Wake Maintenance Zone Research Articles

Investigating the wake maintenance zone with acute sleep restriction: a promising diagnostic

Investigating the wake maintenance zone with acute sleep restriction: a promising diagnostic

The forbidden zone for sleep is more robust in adolescents compared to adults

IntroductionThe propensity for sleep shifts later as puberty progresses. The present analysis examines whether the circadian-dependent wake maintenance zone, or forbidden zone for sleep observed in the evening just before habitual bedtime is more pronounced in late to post-pubertal adolescents compared to adults and may partly explain late sleep onset in maturing adolescents.MethodsForty four healthy late/post-pubertal adolescents (aged 14.3–17.8 years, 23 female) and 44 healthy adults (aged 30.8–45.8 years, 21 female) participated in an ultradian light/dark protocol for 3 days cycling between 2-h wake periods (~20 lux) and 2-h nap periods (~0 lux) without external time cues. The dim light melatonin onset (DLMO), a measure of circadian phase, was measured immediately before the ultradian protocol by sampling saliva every 30 min in dim light. Wrist actigraphs were used to assess sleep onset latency and total sleep time during the naps that occurred during the ultradian sleep/wake schedule. Sleep episodes were grouped into 2-h bins relative to individual DLMOs (28–56 naps/bin). Sleep onset and total sleep time were compared between adolescents and adults as well as between males and females within each age group.ResultsAdolescents took significantly longer to fall asleep compared to adults during naps that occurred in the 4 h window surrounding the DLMO [2h before DLMO t(50) = 2.13, p = 0.04; 2 h after DLMO t(33) = 3.25, p = 0.003]. Adolescents also slept significantly less than adults during naps that occurred in the 4-h window surrounding DLMO [2 h before DLMO t(51) = −2.91, p = 0.01; 2 h after DLMO t(33) = −1.99, p = 0.05]. Adolescent males slept less than adolescent females in naps that occurred in the 2 h window after the DLMO [t(14) = −2.24, p = 0.04].DiscussionCompared to adults, late/post-pubertal adolescents showed greater difficulty falling asleep and maintaining sleep around the time of their DLMO, which usually occurs a few hours before habitual sleep onset. A greater amplitude in the circadian-driven forbidden zone for sleep could be an additional physiological mechanism explaining why maturing adolescents find it difficult to fall asleep early, increasing the risk for restricted sleep in the context of early school start times.

How and when EEG reflects changes in neuronal connectivity due to time awake

Being awake means forming new memories, primarily by strengthening neuronal synapses. The increase in synaptic strength results in increasing neuronal synchronicity, which should result in higher amplitude electroencephalography (EEG) oscillations. This is observed for slow waves during sleep but has not been found for wake oscillations. We hypothesized that this was due to a limitation of spectral power analysis, which does not distinguish between changes in amplitudes from changes in number of occurrences of oscillations. By using cycle-by-cycle analysis instead, we found that theta and alpha oscillation amplitudes increase as much as 30% following 24h of extended wake. These increases were interrupted during the wake maintenance zone (WMZ), a window just before bedtime when it is difficult to fall asleep. We found that pupil diameter increased during this window, suggesting the ascending arousal system is responsible. In conclusion, wake oscillation amplitudes reflect increased synaptic strength, except duringthe WMZ.

Working around the Clock: Is a Person's Endogenous Circadian Timing for Optimal Neurobehavioral Functioning Inherently Task-Dependent?

Neurobehavioral task performance is modulated by the circadian and homeostatic processes of sleep/wake regulation. Biomathematical modeling of the temporal dynamics of these processes and their interaction allows for prospective prediction of performance impairment in shift-workers and provides a basis for fatigue risk management in 24/7 operations. It has been reported, however, that the impact of the circadian rhythm—and in particular its timing—is inherently task-dependent, which would have profound implications for our understanding of the temporal dynamics of neurobehavioral functioning and the accuracy of biomathematical model predictions. We investigated this issue in a laboratory study designed to unambiguously dissociate the influences of the circadian and homeostatic processes on neurobehavioral performance, as measured during a constant routine protocol preceded by three days on either a simulated night shift or a simulated day shift schedule. Neurobehavioral functions were measured every 2 h using three functionally distinct assays: a digit symbol substitution test, a psychomotor vigilance test, and the Karolinska Sleepiness Scale. After dissociating the circadian and homeostatic influences and accounting for inter-individual variability, peak circadian performance occurred in the late biological afternoon (in the “wake maintenance zone”) for all three neurobehavioral assays. Our results are incongruent with the idea of inherent task-dependent differences in the endogenous circadian impact on performance. Rather, our results suggest that neurobehavioral functions are under top-down circadian control, consistent with the way they are accounted for in extant biomathematical models.

Effects of the selective orexin-2 receptor antagonist JNJ-48816274 on sleep initiated in the circadian wake maintenance zone: a randomised trial

The effects of orexinergic peptides are diverse and are mediated by orexin-1 and orexin-2 receptors. Antagonists that target both receptors have been shown to promote sleep initiation and maintenance. Here, we investigated the role of the orexin-2 receptor in sleep regulation in a randomised, double-blind, placebo-controlled, three-period crossover clinical trial using two doses (20 and 50 mg) of a highly selective orexin-2 receptor antagonist (2-SORA) (JNJ-48816274). We used a phase advance model of sleep disruption where sleep initiation is scheduled in the circadian wake maintenance zone. We assessed objective and subjective sleep parameters, pharmacokinetic profiles and residual effects on cognitive performance in 18 healthy male participants without sleep disorders. The phase advance model alone (placebo condition) resulted in disruption of sleep at the beginning of the sleep period compared to baseline sleep (scheduled at habitual time). Compared to placebo, both doses of JNJ-48816274 significantly increased total sleep time, REM sleep duration and sleep efficiency, and reduced latency to persistent sleep, sleep onset latency, and REM latency. All night EEG spectral power density for both NREM and REM sleep were unaffected by either dose. Participants reported significantly better quality of sleep and feeling more refreshed upon awakening following JNJ-48816274 compared to placebo. No significant residual effects on objective performance measures were observed and the compound was well tolerated. In conclusion, the selective orexin-2 receptor antagonist JNJ-48816274 rapidly induced sleep when sleep was scheduled earlier in the circadian cycle and improved self-reported sleep quality without impact on waking performance.

The impact of the wake maintenance zone on attentional capacity, physiological drowsiness, and subjective task demands during sleep deprivation.

We aimed to investigate the impact of the Wake Maintenance Zone (WMZ) on measures of drowsiness, attention, and subjective performance under rested and sleep deprived conditions. We studied 23 healthy young adults (18 males; mean age=25.41±5.73years) during 40hr of total sleep deprivation under constant routine conditions. Participants completed assessments of physiological drowsiness (EEG-scored slow eye movements and microsleeps), sustained attention (PVT), and subjective task demands every two hours, and four-hourly ocular motor assessment of inhibitory control (inhibition of reflexive saccades on an anti-saccade task). Tests were analyzed relative to dim light melatonin onset (DLMO); the WMZ was defined as the 3hr prior to DLMO, and the preceding 3hr window was deemed the pre-WMZ. The WMZ did not mitigate the adverse impact of ~37hr sleep deprivation on drowsiness, sustained attention, response inhibition, and self-rated concentration and difficulty, relative to rested WMZ performance (~13hr of wakefulness). Compared to the pre-WMZ, though, the WMZ improved measures of sustained attention, and subjective concentration and task difficulty, during sleep deprivation. Cumulatively, these results expand on previous work by characterizing the beneficial effects of the WMZ on operationally-relevant indices of drowsiness, inhibitory attention control, and self-rated concentration and task difficulty relative to the pre-WMZ during sleep deprivation. These results may inform scheduling safety-critical tasks at more optimal circadian times to improve workplace performance and safety.

Circadian VIPergic Neurons of the Suprachiasmatic Nuclei Sculpt the Sleep-Wake Cycle

SummaryAlthough the mammalian rest-activity cycle is controlled by a “master clock” in the suprachiasmatic nucleus (SCN) of the hypothalamus, it is unclear how firing of individual SCN neurons gates individual features of daily activity. Here, we demonstrate that a specific transcriptomically identified population of mouse VIP+ SCN neurons is active at the “wrong” time of day—nighttime—when most SCN neurons are silent. Using chemogenetic and optogenetic strategies, we show that these neurons and their cellular clocks are necessary and sufficient to gate and time nighttime sleep but have no effect upon daytime sleep. We propose that mouse nighttime sleep, analogous to the human siesta, is a “hard-wired” property gated by specific neurons of the master clock to favor subsequent alertness prior to dawn (a circadian “wake maintenance zone”). Thus, the SCN is not simply a 24-h metronome: specific populations sculpt critical features of the sleep-wake cycle.

Task-dependent effects of the wake maintenance zone on cognition and alertness, with and without sleep loss

Task-dependent effects of the wake maintenance zone on cognition and alertness, with and without sleep loss

Longitudinal study of sleep and diurnal rhythms in Drosophila ananassae.

Mistiming of circadian rhythms impairs quality of life. The sleep fragmentation that results can lead to fatigue, mood alteration, and short-term memory problems. Unfortunately, this suite occurs in humans as we age. In the current study, we used high-resolution monitors to track how circadian patterns of locomotor activity change in female Drosophila ananassae as they enter mid-to-late life. This equipment is a more recent addition to the fly circadian field and has not been previously used for long-term activity tracking. At 2-3 days post-eclosion, D. ananassae were placed into climate-controlled vivariums for 60 days. Daily actograms were generated for each animal, along with a time series of activity across the observational period. Consistent with findings from older rodents and humans, older D. ananassae exhibited degraded patterns of wake and sleep that were fragmented-but still rhythmic-across the 24-h cycle. Overall levels of daily activity declined with age, with particular loss of circadian arousal in the wake-maintenance zone a few hours before bedtime. Interestingly, our high-resolution monitoring strategy was also able to document a sleep correlation previously associated with human aging in flies: displacement of sleep timing arising from possible changes in circadian and homeostatic regulation. Future experiments may determine whether the age-related impairments seen in the sleep-circadian system of D. ananassae can be mitigated through precision light treatment.

The wake maintenance zone shows task dependent changes in cognitive function following one night without sleep.

The interaction between homeostatic sleep pressure and circadian timing modulates the impact of sleep deprivation on cognition. We aimed to investigate how this interaction affects different cognitive functions. Twenty-three healthy volunteers (18 males; mean age = 25.4 ± 5.7 years) underwent 40 hours of sleep deprivation under constant routine conditions. Performance on the Psychomotor Vigilance Test and a cognitive battery assessing vigilant attention, complex attention, recognition memory, and working memory was assessed in the morning (27 hours awake) and evening (37 hours awake) during sleep deprivation and compared to well-rested performance 24 hours earlier. Circadian phase assessments confirmed evening tests occurred in the wake maintenance zone (WMZ). Increased time awake significantly impacted performance on all measures except recognition memory. Post hoc analyses found performance on all measures was significantly impaired in the morning following 27 hours of sleep deprivation compared to well-rested performance 24 hours earlier. In contrast, complex attention and working memory were preserved in the WMZ after 37 hours awake compared to 24 hours earlier, while vigilant attention and PVT performance were significantly impaired. During sleep deprivation, composite scores of speed and accuracy were both impaired in the morning, while only speed was impaired during the WMZ. We observed task- and time-dependent effects of sleep deprivation, such that vigilant attention was significantly impaired after both 27 hours and 37 hours awake (compared to when well-rested at the same circadian clock time). In contrast, complex attention and working memory were impaired at 27 hours awake, but preserved in the WMZ despite increased homeostatic sleep pressure (37 hours awake).

The alerting effect of the wake maintenance zone during 40 hours of sleep deprivation

Under entrained conditions, the accumulation of homeostatic sleep pressure in the evening is opposed by a strong circadian arousal signal prior to the dim light melatonin onset, called the Wake Maintenance Zone (WMZ). This study aimed at investigating the impact of the WMZ on different cognitive performance tests, as well as on subjective and objective sleepiness. Twelve young male participants completed a constant routine protocol with 40 h of extended wakefulness that included two WMZs. Cognitive tests and saliva samples were assessed hourly, while the electroencephalogram (EEG) was recorded continuously. Participants improved in cognitive response inhibition during WMZ1 (13.5 h awake) and sustained attention during WMZ2 (37.5 h awake), but not in higher executive function tests. There were significant EEG power density reductions in the delta/theta frequency range during WMZ1 and in delta/theta, alpha, and sigma/beta ranges during WMZ2, with a greater change in the sigma/beta range during WMZ2 compared to WMZ1. EEG power reductions coincided during WMZ1 with stable subjective sleepiness and sustained attention. During WMZ2, EEG power reductions were more pronounced and coincided with improved sustained attention. Our results suggest the circadian arousal signal in the evening differently modulates cognitive functions and EEG power depending on the duration of prior wakefulness.

Higher order cognition is preserved in the wake maintenance zone during 40 h sleep deprivation

Higher order cognition is preserved in the wake maintenance zone during 40 h sleep deprivation

0256 IMPROVEMENT IN COGNITION DURING THE WAKE MAINTENANCE ZONE FOLLOWING SLEEP LOSS IS DEPENDENT ON COGNITIVE DOMAIN

The wake-promoting signal from the circadian system enhances alertness in the early evening when the homeostatic signal for sleep is increasing. This ‘wake maintenance zone’ (WMZ), which precedes the onset of evening melatonin secretion, is associated with improved vigilant attention even under conditions of elevated sleep pressure, such as 40 hours of sleep deprivation (SD). The impact of the WMZ on different cognitive domains during SD is not well established, and forms the basis of this study. Twenty-three healthy volunteers (18 males; mean age=25.4 ± 5.7y) underwent 40 hours of SD under constant routine conditions. The Psychomotor Vigilance Test (PVT) and Karolinska Sleepiness Scale (KSS) were completed bi-hourly. An additional test battery assessing the cognitive domains of processing speed, visual learning, visual attention, and working memory was administered at 3h, 13h, 27h, and 37h after habitual wake time. Melatonin onset timing confirmed that tests administered at 13h and 37h occurred during the WMZ. Paired t-tests compared performance during SD with performance at a circadian matched control, during the morning (3h versus 27h post-wake) and early evening/WMZ (13h versus 37h). As expected, PVT mean reaction time and number of lapses significantly increased at 27h and 37h, relative to control. This effect was also observed for processing speed. In contrast, measures of visual attention, visual learning, and working memory significantly deteriorated after 27h of SD (relative to 3hr post-wake), yet no effect of SD was observed at 37h (relative to 13h post wake). Vigilant attention and processing speed deteriorated with SD, with no improvement observed during the WMZ. In contrast, visual attention, visual learning, and working memory were also adversely impacted by SD (27h awake), but preserved in the WMZ despite increased homeostatic sleep pressure (37h awake). These data highlight the need to examine a variety of cognitive domains when examining the impact of sleep and circadian factors on performance. The study was supported by the Cooperative Research Centre for Alertness, Safety and Productivity.

Sleep Propensity under Forced Desynchrony in a Model of Arousal State Dynamics.

An improvement to our current quantitative model of arousal state dynamics is presented that more accurately predicts sleep propensity as measured with sleep dynamics depending on circadian phase and prior wakefulness. A nonlinear relationship between the circadian variables within the dynamic circadian oscillator model is introduced to account for the skewed shape of the circadian rhythm of alertness that peaks just prior to the onset of the biological night (the "wake maintenance zone") and has a minimum toward the end of the biological night. The revised circadian drive thus provides a strong inhibitory input to the sleep-active neuronal population in the evening, counteracting the excitatory effects of the increased homeostatic sleep drive as originally proposed in the opponent process model of sleep-wake regulation. The revised model successfully predicts the sleep propensity profile as reflected in the dynamics of the total sleep time, sleep onset latency, wake/sleep ratio, and sleep efficiency during a wide range of experimental protocols. Specifically, all of these sleep measures are predicted for forced desynchrony schedules with day lengths ranging from 1.5 to 42.85 h and scheduled time in bed from 0.5 to 14.27 h. The revised model is expected to facilitate more accurate predictions of sleep under normal conditions as well as during circadian misalignment, for example, during shiftwork and jetlag.

Improved Neurobehavioral Performance during the Wake Maintenance Zone

Although impairment of daytime functioning is a symptom of many sleep disorders, there are limited data on their nature for some patient groups. The role of the circadian system on impaired functioning, specifically the wake maintenance zone (WMZ)-a ∼3-h window of reduced sleep propensity that occurs shortly before the onset of melatonin synthesis-has received little attention. The study examined the influence of the WMZ on neurobehavioral performance under normal conditions and following sleep deprivation. Thirty-one adults (8 F; 18-29 y) completed an in-patient protocol including a baseline day (8-h sleep:16-h wake) and a ∼50-h constant routine (CR), including regular assessment of plasma melatonin and neurobehavioral performance (i.e., auditory and visual psychomotor vigilance tests [aPVT, vPVT], Digit Symbol Substitution Test [DSST], and subjective sleepiness). Performance in the 3 hours before the onset of melatonin secretion (i.e., the expected WMZ) was significantly improved compared to performance during a 3-hour block earlier in the biological day, despite a longer time awake. The improvement during WMZ was most prominent after extended wakefulness (i.e., day 2 of the CR). These results suggest that alignment of circa-dian phase with respect to sleep-wake timing may affect cognitive performance, particularly when homeostatic sleep pressure is high, and especially when performance is assessed in the evening, near the predicted WMZ. The potential contribution of the WMZ to sleep-onset insomnia complaints should be assessed further, using objective neurobehavioral testing and simultaneous circadian phase measurement.

Effects of Partial and Acute Total Sleep Deprivation on Performance across Cognitive Domains, Individuals and Circadian Phase

BackgroundCognitive performance deteriorates during extended wakefulness and circadian phase misalignment, and some individuals are more affected than others. Whether performance is affected similarly across cognitive domains, or whether cognitive processes involving Executive Functions are more sensitive to sleep and circadian misalignment than Alertness and Sustained Attention, is a matter of debate.Methodology/Principal FindingsWe conducted a 2 × 12-day laboratory protocol to characterize the interaction of repeated partial and acute total sleep deprivation and circadian phase on performance across seven cognitive domains in 36 individuals (18 males; mean ± SD of age = 27.6±4.0 years). The sample was stratified for the rs57875989 polymorphism in PER3, which confers cognitive susceptibility to total sleep deprivation. We observed a deterioration of performance during both repeated partial and acute total sleep deprivation. Furthermore, prior partial sleep deprivation led to poorer cognitive performance in a subsequent total sleep deprivation period, but its effect was modulated by circadian phase such that it was virtually absent in the evening wake maintenance zone, and most prominent during early morning hours. A significant effect of PER3 genotype was observed for Subjective Alertness during partial sleep deprivation and on n-back tasks with a high executive load when assessed in the morning hours during total sleep deprivation after partial sleep loss. Overall, however, Subjective Alertness and Sustained Attention were more affected by both partial and total sleep deprivation than other cognitive domains and tasks including n-back tasks of Working Memory, even when implemented with a high executive load.Conclusions/SignificanceSleep loss has a primary effect on Sleepiness and Sustained Attention with much smaller effects on challenging Working Memory tasks. These findings have implications for understanding how sleep debt and circadian rhythmicity interact to determine waking performance across cognitive domains and individuals.

M-B-043 THE “FORBIDDEN ZONE FOR SLEEP” MIGHT BE CAUSED BY THE EVENING THYROTROPIN SURGE AND ITS BIOLOGICAL PURPOSE IS TO ENHANCE SURVIVAL: A HYPOTHESIS

Departamento de Pediatria da Faculdade de Medicina de Jundiai, Jundiai (SP), Brazil. Departamento de Neurologia da Faculdade de Medicina, Universidade de Sao Paulo (USP), Sao Paulo (SP), Brazil. Financial support: none. Conflict of interests: nothing to declare. Corresponding author: Jose Carlos Pereira Jr � Rua Francisco Telles, 2�0 � Vila Arens � CEP 13202-��0 � Jundiai (SP), Brazil � E-mail: jcpereirajr@uol.com.br Received: April 3, 2011; Accepted: July 1�, 2011 AbSTRACT It is possible for normal subjects to fall asleep during daytime wakefulness, and the propensity for daytime sleep varies being high in the mid-afternoon and lower in the early evening 2 or 3 hours before overnight sleep onset. This lowering of propensity for sleep in the few hours that precede overnight sleep is a paradoxical phenomenon termed the “Forbidden Zone for Sleep” or “Wake Maintenance Zone”. During the day, thyrotropin levels, which reflect the activity of the hypothalamus-pituitary-thyroid axis, oscillate in a predictable rhythm: lower levels during afternoon and higher levels during the early evening Forbidden Zone for Sleep. The steep increase in thyrotropin levels in the early evening is called the “thyrotropin-evening-surge”, with the higher levels just before overnight sleep onset. Thereafter thyrotropin levels decrease over the rest of the night reaching their low daytime levels. Considering the well-known role of the thyroid in vigilance and alertness, we propose that the negative correlation between thyrotropin levels and propensity to sleep is not a coincidence. Assuming that the circadian rhythms of any species are turned to facilitate survival, we propose that the Forbidden Zone for Sleep is an inherent part of the human circadian rhythm increases biological fitness. In this article, a medical hypothesis, we present evidence that in human’s circadian rhythms the Forbidden Zone for Sleep is secondary to the thyrotropin evening surge.

Effects of Light on Cognitive Brain Responses Depend on Circadian Phase and Sleep Homeostasis

Light is a powerful modulator of cognition through its long-term effects on circadian rhythmicity and direct effects on brain function as identified by neuroimaging. How the direct impact of light on brain function varies with wavelength of light, circadian phase, and sleep homeostasis, and how this differs between individuals, is a largely unexplored area. Using functional MRI, we compared the effects of 1 minute of low-intensity blue (473 nm) and green light (527 nm) exposures on brain responses to an auditory working memory task while varying circadian phase and status of the sleep homeostat. Data were collected in 27 subjects genotyped for the PER3 VNTR (12 PER3(5/5) and 15 PER3(4/4) ) in whom it was previously shown that the brain responses to this task, when conducted in darkness, depend on circadian phase, sleep homeostasis, and genotype. In the morning after sleep, blue light, relative to green light, increased brain responses primarily in the ventrolateral and dorsolateral prefrontal cortex and in the intraparietal sulcus, but only in PER3(4/4) individuals. By contrast, in the morning after sleep loss, blue light increased brain responses in a left thalamofrontoparietal circuit to a larger extent than green light, and only so in PER3(5/5) individuals. In the evening wake maintenance zone following a normal waking day, no differential effect of 1 minute of blue versus green light was observed in either genotype. Comparison of the current results with the findings observed in darkness indicates that light acts as an activating agent particularly under those circumstances in which and in those individuals in whom brain function is jeopardized by an adverse circadian phase and high homeostatic sleep pressure.

The relationship between insomnia and body temperatures

Sleepiness and sleep propensity are strongly influenced by our circadian clock as indicated by many circadian rhythms, most commonly by that of core body temperature. Sleep is most conducive in the temperature minimum phase, but is inhibited in a "wake maintenance zone" before the minimum phase, and is disrupted in a zone following that phase. Different types of insomnia symptoms have been associated with abnormalities of the body temperature rhythm. Sleep onset insomnia is associated with a delayed temperature rhythm presumably, at least partly, because sleep is attempted during a delayed evening wake maintenance zone. Morning bright light has been used to phase advance circadian rhythms and successfully treat sleep onset insomnia. Conversely, early morning awakening insomnia has been associated with a phase advanced temperature rhythm and has been successfully treated with the phase delaying effects of evening bright light. Sleep maintenance insomnia has been associated not with a circadian rhythm timing abnormality, but with nocturnally elevated core body temperature. Combination of sleep onset and maintenance insomnia has been associated with a 24-h elevation of core body temperature supporting the chronic hyper-arousal model of insomnia. The possibility that these last two types of insomnia may be related to impaired thermoregulation, particularly a reduced ability to dissipate body heat from distal skin areas, has not been consistently supported in laboratory studies. Further studies of thermoregulation are needed in the typical home environment in which the insomnia is most evident.

Treating chronobiological components of chronic insomnia

Circadian rhythms have a strong effect on the ability to sleep across the 24-h period. Maximum sleepiness occurs at the phase of lower endogenous core body temperature. This period is bracketed by two periods of alertness: a “wake-maintenance zone” occurring 6–10 h before the time of core temperature minimum, and a “wake-up zone” occurring 4–7 h after the minimum. Therefore, if the circadian rhythm drifts earlier with respect to the attempted sleep period, the wake-up zone can impinge on the end of the normal sleep period resulting in premature awakening and the development of early morning awakening insomnia. Similarly, a delay of the circadian rhythm can impose the wake-maintenance zone on the attempted bedtime and lead to sleep onset insomnia. Therefore, these two types of insomnia should be treatable with chronobiologic effects such as bright light and, possibly, melatonin administration. Bright light stimulation at normal wake-up time and melatonin administration 4–8 h before normal bedtime can phase advance circadian rhythms to an earlier time. While morning bright light has been efficacious for sleep onset insomnia, evening melatonin administration has yet to be tested. Early morning awakening insomnia has been treated with phase delays imposed by evening bright light but not yet with morning melatonin administration. There is now sufficient evidence to warrant the consideration of chronobiologic manipulations such as bright light therapy for the treatment of chronic sleep onset and early morning awakening insomnia that show evidence of circadian delay or advance, respectively.