The Phase-Shifting Effect of Bright Light Exposure on Circadian Rhythmicity in the Human Transcriptome.

Light is a potent synchronizer of the central circadian clock; however, the effect of light exposure on peripheral gene expression is largely unknown. The objective of this study was to explore the effect of bright light exposure on genome-wide peripheral gene expression levels during a 4-day simulated night shift protocol in which the habitual sleep period is delayed by 10 h. Eleven healthy participants (mean age, 24 years; range, 18-30; 10 men/1 woman) were studied under controlled laboratory conditions. Three participants were exposed to bright light (~6,500 lux) for 8 h during the nightly waking period, while the other 8 were maintained in dim-light conditions (~10 lux). At baseline and on the fourth day after the shift in the sleep period, blood samples were collected during two 24-h measurement periods. RNA was extracted from peripheral blood mononuclear cells (PBMCs) and used to obtain transcriptomic data. Using 2 independent approaches to determine phase shifts among rhythmically expressed genes after the shifted sleep schedule compared with baseline, we found that the average phase delay in the bright light group was approximately 8 to 9 h, whereas the average phase delay in the control group was approximately 1 to 2 h, both at the group level and at the individual level. In line with these findings, further analysis using partial least squares regression indicated that the peripheral circadian transcriptome of PBMCs was predictive of the phase of the central circadian pacemaker after only 3 days of bright light exposure. These results indicate that bright light exposure exerts a phase-shifting effect on the circadian transcriptome in PBMCs with a magnitude similar to its effect on the central circadian clock.

Rapid resetting of human peripheral clocks by phototherapy during simulated night shift work.

A majority of night shift workers have their circadian rhythms misaligned to their atypical schedule. While bright light exposure at night is known to reset the human central circadian clock, the behavior of peripheral clocks under conditions of shift work is more elusive. The aim of the present study was to quantify the resetting effects of bright light exposure on both central (plasma cortisol and melatonin) and peripheral clocks markers (clock gene expression in peripheral blood mononuclear cells, PBMCs) in subjects living at night. Eighteen healthy subjects were enrolled to either a control (dim light) or a bright light group. Blood was sampled at baseline and on the 4th day of simulated night shift. In response to a night-oriented schedule, the phase of PER1 and BMAL1 rhythms in PBMCs was delayed by ~2.5-3 h (P < 0.05), while no shift was observed for the other clock genes and the central markers. Three cycles of 8-h bright light induced significant phase delays (P < 0.05) of ~7-9 h for central and peripheral markers, except BMAL1 (advanced by +5h29; P < 0.05). Here, we demonstrate in humans a lack of peripheral clock adaptation under a night-oriented schedule and a rapid resetting effect of nocturnal bright light exposure on peripheral clocks.

Dopamine and light: effects on facial emotion recognition.

Bright light can affect mood states and social behaviours. Here, we tested potential interacting effects of light and dopamine on facial emotion recognition. Participants were 32 women with subsyndromal seasonal affective disorder tested in either a bright (3000 lux) or dim light (10 lux) environment. Each participant completed two test days, one following the ingestion of a phenylalanine/tyrosine-deficient mixture and one with a nutritionally balanced control mixture, both administered double blind in a randomised order. Approximately four hours post-ingestion participants completed a self-report measure of mood followed by a facial emotion recognition task. All testing took place between November and March when seasonal symptoms would be present. Following acute phenylalanine/tyrosine depletion (APTD), compared to the nutritionally balanced control mixture, participants in the dim light condition were more accurate at recognising sad faces, less likely to misclassify them, and faster at responding to them, effects that were independent of changes in mood. Effects of APTD on responses to sad faces in the bright light group were less consistent. There were no APTD effects on responses to other emotions, with one exception: a significant light × mixture interaction was seen for the reaction time to fear, but the pattern of effect was not predicted a priori or seen on other measures. Together, the results suggest that the processing of sad emotional stimuli might be greater when dopamine transmission is low. Bright light exposure, used for the treatment of both seasonal and non-seasonal mood disorders, might produce some of its benefits by preventing this effect.

Phototherapy and orange-tinted goggles for night-shift adaptation of police officers on patrol.

The aim of the present combined field and laboratory study was to assess circadian entrainment in two groups of police officers working seven consecutive 8/8.5-h night shifts as part of a rotating schedule. Eight full-time police officers on patrol (mean age ± SD: 29.8 ± 6.5 yrs) were provided an intervention consisting of intermittent exposure to wide-spectrum bright light at night, orange-tinted goggles at sunrise, and maintenance of a regular sleep/darkness episode in the day. Orange-tinted goggles have been shown to block the melatonin-suppressing effect of light significantly more than neutral gray density goggles. Nine control group police officers (mean age ± SD: 30.3 ± 4.1 yrs) working the same schedule were enrolled. Police officers were studied before, after (in the laboratory), and during (ambulatory) a series of seven consecutive nights. Urine samples were collected at wake time and bedtime throughout the week of night work and during laboratory visits (1 × /3 h) preceding and following the work week to measure urinary 6-sulfatoxymelatonin (UaMT6s) excretion rate. Subjective alertness was assessed at the start, middle, and end of night shifts. A 10-min psychomotor vigilance task was performed at the start and end of each shift. Both laboratory visits consisted of two 8-h sleep episodes based on the prior schedule. Saliva samples were collected 2 × /h during waking episodes to assay their melatonin content. Subjective alertness (3 × /h) and performance (1 × /2 h) were assessed during wake periods in the laboratory. A mixed linear model was used to analyze the progression of UaMt6s excreted during daytime sleep episodes at home, as well as psychomotor performance and subjective alertness during night shifts. Two-way analysis of variance (ANOVA) (factors: laboratory visit and group) were used to compare peak salivary melatonin and UaMT6s excretion rate in the laboratory. In both groups of police officers, the excretion rate of UaMT6s at home was higher during daytime sleep episodes at the end compared to the start of the work week (p < .001). This rate increased significantly more in the intervention than control group (p = .032). A significant phase delay of salivary melatonin was observed in both groups at the end of study (p = .009), although no significant between-group difference was reached. Reaction speed dropped, and subjective alertness decreased throughout the night shift in both groups (p < .001). Reaction speed decreased throughout the work week in the control group (p ≤ .021), whereas no difference was observed in the intervention group. Median reaction time was increased as of the 5th and 6th nights compared to the 2nd night in controls (p ≤ .003), whereas it remained stable in the intervention group. These observations indicate better physiological adaptation in the intervention group compared to the controls.

Amplitude reduction and phase shifts of melatonin, cortisol and other circadian rhythms after a gradual advance of sleep and light exposure in humans.

BACKGROUND: The phase and amplitude of rhythms in physiology and behavior are generated by circadian oscillators and entrained to the 24-h day by exposure to the light-dark cycle and feedback from the sleep-wake cycle. The extent to which the phase and amplitude of multiple rhythms are similarly affected during altered timing of light exposure and the sleep-wake cycle has not been fully characterized. METHODOLOGY/PRINCIPAL FINDINGS: We assessed the phase and amplitude of the rhythms of melatonin, core body temperature, cortisol, alertness, performance and sleep after a perturbation of entrainment by a gradual advance of the sleep-wake schedule (10 h in 5 days) and associated light-dark cycle in 14 healthy men. The light-dark cycle consisted either of moderate intensity 'room' light (∼90-150 lux) or moderate light supplemented with bright light (∼10,000 lux) for 5 to 8 hours following sleep. After the advance of the sleep-wake schedule in moderate light, no significant advance of the melatonin rhythm was observed whereas, after bright light supplementation the phase advance was 8.1 h (SEM 0.7 h). Individual differences in phase shifts correlated across variables. The amplitude of the melatonin rhythm assessed under constant conditions was reduced after moderate light by 54% (17-94%) and after bright light by 52% (range 12-84%), as compared to the amplitude at baseline in the presence of a sleep-wake cycle. Individual differences in amplitude reduction of the melatonin rhythm correlated with the amplitude of body temperature, cortisol and alertness. CONCLUSIONS/SIGNIFICANCE: Alterations in the timing of the sleep-wake cycle and associated bright or moderate light exposure can lead to changes in phase and reduction of circadian amplitude which are consistent across multiple variables but differ between individuals. These data have implications for our understanding of circadian organization and the negative health outcomes associated with shift-work, jet-lag and exposure to artificial light.

Circadian rhythms and clock genes in psychotic disorders.

Numerous lines of evidence suggest that a disordered circadian system contributes to the etiology and symptomatology of major psychiatric disorders. Sleep disturbances, particularly rapid eye movement (REM) sleep, have been observed in bipolar affective disorder (BPD) and schizophrenia. Therapies aimed at altering the timing and duration of sleep and realigning circadian rhythms, including sleep scheduling, wake extension, light therapy and drug therapies that alter sleep and circadian rhythms appear beneficial for affective disorders. Interventional studies aiming to correct sleep and circadian disturbances in schizophrenia are scarce, although exogenous melatonin has been shown to improve both sleep structure and psychotic symptoms. The study of molecular clock mechanisms in psychiatric disorders is also gaining interest. Genetics studies have found associations with CLOCK, PERIOD1, PERIOD3, and TIMELESS in schizophrenia. Most research on BPD has focused on polymorphisms of CLOCK, but the lithium target GSK-3 may also be significant. New research examining the role of circadian rhythms and clock genes in major mental illness is likely to produce rapid advances in circadian-based therapeutics.

Recognizing emotions in faces: effects of acute tryptophan depletion and bright light.

In healthy never-depressed individuals, acute tryptophan depletion (ATD) may selectively decrease the accurate recognition of fearful facial expressions. Here we investigated the perception of facial emotions after ATD in more detail. We also investigated whether bright light, which can reverse ATD's mood-lowering effect, can also reverse its effect on the perception of facial emotions. On two separate test days, spent in a room that was either bright (n = 14) or dim (n = 16), healthy never-depressed women completed a facial emotion perception task six hours after ingesting tryptophan-deficient and balanced amino acid mixtures. Treatments were administered double blind and in randomized order using a crossover design. In dim light ATD decreased recognition accuracy of anger, disgust, and surprise. The labeling of fear and sadness was not affected. In bright light no effects of ATD were seen. Bright light was identified as a potential confounding factor in task performance. The effects of ATD on facial emotion perception may be less emotion-specific than thought previously, and occurred in a direction opposite to what might be expected based on theories of mood-congruent bias.

Bright light exposure during acute tryptophan depletion prevents a lowering of mood in mildly seasonal women.

We investigated the influence of bright light exposure on the mood-lowering effect of acute tryptophan depletion (ATD). Mildly seasonal healthy young women without a personal or family history of psychiatric disorders remained in either dim or bright light during two test days. Tryptophan-deficient and nutritionally balanced amino acid mixtures were administered in counterbalanced order. Mood state was assessed using the Profile of Mood States (POMS) and Visual Analogue Scales (VAS). In dim light, ATD decreased POMS scores across most subscales, indicating a worsening of mood. In bright light, mood was unaffected by ATD. Thus, bright light blocked the worsening of mood caused by ATD. This was also observed on the positive mood VAS. These results indicate a direct, immediate interaction between bright light and serotonin function. Bright light might help protect against ATD-induced mood change by increasing serotonin above the threshold level below which there is a lowering of mood.

A controlled trial of the Litebook light-emitting diode (LED) light therapy device for treatment of Seasonal Affective Disorder (SAD).

BACKGROUND: Recent research has emphasized that the human circadian rhythm system is differentially sensitive to short wavelength light. Light treatment devices using efficient light-emitting diodes (LEDs) whose output is relatively concentrated in short wavelengths may enable a more convenient effective therapy for Seasonal Affective Disorder (SAD). METHODS: The efficacy of a LED light therapy device in the treatment of SAD was tested in a randomized, double-blind, placebo-controlled, multi-center trial. Participants aged 18 to 65 with SAD (DSM-IV major depression with seasonal pattern) were seen at Baseline and Randomization visits separated by 1 week, and after 1, 2, 3 and 4 weeks of treatment. Hamilton Depression Rating Scale scores (SIGH-SAD) were obtained at each visit. Participants with SIGH-SAD of 20 or greater at Baseline and Randomization visits were randomized to active or control treatment: exposure to the Litebook LED treatment device (The Litebook Company Ltd., Alberta, Canada) which delivers 1,350 lux white light (with spectral emission peaks at 464 nm and 564 nm) at a distance of 20 inches or to an inactivated negative ion generator at a distance of 20 inches, for 30 minutes a day upon awakening and prior to 8 A.M. RESULTS: Of the 26 participants randomized, 23 completed the trial. Mean group SIGH-SAD scores did not differ significantly at randomization. At trial end, the proportions of participants in remission (SIGH-SAD less than 9) were significantly greater (Fisher's exact test), and SIGH-SAD scores, as percent individual score at randomization, were significantly lower (t-test), with active treatment than with control, both in an intent-to-treat analysis and an observed cases analysis. A longitudinal repeated measures ANOVA analysis of SIGH-SAD scores also indicated a significant interaction of time and treatment, showing superiority of the Litebook over the placebo condition. CONCLUSION: The results of this pilot study support the hypothesis that light therapy with the Litebook is an effective treatment for SAD. TRIAL REGISTRATION: Clinicaltrials.gov: NCT00139997.

Light treatment and circadian adaptation to shift work.

Work at unconventional hours can have both long and short term consequences. Shift workers are often required to perform their duties at times that are not favoured by the body's endogenous clock, or circadian pacemaker. A typical night shift worker, for example, may report reductions in alertness and performance during shifts, or significant difficulty attaining sleep of recuperative value in the day, all the while being more likely to develop health complications. The study of circadian physiology has significantly contributed to our current ability to aid the shift worker deal with atypical schedules. We discuss the usefulness of light treatment as a countermeasure for maladaptation to atypical work schedules.

Intermittent exposure to bright light in field conditions.

The Interactive Neurobehavioral Model integrates Kronauer's and Jewett's latest mathematical model of the resetting effect of light on the human circadian pacemaker. This model is based on several lines of experimental evidence and considers the endogenous circadian pacemaker as a complex oscillatory system that responds dynamically to the resetting effect of light. This model can help us understand the results of an experiment using intermittent bright light exposure in the workplace environment. Intermittent exposure to bright light was effectively used as part of an intervention to promote circadian re-entrainment of a group of nurses to their permanent night work schedule. Regular exposure to lower light levels and darkness also provided a significant phase delay of endogenous circadian rhythms, although the adaptation was incomplete in this group of workers. These last results are consistent with the intensity-dependent component of the model. The development of better tools to measure retinal exposure to light throughout the 24-h day is required to adequately test modeling predictions under field conditions.

Controlled exposure to light and darkness realigns the salivary cortisol rhythm in night shift workers.

The efficacy of a light/darkness intervention designed to promote circadian adaptation to night shift work was tested in this combined field and laboratory study. Six full-time night shift workers (mean age+/-SD:37.1+/-8.1yrs) were provided an intervention consisting of an intermittent exposure to full-spectrum bright white light (approximately 2000 lux) in the first 6h of their 8 h shift, shielding from morning light by tinted lenses (neutral gray density, 15% visual light transmission), and regular sleep/darkness episodes in darkened quarters beginning 2h after the end of each shift. Five control group workers (41.1+/-9.9 yrs) were observed in the presence of a regular sleep/darkness schedule only. Constant routines (CR) performed before and after a sequence of approximately 12 night shifts over 3 weeks revealed that treatment group workers displayed significant shifts in the time of peak cortisol expression and realignment of the rhythm with the night-oriented schedule. Smaller phase shifts, suggesting an incomplete adaptation to the shift work schedule, were observed in the control group. Our observations support the careful control of the pattern of light and darkness exposure for the adaptation of physiological rhythms to night shift work.