working shrinking) percentage of the world that lives at memory, attention, visual-motor performance, and high latitudes without access to modern lighting, decision-making, with disrupted or irregular sleep and thus could be considered to be an evolution- Downloaded from resulting in declines in workplace productivity and ary mismatch condition [126, 127]. increases in accidents [e.g. 9, 129, 130, 131]. Despite these strong links between sleep and health—and despite the pervasive changes in sleep in developed Sleep-disordered breathing (sleep apnea) countries—few studies have considered the health http://emph.oxfordjournals.org/ We close this section by considering sleep dis- implications of chronic sleep deprivation in a global ordered breathing, which involves a wide range of health context [11]. breathing abnormalities during sleep. We focus es- Perspectives from evolutionary medicine are im- pecially on obstructive sleep apnea. This form of portant for understanding global health challenges sleep apnea occurs when the tone in muscles that associated with changing sleep patterns. These per- support the upper airway decreases during sleep to spectives include the concept of evolutionary mis- the point that they are unable to prevent the forces match, where changes in environments and impinging on the airway from causing a collapse, lifestyles today differ from those in our ancestral past at Duke University Law School on August 4, 2016 which then obstructs the airway (i.e. ‘apneas’). in ways that create new health problems. Potential With obstructive sleep apnea, breathing can be sources of mismatch include: more widespread use blocked multiple times per hour, resulting in of electrical lighting and new social connectivity gasping, awakening and reduced blood oxygenation. enabled by technology; populations that live at ex- It is differentiated from central sleep apnea, which ceptionally high densities, resulting in sleep disrup- involves a central nervous system-mediated ab- tions due to noise and perceived risks at night; sence of effort to breathe [128]. changes in other dimensions of health that may im- Risk factors for obstructive sleep apnea include pact sleep, such as rising rates of obesity; and obesity, large neck circumference, use of alcohol be- changes in diverse sleep practices involving fore bedtime, and smoking, yet genetic and anatom- mother–infant co-sleeping, ambient light and poor ical features are also important, including quality bedding that may affect musculoskeletal characteristics of the airway [129]. Thus, obstructive health. Evolutionary medicine perspectives also sleep apnea may be seen as an example of an evolu- aim to understand adaptations for adjusting sleep tionary mismatch disease, with over-abundant ac- in times of need, such as sleeping less to monitor the cess to high calorie food, distilled alcohol, a environment in risky settings [107], or tradeoffs be- sedentary lifestyle and tobacco fueling the rise in this tween sleep and other fitness (or financial) condition, especially at older, post-reproductive enhancing behaviors (e.g. as shown by extreme ages. However, the genetic-anatomical features sleep deprivation in male pectoral sandpipers dur- may be maintained for reasons that are not yet clear, ing the mating season [133]). Finally, evolutionary and result in increased risk of sleep apnea later in medicine is important for understanding sleep dis- life, potentially independent of behavioral risk fac- orders, which may increase globally as more popu- tors. Although most patients diagnosed with ob- lations adopt Western lifestyles in terms of diet, structive sleep apnea opt for medical treatment, lighting and night-time entertainment. prevention through a healthy diet and exercise may Health disparities are starting to be linked to sleep be an option for some patients. disparities and their drivers, and a multi-disciplinary 238 | Nunn et al. Evolution, Medicine, and Public Health

group of sleep biologists, public health specialists, mammals as an adaptation for obtaining oxygen economists and anthropologists are investigating [142, 143]. It appears that human sleep architecture the ways that sleep, health, ethnicity and differs from our closest living relatives, with humans socioeconomic status are intertwined [134–137]. In packing a higher percentage of REM sleep into one study, for example, Hale and Do [138] found that shorter total daily sleep durations. The large evolu- compared to white Americans, African Americans, tionary changes in sleep along the human lineage Hispanics, and non-Hispanic ‘others’ showed a may be responsible for some sleep disorders that higher rate of ‘short’ (6 h) sleep, which is known are seen in humans, although even some of the most to be associated with poor health outcomes. They striking disorders, such as narcolepsy, also occur in also found that living in an inner city was associated other animals [118]. The rapid transformations in with increased risk of short sleeping, suggesting that sleep that are occurring globally today should be of some of these ‘sleep disparities’ [137]reﬂectstress great concern, yet scientists are only just beginning and noise associated with living in highly urban, to investigate the implications of sleep for health

socioeconomically disadvantaged neighborhoods. disparities in both developing and developed Downloaded from Another study of Americans found that perceived ra- countries. Concepts from evolutionary medicine— cial discrimination covaried with sleep disturbance such as mismatch, tradeoffs, and adaptation to local [139, see also 140]. An important area for the future environmental settings—are important for under- is to apply these perspectives to health in developing standing these transformations. An interdisciplinary countries, particularly in the growing urban environ- perspective will be essential in this endeavor. http://emph.oxfordjournals.org/ ments that represent significant sources of noise, Studying sleep requires a comparative approach, stress and risk, often with inadequate places for sleep. as emphasized throughout this review. Comparative Major efforts are afoot to expand access to electri- approaches are needed to investigate the adaptive city for low- and middle-income countries, e.g. function of sleep and the factors that constrain sleep. through America’s USAID’s ‘Power Africa’ initiative Such approaches also contribute to understanding (https://www.usaid.gov/powerafrica; accessed 19 the sleep disorders that plague a remarkably high per- July 2016). Greater use of electric lighting will be centage of people around the world. In this context, it at Duke University Law School on August 4, 2016 one outcome, which we expect will lead to later bed- is critically important to obtain comparable data on times as people make greater use of the day for work, sleep in different populations, with the aims of better education and socializing [141]. Similarly, television understanding the genetic underpinnings of sleep, and other forms of entertainment and communica- phenotypic plasticity in sleep, and the potential for tion may distract people from healthy sleep practices. adaptive differences in sleep architecture in different Collectively, we expect that these developments will populations. Although many adaptive hypotheses can lead to a greater sleep debt in developing countries, be forwarded for aspects of sleep disorders (as re- and will thus contribute to rising rates of obesity, viewed earlier), we expect that most of these patterns heart disease, diabetes and other non-communicable are not shaped by natural selection as adaptations, diseases in these countries. These effects will be es- but rather reflect weak selection against them in our pecially acute when coupled with increased access to evolutionary past, with resulting variation in the popu- Western diets and lifestyles. Many of these countries lation. Alternatively, it may be that natural selection willcontinue to have a high infectious disease burden, has shaped other aspects of biology—such as human especially near the equator. Evidence points to metabolism, cognition and development—in ways increased risk of infection if sleep times decline [16, that now make us vulnerable to sleep disorders, es- 17], including comparative results noted earlier [93]. pecially in the stress of modern environments. An Thus, it is critical to evaluate the ways that western- understanding of the evolutionary basis for sleep dis- ization impacts sleep patterns, and the health effects orders may bring some consolation to those who face of these changes in different populations. anxieties about their sleep and could guide better outcomes in a globalizing and rapidly developing world. 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