Charles A. Czeisler

Circadian Variation in the Frequency of Onset of Acute Myocardial Infarction

To determine whether the onset of myocardial infarction occurs randomly throughout the day, we analyzed the time of onset of pain in 2999 patients admitted with myocardial infarction. A marked circadian rhythm in the frequency of onset was detected, with a peak from 6 a.m. to noon (P less than 0.01). In 703 of the patients, the time of the first elevation in the plasma creatine kinase MB (CK-MB) level could be used to time the onset of myocardial infarction objectively. CK-MB-estimated timing confirmed the existence of a circadian rhythm, with a three-fold increase in the frequency of onset of myocardial infarction at peak (9 a.m.) as compared with trough (11 p.m.) periods. The circadian rhythm was not detected in patients receiving beta-adrenergic blocking agents before myocardial infarction but was present in those not receiving such therapy. If coronary arteries become vulnerable to occlusion when the intima covering an atherosclerotic plaque is disrupted, the circadian timing of myocardial infarction may result from a variation in the tendency to thrombosis. If the rhythmic processes that drive the circadian rhythm of myocardial-infarction onset can be identified, their modification may delay or prevent the occurrence of infarction.

Concurrent Morning Increase in Platelet Aggregability and the Risk of Myocardial Infarction and Sudden Cardiac Death

Abstract We have previously reported that the frequencies of myocardial infarction and of sudden cardiac death are highest during the period from 6 a.m. to noon. Since platelet aggregation may have a role in triggering these disorders, we measured platelet activity at 3-hour intervals for 24 hours in 15 healthy men. In vitro platelet responsiveness to either adenosine diphosphate (ADP) or epinephrine was lower at 6 a.m. (before the subjects arose) than at 9 a.m. (60 minutes after they arose). The lowest concentration of these agents required to produce biphasic platelet aggregation decreased (i.e., aggregability increased) from a mean ±SEM of 4.7±0.6 to 3.7±0.6 μM (P<0.01) for ADP and from 3.7±0.8 to 1.8±0.5 μM (P<0.01) for epinephrine. The period from 6 to 9 a.m. was the only interval in the 24-hour period during which platelet aggregability increased significantly. We subsequently studied 10 subjects on alternate mornings after they arose at the normal time and after delayed arising. The morning increas...

Sensitivity of the human circadian pacemaker to nocturnal light: melatonin phase resetting and suppression

1 Ocular exposure to early morning room light can significantly advance the timing of the human circadian pacemaker. The resetting response to such light has a non‐linear relationship to illuminance. The dose‐response relationship of the human circadian pacemaker to late evening light of dim to moderate intensity has not been well established. 2 Twenty‐three healthy young male and female volunteers took part in a 9 day protocol in which a single experimental light exposure6.5 h in duration was given in the early biological night. The effects of the light exposure on the endogenous circadian phase of the melatonin rhythm and the acute effects of the light exposure on plasma melatonin concentration were calculated. 3 We demonstrate that humans are highly responsive to the phase‐delaying effects of light during the early biological night and that both the phase resetting response to light and the acute suppressive effects of light on plasma melatonin follow a logistic dose‐response curve, as do many circadian responses to light in mammals. 4 Contrary to expectations, we found that half of the maximal phase‐delaying response achieved in response to a single episode of evening bright light (≈9000 lux (lx)) can be obtained with just over 1 % of this light (dim room light of ≈100 lx). The same held true for the acute suppressive effects of light on plasma melatonin concentrations. This indicates that even small changes in ordinary light exposure during the late evening hours can significantly affect both plasma melatonin concentrations and the entrained phase of the human circadian pacemaker.

A phase response curve to single bright light pulses in human subjects

The circadian pacemaker is differentially sensitive to the resetting effects of retinal light exposure, depending upon the circadian phase at which the light exposure occurs. Previously reported human phase response curves (PRCs) to single bright light exposures have employed small sample sizes, and were often based on relatively imprecise estimates of circadian phase and phase resetting. In the present study, 21 healthy, entrained subjects underwent pre‐ and post‐stimulus constant routines (CRs) in dim light (∼2–7 lx) with maintained wakefulness in a semi‐recumbent posture. The 6.7 h bright light exposure stimulus consisted of alternating 6 min fixed gaze (∼10 000 lx) and free gaze (∼5000–9000 lx) exposures. Light exposures were scheduled across the circadian cycle in different subjects so as to derive a PRC. Plasma melatonin was used to determine the phase of the onset, offset, and midpoint of the melatonin profiles during the CRs. Phase shifts were calculated as the difference in phase between the pre‐ and post‐stimulus CRs. The resultant PRC of the midpoint of the melatonin rhythm revealed a characteristic type 1 PRC with a significant peak‐to‐trough amplitude of 5.02 h. Phase delays occurred when the light stimulus was centred prior to the critical phase at the core body temperature minimum, phase advances occurred when the light stimulus was centred after the critical phase, and no phase shift occurred at the critical phase. During the subjective day, no prolonged ‘dead zone’ of photic insensitivity was apparent. Phase shifts derived using the melatonin onsets showed larger magnitudes than those derived from the melatonin offsets. These data provide a comprehensive characterization of the human PRC under highly controlled laboratory conditions.

Exposure to bright light and darkness to treat physiologic maladaptation to night work.

Working at night results in a misalignment between the sleep-wake cycle and the output of the hypothalamic pacemaker that regulates the circadian rhythms of certain physiologic and behavioral variables. We evaluated whether such physiologic maladaptation to nighttime work could be prevented effectively by a treatment regimen of exposure to bright light during the night and darkness during the day. We assessed the functioning of the circadian pacemaker in five control and five treatment studies in order to assess the extent of adaptation in eight normal young men to a week of night work. In the control studies, on the sixth consecutive night of sedentary work in ordinary light (approximately 150 lux), the mean (+/- SEM) nadir of the endogenous temperature cycle continued to occur during the night (at 3:31 +/- 0:56 hours), indicating a lack of circadian adaptation to the nighttime work schedule. In contrast, the subjects in the treatment studies were exposed to bright light (7000 to 12,000 lux) at night and to nearly complete darkness during the day, and the temperature nadir shifted after four days of treatment to a significantly later, midafternoon hour (14:53 +/- 0:32; P less than 0.0001), indicating a successful circadian adaptation to daytime sleep and nighttime work. There were concomitant shifts in the 24-hour patterns of plasma cortisol concentration, urinary excretion rate, subjective assessment of alertness, and cognitive performance in the treatment studies. These shifts resulted in a significant improvement in both alertness and cognitive performance in the treatment group during the night-shift hours. We conclude that maladaptation of the human circadian system to night work, with its associated decline in alertness, performance, and quality of daytime sleep, can be treated effectively with scheduled exposure to bright light at night and darkness during the day.

Paradoxical timing of the circadian rhythm of sleep propensity serves to consolidate sleep and wakefulness in humans

The contribution of the circadian pacemaker and the sleep homeostat to sleep tendency and consolidation was quantified by forced desynchrony of the sleep-wake cycle from the circadian pacemaker in eight men who lived in time-isolation for 33-36 days. Analysis of 175 polygraphically recorded sleep episodes revealed that the circadian pacemaker and the sleep homeostat contribute about equally to sleep consolidation, and that the phase relationship between these oscillatory processes during entrainment to the 24-h day is uniquely timed to facilitate the ability to maintain a consolidated bout of sleep at night and a consolidated bout of wakefulness throughout the day.

Rotating shift work, sleep, and accidents related to sleepiness in hospital nurses

A hospital-based survey on shift work, sleep, and accidents was carried out among 635 Massachusetts nurses. In comparison to nurses who worked only day/evening shifts, rotators had more sleep/wake cycle disruption and nodded off more at work. Rotators had twice the odds of nodding off while driving to or from work and twice the odds of a reported accident or error related to sleepiness. Application of circadian principles to the design of hospital work schedules may result in improved health and safety for nurses and patients.

Dose-response relationship for light intensity and ocular and electroencephalographic correlates of human alertness

Light can elicit both circadian and acute physiological responses in humans. In a dose response protocol men and women were exposed to illuminances ranging from 3 to 9100 lux for 6.5 h during the early biological night after they had been exposed to <3 lux for several hours. Light exerted an acute alerting response as assessed by a reduction in the incidence of slow-eye movements, a reduction of EEG activity in the theta-alpha frequencies (power density in the 5-9 Hz range) as well as a reduction in self-reported sleepiness. This alerting response was positively correlated with the degree of melatonin suppression by light. In accordance with the dose response function for circadian resetting and melatonin suppression, the responses of all three indices of alertness to variations in illuminance were consistent with a logistic dose response curve. Half of the maximum alerting response to bright light of 9100 lux was obtained with room light of approximately 100 lux. This sensitivity to light indicates that variations in illuminance within the range of typical, ambient, room light (90-180 lux) can have a significant impact on subjective alertness and its electrophysiologic concomitants in humans during the early biological night.

Association of sleep-wake habits in older people with changes in output of circadian pacemaker

Many elderly people complain of disturbed sleep patterns but there is not evidence that the need to sleep decreases with age; it seems rather that the timing and consolidation of sleep change. We tried to find out whether there is a concurrent change in the output of the circadian pacemaker with age. The phase and amplitude of the pacemakers output were assessed by continuous measurement of the core body temperature during 40 h of sustained wakefulness under constant behavioural and environmental conditions. 27 young men (18-31 years) were compared with 21 older people (65-85 years; 11 men, 10 women); all were healthy and without sleep complaints. The mean amplitude of the endogenous circadian temperature oscillation (ECA) was 40% greater in young men than in the older group. Older men had a lower mean temperature ECA than older women. The minimum of the endogenous phase of the circadian temperature oscillation (ECP) occurred 1 h 52 min earlier in the older than in the young group. Customary bedtimes and waketimes were also earlier in the older group, as was their daily alertness peak. There was a close correlation between habitual waketime and temperature ECP in young men, which may lose precision with age, especially among women. These findings provide evidence for systematic age-related changes in the output of the human circadian pacemaker. We suggest that these changes may underlie the common complaints of sleep disturbance among elderly people. These changes could reflect the observed age-related deterioration of the hypothalamic nuclei that drive mammalian circadian rhythms.

Adverse Metabolic Consequences in Humans of Prolonged Sleep Restriction Combined with Circadian Disruption

Sleep deficiency and out-of-synch circadian rhythms impair pancreatic insulin secretion, a possible precursor to metabolic syndrome and diabetes. A Reason to Go to Bed on Time Our own experience tells us that getting too little sleep or traveling across multiple time zones can impair our ability to function. And people who work on the night shift or who habitually sleep too little are more likely to be obese or have diabetes. But what is it about these stresses that translate into faulty physiology? By simulating the life-style of a shift worker or world traveler in controlled laboratory conditions, Buxton et al. now find that prolonged, simultaneous disruption of our normal sleep and circadian rhythms affects the workings of our insulin-secreting pancreatic cells, creating a prediabetic state. And even worse, under these conditions, people show a drop in their resting metabolic rate that could translate into a yearly weight gain of more than 10 pounds. Getting a firm handle on the effects of life-style changes such as sleep, activity schedule, and diet on pancreatic function is much easier in small animals than humans. But Buxton et al. successfully investigated these questions by hosting 21 human participants in a completely controlled environment for almost 6 weeks and simulating disturbances in sleep and circadian rhythms, while keeping diet constant and scheduling all activities. Because sleep and circadian rhythms are intimately related, they designed a special protocol to independently manipulate these variables. After a stabilization segment in which the participants had adequate sleep at the appropriate time within their circadian rhythms, the participants spent 3 weeks in which they got only 5.6 hours of sleep per 24-hour period, while simultaneously experiencing 28-hour circadian days—a state similar to 4 hours of jet lag accumulating each day. During this time, the participants were often trying to sleep at unusual times within their circadian cycle. A segment of 9 recovery days followed. During the 3-week disruption, the participants’ glucose control went haywire, and they were unable to mount a sufficiently high insulin response after a meal, resulting in too much glucose in their blood, in some cases at a level considered prediabetic. This magnitude of disruption, coupled with a lower resting metabolic rate that also emerged during the 3 treatment weeks, could easily set the stage for development of diabetes and obesity, although the exact process by which this happens awaits further study. These results carry a cautionary message for employers to guard against causing adverse metabolic effects in workers by their shift scheduling practices—and a reinforcement of your mother’s message to go to bed on time and get enough sleep. Epidemiological studies link short sleep duration and circadian disruption with higher risk of metabolic syndrome and diabetes. We tested the hypotheses that prolonged sleep restriction with concurrent circadian disruption, as can occur in people performing shift work, impairs glucose regulation and metabolism. Healthy adults spent >5 weeks under controlled laboratory conditions in which they experienced an initial baseline segment of optimal sleep, 3 weeks of sleep restriction (5.6 hours of sleep per 24 hours) combined with circadian disruption (recurring 28-hour “days”), followed by 9 days of recovery sleep with circadian re-entrainment. Exposure to prolonged sleep restriction with concurrent circadian disruption, with measurements taken at the same circadian phase, decreased the participants’ resting metabolic rate and increased plasma glucose concentrations after a meal, an effect resulting from inadequate pancreatic insulin secretion. These parameters normalized during the 9 days of recovery sleep and stable circadian re-entrainment. Thus, in humans, prolonged sleep restriction with concurrent circadian disruption alters metabolism and could increase the risk of obesity and diabetes.