Brown, Lee K.a,b
Sleep is for wimps.
– Margaret Thatcher, as reported by Méabh Ritchie and Anita Sethi, The Observer, Saturday 26 April 2008.
The opinion of Great Britain's ‘Iron Lady’ notwithstanding, sleep is a ubiquitous behavior that the vast majority of humans find useful regardless of whether they are strong or weak of character. Moreover, depending on whether your definition of sleep is behavioral or electrophysiological, sleep can be identified in many of the earliest appearing phyla of the animal kingdom. The most commonly accepted behavioral definition of sleep is that of Carskadon and Dement [1▪▪], who described sleep as ‘a reversible behavioral state of perceptual disengagement from and unresponsiveness to the environment’. The first proposal for behavioral criteria that would identify the existence of a sleep state in any member of the animal kingdom is attributed to Pieron , in a publication from 1913. These criteria consisted of motor rest; the stimulus required to elicit a response is greater asleep than while awake; and easy reversibility. An important additional criterion was added in 1973 by Flanagan , that of a species-specific stereotypic posture. Further criteria have been proposed over the ensuing years, particularly rebound increase after deprivation and circadian rhythmicity. These six still make up the most commonly accepted paradigm, with some proposing that a minimum of four of the six criteria are sufficient to define the presence of sleep. It may be argued that the advent of an electrophysiological definition of sleep in studies of mammalian and avian species has superseded the need for a behavioral definition. However, Campbell and Tobler  point out that behavioral wakefulness (e.g. motor activity) with electroencephalographic (EEG) evidence of sleep may be observed in some animals (e.g. rats and cats) [4,5], as well as humans [e.g. somnambulism, motor activity in rapid eye movement (REM) sleep behavior disorder] [1▪▪]. Consequently, a combination of behavioral and electrophysiological criteria may be most useful in higher animals. In evolutionarily more primitive species (e.g. reptiles, amphibians) mammalian and avian electrophysiological criteria do not apply, but alternative electrographic definitions are possible, particularly when correlated with behavior . In the most primitive species (e.g. the zebra fish, Danio rerio, and invertebrates such as the fruit fly, Drosophila melanogaster, or the roundworm Caenorhabditis elegans) behavioral criteria take the fore, although attempts have been made to associate electrical activity in certain groups of neurons with behavioral manifestation consistent with the sleep state [4,6,7].
Further complicating the definition of sleep is the fact that, electrophysiologically, every mammalian and avian species studied thus far exhibits two very different varieties of sleep: nonrapid eye movement (NREM) and REM. As Carskadon and Dement [1▪▪] have famously observed, ‘they are as distinct from one another as each is from wakefulness’. That REM sleep interrupts periods of behavioral and electrophysiological NREM sleep presumably represents the survival advantage of not experiencing the inconvenience of REM sleep (or its components) during activity periods, as any narcolepsy patient with cataplexy will certainly confirm.
What becomes clear from this body of literature, however, is just how widely the presence of a sleep state is conserved throughout evolutionary time, beginning with a roundworm comprised of only 959 somatic cells all the way through to Homo sapiens. Moreover, the sheer number of mammalian central nervous system structures devoted to the initiation, control, and termination of NREM and REM sleep, and the complexity of their interconnections, suggest the importance of both sleep states to the human organism. We must therefore conclude that sleep provides a survival advantage due to a critical function or several such functions. Although definitively identifying the purpose of sleep continues to elude us, there are a multitude of theories, many supported by experimental evidence. The most generally accepted theories revolve around the role of sleep in recovery, energy conservation, and ethological survival. The latter two hypotheses most closely impact the process of evolution, and so let us here concentrate on the issue of recovery as it relates to overall functioning and specific organ systems.
RECOVERY: OVERALL FUNCTIONS
As Mignot  has observed, studies of the behavioral effects of sleep deprivation provide the most robust rationale for the vital role of sleep on a systemic level. Most involve total sleep deprivation, long-term partial sleep deprivation, or disruption of sleep continuity, and are relatively nonselective with respect to which sleep state (NREM vs. REM) is compromised. Nevertheless, nonspecific sleep deprivation (and for the most part, selective NREM deprivation) in humans results in measurable deficits in cognition, vigilance, and emotional stability [9–12]. Appetite is increased , perhaps accounting for the association between disordered or decreased sleep and obesity . Epidemiologic evidence associates short sleep duration with incident diabetes, hypertension, and markers of cardiovascular disease , and sleep deprivation has been shown to induce glucose intolerance and insulin resistance . No studies have emerged demonstrating an increased risk of infection after sleep deprivation, but this may be due to the difficulty of implementing the experimental paradigm .
Particularly interesting aspects of sleep deprivation involve risk-taking behavior and moral judgment. Investigations involving sleep-deprived individuals using gambling simulations generally demonstrate increased risk-taking, although some studies found that the effect varied with type of risk (gain vs. loss) and sex [18–20]. Effects on moral judgment have been more variable. In one study in military officers, sleep deprivation caused a shift from internal, mature moral reasoning to decision-making based simply on rules, but only in individuals with high levels of emotional maturity and only for emotion-laden scenarios . In another study, sleep deprivation resulted in slowing of decision-making with respect to the moral–personal (emotion-laden) scenarios, with an interaction detected between likelihood of agreeing with a course of action and lower ‘emotional intelligence’ . A third study has suggested that one night of lost sleep is not sufficient to substantially affect moral judgement .
Finally, a large body of literature has emerged with respect to the effects of sleep deprivation on memory and learning. As in much of neurobiology, the science of memory consists of a myriad of definitions, small bits of experimental information, and overall theories rather than a detailed understanding of what is undoubtedly a complex process. Memory is thought to consist of a series of steps that involve the acquisition of new information that is encoded in a transient manner, integrated with other pieces of information to form what may best be described as a relational database, and then re-encoded in a manner that enhances stability and long-term retention. In addition, memory has been subdivided into a vast array of subtypes. These include explicit or declarative memory (memory that must be summoned by conscious thought), which is then further characterized as episodic memory (memory of specific events in a time and place context) and semantic memory (knowledge that is more general and not specifically related to a time and place); implicit memory (retrieved unconsciously, e.g. by rote) that is procedural (knowledge of how to perform various tasks) or priming (associated with previous experiences); and emotional memory (memory that relates various experiences and situations with either negative or positive emotion). Furthermore, there is evidence that operations involving the various types of memory take place in different locations in the central nervous system (CNS) [24▪▪]. Consequently, when examining the relationship between sleep deprivation and memory one must consider what stage of the memory formation process is being investigated, as well as the type of memory, making generalizations difficult if not impossible. Moreover, experimental paradigms that have been devised to test the effect of sleep deprivation (or other variables) on the different types of memory invariably differ in subtle ways, such that each may be testing a slightly different sub-sub-type of memory . In general, strong evidence suggests that procedural and declarative learning tasks require sleep after learning in order to consolidate the information into long-term memories . Emotional memory seems also to be impaired by sleep restriction, particularly that associated with positive emotion .
The effects of selective deprivation of REM sleep are more enigmatic: there is evidence of rebound after deprivation , but in general REM sleep deprivation appears to be activating rather than a cause of sleepiness . Deprivation of REM sleep has been shown to increase the response to pain, perhaps another indication of the activating nature of this experimental paradigm . These factors have led to the hypothesis that REM sleep exerts a calming effect; this has been demonstrated in rodents but has been questioned in humans, given the calming effects of antidepressant medications, which by and large are REM suppressants . Moreover, studies of REM-predominant obstructive sleep apnea (OSA) have failed to consistently demonstrate impaired function in these patients compared with the known deleterious effects of OSA occurring in NREM sleep . A popular concept of REM sleep function holds that processing and consolidation of memory occur during this sleep state, and some studies support this theory by demonstrating defects in the retention of procedural memory after selective REM deprivation . However, several recent reviews have highlighted the ambiguous nature of the evidence when tested on humans, particularly in light of the failure to identify any defects in memory accompanying the ubiquitous prescribing of REM-reducing antidepressant medications [34–36].
RECOVERY: ORGAN SYSTEMS AND THEIR NETWORKS
On the network level (e.g. organ system or tissue level), nonselective sleep deprivation impacts functional MRI (fMRI) activation of task-specific cortical areas [37▪,38], activates regions of the brain involved in promoting food intake [39▪▪,40], increases the level of the orexigenic hormone ghrelin, and decreases the level of the anorexigenic hormone leptin [13,16]. Sleep deprivation increases night-time concentrations of adrenocorticotropic hormone and cortisol  and has a profound effect on inflammatory cytokines, increasing most [42,43] but also increasing some anti-inflammatory mediators . Immunoglobulin and complement levels may be augmented , and sleep deprivation appears to alter the functional rhythm of nT(reg) and CD4(+)CD25(−) T cells, with reduced CD4(+)CD25(−) T-cell proliferation . Bryant et al. have observed a lack of consistency throughout the literature on immune function and sleep deprivation that they attribute to variations in the duration of sleep deprivation as well as the timing of sample collection, choice of immune markers, and assays employed by the various investigators. They also draw a distinction between acute sleep loss, which may act to enhance immune function, and chronic sleep deprivation, which may eventually lead to suppression of immunity .
Studies involving fMRI to identify areas of the brain involved in memory encoding and consolidation have also been employed to assess the effects of sleep restriction. Sleep-deprived individuals appear to recruit areas of the prefrontal cortex not required by rested individuals when retrieving from working memory or performing a verbal memory task [47,48]. A picture recognition task, with images not chosen for emotional content, revealed decreased bilateral posterior hippocampal activation after sleep deprivation compared with rested individuals and correlated with poorer recognition performance . Congruent with the literature on sleep deprivation and emotional memory, an fMRI study has demonstrated reduced activity in brain regions associated with the recall of emotional memory after sleep deprivation . Individuals were shown standardized pictures meant to provoke positive, negative, or neutral emotional reactions. One half of the individuals were totally sleep-deprived that night, whereas the rest were allowed to sleep at home as usual. At 6 months’ follow-up, all individuals were shown a combination of pictures previously seen (which would normally provoke recall of an emotional memory), masked by presentation of pictures not previously seen. While undergoing fMRI during the picture viewing, individuals who were sleep-deprived the night after the emotional memories were formed demonstrated reduced activity in ventral medial prefrontal cortex (VMPFC) and the precuneus, the amygdala, and the occipital cortex. Functional connectivity between these regions by fMRI was also lower in the sleep-deprived group compared with the controls.
A lesser number of studies are available concerning the effects of selective REM sleep deprivation at the network and tissue level. Consistent with the activating nature of REM deprivation at the systemic level, this manipulation has been shown to enhance fMRI indices of activity in cortical regions known to be involved in emotional processing when individuals are presented with a threatening visual stimulus [51▪]. One study of REM-specific deprivation demonstrated a lesser effect on immune mediators than total sleep deprivation, although suppression of IgA levels occurred that tended to persist after normal sleep was allowed . In contrast to the literature on total sleep deprivation, little is known concerning specific deprivation of REM with respect to metabolic signaling.
One can learn a great deal about the importance of a thing by assessing the consequences of its loss. The increasing body of knowledge concerning the specific behavioral, cognitive, immune, and metabolic effects of sleep deprivation speaks volumes about the importance of these states of being, although the consequences of selective REM sleep deprivation remain enigmatic. In light of this evidence, I believe it is safe to say that sleep is decidedly not ‘for wimps,’ but is for all of us, every day, if we expect to perform at our best.
Conflicts of interest
Financial disclosures: Dr Brown serves on the Polysomnography Practice Advisory Committee of the New Mexico Medical Board and on the New Mexico Respiratory Care Advisory Board. He is on the Board of Trustees and an officer (Secretary) of the Greater Albuquerque Medical Association. He currently receives no grant or commercial funding pertinent to the subject of this article.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
▪ of special interest
▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 639).
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