Diane B. Boivin

Circadian Adaptation to Night-Shift Work by Judicious Light and Darkness Exposure:

In this combined field and laboratory investigation, the authors tested the efficacy of an intervention designed to promote circadian adaptation to night-shift work. Fifteen nurses working permanent night schedules ([.greaterequal] 8 shifts/ 15 days) were recruited from area hospitals. Following a vacation period of [.greaterequal] 10 days on a regular daytime schedule, workers were admitted to the laboratory for the assessment of circadian phase via a 36-h constant routine. They returned to work ~ 12 night shifts on their regular schedules under one of two conditions. Treatment group workers (n = 10, mean age ± SD = 41.7 ± 8.8 years) received an intervention including 6 h of intermittent bright-light exposure in the workplace (~ 3243 lux) and shielding from bright morning outdoor light with tinted goggles (15% visual light transmission). Control group workers (n = 9, mean age ± SD = 42.0 ± 7.2 years) were observed in their habitual work environments. On work days, participants maintained regular sleep/wake schedules including a single 8-h sleep/darkness episode beginning 2 h after the end of the night shift. A second 36-h constant routine was performed following the series of night shifts. In the presence of the intervention, circadian rhythms of core body temperature and salivary melatonin cycles were delayed by an average (± SEM) of –9.32 ± 1.06 h and –11.31 ± 1.13 h, respectively. These were significantly greater than the phase delays of –4.09 ± 1.94 h and –5.08 ± 2.32 h displayed by the control group (p = 0.03 and p = 0.02, respectively). The phase angle between circadian markers and the shifted schedule was reestablished to its baseline position only in the treatment group of workers. These results support the efficacy of a practical intervention for promoting circadian adaptation to night-shift work under field conditions. They also underline the importance of controlling the overall pattern of exposure to light and darkness in circadian adaptation to shifted sleep/wake schedules.

A molecular perspective of human circadian rhythm disorders

A large number of physiological variables display 24-h or circadian rhythms. Genes dedicated to the generation and regulation of physiological circadian rhythms have now been identified in several species, including humans. These clock genes are involved in transcriptional regulatory feedback loops. The mutation of these genes in animals leads to abnormal rhythms or even to arrhythmicity in constant conditions. In this view, and given the similarities between the circadian system of humans and rodents, it is expected that mutations of clock genes in humans may give rise to health problems, in particular sleep and mood disorders. Here we first review the present knowledge of molecular mechanisms underlying circadian rhythmicity, and we then revisit human circadian rhythm syndromes in light of the molecular data.

Circadian clock gene expression in brain regions of Alzheimer 's disease patients and control subjects.

Circadian oscillators have been observed throughout the rodent brain. In the human brain, rhythmic expression of clock genes has been reported only in the pineal gland, and little is known about their expression in other regions. The investigators sought to determine whether clock gene expression could be detected and whether it varies as a function of time of day in the bed nucleus of the stria terminalis (BNST) and cingulate cortex, areas known to be involved in decision making and motivated behaviors, as well as in the pineal gland, in the brains of Alzheimer’s disease (AD) patients and aged controls. Relative expression levels of PERIOD1 (PER1 ), PERIOD2 (PER2), and Brain and muscle Arnt-like protein-1 (BMAL1) were detected by quantitative PCR in all 3 brain regions. A harmonic regression model revealed significant 24-h rhythms of PER1 in the BNST of AD subjects. A significant rhythm of PER2 was found in the cingulate cortex and BNST of control subjects and in all 3 regions of AD patients. In controls, BMAL1 did not show a diurnal rhythm in the cingulate cortex but significantly varied with time of death in the pineal and BNST and in all 3 regions for AD patients. Notable differences in the phase of clock gene rhythms and phase relationships between genes and regions were observed in the brains of AD compared to those of controls. These results indicate the presence of multiple circadian oscillators in the human brain and suggest altered synchronization among these oscillators in the brain of AD patients.

Expression of Clock Genes in Human Peripheral Blood Mononuclear Cells throughout the Sleep/Wake and Circadian Cycles

The rhythmic expression of circadian clock genes in the neurons of the suprachiasmatic nucleus (SCN) underlies the manifestation of endogenous circadian rhythmicity in behavior and physiology. Recent evidence demonstrating rhythmic clock gene expression in non‐SCN tissues suggests that functional clocks exist outside the central circadian pacemaker of the brain. In this investigation, the nature of an oscillator in peripheral blood mononuclear cells (PBMCs) is evaluated by assessing clock gene expression throughout both a typical sleep/wake cycle (LD) and during a constant routine (CR). Six healthy men and women aged (mean±SEM) 23.7±1.6 yrs participated in this five‐day investigation in temporal isolation. Core body temperature and plasma melatonin concentration were measured as markers of the central circadian pacemaker. The expression of HPER1, HPER2, and HBMAL1 was quantified in PBMCs sampled throughout an uninterrupted 72 h period. The core body temperature minimum and the midpoint of melatonin concentration measured during the CR occurred 2:17±0:20 and 3:24 ±0:09 h before habitual awakening, respectively, and were well aligned to the sleep/wake cycle. HPER1 and HPER2 expression in PBMCs demonstrated significant circadian rhythmicity that peaked early after wake‐time and was comparable under LD and CR conditions. HBMAL1 expression was more variable, and peaked in the middle of the wake period under LD conditions and during the habitual sleep period under CR conditions. For the first time, bi‐hourly sampling over three consecutive days is used to compare clock gene expression in a human peripheral oscillator under different sleep/wake conditions.

Sleep, Hormones, and Circadian Rhythms throughout the Menstrual Cycle in Healthy Women and Women with Premenstrual Dysphoric Disorder

A relationship exists between the sleep-wake cycle and hormone secretion, which, in women, is further modulated by the menstrual cycle. This interaction can influence sleep across the menstrual cycle in healthy women and in women with premenstrual dysphoric disorder (PMDD), who experience specific alterations of circadian rhythms during their symptomatic luteal phase along with sleep disturbances during this time. This review will address the variation of sleep at different menstrual phases in healthy and PMDD women, as well as changes in circadian rhythms, with an emphasis on their relationship with female sex hormones. It will conclude with a brief discussion on nonpharmacological treatments of PMDD which use chronotherapeutic methods to realign circadian rhythms as a means of improving sleep and mood in these women.

Glucocorticoids entrain molecular clock components in human peripheral cells

In humans, shift work induces a desynchronization between the circadian system and the outside world, which contributes to shift work‐associated medical disorders. Using a simulated night shift experiment, we previously showed that 3 d of bright light at night fully synchronize the central clock to the inverted sleep schedule, whereas the peripheral clocks located in peripheral blood mononuclear cells (PBMCs) took longer to reset. This underlines the need for testing the effects of synchronizers on both the central and peripheral clocks. Glucocorticoids display circadian rhythms controlled by the central clock and are thought to act as synchronizers of rodent peripheral clocks. In the present study, we tested whether the human central and peripheral clocks were sensitive to exogenous glucocorticoids (Cortef) administered in the late afternoon. We showed that 20 mg Cortef taken orally acutely increased PER1 expression in PBMC peripheral clocks. After 6 d of Cortef administration, the phases of central markers were not affected, whereas those of PER2‐3 and BMAL1 expression in PBMCs were shifted by ~9.5‐11.5 h. These results demonstrate, for the first time, that human peripheral clocks are entrained by glucocorticoids. Importantly, they suggest innovative interventions for shift workers and jet‐lag travelers, combining synchronizing agents for the central and peripheral clocks.—Cuesta, M., Cermakian, N., Boivin, D. B. Glucocorticoids entrain molecular clock components in human peripheral cells. FASEB J. 29, 1360‐1370 (2015). www.fasebj.org

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

BackgroundRecent 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).MethodsThe 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.ResultsOf 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 (Fishers 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.ConclusionThe results of this pilot study support the hypothesis that light therapy with the Litebook is an effective treatment for SAD.Trial registrationClinicaltrials.gov: NCT00139997

Phase-Dependent Effect of Room Light Exposure in a 5-h Advance of the Sleep-Wake Cycle: Implications for Jet Lag:

The acute disruption in sleep quality, vigilance levels, and cognitive and athletic performance observed after transmeridian flights is presumed to be the result of a transient misalignment between the endogenous circadian pacemaker and the shifted sleep schedule. Several laboratory and field experiments have demonstrated that exposure to bright artificial light can accelerate circadian entrainment to a shifted sleep-wake schedule. In the present study, the authors investigated whether the schedule of exposure to indoor room light, to which urban dwellers are typically exposed, can substantially affect circadian adaptation to a simulated eastward voyage. We enrolled 15 healthy young men in a laboratory simulation of a Montreal-to-London voyage. Subjects were exposed to 6 h of room light (mean ± SD: 379 ± 10) prior to bedtime (n = 7) or when on a progressively advancing schedule (n = 8) early in the day. The remaining 10 hours of wakefulness were spent in dim light (4 ± 1 lux). Circadian assessments, performed via the constant routine procedure, evaluated the phase of the endogenous circadian rhythms of core body temperature and plasma melatonin before and after 1 week on the shifted schedule. At the end of the study, only subjects exposed to room light on the advancing schedule expressed oscillations of the endogenous circadian pacemaker in phase with the new sleep-wake cycle. In this group, a mean advance shift of the nadir of core body temperature of +5:22 ± 0:15 h was observed, with parallel shifts in plasma melatonin concentration and subjective alertness. The circadian rhythms of subjects exposed to room light later in the day remained much more adjusted to the departure than to the destination time zone. These results demonstrate that the schedule of exposure to room light can substantially affect circadian adaptation to a shifted sleep-wake schedule.

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 ± 8.1 yrs) were provided an intervention consisting of an intermittent exposure to full-spectrum bright white light (∼2000 lux) in the first 6 h 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 2 h 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 ∼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.

Circadian Variation of Heart Rate Variability Across Sleep Stages

STUDY OBJECTIVES Nocturnal cardiovascular events are more frequent at the beginning and end of the night. It was proposed that this pattern reflects the nocturnal distribution of sleep and sleep stages. Using heart rate variability (HRV), we recently showed an interaction between the circadian system and vigilance states on the regulation of cardiac rhythmicity. Here, we further investigate this interaction in order to clarify the specific effects of sleep stages on the regulation of the heart. DESIGN Participants underwent a 72-h ultradian sleep-wake cycle procedure in time isolation consisting of alternating 60-min wake episodes in dim light and 60-min nap opportunities in total darkness. SETTING Time isolation suite. PATIENTS OR PARTICIPANTS Fifteen healthy young participants; two were subsequently excluded. INTERVENTIONS N/A. MEASUREMENTS AND RESULTS The current study revealed that sleep onset and progression to deeper sleep stages was associated with a shift toward greater parasympathetic modulation, whereas rapid eye movement (REM) sleep was associated with a shift toward greater sympathetic modulation. We found a circadian rhythm of heart rate (HR) and high-frequency power during wakefulness and all non-REM sleep stages. A significant circadian rhythm of HR and sympathovagal balance of the heart was also observed during REM sleep. During slow wave sleep, maximal parasympathetic modulation was observed at ∼02:00, whereas during REM sleep, maximal sympathetic modulation occurred in the early morning. CONCLUSION The circadian and sleep stage-specific effects on heart rate variability are clinically relevant and contribute to the understanding of the degree of cardiovascular vulnerability during sleep.