The circadian and sleep-wake systems interact in a dynamic manner to regulate changes in alertness, performance and the timing of sleep.(1) The circadian system is controlled by an endogenous biological clock, the circadian pacemaker, located in the suprachiasmatic nucleus (SCN) of the anterior hypothalamus.(2) The SCN contributes to the control of waking alertness and performance: in a 'typical' 24-h cycle, with sleep nocturnally placed, performance and alertness variables are at their lowest around 0300-0500 h and 1500-1700 h.(3)(4)

The circadian trough in performance and body temperature associated with a decline in arousal and alertness, and reduced motivation, is known as fatigue.(5)(6) The sleep drive, a homeostatic process of exponential form, is primarily responsible for the timing of sleep and waking.(1) The drive to sleep is at its lowest point in the morning, on awakening, and as the day progresses, the drive to sleep increases. Once sleep is initiated, this drive gradually decreases until awakening.(7)

Circadian Rhythms and Sleep-Wake Cycles: Effects on Alertness, Performance and Sleep Timing

Fatigue, alertness, and performance levels are not only influenced by endogenous circadian rhythms and the homeostatic sleep drive but may also be affected by exogenous factors or zeitgebers (i.e., time givers) which include the light/dark cycle, social interaction and work demands. Although the inherent rhythm of the circadian pacemaker is approximately 24.2-h,(8) under free running conditions the light/dark cycle entrains circadian rhythms to a 24-h day. Light information is received via retinal ganglion cells and is transmitted along the retinohypothalamic tract to the SCN.(2)

Light acts as a powerful stimulus in the regulation of circadian rhythms, contributing to a stable phase relationship between circadian rhythms and the sleep/wake cycle.(2) Light also phase shifts circadian rhythms to an earlier (phase advance) or later (phase delay) time within the biological day. The elderly undergo alterations in the regulation of circadian rhythms, which often contribute to sleep disturbances [reviewed in (9)], and can, therefore, affect alertness and performance.

Sources of Sleep Loss and Sleep Restriction

Sleep deprivation results from either partial or total loss of sleep, of a voluntary or involuntary nature, and ranges in duration from acute to chronic. Partial sleep deprivation occurs when an individual is prevented from obtaining part of the amount of sleep needed to produce normal waking alertness during the daytime. Partial sleep deprivation is often the result of medical conditions, sleep disorders, as well as lifestyle (e.g., shiftwork or jet lag, prolonged work hours).

In contrast to partial sleep deprivation, total sleep deprivation is defined as a complete lack of sleep, with a waking period exceeding 16 h in a healthy adult. Total sleep deprivation extending beyond 24 h reveals the nonlinear interaction of the escalating sleep homeostat and the endogenous circadian clock.(1) Such an interaction produces a counterintuitive outcome -- an individual who remains awake for 40 h is less impaired by sleepiness after being awake for 36-38 h than after being awake for 22-24 h.

This Cyberounds^® reviews research on the sources and consequences of sleep deprivation in adults, including sleep restriction's effects on neurobehavioral and physiological functioning, and discusses various countermeasures for restriction. This is a topic of paramount importance, as estimates indicate at least one-third of the U.S. population suffers from chronic sleep loss.(10)

Sleep Fragmentation

Sleep fragmentation, a form of partial sleep deprivation, occurs when the normal progression and sequencing of sleep stages is disrupted to varying degrees, resulting in less time in consolidated physiological sleep relative to time in bed. If sleep fragmentation is isolated to a specific physiological sleep stage (e.g., when apneic episodes disrupt primarily one stage of sleep such as rapid eye movement [REM] sleep or when medications suppress a specific sleep stage), this is referred to as selective sleep stage deprivation. The elderly are particularly prone to such fragmentation and a reduction in sleep quality, reporting frequent nocturnal awakenings, difficulties falling asleep and early morning awakenings [reviewed in (9)].

Sleep fragmentation also can occur in certain sleep disorders such as obstructive sleep apnea in which patients experience repetitive nocturnal respiratory pauses that produce chronic sleep deprivation and excessive sleepiness. Similarly, patients with narcolepsy syndrome also experience sleep deprivation. The narcolepsy tetrad consists of excessive daytime sleepiness with recurrent episodes of irresistible sleep (sleep attacks), cataplexy (sudden, brief, bilateral losses of muscle tone in response to strong emotions such as laughter or anger), hypnagogic (sleep onset) and/or hypnopompic (waking) hallucinations (dream-like experiences) and sleep paralysis (the inability to move while falling asleep or upon awakening).(11)

In addition, non-sleep disorders can secondarily impose negative effects on sleep. Parkinson's Disease is a common neurodegenerative disorder characterized by motor disability and many disabling non-motor symptoms. Excessive daytime sleepiness is found in up to 45% of patients with Parkinson's Disease and roughly 1% of patients are at risk for sleep attacks without appropriate warning signs.(12) Some patients show a narcolepsy-like phenotype (≥2 sleep-onset REM periods).(13) Overall, such symptoms can cause considerable impairment of quality of life and lead to impaired functioning in daily activities.(14)

Chronic Sleep Restriction: Laboratory Experiments

Sleep restriction, or sleep debt,(15) a common form of partial sleep deprivation, is characterized by reduced sleep duration. Researchers have been particularly interested in the changes that occur when sleep is steadily reduced in duration from 8 to 4 h each day (i.e., the range of sleep restriction many individuals experience regularly), and whether there are cumulative dose response effects of such a reduction on sleep physiology and waking functions. Experimental protocols that restrict healthy adult sleep duration across consecutive days provide the most appropriate paradigms for addressing these questions.

Sleep Restriction: Measures of Physiological Sleep Propensity

The tendency to fall asleep, a well validated measure of sleepiness, is based on the assumption that sleepiness is a physiologic need state that leads to an increased tendency to fall asleep; it is operationalized as the speed of falling asleep in both sleep-conducive and non-conducive conditions.(16) The effects of chronic sleep restriction on daytime physiological sleep propensity have been evaluated using the multiple sleep latency test (MSLT)(17) and the maintenance of wakefulness test (MWT).(18) In the MSLT, a subject is instructed to close his/her eyes and try to fall asleep, while lying supine for 20-min periods, 2 h apart, 4 to 5 times throughout the day, during which polysomnographic (PSG) recordings are made (including EEG, EOG and EMG). The MWT uses a similar protocol to the MSLT but subjects are seated upright and instructed to try and remain awake. For both tests, sleep propensity is measured as the time is takes to fall asleep.

The MSLT varies linearly following a single night of sleep restriction consisting of 1 to 5 h time in bed.(19) In addition, the MSLT shows progressive shortening (i.e., more sleep propensity) when healthy young adults are restricted to 5 h of sleep a night for 7 consecutive nights.(19) This finding was confirmed in a study using the psychomotor vigilance task, a measure of daytime neurobehavioral alertness.(20)

In an epidemiological study of predictors of objective sleep tendency in the general population, a dose-response relationship was found between self-reported nighttime sleep duration and objective sleep tendency as measured by MSLT.(21) Subjects reporting more than 7.5 h of sleep had significantly less probability of falling asleep on the MSLT than those reporting between 6.75 to 7.5 h per night (27% risk of falling asleep) or those reporting sleep durations less than 6.75 h per night [73% risk of falling asleep(21)]. Thus, chronic curtailment of nocturnal sleep increases daytime sleep propensity.

Sleep Restriction: Changes in Sleep Architecture

Although sleep restriction alters sleep architecture, it does not equally affect all sleep stages. For example, healthy adults fell asleep more quickly and had decreased time in non-rapid eye movement (NREM) stage 2 sleep and REM sleep when restricted to 4 h of nocturnal sleep for multiple nights but did not show a decrease in NREM slow wave sleep (SWS) relative to an 8 h nocturnal sleep period.(22)(23)(24)(25) Although visually scored NREM SWS was conserved, slow-wave sleep activity (SWA) derived from power spectral analysis of EEG delta wave activity (0.5-4.0 Hz) during NREM stages 2, 3 and 4 sleep showed dynamic increases when 4 h of sleep restriction continued beyond one day.(23)(24)

Sleep Restriction: Effects on Neurobehavioral and Cognitive Measures

Acute and chronic partial sleep deprivation's effects on neurobehavioral and physiological variables have been examined using a variety of protocols. These include time restriction in bed for sleep opportunities in continuous and distributed schedules, gradual reductions in sleep duration over time, selective deprivation of specific sleep stages and reducing time in bed to a percentage of the individual's habitual time in bed.

Almost all studies investigating sleep during varying work-rest protocols show that actual physiological sleep accounts for only about 50-75% of rest time such that an 8 h recovery bout translates to maximum sleep duration of 4-6 h. More recent experiments on healthy adults have found clear evidence that behavioral alertness and a range of cognitive performance functions -- sustained attention, working memory and cognitive throughput -- deteriorated systematically across days when nightly sleep duration was between 4 and 7 h. (22)(23)(24) By contrast, when time in bed available for sleep was 8 or 9 h, no cumulative cognitive performance deficits were found across days. The cognitive performance findings from these two laboratory-based, dose-response experiments are consistent with studies investigating the effects of sleep restriction on physiological sleep propensity measures (MSLT, MWT).(19)(22)(25)(26)

Beyond cognitive performance, divergent and decision-making skills that involve the prefrontal cortex are also adversely affected by sleep loss.(27) These include skills such as risk assessment, assimilation of changing information, updating strategies based on new information, lateral thinking, innovation, maintaining interest in outcomes, insight, communication and temporal memory skills.(27) In addition, fatigue and deficits in neurocognitive performance from sleep loss compromise many working memory and executive attention functions. These include, but are not limited to, assessment of the scope of a problem secondary to changing or distracting information, remembering the temporal order of information, maintaining focus on relevant cues and flexible thinking, avoiding inappropriate risks, gaining insight into performance deficits, avoiding perseveration on ineffective thoughts and actions and making behavioral modifications based on new information.(27)

While the neurobehavioral effects of chronic sleep restriction appear similar to those of total sleep deprivation,(24) the primary physiologic measure of homeostatic sleep -- slow-wave activity in the spectrally analyzed NREM EEG -- displays a more muted response to chronic sleep restriction, suggesting a different neurobiological mechanism may sub-serve the adverse effects of chronic sleep restriction.

As is true for NREM SWA, subjective sleepiness responses during chronic sleep restriction show a different dynamic profile from those found for total sleep deprivation. While total sleep deprivation immediately increases feelings of sleepiness, fatigue and cognitive confusion, with concomitant decreases in vigor and alertness,(16)(27)(28)(29)(30)(31) chronic sleep restriction yields much smaller changes in these psychometric ratings of internal state.(22)(24)Thus, in contrast to the continuing accumulation of cognitive performance deficits associated with nightly sleep restriction to below 8 h, repeated sleepiness ratings did not parallel performance deficits.(24) Consequently, after a week or more of sleep restriction, subjects were markedly impaired and less alert but rated themselves subjectively as only moderately sleepy. Thus, individuals frequently underestimate the cognitive impact of sleep restriction and overestimate their performance readiness when sleep restricted. Other experiments using driving simulators have found comparable results.(32)

Overall, these studies suggest that when the nightly recovery sleep period is routinely restricted to 7 h or less, the majority of healthy adults develop cognitive performance impairments that systematically increase across days, until a longer duration (recovery) sleep period is provided. Furthermore, these data indicate that the basic principle of providing 8 h for rest between work bouts in regulated industries is inadequate, since studies consistently show that individuals use only 50-75% of rest periods to sleep. Thus, it is advisable for individuals to receive longer rest breaks (e.g., 10-14 h), so that adequate recovery sleep may be obtained.

Sleep Restriction: Individual Differences

Inter-individual variability in sleep and circadian parameters is substantial; this is also true for neurobehavioral and physiological responses to sleep deprivation.(16)(27)(28)(29)(30)(31)(32)(33)(34)(35) Sleep loss not only increases cognitive performance variability within subjects (intra-subject variability, characterized as state instability)(16)(27)(28)(29)(30)(31) but it also uncovers marked neurobehavioral differences between subjects such that, as sleep loss continues over time, inter-subject differences in the degree of cognitive deficits increase markedly.(34)(35) Sleep duration restricted to less than 7 h per day results in cumulative cognitive performance deficits in a majority of healthy adults, though not all subjects are affected to the same degree.(22)(24) At opposite ends of the spectrum are those who experience very severe impairments even with modest sleep restriction (vulnerable) versus those who show few, if any, neurobehavioral deficits until sleep restriction is severe in duration or chronicity (resistant). This differential vulnerability also extends to chronic partial sleep restriction.(36)

Neurobehavioral responses to sleep deprivation are stable and reliable within subjects,(33) suggesting they are trait-like, with intraclass correlations accounting for a very high percentage of the variance.(33)(37) The biological bases of such differential responses to sleep loss are not known, although recent neuroimaging studies suggest that such responses may be predicted prior to sleep deprivation.(38)(39)(40)

Chronic Sleep Deprivation in the "Real World"

Certain occupations require shifted work schedules and irregular sleep/wake cycles. Such shifts induce misalignment between circadian rhythms and the sleep/wake cycle, resulting in circadian disruption. Consequently, dissociation between the timing of circadian physiological and performance rhythms occurs, and this leads to increased sleep disruption, malaise, performance errors, uncontrollable sleep periods intruding into waking hours, negative mood and decrements in social interaction, inefficient communication and accidents.(41) This overall impairment of proficiency results from the shifting of execution times to an unfavorable phase of the performance circadian rhythm. Any occupation that requires individuals to maintain high levels of alertness over extended periods of time is vulnerable to the neurobehavioral and work performance consequences of sleep loss and circadian disruption. The resulting performance effects can compromise safety.(42)

Driving

Driving ability is one example of a real-world situation affected by sleep restriction. Studies have primarily focused on the effects of short-term sleep restriction on driving ability and crash risk.(43)(44) One epidemiological study found an increased incidence of sleep-related crashes in drivers reporting an average of less than 7 h of sleep per night.(45) Other factors that contributed to such crashes included poor sleep quality, dissatisfaction with sleep duration, daytime sleepiness, previous driving drowsy, driving duration and driving time of day (i.e., driving late at night). Individuals who work irregular schedules are also more likely to drive at night, thus increasing the chances of drowsy driving and decreasing the ability to effectively respond to stimuli or emergency situations; both factors can result in sleep-related crashes.(45)

Intrusions of sleep into goal-directed performance intensify a variety of neurobehavioral phenomena: lapses in attention, sleep attacks (i.e., involuntary naps), increased frequency of voluntary naps, shortened sleep latency, slow eyelid closures and slow-rolling eye movements, and intrusive daydreaming while engaged in cognitive work.(28) Sleepiness-related motor vehicle crashes have a fatality rate and injury severity level similar to alcohol-related crashes. Moreover, sleep deprivation produces psychomotor impairments equivalent to those induced by alcohol consumption at or above the legal limit.(27) Drowsy driving is particularly challenging in the truck-driving environment. Fatigue is considered to be a causal factor in 20-40% of heavy truck crashes. Operational demands often force commercial truckers to drive at night to avoid traffic and meet time-sensitive schedules.

Night Shift Work

Night work, irregular and prolonged work schedules, and shift work are not limited to a single operational environment but rather exist across many work environments. Such schedules create physiological disruption of sleep and waking because of misalignment of the endogenous circadian clock and imposed work-rest schedules. Individuals are exposed to competing time cues from the day-night cycle and day-oriented society and are usually inadequately adapted to their temporally displaced work-rest schedule.

Night shift work is particularly disruptive to sleep. Many of the 6 million full-time employees in the U.S. who work at night on a permanent or rotating basis experience daytime sleep disruption leading to sleep loss and nighttime sleepiness on the job.(46) More than 50% of shift workers complain of shortened and disrupted sleep and overall tiredness, with total amounts of sleep loss ranging anywhere from 2 to 4 h per night.(46) Such significant sleep loss affects productivity and performance of shift workers.

Jet Lag

Fatigue associated with jet lag is a major concern in aviation, particularly with travel across multiple time zones. Flight crews consequently experience disrupted circadian rhythms and sleep loss. Studies have documented episodes of fatigue and the occurrence of uncontrolled sleep periods (microsleeps) in pilots.(47) Flight crew members remain at their destination only for a short period of time and therefore do not have the opportunity to adjust physiologically to the new time zone and/or altered work schedule before they embark upon another assignment, further compounding their risk for fatigue.

Notably, although remaining at the new destination after crossing time zones for several days is beneficial, it does not ensure rapid phase shifting (or realignment) of the sleep-wake cycle and circadian system to the new time zone and light-dark cycle. Usually, passengers, pilots and flight crew arrive at their new destination with an accumulated sleep debt (i.e., elevated homeostatic sleep drive) because of extended wake duration incurred during air travel. As a result, the first night of sleep in the new time zone will occur without incident -- even if it is abbreviated because of a wake-up signal from the endogenous circadian clock. However, on subsequent nights, most individuals will find it more difficult to obtain consolidated sleep as a result of circadian rhythm disruption. As a consequence, an individual's sleep is not maximally restorative across consecutive nights, which leads to increased difficulty maintaining alertness during the daytime. Such cumulative effects are incapacitating and often take more than a week to fully dissipate via complete circadian re-entrainment to the new time zone.

The magnitude of jet lag effects is also partly dependent on the direction of travel.(47) Normally, eastward travel is more difficult for physiological adjustment than westward travel because it imposes a phase advance on the circadian clock, while westward transit imposes a phase delay. Since the human endogenous clock is longer than 24 h, lengthening a day is easier to adjust to physiologically and behaviorally than shortening a day by the same amount of time.(47) However, adjustment to either eastward or westward phase shifts often requires at least a 24-h period for each time zone crossed (e.g., transiting six time zones can require 5-7 days), assuming proper daily exposure to the new light-dark cycle. Regardless of the direction of phase shift imposed on flight crews and passengers, if there is inadequate time to adjust physiologically to the new time zone, cumulative sleep debt will develop across days and waking performance deficits will manifest -- even if no such deficits are reported.(24)

Prolonged Work Hours: Medical Professionals

As a result of the need to provide acute medical care 24-h a day, physicians, nurses and allied health care providers are awake at night and often work for durations well in excess of 12 h. Chronic partial sleep deprivation is an inherent consequence of such schedules and has been noted particularly in physicians in training.(48) Human error also increases with such prolonged work schedules.(49)(50)

In 2003, the Accreditation Council for Graduate Medical Education (ACGME) imposed duty hour limits for resident physicians in order to address performance errors resulting from sleep loss. Such duty limits were intended to reduce the risks of performance errors from both acute and chronic sleep loss by limiting residents to an 80 h workweek and by limiting continuous duty periods to 24-30 h. The ACGME also mandated that 1 out of every 7 days is free from duty, averaged over a 4-week period, and mandated 10-h rest opportunities between duty periods. Studies of residents operating under these duty hour limits reveal significant numbers of medical errors and motor vehicle crashes occurring on the way home from shifts.(50)(51) Thus, work schedules that permit extended duty days to 16 h or beyond result in sleep deprivation and substantial operational errors, as has been demonstrated in laboratory studies.

Countermeasures for Sleepiness/Treatments for Sleep Deprivation

Travel across time zones, prolonged work hours and work environments with irregular schedules contribute to performance decrements and fatigue, leading to safety risks, which require countermeasures. The best countermeasure for sleep deprivation is to receive adequate sleep, if possible. An open question remains as to what constitutes "adequate;" research on inter-individual differences suggests that this answer will vary across individuals.

A number of therapeutic countermeasures are available for individuals who are unable to obtain adequate sleep because of medical or sleep-related conditions (e.g., narcolepsy, obstructive sleep apnea), when excessive daytime sleepiness is the main feature of the condition, or when residual sleepiness exists despite treatment for the main condition.

Continuous Positive Airway Pressure

Continuous Positive Airway Pressure (CPAP) is considered the most effective treatment for obstructive sleep apnea in both middle-aged and older adults [reviewed in (52)]. CPAP increases alertness, improves neurobehavioral outcomes in cognitive processing, memory and executive function.

Modafinil

In some patients, CPAP does not completely eliminate excessive sleepiness; as such, modafinil, an alerting agent with an unknown mechanism of action, is effective as an adjunctive treatment for residual symptoms(53)(54) and improves functional status (subscales for vigilance, general productivity and activity level) as measured by the Functional Outcomes of Sleep Questionnaire.(53) In addition, modafinil is effective in the treatment of narcolepsy(55) and the excessive daytime sleepiness of Parkinson's Disease.(56)

Caffeine

Caffeine improves alertness and vigilance, with the size of the effects increasing with caffeine dose,(57) and is as effective as modafinil.(58) Caffeine can block sleep inertia -- the grogginess and disorientation that a person experiences for minutes to hours after awakening from sleep(35) -- a fact which may explain why this common stimulant is often used in the morning, after a night of sleep.

Bright Light

Bright light presentation produces significant improvement in performance and alertness levels, with rapid, safe and acute effects [reviewed in (59)]. Spectral characteristics of light appear to play a role in such improvements. For example, compared with those exposed to 555-nm light, subjects exposed to 460-nm light had significantly lower subjective sleepiness ratings, decreased auditory psychomotor reaction times, fewer attentional failures, decreased EEG power density in the delta-theta range (0.5-5.5 Hz) and increased EEG power density in the high-alpha range [9.5-10.5 Hz(60)]. In addition, light effectively ameliorates the circadian and sleep misalignments that result from jet lag and shiftwork [reviewed in (61)] and from aging [reviewed in (9)].

Conclusion

Fatigue, sleepiness and performance decrement -- including attentional lapses, increased reaction times, cognitive slowing and memory difficulties -- result from acute and chronic sleep loss and circadian displacement of sleep-wake schedules. As such, these factors are common occurrences in situations which utilize 24-h work schedules or result from medical conditions, sleep disorders or jet lag, and contribute to increased cognitive errors and risk of adverse events -- although the magnitude of such effects varies across individuals. Neurobehavioral and neurobiological research have demonstrated that waking neurocognitive functions depend upon stable alertness that is the result of adequate daily recovery sleep. Thus, understanding and mitigating the risks imposed by physiologically-based variations in fatigue and alertness are essential for the development and use of countermeasures.