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Circadian Rhythms in Sleepiness, Alertness, and Performance
Circadian Rhythms in Sleepiness, Alertness, and Performance 965
Circadian Rhythms in Sleepiness, Alertness, and Performance J D Minkel and D F Dinges, University of Pennsylvania School of Medicine, Philadelphia, PA, USA ã 2009 Elsevier Ltd. All rights reserved.
Introduction Circadian rhythms (i.e., biological processes that repeat about every 24 h) reflect the incorporation of Earth’s daily rotation into living systems. Internal circadian clocks are found in all eukaryotic and even some prokaryotic organisms indicating that natural selection has highly favored circadian rhythms from the beginnings of life for virtually all species. The suprachiasmatic nucleus (SCN) in the hypothalamus serves as the brain’s master clock, in humans and many other animals as well. Neurons in the SCN fire in a 24 h cycle that is driven by a transcriptional–translational feedback loop. Loss of the SCN abolishes the circadian rhythms of a range of behaviors and physiological processes, including sleep, if the animals are not given other external timing cues. Under normal circumstances, the SCN is reset on a daily basis by light inputs from the retina during the day and by melatonin secretion from the pineal gland at night. The SCN temporally organizes physiological and behavioral tendencies, but the circadian rhythms it promotes are not fixed. This plasticity is believed to reflect adaptation to dynamic demands of the environment such as seasonal changes in daylight. Humans in industrialized societies, however, routinely push the limits of the adaptive capacity of circadian rhythms. Social demands and opportunities (e.g., night shift work, travel across time zones) often lead to abnormal sleep and wake times that are out of phase with biological requirements. The circadian clock has been shaped by natural selection to regulate physiological processes to occur at optimal times relative to each other or relative to the external environment. With the introduction of artificial lighting and 24 h services, however, many humans are awake when their biological clocks are telling them it is time to sleep and trying to sleep when the circadian clock is sending signals throughout the brain that it is time to be awake. The combination of restricting sleep and attaining it at biologically misaligned times is problematic. Approximately 6 million people in the US alone work during the biological night without adapting their internal physiology to these conditions.
In this article, we review what is currently known about circadian modulation of neurobehavioral and affective systems in humans.
Identifying the Circadian Rhythm in Sleep and Wakefulness Subjective Measures of Fatigue and Alertness
Circadian rhythmicity in neurobehavioral variables has been successfully identified using a wide array of subjective measures of alertness and fatigue. Visual analog scales, Likert-type rating scales, the Karolinska sleepiness scale, the activation–deactivation adjective check list, and the profile of mood states have all demonstrated sensitivity to circadian fluctuations in sleepiness and mood. Subjective measures may be particularly vulnerable to numerous confounding influences, however. Masking (i.e., the effects of noncircadian factors on the measurement of circadian rhythmicity) frequently prevents underlying circadian signals from being separated from noise. The context in which such measurements are taken (regardless of whether the setting is experimental or environmental) is a major source of masking effects. Demand characteristics, levels of motivation or boredom, distractions, stress, food intake, posture, background noise, ambient temperature, lighting conditions, and pharmacological factors (e.g., caffeine use) are some of the influences that have been identified to mask underlying circadian rhythmicity in subjective measures. These same variables can also create the false appearance of a circadian rhythm, especially in uncontrolled studies where daily schedules may be influenced by sociocultural factors as much as underlying biology. Circadian rhythms in mood states and sleepiness can be masked by physical, mental, and social activity as well, even in highly controlled experiments. For example, subjects have reported feeling less alert after being challenged to perform. Thus, if not properly controlled, the drop in subjective alertness due to performance effort can mask circadian effects. Similarly, social interactions with staff and/or other subjects in a study can influence subjective variables. In experimental studies, this potential confound can be reduced through careful training of staff and attention to interpersonal interactions among study participants. However, experiments that fail to control social variables risk contaminating true endogenous circadian variance in self-report measures of alertness and fatigue.
966 Circadian Rhythms in Sleepiness, Alertness, and Performance
These outcomes can also be masked by prior sleep– wake schedules. Sleep and sleep loss have large effects on alertness and performance that can interact with and alter subtler circadian fluctuations. Despite their sensitivity to masking factors, however, subjective scales have been used to index circadian rhythmicity by repeated administration across the day under carefully controlled conditions.
concluded that different tasks and task parameters may yield different peak phases of circadian rhythmicity, but under strictly controlled laboratory conditions, most of these intertask differences disappear. Thus, it can generally be stated that circadian rhythms of cognitive and psychomotor performance covary. Furthermore, these rhythms are synchronized with physiological markers of circadian phase, such as body temperature.
Cognitive Performance
Objective performance measures also demonstrate circadian rhythmicity and are generally less susceptible to masking influences than subjective reports of mood and sleepiness. Tasks that assess psychomotor and/or cognitive speed are particularly sensitive to circadian fluctuations in arousal and somewhat more resistant to masking effects than many other measures. For example, performance on the well-validated Psychomotor Vigilance Test, which shows almost no learning curve and little variance within and between healthy subjects who are fully rested, has been demonstrated to vary with other markers of circadian phase such as melatonin and core body temperature (see Figure 1). Circadian variation has also been demonstrated in a wide range of cognitive tests including searchand-detection tasks, simple sorting, logical reasoning, memory access, and even school performance and meter-reading accuracy. A number of studies have
Electroencephalographic and Ocular Measures
The circadian rhythm in task performance and subjective states reflects functional changes in the brain. Neural activity, as measured by evoked potentials or event-related potentials (ERPs), has been used to measure alertness. ERPs are relatively subtle signals that must be measured over many consecutive stimulus probes in order to separate them from background electroencephalographic (EEG) noise. Therefore, ERPs are usually recorded during repetitive tasks, such as reaction time tasks and search-and-detection tasks. Circadian rhythms in the changes to amplitude and location of ERP waves have been identified and interpreted to reflect fluctuations in alertness. Measurement of EEG during wakefulness has demonstrated circadian rhythmicity, especially in theta and alpha frequencies. The amounts of theta and alpha activity in the resting EEG are associated with levels of alertness.
Lapses of attention
6 14 22 30 38 46 54 62
Body temperature
36.85 36.75
4h
36.65 36.55 36.45 36.35 36.25 36.15 11 13 15 17 19 21 23 1 3 5 7 9 11 13 15 17 19 21 23 1 Time of day (h)
Figure 1 The mean (SEM) circadian minimum (nadir) in body temperature occurred approximately 4 h before the maximum of lapses of attention (note downward deflection on the upper graph indicates worse performance).
Circadian Rhythms in Sleepiness, Alertness, and Performance 967
Sleep latency measured by EEG and electrooculographic (EOG) activity has been found to exhibit marked circadian variation. Since sleep latency is an indication of propensity of the brain to fall asleep, the circadian system is actively regulating sleepiness and sleep–wake cycles. In addition to shifts toward lower EEG frequencies at night, there is a circadian-mediated increase in slow eyelid closure and slow rolling movements, both of which herald the onset of sleep. Finally, autonomic tone has also been shown to covary with sleep pressure as measured by pupillometry (pupils dilate with sympathetic activation). Midafternoon Dip
In addition to circadian fluctuations in performance that are tightly linked to physiological markers of phase, some individuals appear to demonstrate a short-term dip in performance in the afternoon (sometimes called the midafternoon dip, siesta, or postprandial dip). This dip has been observed in both field and laboratory studies, but is not consistently demonstrated, suggesting that it may be a relatively weak variable. The best evidence for the existence of such a midafternoon dip comes from studies of sleep propensity and on the timing of daytime naps. There is much less evidence that the midafternoon dip has deleterious effects on performance measures, which makes the phenomenon’s relationship to the biological clock somewhat unclear. Although field studies have reported a decline in performance at this time of day the uncontrolled nature of such experiments prevents strong conclusions about the underlying biology of the phenomenon. As mentioned earlier, external variables can produce the illusion of circadian rhythmicity as well as mask it.
Problems in Detecting Circadian Rhythmicity in Performance Practice Effects and Other Artifacts
Although repeated administration of the same task is important for identifying circadian fluctuations in performance, increasing familiarity with a task also produces a practice effect (i.e., improved performance with practice on a given task). Practice effects can be difficult to distinguish from the circadian rhythm, but the problem can be circumvented by testing subjects in different orders across times of day, thus balancing out improvements in performance due to learning. This solution assumes however that the practice effect and circadian rhythm are merely additive influences on performance that have
the same relationship in every subject. For most tasks, neither assumption can be made with certainty. A better way to deal with the practice effect is simply to train subjects to their full capacity (i.e., until performance levels reach an asymptote) on tasks before attempting to assess circadian rhythms. When possible, the best way to deal with this problem is to use a measure that has no practice effects like simple psychomotor vigilance tasks. In addition to the practice effect, many of the same variables that serve to mask circadian rhythmicity in subjective estimates of fatigue and alertness can also conceal, accentuate, or otherwise distort such rhythmicity on objective performance measures. The effects of masking can vary from changes in the shape of the circadian curve to fully obscuring the circadian influence. It is therefore difficult to extract meaningful information about the mathematical characteristics of the circadian phase without an understanding of the masking effects that influence the variables under investigation. Not only is performance affected by learning, aptitude, and other masking factors, but also by neurocognitive processes and strategies that can be conscious or unconscious. For example, subvocalization (a strategy that can improve performance on certain tasks) has been reported to fluctuate with a circadian rhythmicity. Similarly, compensatory effort in the face of drowsiness can maintain objective performance at steady levels despite underlying circadian fluctuations. Finally, neuroimaging studies have begun to demonstrate that a given task can be accomplished using multiple neural pathways. Sleep-deprived subjects have been shown to compensate for their performance impairment by increasing activation in the parietal lobes. Such compensatory plasticity in neural function illustrates that the effects of sleepiness and arousal are not always expressed through differences in performance. For all of these reasons, successful demonstration of circadian rhythmicity in performance measures requires that tasks be structured in ways that minimize or eliminate masking effects. Interindividual and Intraindividual Variability
A large body of literature supports relatively stable interindividual differences in many parameters related to the human circadian system. An important exception however is the period of the human circadian pacemaker. Although published reports spanning several decades asserted that the period could range from 13 h to 65 h, highly controlled data demonstrated that the period is very close to 24 h with little variation between or within subjects. The free running
968 Circadian Rhythms in Sleepiness, Alertness, and Performance
period of the human pacemaker is also not heavily influenced by age in healthy subjects. The large variance reported in less-controlled studies therefore probably represents individual differences in the sensitivity of the circadian system’s response to masking factors such as physical activity, knowledge of time of day, and exposure to artificial light. In contrast to the human circadian period, individual differences in circadian amplitude, phase, and mean performance level have been demonstrated. Differences in phase are particularly important because they determine differences in circadian variables relative to time of day. For example, personal preference in timing of work hours is related to individual differences in circadian phase. The tendency for people to prefer to be active and alert earlier or later (often referred to as ‘morningness’ or ‘eveningness,’ respectively) is probably the most substantial source of interindividual variation in circadian rhythmicity. Individuals who prefer different times of day differ endogenously in the circadian phase of their biological clocks. Objective performance measures and physiological variables (e.g., core body temperature) support the morningness/ eveningness distinction. This traitlike difference in performance may be seen as a phenotypic aspect of circadian rhythmicity in humans. Intraindividual differences in circadian rhythms refer to changes within one individual over time, such as differences in morning alertness during the summer compared to the winter. The circadian trough is associated with increased intraindividual variability in performance, reflecting increased wake-state instability similar to what is seen with extended wakefulness. Age is also a source of interindividual variability in the circadian rhythm of alertness and performance, but no consistent relevance of sex has been found.
Sleep deprivation, however, can still exert a masking influence on neurobehavioral variables because sleep loss adversely affects performance. Performance may be pushed to extremes by a single night of sleep loss, making circadian fluctuations impossible to detect. This is precisely what happens to sleep latency in the widely used multiple sleep latency test (MSLT). Subjects with extremely high homeostatic sleep pressure fall asleep as quickly as possible regardless of their circadian phase. Nevertheless, when sleep pressure is not extremely elevated and the constant routine procedure is used, both circadian and homeostatic influences on performance can be seen. Sleep–Wake Regulation
The interaction of circadian and homeostatic influences on performance and alertness has prompted efforts to mathematically model the regulatory processes involved. Current theory and mathematical models posit that the homeostatic process represents the drive for sleep which increases linearly during wakefulness and decreases with sleep. When the ‘homeostat’ reaches a certain threshold, sleep is triggered; when it is sufficiently dissipated, wakefulness is initiated. The circadian process represents daily oscillatory modulation of these threshold levels, but may have an additional role in promoting wakefulness even in the absence of sleep. These two processes not only determine the timing of sleep and wakefulness, but also interact to determine waking neurobehavioral performance during sustained wakefulness. Sleep-deprivation experiments clearly show that the circadian process continues to influence performance even as the homeostat increases beyond what would normally initiate sleep. Forced Desynchrony
Circadian Rhythmicity and Sleep–Wake Cycles Sleep Deprivation
Unmasking the circadian rhythm has been a priority in sleep research for many years. An important method in this domain has been the constant routine procedure (also called the unmasking procedure) which involves keeping subjects awake with a fixed posture in a constant laboratory environment for at least 24 h. By maintaining such a static environment, many of the potential confounding factors (changes in lighting and noise, social interaction, cognitive fatigue, etc.) are eliminated or minimized. Relatively subtle circadian fluctuations can then be readily separated from background noise.
Like the constant routine procedure, forced desynchrony is an experimental paradigm that unmasks circadian rhythmicity. In this procedure, study participants stay in an isolated laboratory in which the times for sleep and waking are scheduled to deviate from the normal day. Although humans can entrain to days that are not exactly 24 h, artificial days that are extremely short (e.g., 20 h) or very long (e.g., 28 h) are outside the adaptive capacity of the biological clock. When such a routine is kept for several days, the sleep–wake schedule cannot entrain to endogenous circadian rhythms. Studies using this method have clearly demonstrated that both circadian and homeostatic processes influence sleepiness, performance, and mood. The interaction of the two processes is oppositional during natural waking periods such that
Circadian Rhythms in Sleepiness, Alertness, and Performance 969
a relatively stable level of alertness and performance can be maintained throughout the day.
and psychiatric conditions relative to those who work during the day. Field studies have estimated that at best, it takes at least 1 week before the biological clock adjusts to shift work. Complicating the problem is the circadian system’s sensitivity to both light and dark. Although in a controlled environment the human circadian system can be shifted a full 12 h over a number of days, in natural settings sunlight will disrupt the reentrainment process. Many shift workers therefore never fully adjust physiologically to their schedules. Melatonin has been investigated as a means of facilitating phase shifts, but its ability to shift circadian phase in the presence of natural light has been found to be fairly weak. Jetlag is also a common chronobiological problem in modern society. At any given time, approximately 500 000 people are traveling in planes, many of whom will cross many time zones. Most individuals experience unpleasant symptoms for several days after arriving at a destination in a new time zone. Because humans have only very recently achieved high-speed transportation, our circadian systems have not been shaped by evolution to entrain quickly to shifted light–dark cycles. As a result, people experience daytime sleepiness, fatigue, impaired alertness, and difficulty initiating and maintaining sleep for several days after crossing time zones.
Ultraradian Days
The ‘ultradian’ day (meaning ‘very short day’) paradigm was designed to sample waking behavior across the circadian cycle without significantly curtailing the total amount of sleep allowed. Studies using this method allow subjects relatively brief periods of sleep and wakefulness (e.g., 30 min of sleep followed by 60 min of wakefulness). Thus, ultraradian schedules maintain the normal ratio of sleep to wakefulness (i.e., 1:2). In one such experiment using 7 min of sleep to 13 min of wakefulness, a clear circadian rhythm emerged for the response time on a choice reaction time task. A movement time component was also recorded. This study showed that even in conditions of extremely short artificial days both circadian and homeostatic influences still interact to determine performance. Circadian Disorders
The laboratory is not the only place one finds people divorcing their sleep–wake pattern from the tendencies of the biological clocks. Recent labor statistics estimate that about 6 million members of the American workforce engage in work at night. While emergency services have been offered 24 h a day for many years, nonessential services are increasingly being offered throughout the night as well. As expected from the research reviewed above, those who work at the circadian phase for sleep show an increased prevalence of sleep disturbance and related medical
Accident Risk
Circadian lows in alertness and performance increase the risk of human-error-related accidents. Motor vehicle accidents caused by drivers falling asleep at
450 400 Number of crashes
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Time of day Figure 2 Frequency histogram of time of occurrence during the day of crashes in which the driver was judged to be asleep but not intoxicated. Data for years 1990–92, inclusive. Reprinted from Pack AM, Rodgman E, Cucchiara A, Dinges DF, and Schwab CW (1995) Characteristics of crashes attributed to the driver having fallen asleep. Accident; Analysis and Prevention 27: 769–775, with permission from Elsevier.
970 Circadian Rhythms in Sleepiness, Alertness, and Performance
the wheel show a circadian rhythm quite similar to laboratory-based findings (see Figure 2). Fall-asleep accidents increase throughout the night as sustained attention decreases. Such accidents peak around 8:00 a.m., when vigilant performance is at its lowest, then begin to fall as the circadian system increases alertness and arousal.
Conclusion Despite the difficulties inherent in identifying circadian influences on performance at various levels of alertness, a large body of research employing diverse methodology has clearly dissociated the effects of oscillating circadian rhythms from homeostatic influences on performance and mood. While controlling for factors that mask circadian rhythms is important for scientific and theoretical purposes, it is important to remember that these factors are also an integral part of the regulation of neurobehavioral functions that allow for adaptation to rhythmic changes in the environment. Understanding circadian rhythmicity in performance and affective processes is important for understanding circadian disorders (such as shift-work- and jet-lag-induced sleep problems) and for correctly anticipating performance lapses and fatigue-related impairments (e.g., drowsy driving). When sleep is chronically restricted, both homeostatic and circadian influences must be understood in order to correctly predict levels of performance impairment that result from the interaction of these two systems. See also: Circadian Systems: Evolution; Circadian Oscillations in the Suprachiasmatic Nucleus; Circadian
Regulation by the Suprachiasmatic Nucleus; Electroencephalography (EEG); Metabolic Syndrome and Sleep; Psychophysics of Attention; Shift Work and Circadian Rhythms; Sleep and Waking in Drosophila.
Further Reading Boivin DB, Czeisler CA, Dijk DJ, et al. (1997) Complex interaction of the sleep–wake cycle and circadian phase modulates mood in healthy subjects. Archives of General Psychiatry 54: 145–152. Cajochen C, Zeitzer JM, Czeisler CA, and Dijk DJ (2000) Dose– response relationship for light intensity and ocular and electroencephalographic correlates of human alertness. Behavioral Brain Research 115: 75–83. Czeisler CA, Buxton OM, and Khalsa SB (2005) The human circadian timing system and sleep–wake regulation. In: Kryger MH, Roth T, and Dement WC (eds.) Principles and Practice of Sleep Medicine, 4th edn., pp. 375–394. Philadelphia: W.B. Saunders. Czeisler CA, Duffy JF, Shanahan TL, et al. (1999) Stability, precision, and near-24-hour period of the human circadian pacemaker. Science 284: 2177–2181. Dijk DJ and Von Schantz M (2005) Timing and consolidation of human sleep, wakefulness, and performance by a symphony of oscillators. Journal of Biological Rhythms 20: 279–290. Monk TH (ed.) (1991) Sleep, Sleepiness, and Performance. Chichester: Wiley. Phipps-Nelson J, Redman JR, Dijk DJ, and Rajaratnam SM (2003) Daytime exposure to bright light, as compared to dim light, decreases sleepiness and improves psychomotor vigilance performance. Sleep 26: 695–700. Van Dongen HP and Dinges DF (2005) Sleep, circadian rhythms, and psychomotor vigilance. Clinics in Sports Medicine 24: 237–249. Van Dongen HP and Dinges DF (2005) Circadian rhythms in sleepiness, alertness, and performance. In: Kryger MH, Roth T, and Dement WC (eds.) Principles and Practice of Sleep Medicine, 4th edn., pp. 435–443. Philadelphia: W.B. Saunders. Wright KP Jr., Hull JT, and Czeisler CA (2002) Relationship between alertness, performance, and body temperature in humans. American Journal of Physiology-Regulatory Integrative and Comparative Physiology 283: 1370–1377.
Circadian Rhythms in Sleepiness, Alertness, and Performance J D Minkel and D F Dinges, University of Pennsylvania School of Medicine, Philadelphia, PA, USA ã 2009 Elsevier Ltd. All rights reserved.
Introduction Circadian rhythms (i.e., biological processes that repeat about every 24 h) reflect the incorporation of Earth’s daily rotation into living systems. Internal circadian clocks are found in all eukaryotic and even some prokaryotic organisms indicating that natural selection has highly favored circadian rhythms from the beginnings of life for virtually all species. The suprachiasmatic nucleus (SCN) in the hypothalamus serves as the brain’s master clock, in humans and many other animals as well. Neurons in the SCN fire in a 24 h cycle that is driven by a transcriptional–translational feedback loop. Loss of the SCN abolishes the circadian rhythms of a range of behaviors and physiological processes, including sleep, if the animals are not given other external timing cues. Under normal circumstances, the SCN is reset on a daily basis by light inputs from the retina during the day and by melatonin secretion from the pineal gland at night. The SCN temporally organizes physiological and behavioral tendencies, but the circadian rhythms it promotes are not fixed. This plasticity is believed to reflect adaptation to dynamic demands of the environment such as seasonal changes in daylight. Humans in industrialized societies, however, routinely push the limits of the adaptive capacity of circadian rhythms. Social demands and opportunities (e.g., night shift work, travel across time zones) often lead to abnormal sleep and wake times that are out of phase with biological requirements. The circadian clock has been shaped by natural selection to regulate physiological processes to occur at optimal times relative to each other or relative to the external environment. With the introduction of artificial lighting and 24 h services, however, many humans are awake when their biological clocks are telling them it is time to sleep and trying to sleep when the circadian clock is sending signals throughout the brain that it is time to be awake. The combination of restricting sleep and attaining it at biologically misaligned times is problematic. Approximately 6 million people in the US alone work during the biological night without adapting their internal physiology to these conditions.
In this article, we review what is currently known about circadian modulation of neurobehavioral and affective systems in humans.
Identifying the Circadian Rhythm in Sleep and Wakefulness Subjective Measures of Fatigue and Alertness
Circadian rhythmicity in neurobehavioral variables has been successfully identified using a wide array of subjective measures of alertness and fatigue. Visual analog scales, Likert-type rating scales, the Karolinska sleepiness scale, the activation–deactivation adjective check list, and the profile of mood states have all demonstrated sensitivity to circadian fluctuations in sleepiness and mood. Subjective measures may be particularly vulnerable to numerous confounding influences, however. Masking (i.e., the effects of noncircadian factors on the measurement of circadian rhythmicity) frequently prevents underlying circadian signals from being separated from noise. The context in which such measurements are taken (regardless of whether the setting is experimental or environmental) is a major source of masking effects. Demand characteristics, levels of motivation or boredom, distractions, stress, food intake, posture, background noise, ambient temperature, lighting conditions, and pharmacological factors (e.g., caffeine use) are some of the influences that have been identified to mask underlying circadian rhythmicity in subjective measures. These same variables can also create the false appearance of a circadian rhythm, especially in uncontrolled studies where daily schedules may be influenced by sociocultural factors as much as underlying biology. Circadian rhythms in mood states and sleepiness can be masked by physical, mental, and social activity as well, even in highly controlled experiments. For example, subjects have reported feeling less alert after being challenged to perform. Thus, if not properly controlled, the drop in subjective alertness due to performance effort can mask circadian effects. Similarly, social interactions with staff and/or other subjects in a study can influence subjective variables. In experimental studies, this potential confound can be reduced through careful training of staff and attention to interpersonal interactions among study participants. However, experiments that fail to control social variables risk contaminating true endogenous circadian variance in self-report measures of alertness and fatigue.
966 Circadian Rhythms in Sleepiness, Alertness, and Performance
These outcomes can also be masked by prior sleep– wake schedules. Sleep and sleep loss have large effects on alertness and performance that can interact with and alter subtler circadian fluctuations. Despite their sensitivity to masking factors, however, subjective scales have been used to index circadian rhythmicity by repeated administration across the day under carefully controlled conditions.
concluded that different tasks and task parameters may yield different peak phases of circadian rhythmicity, but under strictly controlled laboratory conditions, most of these intertask differences disappear. Thus, it can generally be stated that circadian rhythms of cognitive and psychomotor performance covary. Furthermore, these rhythms are synchronized with physiological markers of circadian phase, such as body temperature.
Cognitive Performance
Objective performance measures also demonstrate circadian rhythmicity and are generally less susceptible to masking influences than subjective reports of mood and sleepiness. Tasks that assess psychomotor and/or cognitive speed are particularly sensitive to circadian fluctuations in arousal and somewhat more resistant to masking effects than many other measures. For example, performance on the well-validated Psychomotor Vigilance Test, which shows almost no learning curve and little variance within and between healthy subjects who are fully rested, has been demonstrated to vary with other markers of circadian phase such as melatonin and core body temperature (see Figure 1). Circadian variation has also been demonstrated in a wide range of cognitive tests including searchand-detection tasks, simple sorting, logical reasoning, memory access, and even school performance and meter-reading accuracy. A number of studies have
Electroencephalographic and Ocular Measures
The circadian rhythm in task performance and subjective states reflects functional changes in the brain. Neural activity, as measured by evoked potentials or event-related potentials (ERPs), has been used to measure alertness. ERPs are relatively subtle signals that must be measured over many consecutive stimulus probes in order to separate them from background electroencephalographic (EEG) noise. Therefore, ERPs are usually recorded during repetitive tasks, such as reaction time tasks and search-and-detection tasks. Circadian rhythms in the changes to amplitude and location of ERP waves have been identified and interpreted to reflect fluctuations in alertness. Measurement of EEG during wakefulness has demonstrated circadian rhythmicity, especially in theta and alpha frequencies. The amounts of theta and alpha activity in the resting EEG are associated with levels of alertness.
Lapses of attention
6 14 22 30 38 46 54 62
Body temperature
36.85 36.75
4h
36.65 36.55 36.45 36.35 36.25 36.15 11 13 15 17 19 21 23 1 3 5 7 9 11 13 15 17 19 21 23 1 Time of day (h)
Figure 1 The mean (SEM) circadian minimum (nadir) in body temperature occurred approximately 4 h before the maximum of lapses of attention (note downward deflection on the upper graph indicates worse performance).
Circadian Rhythms in Sleepiness, Alertness, and Performance 967
Sleep latency measured by EEG and electrooculographic (EOG) activity has been found to exhibit marked circadian variation. Since sleep latency is an indication of propensity of the brain to fall asleep, the circadian system is actively regulating sleepiness and sleep–wake cycles. In addition to shifts toward lower EEG frequencies at night, there is a circadian-mediated increase in slow eyelid closure and slow rolling movements, both of which herald the onset of sleep. Finally, autonomic tone has also been shown to covary with sleep pressure as measured by pupillometry (pupils dilate with sympathetic activation). Midafternoon Dip
In addition to circadian fluctuations in performance that are tightly linked to physiological markers of phase, some individuals appear to demonstrate a short-term dip in performance in the afternoon (sometimes called the midafternoon dip, siesta, or postprandial dip). This dip has been observed in both field and laboratory studies, but is not consistently demonstrated, suggesting that it may be a relatively weak variable. The best evidence for the existence of such a midafternoon dip comes from studies of sleep propensity and on the timing of daytime naps. There is much less evidence that the midafternoon dip has deleterious effects on performance measures, which makes the phenomenon’s relationship to the biological clock somewhat unclear. Although field studies have reported a decline in performance at this time of day the uncontrolled nature of such experiments prevents strong conclusions about the underlying biology of the phenomenon. As mentioned earlier, external variables can produce the illusion of circadian rhythmicity as well as mask it.
Problems in Detecting Circadian Rhythmicity in Performance Practice Effects and Other Artifacts
Although repeated administration of the same task is important for identifying circadian fluctuations in performance, increasing familiarity with a task also produces a practice effect (i.e., improved performance with practice on a given task). Practice effects can be difficult to distinguish from the circadian rhythm, but the problem can be circumvented by testing subjects in different orders across times of day, thus balancing out improvements in performance due to learning. This solution assumes however that the practice effect and circadian rhythm are merely additive influences on performance that have
the same relationship in every subject. For most tasks, neither assumption can be made with certainty. A better way to deal with the practice effect is simply to train subjects to their full capacity (i.e., until performance levels reach an asymptote) on tasks before attempting to assess circadian rhythms. When possible, the best way to deal with this problem is to use a measure that has no practice effects like simple psychomotor vigilance tasks. In addition to the practice effect, many of the same variables that serve to mask circadian rhythmicity in subjective estimates of fatigue and alertness can also conceal, accentuate, or otherwise distort such rhythmicity on objective performance measures. The effects of masking can vary from changes in the shape of the circadian curve to fully obscuring the circadian influence. It is therefore difficult to extract meaningful information about the mathematical characteristics of the circadian phase without an understanding of the masking effects that influence the variables under investigation. Not only is performance affected by learning, aptitude, and other masking factors, but also by neurocognitive processes and strategies that can be conscious or unconscious. For example, subvocalization (a strategy that can improve performance on certain tasks) has been reported to fluctuate with a circadian rhythmicity. Similarly, compensatory effort in the face of drowsiness can maintain objective performance at steady levels despite underlying circadian fluctuations. Finally, neuroimaging studies have begun to demonstrate that a given task can be accomplished using multiple neural pathways. Sleep-deprived subjects have been shown to compensate for their performance impairment by increasing activation in the parietal lobes. Such compensatory plasticity in neural function illustrates that the effects of sleepiness and arousal are not always expressed through differences in performance. For all of these reasons, successful demonstration of circadian rhythmicity in performance measures requires that tasks be structured in ways that minimize or eliminate masking effects. Interindividual and Intraindividual Variability
A large body of literature supports relatively stable interindividual differences in many parameters related to the human circadian system. An important exception however is the period of the human circadian pacemaker. Although published reports spanning several decades asserted that the period could range from 13 h to 65 h, highly controlled data demonstrated that the period is very close to 24 h with little variation between or within subjects. The free running
968 Circadian Rhythms in Sleepiness, Alertness, and Performance
period of the human pacemaker is also not heavily influenced by age in healthy subjects. The large variance reported in less-controlled studies therefore probably represents individual differences in the sensitivity of the circadian system’s response to masking factors such as physical activity, knowledge of time of day, and exposure to artificial light. In contrast to the human circadian period, individual differences in circadian amplitude, phase, and mean performance level have been demonstrated. Differences in phase are particularly important because they determine differences in circadian variables relative to time of day. For example, personal preference in timing of work hours is related to individual differences in circadian phase. The tendency for people to prefer to be active and alert earlier or later (often referred to as ‘morningness’ or ‘eveningness,’ respectively) is probably the most substantial source of interindividual variation in circadian rhythmicity. Individuals who prefer different times of day differ endogenously in the circadian phase of their biological clocks. Objective performance measures and physiological variables (e.g., core body temperature) support the morningness/ eveningness distinction. This traitlike difference in performance may be seen as a phenotypic aspect of circadian rhythmicity in humans. Intraindividual differences in circadian rhythms refer to changes within one individual over time, such as differences in morning alertness during the summer compared to the winter. The circadian trough is associated with increased intraindividual variability in performance, reflecting increased wake-state instability similar to what is seen with extended wakefulness. Age is also a source of interindividual variability in the circadian rhythm of alertness and performance, but no consistent relevance of sex has been found.
Sleep deprivation, however, can still exert a masking influence on neurobehavioral variables because sleep loss adversely affects performance. Performance may be pushed to extremes by a single night of sleep loss, making circadian fluctuations impossible to detect. This is precisely what happens to sleep latency in the widely used multiple sleep latency test (MSLT). Subjects with extremely high homeostatic sleep pressure fall asleep as quickly as possible regardless of their circadian phase. Nevertheless, when sleep pressure is not extremely elevated and the constant routine procedure is used, both circadian and homeostatic influences on performance can be seen. Sleep–Wake Regulation
The interaction of circadian and homeostatic influences on performance and alertness has prompted efforts to mathematically model the regulatory processes involved. Current theory and mathematical models posit that the homeostatic process represents the drive for sleep which increases linearly during wakefulness and decreases with sleep. When the ‘homeostat’ reaches a certain threshold, sleep is triggered; when it is sufficiently dissipated, wakefulness is initiated. The circadian process represents daily oscillatory modulation of these threshold levels, but may have an additional role in promoting wakefulness even in the absence of sleep. These two processes not only determine the timing of sleep and wakefulness, but also interact to determine waking neurobehavioral performance during sustained wakefulness. Sleep-deprivation experiments clearly show that the circadian process continues to influence performance even as the homeostat increases beyond what would normally initiate sleep. Forced Desynchrony
Circadian Rhythmicity and Sleep–Wake Cycles Sleep Deprivation
Unmasking the circadian rhythm has been a priority in sleep research for many years. An important method in this domain has been the constant routine procedure (also called the unmasking procedure) which involves keeping subjects awake with a fixed posture in a constant laboratory environment for at least 24 h. By maintaining such a static environment, many of the potential confounding factors (changes in lighting and noise, social interaction, cognitive fatigue, etc.) are eliminated or minimized. Relatively subtle circadian fluctuations can then be readily separated from background noise.
Like the constant routine procedure, forced desynchrony is an experimental paradigm that unmasks circadian rhythmicity. In this procedure, study participants stay in an isolated laboratory in which the times for sleep and waking are scheduled to deviate from the normal day. Although humans can entrain to days that are not exactly 24 h, artificial days that are extremely short (e.g., 20 h) or very long (e.g., 28 h) are outside the adaptive capacity of the biological clock. When such a routine is kept for several days, the sleep–wake schedule cannot entrain to endogenous circadian rhythms. Studies using this method have clearly demonstrated that both circadian and homeostatic processes influence sleepiness, performance, and mood. The interaction of the two processes is oppositional during natural waking periods such that
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a relatively stable level of alertness and performance can be maintained throughout the day.
and psychiatric conditions relative to those who work during the day. Field studies have estimated that at best, it takes at least 1 week before the biological clock adjusts to shift work. Complicating the problem is the circadian system’s sensitivity to both light and dark. Although in a controlled environment the human circadian system can be shifted a full 12 h over a number of days, in natural settings sunlight will disrupt the reentrainment process. Many shift workers therefore never fully adjust physiologically to their schedules. Melatonin has been investigated as a means of facilitating phase shifts, but its ability to shift circadian phase in the presence of natural light has been found to be fairly weak. Jetlag is also a common chronobiological problem in modern society. At any given time, approximately 500 000 people are traveling in planes, many of whom will cross many time zones. Most individuals experience unpleasant symptoms for several days after arriving at a destination in a new time zone. Because humans have only very recently achieved high-speed transportation, our circadian systems have not been shaped by evolution to entrain quickly to shifted light–dark cycles. As a result, people experience daytime sleepiness, fatigue, impaired alertness, and difficulty initiating and maintaining sleep for several days after crossing time zones.
Ultraradian Days
The ‘ultradian’ day (meaning ‘very short day’) paradigm was designed to sample waking behavior across the circadian cycle without significantly curtailing the total amount of sleep allowed. Studies using this method allow subjects relatively brief periods of sleep and wakefulness (e.g., 30 min of sleep followed by 60 min of wakefulness). Thus, ultraradian schedules maintain the normal ratio of sleep to wakefulness (i.e., 1:2). In one such experiment using 7 min of sleep to 13 min of wakefulness, a clear circadian rhythm emerged for the response time on a choice reaction time task. A movement time component was also recorded. This study showed that even in conditions of extremely short artificial days both circadian and homeostatic influences still interact to determine performance. Circadian Disorders
The laboratory is not the only place one finds people divorcing their sleep–wake pattern from the tendencies of the biological clocks. Recent labor statistics estimate that about 6 million members of the American workforce engage in work at night. While emergency services have been offered 24 h a day for many years, nonessential services are increasingly being offered throughout the night as well. As expected from the research reviewed above, those who work at the circadian phase for sleep show an increased prevalence of sleep disturbance and related medical
Accident Risk
Circadian lows in alertness and performance increase the risk of human-error-related accidents. Motor vehicle accidents caused by drivers falling asleep at
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Time of day Figure 2 Frequency histogram of time of occurrence during the day of crashes in which the driver was judged to be asleep but not intoxicated. Data for years 1990–92, inclusive. Reprinted from Pack AM, Rodgman E, Cucchiara A, Dinges DF, and Schwab CW (1995) Characteristics of crashes attributed to the driver having fallen asleep. Accident; Analysis and Prevention 27: 769–775, with permission from Elsevier.
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the wheel show a circadian rhythm quite similar to laboratory-based findings (see Figure 2). Fall-asleep accidents increase throughout the night as sustained attention decreases. Such accidents peak around 8:00 a.m., when vigilant performance is at its lowest, then begin to fall as the circadian system increases alertness and arousal.
Conclusion Despite the difficulties inherent in identifying circadian influences on performance at various levels of alertness, a large body of research employing diverse methodology has clearly dissociated the effects of oscillating circadian rhythms from homeostatic influences on performance and mood. While controlling for factors that mask circadian rhythms is important for scientific and theoretical purposes, it is important to remember that these factors are also an integral part of the regulation of neurobehavioral functions that allow for adaptation to rhythmic changes in the environment. Understanding circadian rhythmicity in performance and affective processes is important for understanding circadian disorders (such as shift-work- and jet-lag-induced sleep problems) and for correctly anticipating performance lapses and fatigue-related impairments (e.g., drowsy driving). When sleep is chronically restricted, both homeostatic and circadian influences must be understood in order to correctly predict levels of performance impairment that result from the interaction of these two systems. See also: Circadian Systems: Evolution; Circadian Oscillations in the Suprachiasmatic Nucleus; Circadian
Regulation by the Suprachiasmatic Nucleus; Electroencephalography (EEG); Metabolic Syndrome and Sleep; Psychophysics of Attention; Shift Work and Circadian Rhythms; Sleep and Waking in Drosophila.
Further Reading Boivin DB, Czeisler CA, Dijk DJ, et al. (1997) Complex interaction of the sleep–wake cycle and circadian phase modulates mood in healthy subjects. Archives of General Psychiatry 54: 145–152. Cajochen C, Zeitzer JM, Czeisler CA, and Dijk DJ (2000) Dose– response relationship for light intensity and ocular and electroencephalographic correlates of human alertness. Behavioral Brain Research 115: 75–83. Czeisler CA, Buxton OM, and Khalsa SB (2005) The human circadian timing system and sleep–wake regulation. In: Kryger MH, Roth T, and Dement WC (eds.) Principles and Practice of Sleep Medicine, 4th edn., pp. 375–394. Philadelphia: W.B. Saunders. Czeisler CA, Duffy JF, Shanahan TL, et al. (1999) Stability, precision, and near-24-hour period of the human circadian pacemaker. Science 284: 2177–2181. Dijk DJ and Von Schantz M (2005) Timing and consolidation of human sleep, wakefulness, and performance by a symphony of oscillators. Journal of Biological Rhythms 20: 279–290. Monk TH (ed.) (1991) Sleep, Sleepiness, and Performance. Chichester: Wiley. Phipps-Nelson J, Redman JR, Dijk DJ, and Rajaratnam SM (2003) Daytime exposure to bright light, as compared to dim light, decreases sleepiness and improves psychomotor vigilance performance. Sleep 26: 695–700. Van Dongen HP and Dinges DF (2005) Sleep, circadian rhythms, and psychomotor vigilance. Clinics in Sports Medicine 24: 237–249. Van Dongen HP and Dinges DF (2005) Circadian rhythms in sleepiness, alertness, and performance. In: Kryger MH, Roth T, and Dement WC (eds.) Principles and Practice of Sleep Medicine, 4th edn., pp. 435–443. Philadelphia: W.B. Saunders. Wright KP Jr., Hull JT, and Czeisler CA (2002) Relationship between alertness, performance, and body temperature in humans. American Journal of Physiology-Regulatory Integrative and Comparative Physiology 283: 1370–1377.