Mark R. Smith

Phase advancing the human circadian clock with blue-enriched polychromatic light

BACKGROUND Previous studies have shown that the human circadian system is maximally sensitive to short-wavelength (blue) light. Whether this sensitivity can be utilized to increase the size of phase shifts using light boxes and protocols designed for practical settings is not known. We assessed whether bright polychromatic lamps enriched in the short-wavelength portion of the visible light spectrum could produce larger phase advances than standard bright white lamps. METHODS Twenty-two healthy young adults received either a bright white or bright blue-enriched 2-h phase advancing light pulse upon awakening on each of four treatment days. On the first treatment day the light pulse began 8h after the dim light melatonin onset (DLMO), on average about 2h before baseline wake time. On each subsequent day, light treatment began 1h earlier than the previous day, and the sleep schedule was also advanced. RESULTS Phase advances of the DLMO for the blue-enriched (92+/-78 min, n=12) and white groups (76+/-45 min, n=10) were not significantly different. CONCLUSION Bright blue-enriched polychromatic light is no more effective than standard bright light therapy for phase advancing circadian rhythms at commonly used therapeutic light levels.

Phase Delaying the Human Circadian Clock with Blue-Enriched Polychromatic Light

The human circadian system is maximally sensitive to short-wavelength (blue) light. In a previous study we found no difference between the magnitude of phase advances produced by bright white versus bright blue-enriched light using light boxes in a practical protocol that could be used in the real world. Since the spectral sensitivity of the circadian system may vary with a circadian rhythm, we tested whether the results of our recent phase-advancing study hold true for phase delays. In a within-subjects counterbalanced design, this study tested whether bright blue-enriched polychromatic light (17000 K, 4000 lux) could produce larger phase delays than bright white light (4100 K, 5000 lux) of equal photon density (4.2×1015 photons/cm2/sec). Healthy young subjects (n = 13) received a 2 h phase delaying light pulse before bedtime combined with a gradually delaying sleep/dark schedule on each of 4 consecutive treatment days. On the first treatment day the light pulse began 3 h after the dim light melatonin onset (DLMO). An 8 h sleep episode began at the end of the light pulse. Light treatment and the sleep schedule were delayed 2 h on each subsequent treatment day. A circadian phase assessment was conducted before and after the series of light treatment days to determine the time of the DLMO and DLMOff. Phase delays in the blue-enriched and white conditions were not significantly different (DLMO: −4.45±2.02 versus −4.48±1.97 h; DLMOff: −3.90±1.97 versus −4.35±2.39 h, respectively). These results indicate that at light levels commonly used for circadian phase shifting, blue-enriched polychromatic light is no more effective than the white polychromatic lamps of a lower correlated color temperature (CCT) for phase delaying the circadian clock. (Author correspondence: ceastman@rush.edu)

A Compromise Phase Position for Permanent Night Shift Workers: Circadian Phase after Two Night Shifts with Scheduled Sleep and Light/Dark Exposure

Night shift work is associated with a myriad of health and safety risks. Phase‐shifting the circadian clock such that it is more aligned with night work and day sleep is one way to attenuate these risks. However, workers will not be satisfied with complete adaptation to night work if it leaves them misaligned during days off. Therefore, the goal of this set of studies is to produce a compromise phase position in which individuals working night shifts delay their circadian clocks to a position that is more compatible with nighttime work and daytime sleep yet is not incompatible with late nighttime sleep on days off. This is the first in the set of studies describing the magnitude of circadian phase delays that occurs on progressively later days within a series of night shifts interspersed with days off. The series will be ended on various days in order to take a “snapshot” of circadian phase. In this set of studies, subjects sleep from 23:00 to 7:00 h for three weeks. Following this baseline period, there is a series of night shifts (23:00 to 07:00 h) and days off. Experimental subjects receive five 15 min intermittent bright light pulses (∼3500 lux; ∼1100 µW/cm2) once per hour during the night shifts, wear sunglasses that attenuate all visible wavelengths—especially short wavelengths (“blue‐blockers”)—while traveling home after the shifts, and sleep in the dark (08:30–15:30 h) after each night shift. Control subjects remain in typical dim room light (<50 lux) throughout the night shift, wear sunglasses that do not attenuate as much light, and sleep whenever they want after the night shifts. Circadian phase is determined from the circadian rhythm of melatonin collected during a dim light phase assessment at the beginning and end of each study. The sleepiest time of day, approximated by the body temperature minimum (Tmin), is estimated by adding 7 h to the dim light melatonin onset. In this first study, circadian phase was measured after two night shifts and day sleep periods. The Tmin of the experimental subjects (n=11) was 04:24±0.8 h (mean±SD) at baseline and 7:36±1.4 h after the night shifts. Thus, after two night shifts, the Tmin had not yet delayed into the daytime sleep period, which began at 08:30 h. The Tmin of the control subjects (n=12) was 04:00±1.2 h at baseline and drifted to 4:36±1.4 h after the night shifts. Thus, two night shifts with a practical pattern of intermittent bright light, the wearing of sunglasses on the way home from night shifts, and a regular sleep period early in the daytime, phase delayed the circadian clock toward the desired compromise phase position for permanent night shift workers. Additional night shifts with bright light pulses and daytime sleep in the dark are expected to displace the sleepiest time of day into the daytime sleep period, improving both nighttime alertness and daytime sleep but not precluding adequate sleep on days off.

Practical Interventions to Promote Circadian Adaptation to Permanent Night Shift Work: Study 4

Scheduled bright light and darkness can phase shift the circadian clocks of night workers for complete adaptation to a night work, day sleep schedule, but few night workers would want this because it would leave them out of phase with the diurnal world on days off. This is the final study in a series designed to produce a compromise circadian phase position for permanent night shift work in which the sleepiest circadian time is delayed out of the night work period and into the first half of the day sleep episode. The target compromise phase position was a dim light melatonin onset (DLMO) of 3:00, which puts the sleepiest circadian time at ~10:00. This was predicted to improve night shift alertness and performance while permitting sufficient daytime sleep after work as well as late-night sleep on days off. In a between-subjects design, 19 healthy subjects underwent 3 simulated night shifts (23:00-7:00), 2 days off, 4 more night shifts, and 2 more days off. Subjects “worked” in the lab and slept at home. Experimental subjects received four 15-min bright light pulses during each night shift, wore dark sunglasses when outside, slept in dark bedrooms at scheduled times, and received outdoor afternoon light exposure (“light brake”) to keep their rhythms from delaying too far. Control subjects remained in normal room light during night shifts, wore lighter sunglasses, and had unrestricted sleep and outdoor light exposure. The final DLMO of the experimental group was 3:22 ± 2.0 h, close to the target of 3:00, and later than the control group at 23:24 ± 3.8 h. Experimental subjects slept for nearly all the permitted time in bed. Some control subjects who slept late on weekends also reached the compromise phase position and obtained more daytime sleep. Subjects who phase delayed (whether in the experimental or control group) close to the target phase performed better during night shifts. A compromise circadian phase position improved performance during night shifts, allowed sufficient sleep during the daytime after night shifts and during the late nighttime on days off, and can be produced by inexpensive and feasible interventions.

Racial Differences in the Human Endogenous Circadian Period

The length of the endogenous period of the human circadian clock (tau) is slightly greater than 24 hours. There are individual differences in tau, which influence the phase angle of entrainment to the light/dark (LD) cycle, and in doing so contribute to morningness-eveningness. We have recently reported that tau measured in subjects living on an ultradian LD cycle averaged 24.2 hours, and is similar to tau measured using different experimental methods. Here we report racial differences in tau. Subjects lived on an ultradian LD cycle (1.5 hours sleep, 2.5 hours wake) for 3 days. Circadian phase assessments were conducted before and after the ultradian days to determine the change in circadian phase, which was attributed to tau. African American subjects had a significantly shorter tau than subjects of other races. We also tested for racial differences in our previous circadian phase advancing and phase delaying studies. In the phase advancing study, subjects underwent 4 days of a gradually advancing sleep schedule combined with a bright light pulse upon awakening each morning. In the phase delaying study, subjects underwent 4 days of a gradually delaying sleep schedule combined with evening light pulses before bedtime. African American subjects had larger phase advances and smaller phase delays, relative to Caucasian subjects. The racial differences in tau and circadian phase shifting have important implications for understanding normal phase differences between individuals, for developing solutions to the problems of jet lag and shift work, and for the diagnosis and treatment of circadian rhythm based sleep disorders such as advanced and delayed sleep phase disorder.

Shift work: health, performance and safety problems, traditional countermeasures, and innovative management strategies to reduce circadian misalignment

There are three mechanisms that may contribute to the health, performance, and safety problems associated with night-shift work: (1) circadian misalignment between the internal circadian clock and activities such as work, sleep, and eating, (2) chronic, partial sleep deprivation, and (3) melatonin suppression by light at night. The typical countermeasures, such as caffeine, naps, and melatonin (for its sleep-promoting effect), along with education about sleep and circadian rhythms, are the components of most fatigue risk-management plans. We contend that these, while better than nothing, are not enough because they do not address the underlying cause of the problems, which is circadian misalignment. We explain how to reset (phase-shift) the circadian clock to partially align with the night-work, day-sleep schedule, and thus reduce circadian misalignment while preserving sleep and functioning on days off. This involves controlling light and dark using outdoor light exposure, sunglasses, sleep in the dark, and a little bright light during night work. We present a diagram of a sleep-and-light schedule to reduce circadian misalignment in permanent night work, or a rotation between evenings and nights, and give practical advice on how to implement this type of plan.

Blacks (African Americans) have shorter free-running circadian periods than whites (Caucasian Americans).

The length of the free-running period (τ) affects how an animal re-entrains after phase shifts of the light-dark (LD) cycle. Those with shorter periods adapt faster to phase advances than those with longer periods, whereas those with longer periods adapt faster to phase delays than those with shorter periods. The free-running period of humans, measured in temporal isolation units and in forced desychrony protocols in which the day length is set beyond the range of entrainment, varies from about 23.5 to 26 h, depending on the individual and the experimental conditions (e.g., temporal isolation vs. forced desychrony). We studied 94 subjects free-running through an ultradian LD cycle, which was a forced desychrony with a day length of 4 h (2.5 h awake in dim light, ∼35 lux, alternating with 1.5 h for sleep in darkness). Circadian phase assessments were conducted before (baseline) and after (final) three 24-h days of the ultradian LD cycle. During these assessments, saliva samples were collected every 30 min and subsequently analyzed for melatonin. The phase shift of the dim light melatonin onset (DLMO) from baseline to final phase assessment gave the free-running period. The mean ± SD period was 24.31 ± .23 h and ranged from 23.7 to 24.9 h. Black subjects had a significantly shorter free-running period than Whites (24.18 ± .23 h, N =20 vs. 24.37 ± .22 h, N = 55). We had a greater proportion of women than men in our Black sample, so to check the τ difference we compared the Black women to White women. Again, Black subjects had a significantly shorter free-running period (24.18 ± .23, N = 17 vs. 24.41 ± .23, N = 23). We did not find any sex differences in the free-running period. These findings give rise to several testable predictions: on average, Blacks should adapt quicker to eastward flights across time zones than Whites, whereas Whites should adjust quicker to westward flights than Blacks. Also, Blacks should have more difficulty adjusting to night-shift work and day sleep, which requires a phase delay. On the other hand, Whites should be more likely to have trouble adapting to the early work and school schedules imposed by society. More research is needed to confirm these results and predictions. (Author correspondence: ceastman@rush.edu)

Shaping the light/dark pattern for circadian adaptation to night shift work

This is the second in a series of simulated night shift studies designed to achieve and subsequently maintain a compromise circadian phase position between complete entrainment to the daytime sleep period and no phase shift at all. We predict that this compromise will yield improved night shift alertness and daytime sleep, while still permitting adequate late night sleep and daytime wakefulness on days off. Our goal is to delay the dim light melatonin onset (DLMO) from its baseline phase of approximately 21:00 to our target of approximately 3:00. Healthy young subjects (n=31) underwent three night shifts followed by two days off. Two experimental groups received intermittent bright light pulses during night shifts (total durations of 75 and 120 min per night shift), wore dark sunglasses when outside, slept in dark bedrooms at scheduled times after night shifts and on days off, and received outdoor light exposure upon awakening from sleep. A control group remained in dim room light during night shifts, wore lighter sunglasses, and had unrestricted sleep and outdoor light exposure. After the days off, the DLMO of the experimental groups was approximately 00:00-1:00, not quite at the target of 3:00, but in a good position to reach the target after subsequent night shifts with bright light. The DLMO of the control group changed little from baseline. Experimental subjects performed better than control subjects during night shifts on a reaction time task. Subsequent studies will reveal whether the target phase is achieved and maintained through more alternations of night shifts and days off.

Morning melatonin has limited benefit as a soporific for daytime sleep after night work

Exogenous melatonin administration in humans is known to exert both chronobiotic (phase shifting) and soporific effects. In a previous study in our lab, young, healthy, subjects worked five consecutive simulated night shifts (23:00 to 07:00 h) and slept during the day (08:30 to 15:30 h). Large phase delays of various magnitudes were produced by the study interventions, which included bright light exposure during the night shifts, as assessed by the dim light melatonin onset (DLMO) before (baseline) and after (final) the five night shifts. Subjects also ingested either 1.8 mg sustained‐release melatonin or placebo before daytime sleep. Although melatonin at this time should delay the circadian clock, this previous study found that it did not increase the magnitude of phase delays. To determine whether melatonin had a soporific effect, we controlled the various magnitudes of phase delay produced by the other study interventions. Melatonin (n=18) and placebo (n=18) groups were formed by matching a melatonin participant with a placebo participant that had a similar baseline and final DLMO (±1 h). Sleep log measurements of total sleep time (TST) and actigraphic measurements of sleep latency, TST, and three movement indices for the two groups were examined. Although melatonin was associated with small improvements in sleep quality and quantity, the differences were not statistically significant by analysis of variance. However, binomial analysis indicated that melatonin participants were more likely to sleep better than their placebo counterparts on some days with some measures. It was concluded that, the soporific effect of melatonin is small when administered prior to 7 h daytime sleep periods following night shift work.

Can small shifts in circadian phase affect performance

Small shifts in circadian timing occur frequently as a result of daylight saving time or later weekend sleep. These subtle shifts in circadian phase have been shown to influence subjective sleepiness, but it remains unclear if they can significantly affect performance. In a retrospective analysis we examined performance on the Psychomotor Vigilance Test before bedtime and after wake time in 11 healthy adults on fixed sleep schedules based on their habitual sleep times. The dim light melatonin onset, a marker of circadian timing, was measured on two occasions. An average 1.1 h shift away from a proposed optimal circadian phase angle (6 h between melatonin onset and midpoint of sleep) significantly slowed mean, median and fastest 10% reaction times before bedtime and after wake time (p < 0.05). These results add to previous reports that suggest that humans may be sensitive to commonly occurring small shifts in circadian timing.