Neuropsychological Outcomes of Nocturnal Asthma

In spite of frequent reports that nocturnal asthma results in fatigue and impaired cognitive performance, there exists little objective evidence as to the daytime consequences of this disorder. Treatment studies have established that the symptoms of nocturnal asthma improve with medication intervention, but performance does not. Studies of obstructive sleep apnea (OSA), a source of generally more severe sleep fragmentation, have demonstrated that measurement of sleep-deprivation effects is limited to tasks requiring heightened alertness and rapid information processing, and that the degree of score change is related to the degree of sleep disruption. Studies of normal, but sleep-deprived, subjects indicate that (1) utilization of repetitive measures sustained for long duration can potentiate motivation to overcome the effects of fatigue in the laboratory, and (2) even when average scores do not change significantly, performance becomes more irregular. These collective findings about the measurement of performance impairment secondary to sleep deprivation can be used to guide new studies of nocturnal asthma. Finally, children must be included in future investigations because they may be at even greater risk for daytime consequences of nocturnal asthma than adults.     

Circadian Rhythms in the Pharmacokinetics and Clinical Effects of Beta-agonist,Theophylline, and Anticholinergic Medications in the Treatment of Nocturnal Asthma

Published asthma consensus reports now acknowledge that asthma is a nocturnal disease in as many as 75% of those afflicted by this medical condition. Nonetheless, the treatment of this chronic obstructive pulmonary disease in the clinic continues to be based primarily on homeostatic considerations in that it relies on long-acting bronchodilator and other therapies formulated and scheduled to ensure constant or near-constant levels of medication during the 24h. The need of asthma patients prone to nighttime attacks is not the same during the day and night; the therapeutic requirements of patients who experience nocturnal asthma, especially ones with the more severe forms of the disease, are often not satisfied by conventional medications. The therapeutic response and patient tolerance to bronchodilator medications can be improved markedly when the medications are proportioned during the 24h as a chronotherapy, that is, when more medication is delivered during nighttime sleep than daytime activity, as verified by numerous studies. This article reviews how the body's circadian rhythms influence the pharmacokinetics and effects of commonly prescribed asthma therapies and addresses why and how they must be taken into consideration to increase the effectiveness of asthma treatment.     

Circadian Rhythms in the Pharmacokinetics and Clinical Effects of Beta-agonist, Theophylline, and Anticholinergic Medications in the Treatment of Nocturnal Asthma

Published asthma consensus reports now acknowledge that asthma is a nocturnal disease in as many as 75% of those afflicted by this medical condition. Nonetheless, the treatment of this chronic obstructive pulmonary disease in the clinic continues to be based primarily on homeostatic considerations in that it relies on long-acting bronchodilator and other therapies formulated and scheduled to ensure constant or near-constant levels of medication during the 24h. The need of asthma patients prone to nighttime attacks is not the same during the day and night; the therapeutic requirements of patients who experience nocturnal asthma, especially ones with the more severe forms of the disease, are often not satisfied by conventional medications. The therapeutic response and patient tolerance to bronchodilator medications can be improved markedly when the medications are proportioned during the 24h as a chronotherapy, that is, when more medication is delivered during nighttime sleep than daytime activity, as verified by numerous studies. This article reviews how the body's circadian rhythms influence the pharmacokinetics and effects of commonly prescribed asthma therapies and addresses why and how they must be taken into consideration to increase the effectiveness of asthma treatment.     

Comparing the Effects of Nocturnal Sleep and Daytime Napping on Declarative Memory Consolidation

Nocturnal sleep and daytime napping facilitate memory consolidation for semantically related and unrelated word pairs. We contrasted forgetting of both kinds of materials across a 12-hour interval involving either nocturnal sleep or daytime wakefulness (experiment 1) and a 2-hour interval involving either daytime napping or wakefulness (experiment 2). Beneficial effects of post-learning nocturnal sleep and daytime napping were greater for unrelated word pairs (Cohen’s d = 0.71 and 0.68) than for related ones (Cohen’s d = 0.58 and 0.15). While the size of nocturnal sleep and daytime napping effects was similar for unrelated word pairs, for related pairs, the effect of nocturnal sleep was more prominent. Together, these findings suggest that sleep preferentially facilitates offline memory processing of materials that are more susceptible to forgetting.     

Fatigue and mood correlates of sleep length in three age-social groups: School children, students, and employees

The aim of the study was to trace the consequences of insufficient sleep, in terms of chronic sleep reduction rather than acute sleep deprivation, on fatigue, mood, cognitive performance self-estimations, and daytime sleepiness in different age-social groups. The age group of the subjects reflects their social situation and their working time organization: adolescents (n = 191) obeyed the strict school schedules with starting times often before 08:00 h; university students (n = 115) had more flexible timetables; young employees (n = 126) were engaged in regular morning schedules or irregular daytime hours or day and night shifts. A questionnaire study determined the declared need of sleep, self-reported sleep length, chronic fatigue (using a scale comprised of eight fatigue symptoms and four mood and three cognitive items), and daytime sleepiness (Epworth Sleepiness Scale). The declared need for sleep decreased in subsequent age groups from 9 h 23 min in school children to 8 h 22 min in university students and to 7 h 37 min in young employees. Consequently, the discrepancy between preferred and real sleep length (sleep deficit) was the largest in adolescents: 106 min. Females showed a greater need of sleep than males (p = .025) and significantly more fatigue, mood, and cognitive problems; they also exhibited higher level of daytime sleepiness (p < .000). The sleep index (reported sleep length related to requirements) correlated significantly with all health issues in women (p < .000), while only with fatigue symptoms in men (p = .013). Actual sleep length was unrelated to mood and fatigue issues; the declared individual need of sleep and sleep index showed significant associations, especially in the group of adolescents. The most frequent complaints of adolescents included tiredness on awakening (46%), nervousness, and general weakness; university students reported excessive drowsiness (50%), tension, and nervousness; employees suffered mostly from negative moods, such as tension (49%), nervousness, and irritability. The findings of the study indicate that chronic sleep loss seems to affect females more severely than males. The associations of fatigue and mood with sleep need and sleep index were more pronounced in younger subjects. Surprisingly, fatigue symptoms in school children and university students were as frequent as in hard-working adults. Because the problem of insufficient sleep is already present in youngsters, their work time organization needs more attention.     

Abnormalities of sleep in patients with the chronic fatigue syndrome.

OBJECTIVE--To determine whether patients with the chronic fatigue syndrome have abnormalities of sleep which may contribute to daytime fatigue. DESIGN--A case-control study of the sleep of patients with the chronic fatigue syndrome and that of healthy volunteers. SETTING--An infectious disease outpatient clinic and subjects'' homes. SUBJECTS--12 patients who met research criteria for the chronic fatigue syndrome but not for major depressive disorder and 12 healthy controls matched for age, sex, and weight. MAIN OUTCOME MEASURES--Subjective reports of sleep from patients'' diaries and measurement of sleep patterns by polysomnography. Subjects'' anxiety, depression, and functional impairment were assessed by interview. RESULTS--Patients with the chronic fatigue syndrome spent more time in bed than controls (544 min v 465 min, p < 0.001) but slept less efficiently (90% v 96%, p < 0.05) and spent more time awake after initially going to sleep (31.9 min v 16.6 min, p < 0.05). Seven patients with the chronic fatigue syndrome had a sleep disorder (four had difficulty maintaining sleep, one had difficulty getting to sleep, one had difficulty in both initiating and maintaining sleep, and one had hypersomnia) compared with none of the controls (p = 0.003). Those with sleep disorders showed greater functional impairment than the remaining five patients (score on general health survey 50.4% v 70.4%, p < 0.05), but their psychiatric scores were not significantly different. CONCLUSIONS--Most patients with the chronic fatigue syndrome had sleep disorders, which are likely to contribute to daytime fatigue. Sleep disorders may be important in the aetiology of the syndrome.     

Fatigue and Mood Correlates of Sleep Length in Three Age‐Social Groups: School Children,Students, and Employees

The aim of the study was to trace the consequences of insufficient sleep, in terms of chronic sleep reduction rather than acute sleep deprivation, on fatigue, mood, cognitive performance self‐estimations, and daytime sleepiness in different age‐social groups. The age group of the subjects reflects their social situation and their working time organization: adolescents (n=191) obeyed the strict school schedules with starting times often before 08:00 h; university students (n=115) had more flexible timetables; young employees (n=126) were engaged in regular morning schedules or irregular daytime hours or day and night shifts. A questionnaire study determined the declared need of sleep, self‐reported sleep length, chronic fatigue (using a scale comprised of eight fatigue symptoms and four mood and three cognitive items), and daytime sleepiness (Epworth Sleepiness Scale). The declared need for sleep decreased in subsequent age groups from 9 h 23 min in school children to 8 h 22 min in university students and to 7 h 37 min in young employees. Consequently, the discrepancy between preferred and real sleep length (sleep deficit) was the largest in adolescents: 106 min. Females showed a greater need of sleep than males (p=.025) and significantly more fatigue, mood, and cognitive problems; they also exhibited higher level of daytime sleepiness (p<.000). The sleep index (reported sleep length related to requirements) correlated significantly with all health issues in women (p<.000), while only with fatigue symptoms in men (p=.013). Actual sleep length was unrelated to mood and fatigue issues; the declared individual need of sleep and sleep index showed significant associations, especially in the group of adolescents. The most frequent complaints of adolescents included tiredness on awakening (46%), nervousness, and general weakness; university students reported excessive drowsiness (50%), tension, and nervousness; employees suffered mostly from negative moods, such as tension (49%), nervousness, and irritability. The findings of the study indicate that chronic sleep loss seems to affect females more severely than males. The associations of fatigue and mood with sleep need and sleep index were more pronounced in younger subjects. Surprisingly, fatigue symptoms in school children and university students were as frequent as in hard‐working adults. Because the problem of insufficient sleep is already present in youngsters, their work time organization needs more attention.     

Daytime Sleep Enhances Consolidation of the Spatial but Not Motoric Representation of Motor Sequence Memory

Motor sequence learning is known to rely on more than a single process. As the skill develops with practice, two different representations of the sequence are formed: a goal representation built under spatial allocentric coordinates and a movement representation mediated through egocentric motor coordinates. This study aimed to explore the influence of daytime sleep (nap) on consolidation of these two representations. Through the manipulation of an explicit finger sequence learning task and a transfer protocol, we show that both allocentric (spatial) and egocentric (motor) representations of the sequence can be isolated after initial training. Our results also demonstrate that nap favors the emergence of offline gains in performance for the allocentric, but not the egocentric representation, even after accounting for fatigue effects. Furthermore, sleep-dependent gains in performance observed for the allocentric representation are correlated with spindle density during non-rapid eye movement (NREM) sleep of the post-training nap. In contrast, performance on the egocentric representation is only maintained, but not improved, regardless of the sleep/wake condition. These results suggest that motor sequence memory acquisition and consolidation involve distinct mechanisms that rely on sleep (and specifically, spindle) or simple passage of time, depending respectively on whether the sequence is performed under allocentric or egocentric coordinates.     

Sleep and sleepiness among Brazilian shift-working bus drivers

The aim of this study was to evaluate daytime and nighttime sleep, as well as daytime and nighttime sleepiness of professional shift-working bus drivers. Thirty-two licensed bus drivers were assessed by nocturnal and diurnal polysomnography (PSG) recording and multiple sleep latency testing (MSLT) sessions. Sleep length was shorter and sleep efficiency reduced during daytime sleep compared with nighttime sleep. Thirty-eight percent of the drivers had indices of obstructive apnea and hypopnea syndrome (>5/h sleep) during nighttime and daytime sleep; more drivers snored during daytime than nighttime sleep (50% vs. 35%, p < 0.05), and 38% of the drivers evidenced periodic leg movements. The MSLT revealed that 42 and 38% of the bus drivers met the criteria for sleepiness when the test was conducted during the day and night, respectively. The daytime as compared to nighttime sleep of shift-working bus drivers was shorter and more fragmented and was associated in many with evidence of excessive sleepiness. Respiratory disorder was a common finding among the professional shift-working bus drivers. All these sleep deficiencies may adversely affect on the job driving performance.     

Sleep related O2 desaturation in COPD patients with normoxaemia and mild hypoxyaemia

It is unknown whether daytime features predict oxygenation during sleep in COPD patients with normoxaemia or mild hypoxaemia. In this study our purpose was to evaluate by a pulse oxymeter, nocturnal desaturation in 33 COPD with PaO2 > 60 mmHg and to examine some daytime parameters as possible predictors of nocturnal hypoxaemia. A significant nocturnal desaturation has been defined by spending > or = 30% of total sleep-time with a TSTSaO2 < 90% > 30. According to this criterion we classified our patients in Desaturators (D) and Non Desaturators (ND). Our results showed that 39% of our patients were D and 61% ND. Among anthropometric and respiratory functional data we found that daytime SaO2B (r = 0.74 p < 0.001) daytime PaO2 (r = 0.47 p < 0.01) and daytime PaCO2 (r = 0.45 p < 0.05) were significantly correlated with the nocturnal oxygen desaturation and can predict the presence of sleep related hypoxaemia. In conclusion, our study confirms that a relatively high percentage of COPD patients with normoxaemia or borderline hypoxaemia exhibits significant nocturnal hypoxaemia. Further studies will suggest whether sleep related hypoxaemia deserves nocturnal oxygen therapy.     

Sleep and Sleepiness among Brazilian Shift-Working Bus Drivers

The aim of this study was to evaluate daytime and nighttime sleep, as well as daytime and nighttime sleepiness of professional shift-working bus drivers. Thirty-two licensed bus drivers were assessed by nocturnal and diurnal polysomnography (PSG) recording and multiple sleep latency testing (MSLT) sessions. Sleep length was shorter and sleep efficiency reduced during daytime sleep compared with nighttime sleep. Thirty-eight percent of the drivers had indices of obstructive apnea and hypopnea syndrome (>5/h sleep) during nighttime and daytime sleep; more drivers snored during daytime than nighttime sleep (50% vs. 35%, p < 0.05), and 38% of the drivers evidenced periodic leg movements. The MSLT revealed that 42 and 38% of the bus drivers met the criteria for sleepiness when the test was conducted during the day and night, respectively. The daytime as compared to nighttime sleep of shift-working bus drivers was shorter and more fragmented and was associated in many with evidence of excessive sleepiness. Respiratory disorder was a common finding among the professional shift-working bus drivers. All these sleep deficiencies may adversely affect on the job driving performance.     

Salmeterol in nocturnal asthma: a double blind,placebo controlled trial of a long acting inhaled beta 2 agonist.

OBJECTIVE--To determine whether inhaled salmeterol, a new long acting inhaled beta adrenergic agonist, reduces nocturnal bronchoconstriction and improves sleep quality in patients with nocturnal asthma. DESIGN--Randomised, double blind, placebo controlled crossover study. SETTING--Hospital outpatient clinics in Edinburgh. SUBJECTS--Twenty clinically stable patients (13 women, seven men) with nocturnal asthma, median age 39 (range 18-60) years. INTERVENTIONS--Salmeterol 50 micrograms and 100 micrograms and placebo taken each morning and evening by metered dose inhaler. Rescue salbutamol inhalers were provided throughout the run in and study periods. MAIN OUTCOME MEASURES--Improvement in nocturnal asthma as measured by peak expiratory flow rates and change in sleep quality as measured by electroencephalography. RESULTS--Salmeterol improved the lowest overnight peak flow rate at both 50 micrograms (difference in median values (95% confidence interval for difference in medians) 69 (18 to 88) l/min) and 100 micrograms (72 (23 to 61) l/min) doses twice daily. While taking salmeterol 50 micrograms twice daily patients had an objective improvement in sleep quality, spending less time awake or in light sleep (-9 (-4 to -44) min) and more time in stage 4 sleep (26 (6-34) min). CONCLUSIONS--Salmeterol is an effective long acting inhaled bronchodilator for patients with nocturnal asthma and at a dose of 50 micrograms twice daily improves objective sleep quality.     

Differential effects of circadian typology on sleep-related symptoms,physical fatigue and psychological well-being in relation to resilience

Various physiological and psychological functions are influenced by circadian typology (CT), which was reported to be related to resilience. However, few studies have assessed the effects of CT in relation to resilience. The aim of the present study was to assess the influence of CT on sleep-related symptoms, physical fatigue and psychological well-being in relation to resilience. The present study included a total of 1794 healthy hospital employees, and they completed the Morningness–Eveningness Questionnaire, Connor–Davidson Resilience Scale, Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale, Fatigue Severity Scale, Hospital Anxiety and Depression Scale and World Health Organization Quality of Life Scale Abbreviated Version. Subjects with evening type showed lower sleep quality, more daytime sleepiness and physical fatigue than neither types and morning types. Additionally, evening types were more depressed and anxious and reported a poorer quality of life. CT was found to be a significant predictor of sleep quality, but CT was minimally associated with physical fatigue and psychological well-being in the regression analysis. Instead, resilience was substantially related to all of the variables measured. In conclusion, CT independently predicts sleep quality, but the effects of CT on physical fatigue and psychological well-being are negligible compared to those of resilience.     

Effects of an adjunctive,chronotype-based light therapy in hospitalized patients with severe burnout symptoms - a pilot study

Light therapy is a well-established treatment option for seasonal affective disorders and is effective in reducing sleep problems and daytime fatigue. Symptoms of severe burnout include feelings of exhaustion and impaired sleep and mood. Thus, light therapy seems promising for burnout treatment. So far, light therapy effects in burnout were investigated in outpatient settings only, with inconclusive results. The present study targeted light therapy effects in an inpatient setting. Participants with severe burnout were recruited in two psychosomatic clinics and randomly assigned to a control group with multimodal psychiatric treatment or an add-on light treatment group. Participants in the latter group were additionally exposed to morning bright light (illuminance: 4246 lux, irradiance: 1802.81 µW.cm^?2) for 3 weeks, 30 minutes a day, timed to their chronotypes. Light effects on burnout symptoms, depression, well-being, daytime sleepiness, sleep quality, and attentional performance were measured twice (pre-/postintervention design). Adjunctive chronotype-based bright light therapy was well tolerated and improved burnout symptoms and well-being without additional effect on severity of depression. Furthermore, reduced daytime sleepiness, improved nighttime sleep quality, a sleep phase advance of 25 minutes, shortened sleep latency, less sleep disturbances and increased sleep duration were observed in the light treatment group. No group differences were found in attentional performance. Chronotype-based bright light therapy seems to be effective in improving burnout symptoms and sleep problems in patients with severe burnout symptoms. Further studies with larger sample sizes and objective measures of sleep are necessary to confirm these preliminary results before practical recommendations can be made.     

Longitudinal Study of Mothers’ Sleep-Wake Behaviors and Circadian Time Patterns from Late Pregnancy to Postpartum – Monitoring of Wrist Actigraphy and Sleep Logs

This longitudinal study investigated sleep-wake behavior patterns during and after pregnancy, using an actimeter worn on the non-dominant wrist and a sleep log. Records were obtained from ten mothers, from the 34th week of gestation until the 15th week postpartum. Ten non-pregnant women were used as a control group, data being collected from them for 2 weeks. The sleep-wake behavior after delivery, obtained from wrist actigraphy, was greater in the postpartum period. Total sleep time, sleep efficiency, and circadian amplitude decreased in the weeks immediately following parturition, but wake after sleep onset increased. Subsequently, all the sleep and circadian variables improved slightly, but they had not returned to the levels of the non-pregnant control group even by the 15th postpartum week. The length of daytime naps increased, in order to make up for nocturnal sleep deprivation when the number of awakenings during nighttime had increased. There were significant positive correlations between total sleep time, sleep efficiency, wake after sleep onset, and the length of daytime naps, but the numbers of awakenings at night and daytime naps did not show this correlation. The total sleep time indicated by sleep logs tended to be greater than that indicated by actigraphy, but wake after sleep onset tended to be underestimated by the sleep logs. The implications of these results are discussed.     

Longitudinal Study of Mothers' Sleep-Wake Behaviors and Circadian Time Patterns from Late Pregnancy to Postpartum - Monitoring of Wrist Actigraphy and Sleep Logs

This longitudinal study investigated sleep-wake behavior patterns during and after pregnancy, using an actimeter worn on the non-dominant wrist and a sleep log. Records were obtained from ten mothers, from the 34th week of gestation until the 15th week postpartum. Ten non-pregnant women were used as a control group, data being collected from them for 2 weeks. The sleep-wake behavior after delivery, obtained from wrist actigraphy, was greater in the postpartum period. Total sleep time, sleep efficiency, and circadian amplitude decreased in the weeks immediately following parturition, but wake after sleep onset increased. Subsequently, all the sleep and circadian variables improved slightly, but they had not returned to the levels of the non-pregnant control group even by the 15th postpartum week. The length of daytime naps increased, in order to make up for nocturnal sleep deprivation when the number of awakenings during nighttime had increased. There were significant positive correlations between total sleep time, sleep efficiency, wake after sleep onset, and the length of daytime naps, but the numbers of awakenings at night and daytime naps did not show this correlation. The total sleep time indicated by sleep logs tended to be greater than that indicated by actigraphy, but wake after sleep onset tended to be underestimated by the sleep logs. The implications of these results are discussed.     

Effects of Light Interruption on Sleep and Viability of Drosophila melanogaster

Light is a very important regulator of the daily sleep rhythm. Here, we investigate the influence of nocturnal light stimulation on Drosophila sleep. Results showed that total daytime sleep was reduced due to a decrease in daytime sleep episode duration caused by discontinuous light stimulation, but sleep was not strongly impacted at nighttime although the discontinuous light stimulation occurred during the scotophase. During a subsequent recovery period without light interruption, the sleep quality of nighttime sleep was improved and of daytime sleep reduced, indicating flies have a persistent response to nocturnal light stimulation. Further studies showed that the discontinuous light stimulation damped the daily rhythm of a circadian light-sensitive protein cryptochrome both at the mRNA and protein levels, which subsequently caused disappearance of circadian rhythm of the core oscillator timeless and decrease of TIMLESS protein at nighttime. These data indicate that the nocturnal light interruption plays an important role in sleep through core proteins CRYTOCHROME and TIMLESS, Moreover, interruption of sleep further impacted reproduction and viability.     

Restricted and unrestricted sleep schedules of Asian adolescent,high-level student athletes: effects on sleep durations,marksmanship and cognitive performance

The present study sought to compare the effects of a restricted and unrestricted sleep schedule on shooting, cognitive performance and measures of sleepiness and fatigue of Asian, adolescent high-level student athletes. Twenty-four (12 female; 14.1 ± 1.4 years) athletes performed assessments of shooting and cognitive performance (psychomotor vigilance and working memory) at the start and end of five-day restricted or unrestricted sleep (two conditions). Restricted sleep during a five-day training week resulted in no significant performance changes in cognitive or shooting performance compared with unrestricted sleep during a five-day training week, despite there being moderate-to-strong associations between increases in total sleep time and certain aspects of shooting performance. Daytime fatigue levels during the unrestricted sleep period were significantly lower than during sleep restriction. These findings highlight the relationships between nocturnal sleep extension and shooting performance amongst high-level athletes.     

Sustained release choline theophyllinate in nocturnal asthma.

Nocturnal wheeze is common in patients with asthma, and slow release theophyllines may reduce symptoms. As theophyllines are stimulants of the central nervous system the effect of 10 days'' twice daily treatment with sustained release choline theophyllinate or placebo on symptoms, overnight bronchoconstriction, nocturnal oxygen saturation, and quality of sleep were studied in a double blind crossover study in nine stable patients with nocturnal asthma (five men, four women, age range 23-64 years; forced expiratory volume in one second (FEV1) 0.85-3.8 1; vital capacity 1.95-6.1 1). When treated with the active drug all patients had plasma theophylline concentrations of at least 28 mmol/l (5 micrograms/ml) (peak plasma theophylline concentrations 50-144 mmol/l (9-26 micrograms/ml]. Morning FEV1 was higher when treated with sustained release choline theophyllinate (2.7 (SEM 0.3) 1) than placebo (2.1 (0.3) 1) (p less than 0.01). Both daytime and nocturnal symptoms were reduced when the patients were treated with sustained release choline theophyllinate and subjective quality of sleep was improved (p less than 0.002). When treated with the active drug, however, quality of sleep determined by electroencephalography deteriorated with an increase in wakefulness and drowsiness (p less than 0.05) and a reduction in non-rapid eye movement sleep (p less than 0.005). Treatment with choline theophyllinate had no effect on either the occurrence or the severity of transient nocturnal hypoxaemic episodes or apnoeas or hypopnoeas. In conclusion, sustained release choline theophyllinate prevents overnight bronchoconstriction, but impairs quality of sleep defined by electroencephalography.     

Daytime naps in darkness phase shift the human circadian rhythms of melatonin and thyrotropin secretion

To systematically determine the effects of daytime exposure to sleep in darkness on human circadian phase, four groups of subjects participated in 4-day studies involving either no nap (control), a morning nap (0900-1500), an afternoon nap (1400-2000), or an evening nap (1900-0100) in darkness. Except during the scheduled sleep/dark periods, subjects remained awake under constant conditions, i.e., constant dim light exposure (36 lx), recumbence, and caloric intake. Blood samples were collected at 20-min intervals for 64 h to determine the onsets of nocturnal melatonin and thyrotropin secretion as markers of circadian phase before and after stimulus exposure. Sleep was polygraphically recorded. Exposure to sleep and darkness in the morning resulted in phase delays, whereas exposure in the evening resulted in phase advances relative to controls. Afternoon naps did not change circadian phase. These findings indicate that human circadian phase is dependent on the timing of darkness and/or sleep exposure and that strategies to treat circadian misalignment should consider not only the timing and intensity of light, but also the timing of darkness and/or sleep.