Effect of shortened sleep on energy expenditure, core body temperature, and appetite: a human randomised crossover trial.

The effects of sleep restriction on energy metabolism and appetite remain controversial. We examined the effects of shortened sleep duration on energy metabolism, core body temperature (CBT), and appetite profiles. Nine healthy men were evaluated in a randomised crossover study under two conditions: a 3.5-h sleep duration and a 7-h sleep duration for three consecutive nights followed by one 7-h recovery sleep night. The subjects' energy expenditure (EE), substrate utilisation, and CBT were continually measured for 48 h using a whole-room calorimeter. The subjects completed an appetite questionnaire every hour while in the calorimeter. Sleep restriction did not affect total EE or substrate utilisation. The 48-h mean CBT decreased significantly during the 3.5-h sleep condition compared with the 7-h sleep condition (7-h sleep, 36.75 ± 0.11 °C; 3.5-h sleep, 36.68 ± 0.14 °C; p = 0.016). After three consecutive nights of sleep restriction, fasting peptide YY levels and fullness were significantly decreased (p = 0.011), whereas hunger and prospective food consumption were significantly increased, compared to those under the 7-h sleep condition. Shortened sleep increased appetite by decreasing gastric hormone levels, but did not affect EE, suggesting that greater caloric intake during a shortened sleep cycle increases the risk of weight gain.

Later sleep schedule and depressive symptoms are associated with usage of multiple kinds of hypnotics.

OBJECTIVE: Usage of high doses of hypnotics possibly causes various adverse events. However, the risk factors of using multiple kinds of hypnotics have been inconclusive. To clarify this, we conducted a web-based cross-sectional questionnaire survey on the Japanese adult population. METHODS: A cross-sectional Internet-linked survey was conducted on 10,016 individuals and 1030 participants (10.3%) having subjective insomnia proceeded to subsequent analyses. The analyzed subjects were categorized into non-users of hypnotics (n = 833; 80.9%), users of a single kind of hypnotic (n = 96; 9.3%), and users of multiple kinds of hypnotics (n = 101; 9.8%). The descriptive variables including demographic data, scores of Center for Epidemiological Studies Depression Scale (CES-D), Short Form-8 Health-Related Quality of Life [QOL (SF-8)], Pittsburgh Sleep Quality Index (PSQI), and other parameters were compared among the groups. RESULTS: The users of multiple kinds of hypnotics had the highest mean score of CES-D, the lowest mental component summary of QOL (SF-8), and the latest sleep schedule among the three groups (p < 0.001). Logistic regression analyses revealed that sex (female: OR = 2.38; p < 0.001) and age (≥43 years old: OR = 2.61; p < 0.001) were independently associated with use of a single kind of hypnotic, while later sleep schedule (midpoint of sleep ≥5:30 a.m.: OR = 2.26; p < 0.001) and higher CES-D score (≥16 points: OR = 2.41; p < 0.001) were independently associated with use of multiple kinds of hypnotics. CONCLUSIONS: Characteristics of users of multiple kinds of hypnotics were different from those of users of a single kind of hypnotic.

Prevalence and associations of respiratory-related leg movements: the MrOS sleep study.

OBJECTIVES: Obstructive respiratory events often terminate with an associated respiratory-related leg movement (RRLM). Such leg movements are not scored as periodic leg movements (periodic limb movements during sleep, PLMS), although the criteria for distinguishing RRLM from PLMS differ between the American Academy of Sleep Medicine (AASM) and the World Association of Sleep Medicine (WASM)/ International Restless Legs Syndrome Study Group (IRLSSG) scoring manuals. Such LMs may be clinically significant in patients with obstructive sleep apnea (OSA). The prevalence and correlation of RRLM in men with OSA were examined. METHODS: A case-control sample of 575 men was selected from all men with an apnea-hypopnea index (AHI, ≥3% desaturation criteria) ≥ 10 and good data from piezoelectric leg movement sensors at the first in-home sleep study in the MrOS cohort (mean age = 76.8 years). Sleep studies were rescored for RRLMs using five different RRLM definitions varying in both latency of leg movement onset from respiratory event termination and duration of the leg movement. The quartile of RRLM% (the number of RRLM/the number of hypopneas + apneas) was derived. RESULTS: The nonparametric densities of RRLM% were most influenced by alterations in the latency rather than the duration of the LM. The most liberal RRLM definition (latency 0-5 s, duration 0.5-10 s) led to a median RRLM% of 23.4 (interquartile range 12.41, 37.12) in this sample. The average AHI and arousal index increased as the quartile of RRLM% increased, as well as the prevalence of chronic obstructive pulmonary disease (COPD). The prevalence of those with a history of hypertension decreased as RRLM% increased. The non-Caucasian race was associated with lower RRLM%. CONCLUSION: Within an elderly sample with moderate to severe OSA, piezoelectric-defined RRLM% is associated with a number of sleep-related and demographic factors. Further study of the optimal definition, predictors, and consequences of RRLM is warranted.

Modeling circadian and sleep-homeostatic effects on short-term interval timing.

Short-term interval timing i.e., perception and action relating to durations in the seconds range, has been suggested to display time-of-day as well as wake dependent fluctuations due to circadian and sleep-homeostatic changes to the rate at which an underlying pacemaker emits pulses; pertinent human data being relatively sparse and lacking in consistency however, the phenomenon remains elusive and its mechanism poorly understood. To better characterize the putative circadian and sleep-homeostatic effects on interval timing and to assess the ability of a pacemaker-based mechanism to account for the data, we measured timing performance in eighteen young healthy male subjects across two epochs of sustained wakefulness of 38.67 h each, conducted prior to (under entrained conditions) and following (under free-running conditions) a 28 h sleep-wake schedule, using the methods of duration estimation and duration production on target intervals of 10 and 40 s. Our findings of opposing oscillatory time courses across both epochs of sustained wakefulness that combine with increasing and, respectively, decreasing, saturating exponential change for the tasks of estimation and production are consistent with the hypothesis that a pacemaker emitting pulses at a rate controlled by the circadian oscillator and increasing with time awake determines human short-term interval timing; the duration-specificity of this pattern is interpreted as reflecting challenges to maintaining stable attention to the task that progressively increase with stimulus magnitude and thereby moderate the effects of pacemaker-rate changes on overt behavior.

Internet-based survey of factors associated with subjective feeling of insomnia, depression, and low health-related quality of life among Japanese adults with sleep difficulty.

BACKGROUND: This study was conducted to determine what symptom components or conditions of insomnia are related to subjective feelings of insomnia, low health-related quality of life (HRQOL), or depression. METHOD: Data from 7,027 Japanese adults obtained using an Internet-based questionnaire survey was analyzed to examine associations between demographic variables and each sleep difficulty symptom item on the Pittsburgh Sleep Quality Index (PSQI) with the presence/absence of subjective insomnia and scores on the Short Form-8 (SF-8) and Center for Epidemiologic Studies Depression Scale (CES-D). RESULTS: Prevalence of subjective insomnia was 12.2% (n = 860). Discriminant function analysis revealed that item scores for sleep quality, sleep latency, and sleep medication use on the PSQI and CES-D showed relatively high discriminant function coefficients for identifying positivity for the subjective feeling of insomnia. Among respondents with subjective insomnia, a low SF-8 physical component summary score was associated with higher age, depressive state, and PSQI items for sleep difficulty and daytime dysfunction, whereas a low SF-8 mental component summary score was associated with depressive state, PSQI sleep latency, sleeping medication use, and daytime dysfunction. Depressive state was significantly associated with sleep latency, sleeping medication use, and daytime dysfunction. CONCLUSION: Among insomnia symptom components, disturbed sleep quality and sleep onset insomnia may be specifically associated with subjective feelings of the disorder. The existence of a depressive state could be significantly associated with not only subjective insomnia but also mental and physical QOL. Our results also suggest that different components of sleep difficulty, as measured by the PSQI, might be associated with mental and physical QOL and depressive status.

Effect of delayed sleep phase during university life on the daytime functioning in work life after graduation.

OBJECTIVE: To examine the effects of changes in sleep phase on the daytime functioning of new university graduates. METHODS: Questionnaire data of university students (n = 745) and university graduates working full time (n = 360) were analyzed to explore sleep phase changes during this life stage. The newly graduated full-time workers (n = 117) were divided into 2 (bedtime at investigation: earlier/later) × 2 groups (bedtime at one year prior to investigation: earlier/later), and depressive symptoms and health-related quality of life were compared among groups. RESULTS: New university graduates experienced ~1 h of sleep phase advancement and shortened time in bed compared to one year before investigation. In addition, those who experienced such sleep changes showed larger daytime dysfunction. CONCLUSION: Prevention of extreme sleep phase delay during university days might be helpful for students' adaptation to work environment after graduation.

Validity of the Japanese version of the Munich ChronoType Questionnaire.

To assess circadian preference with a score, the Morningness-Eveningness Questionnaire (MEQ) has been used for more than 3 decades now. More recently, the Munich ChronoType Questionnaire (MCTQ) was developed: it asks for sleep-wake behavior on work and free days and uses the midpoint of sleep on free days (MSF), corrected for sleep debt accumulated during the work week as an indicator of chronotype (MSFsc). In this study, we developed a Japanese version of the MCTQ by using a translation/back-translation approach including an examination of its semantic validity. In a subsequent questionnaire survey, 450 adult men and women completed the Japanese versions of the MCTQ and MEQ. Results showed that MEQ scores were significantly negatively correlated with mid-sleep parameters assessed by the MCTQ, on both, work and free days, as well as with the chronotype measure MSFsc (r = -0.580 to -0.652, all p < 0.001). As in the original German version, the strongest correlation was observed between MEQ score and MSF. A physiological validation study using dim light melatonin onset as a circadian phase marker (N = 37) showed a high correlation between chronotype as assessed with the MSFsc (r = 0.542, p < 0.001), and less so for MEQ score (r = -0.402, p = 0.055). These results demonstrate the validity of the Japanese MCTQ and provide further support of the adequacy of the MCTQ as a chronotype measure.

In vitro circadian period is associated with circadian/sleep preference.

Evaluation of circadian phenotypes is crucial for understanding the pathophysiology of diseases associated with disturbed biological rhythms such as circadian rhythm sleep disorders (CRSDs). We measured clock gene expression in fibroblasts from individual subjects and observed circadian rhythms in the cells (in vitro rhythms). Period length of the in vitro rhythm (in vitro period) was compared with the intrinsic circadian period, τ, measured under a forced desynchrony protocol (in vivo period) and circadian/sleep parameters evaluated by questionnaires, sleep log, and actigraphy. Although no significant correlation was observed between the in vitro and in vivo periods, the in vitro period was correlated with chronotype, habitual sleep time, and preferred sleep time. Our data demonstrate that the in vitro period is significantly correlated with circadian/sleep preference. The findings suggest that fibroblasts from individual patients can be utilized for in vitro screening of therapeutic agents to provide personalized therapeutic regimens for CRSD patients.

A cross-sectional study of the association between working hours and sleep duration among the Japanese working population.

OBJECTIVES: This study aimed to clarify the association between long working hours and short sleep duration among Japanese workers. METHODS: We selected 4,000 households from across Japan by stratified random sampling and conducted an interview survey of a total of 662 participants (372 men; 290 women) in November 2009. Logistic regression analyses were performed using "sleep duration <6 hours per day" as a dependent variable to examine the association between working hours/overtime hours and short sleep duration. RESULTS: When male participants who worked for ≥7 but <9 hours per day were used as a reference, the odds ratio (OR) for short sleep duration in those who worked for ≥ 11 hours was 8.62 (95% confidence interval [CI]: 3.94-18.86). With regard to overtime hours among men, when participants without overtime were used as a reference, the OR for those whose period of overtime was ≥ 3 hours but <4 hours was 3.59 (95% CI: 1.42-9.08). For both men and women, those with long weekday working hours tended to have a short sleep duration during weekdays and holidays. CONCLUSIONS: It is essential to avoid working long hours in order to prevent short sleep duration.

Factors associated with shift work disorder in nurses working with rapid-rotation schedules in Japan: the nurses' sleep health project.

Workers who meet the criteria for shift work disorder (SWD) have elevated levels of risk for various health and behavioral problems. However, the impact of having SWD on shiftworkers engaged in rapid-rotation schedules is unknown. Moreover, the risk factors for the occurrence of SWD remain unclear. To clarify these issues, we conducted a questionnaire-based, cross-sectional survey on a sample of shiftworking nurses. Responses were obtained from 1202 nurses working at university hospitals in Tokyo, Japan, including 727 two-shift workers and 315 three-shift workers. The questionnaire included items relevant to age, gender, family structure, work environment, health-related quality of life (QOL), diurnal type, depressive symptoms, and SWD. Participants who reported insomnia and/or excessive sleepiness for at least 1 mo that was subjectively relevant to their shiftwork schedules were categorized as having SWD. The prevalence of SWD in the sampled shiftworking nurses was 24.4%; shiftworking nurses with SWD showed lower health-related QOL and more severe depressive symptoms, with greater rates of both actual accidents/errors and near misses, than those without SWD. The results of logistic regression analyses showed that more time spent working at night, frequent missing of nap opportunities during night work, and having an eveningness-oriented chronotype were significantly associated with SWD. The present study indicated that SWD might be associated with reduced health-related QOL and decreased work performance in shiftworking nurses on rapid-rotation schedules. The results also suggested that missing napping opportunities during night work, long nighttime working hours, and the delay of circadian rhythms are associated with the occurrence of SWD among shiftworking nurses on rapid-rotation schedules.

Intrinsic circadian period of sighted patients with circadian rhythm sleep disorder, free-running type.

BACKGROUND: Circadian rhythm sleep disorder, free-running type (FRT), is an intractable sleep disorder in which sleep and wake times progressively delay each day even in normal living environments. This disorder severely affects the social functioning of patients because of periodic nighttime insomnia, excessive daytime sleepiness, and a high rate of comorbid psychiatric disorders. Although abnormal regulation of the biological clock is suspected, the pathophysiology of FRT has yet to be elucidated. In this study, the endogenous circadian period, τ, of FRT patients with normal vision was compared with that of healthy individuals whose circadian rhythms are entrained to a 24-hour cycle. METHODS: Six FRT patients and 17 healthy individuals (9 intermediate chronotypes and 8 evening chronotypes) were subjected to a 7-day, 28-hour sleep-wake schedule according to the forced desynchrony protocol. Phase shifts in melatonin rhythm were measured under constant routine conditions to calculate τ. RESULTS: In FRT patients, τ was significantly longer than in intermediate chronotypes, whereas in evening chronotypes, it ranged widely and was not significantly different from that in FRT patients. Moreover, τ of melatonin rhythm in FRT patients showed no significant correlation with τ of sleep-wake cycles measured before the study. CONCLUSIONS: The findings suggest that although a prolongation of τ may be involved in the onset mechanism of FRT, a prolonged τ is not the only factor involved. It appears that several factors including abnormal entrainment of circadian rhythms are involved in the onset of FRT in a multilayered manner.

Increased cerebral blood flow in the right frontal lobe area during sleep precedes self-awakening in humans.

BACKGROUND: Some people can subconsciously wake up naturally (self-awakening) at a desired/planned time without external time stimuli. However, the underlying mechanism regulating this ability remains to be elucidated. This study sought to examine the relationship between hemodynamic changes in oxyhemoglobin (oxy-Hb) level in the prefrontal cortex and sleep structures during sleep in subjects instructed to self-awaken. RESULTS: Fifteen healthy right-handed male volunteers with regular sleep habits participated in a consecutive two-night crossover study. The subjects were instructed to wake up at a specified time ("request" condition) or instructed to sleep until the morning but forced to wake up at 03:00 without prior notice ("surprise" condition). Those who awoke within ± 30 min of the planned waking time were defined as those who succeeded in self-awakening ("success" group). Seven subjects succeeded in self-awakening and eight failed.No significant differences were observed in the amounts of sleep in each stage between conditions or between groups. On the "request" night, an increase in oxy-Hb level in the right prefrontal cortex and a decrease in δ power were observed in the "success" group around 30 min before self-awakening, whereas no such changes were observed in the "failure" group. On the "surprise" night, no significant changes were observed in oxy-Hb level or δ power in either group. CONCLUSIONS: These findings demonstrate a correlation between self-awakening and a pre-awakening increase in hemodynamic activation in the right prefrontal cortex, suggesting the structure's contribution to time estimation ability.

Alpha activity during rem sleep contributes to overnight improvement in performance on a visual discrimination task.

The purpose of this preliminary study was to clarify the association between cortical and subcortical activities during REM and non-REM sleep with overnight improvement of performance on a procedural memory task. Eleven healthy volunteers (M age = 23.8 yr., SD = 3.1) participated in this study which was conducted over two consecutive nights: an adaptation night and the experimental night. They underwent a visual discrimination task before and after the experimental night. A positive correlation was observed between overnight performance improvement on the visual discrimination task and EEG alpha band power during REM sleep, while no significant correlation was observed between the performance and either the amount of Stage REM sleep, REM activity, or other sleep variables. The findings corroborate other studies and suggest that cortical activity during REM sleep contributed to procedural memory consolidation and highlights the importance of measuring quantitative REM sleep components to elucidate the role of physiological sleep on memory consolidation in humans.

Rhythmic expression of circadian clock genes in human leukocytes and beard hair follicle cells.

Evaluating individual circadian rhythm traits is crucial for understanding the human biological clock system. The present study reports characterization of physiological and molecular parameters in 13 healthy male subjects under a constant routine condition, where interfering factors were kept to minimum. We measured hormonal secretion levels and examined temporal expression profiles of circadian clock genes in peripheral leukocytes and beard hair follicle cells. All 13 subjects had prominent daily rhythms in melatonin and cortisol secretion. Significant circadian rhythmicity was found for PER1 in 9 subjects, PER2 in 3 subjects, PER3 in all 13 subjects, and BMAL1 in 8 subjects in leukocytes. Additionally, significant circadian rhythmicity was found for PER1 in 5 of 8 subjects tested, PER2 in 2 subjects, PER3 in 6 subjects, and BMAL1 in 3 subjects in beard hair follicle cells. The phase of PER1 and PER3 rhythms in leukocytes correlated significantly with that of physiological rhythms. Our results demonstrate that leukocytes and beard hair follicle cells possess an endogenous circadian clock and suggest that PER1 and PER3 expression would be appropriate biomarkers and hair follicle cells could be a useful tissue source for the evaluation of biological clock traits in individuals.

Carryover effect on next-day sleepiness and psychomotor performance of nighttime administered antihistaminic drugs: a randomized controlled trial.

BACKGROUND: Antihistamines with strong sedative-hypnotic properties are frequently prescribed for insomnia secondary to allergy, but the potential risks of such administration have not been fully elucidated. SUBJECTS AND METHODS: This randomized, double-blind, placebo-controlled crossover study was conducted to evaluate next-day sleepiness and psychomotor performance following the administration of antihistamines. Twenty-two healthy male participants participated in four drug administration sessions with more than a 1-week interval between the sessions. Either zolpidem 10 mg, or diphenhydramine 50 mg, or ketotifen 1 mg, or a placebo was administered before sleep, and polysomnography was conducted to evaluate sleep. In the morning and afternoon of the day after administration, the participants were evaluated for subjective sleepiness, objective sleepiness, and psychomotor performance. RESULTS: The antihistamines with high blood-brain barrier-crossing efficiency were significantly associated with sleepiness and psychomotor performance decline the next day. Ketotifen showed the strongest carryover effect, followed by diphenhydramine. Compared with the placebo, no significant carryover effect was observed with zolpidem. CONCLUSION: The results suggest that the risk-benefit balance should be considered in the ready use of antihistamines that easily cross the blood-brain barrier for alleviating secondary insomnia associated with allergies.

Preferable forms of relaxation for health promotion, and the association between recreational activities and self-perceived health.

Little research has been done on the association between relaxation and health. In the present study, by conducting a nationwide cross-sectional survey, we aimed to obtain scientific data on the preferable forms of relaxation for health promotion, and to clarify the associations between specific recreational activities and self-perceived mental and physical health. We selected 4,000 households by stratified random sampling from across Japan in November 2009 and used the interview method to collect data (number of subjects: 2,206). The questionnaire contained items on sleep, recreation status, recreational activities, and self-perceived mental and physical health status. We obtained responses from 1,224 adults (response rate: 55.5%). Insufficient rest from sleep, short sleep duration (<6 h/day), ineffective use of free time, and less free time used for activities other than rest showed independent positive associations with poor mental and physical health. The results of the logistic regression analyses showed significantly low adjusted odds ratios with regard to the status of poor mental and physical health for outings/walking among men (0.33 [95% confidence interval; 0.16-0.68] and 0.49 [0.26-0.90], respectively), and for community activities among women (0.19 [0.04-0.79] and 0.27 [0.09-0.77], respectively). Relaxation for the promotion of health should include both passive relaxation (rest) and active relaxation (recreation). In addition, ensuring sufficient sleep duration is important for passive relaxation, and engaging in outings/walking for men and community activities for women are important for active relaxation.

Sleep-related problems and use of hypnotics in inpatients of acute hospital wards.

OBJECTIVE: Although sleep disorders are highly prevalent among patients with physical disorders, only limited information is available about the actual status of sleep-related problems in inpatients of acute hospital wards. We conducted a multicenter cross-sectional observational survey investigating the prevalence of sleep disorders and use of hypnotic-sedative drugs among inpatients of acute wards in 44 general hospitals in Japan. METHOD: Questionnaire-, actigraph- and observation-based sleep evaluations were simultaneously performed in 557 adult inpatients [mean age 72.8 + or - 12.8 (S.D.) years] of acute wards during a one-month period in July 2007. RESULTS: Of the 421 patients with data available, 22.3% had at least one of the following sleep disorders: sleep apnea syndrome, restless legs syndrome, periodic limb movement disorder and nocturnal behavior disorder. Similarly, 62.7% had insomnia, 6.9% had severe daytime sleepiness and 12.8% had other sleep-related symptoms. Only 13.8% were free of any sleep-related problem. Although 33.7% of insomnia patients were taking hypnotic-sedative drugs, 65.2% of them complained of residual insomnia symptoms. CONCLUSION: The findings obtained in this study have revealed the remarkably high prevalence of sleep-related problems experienced by inpatients of acute hospital wards in Japan. Proper diagnosis of sleep disorders should be made among patients with physical disorders.

Sleep deprivation influences diurnal variation of human time perception with prefrontal activity change: a functional near-infrared spectroscopy study.

Human short-time perception shows diurnal variation. In general, short-time perception fluctuates in parallel with circadian clock parameters, while diurnal variation seems to be modulated by sleep deprivation per se. Functional imaging studies have reported that short-time perception recruits a neural network that includes subcortical structures, as well as cortical areas involving the prefrontal cortex (PFC). It has also been reported that the PFC is vulnerable to sleep deprivation, which has an influence on various cognitive functions. The present study is aimed at elucidating the influence of PFC vulnerability to sleep deprivation on short-time perception, using the optical imaging technique of functional near-infrared spectroscopy. Eighteen participants performed 10-s time production tasks before (at 21:00) and after (at 09:00) experimental nights both in sleep-controlled and sleep-deprived conditions in a 4-day laboratory-based crossover study. Compared to the sleep-controlled condition, one-night sleep deprivation induced a significant reduction in the produced time simultaneous with an increased hemodynamic response in the left PFC at 09:00. These results suggest that activation of the left PFC, which possibly reflects functional compensation under a sleep-deprived condition, is associated with alteration of short-time perception.

Sleep accelerates the improvement in working memory performance.

Working memory (WM) performance, which is an important factor for determining problem-solving and reasoning ability, has been firmly believed to be constant. However, recent findings have demonstrated that WM performance has the potential to be improved by repetitive training. Although various skills are reported to be improved by sleep, the beneficial effect of sleep on WM performance has not been clarified. Here, we show that improvement in WM performance is facilitated by posttraining naturalistic sleep. A spatial variant of the n-back WM task was performed by 29 healthy young adults who were assigned randomly to three different experimental groups that had different time schedules of repetitive n-back WM task sessions, with or without intervening sleep. Intergroup and intersession comparisons of WM performance (accuracy and response time) profiles showed that n-back accuracy after posttraining sleep was significantly improved compared with that after the same period of wakefulness, independent of sleep timing, subject's vigilance level, or circadian influences. On the other hand, response time was not influenced by sleep or repetitive training schedules. The present study indicates that improvement in n-back accuracy, which could reflect WM capacity, essentially benefits from posttraining sleep.

Inter-individual difference in pupil size correlates to suppression of melatonin by exposure to light.

There are large inter-individual differences in pupil size and suppression of melatonin by exposure to light. It has been reported that melatonin suppression by exposure to light increases when pupils are pharmacologically dilated. However, the correlation between normal inter-individual difference in pupil size and melatonin suppression by exposure to light is not clear. Twenty-three healthy male subjects (22.6+/-2.7 years old) were exposed to light (1000 lx) for 2 h at night. The starting time of exposure to light was set to the ascending phase of melatonin concentration of each subject. Pupil area and saliva melatonin concentration were measured before exposure to light under dim light (15 lx) and during exposure to light. There were large inter-individual differences in melatonin suppression and pupil area. The mean and standard deviation of percentage of melatonin suppression 2 h after exposure to light was 57.2+/-22.1%. The mean and standard deviation of pupil areas before and 2 h after exposure to light were 30.7+/-7.9 mm2 and 15.9+/-4.8 mm2, respectively. The percentage of melatonin suppression by light was positively correlated with pupil area during light exposure (r=0.525, p<0.02). Interestingly, it was also correlated with pupil area measured before exposure to light, under dim light (15 lx) (r=0.658, p<0.001). These results suggest that inter-individual difference in pupil area positively correlates with melatonin suppression by light and that pupil area under dim light is a predictor of inter-individual differences in melatonin suppression by light.