Philippe Boudreau

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.

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.

A Circadian Rhythm in Heart Rate Variability Contributes to the Increased Cardiac Sympathovagal Response to Awakening in the Morning

Morning hours are associated with a heightened risk of adverse cardiovascular events. Recent evidence suggests that the sleep-wake cycle and endogenous circadian system modulate cardiac function in humans and may contribute to these epidemiological findings. The aim of the present study was to investigate the interaction between circadian and sleep-wake–dependent processes on heart rate variability (HRV). Fifteen diurnally active healthy young adults underwent a 72-h ultradian sleep-wake cycle (USW) procedure (alternating 60-min wake episodes in dim light and 60-min nap opportunities in total darkness) in time isolation. The present study revealed a significant main effect of sleep-wake–dependent and circadian processes on cardiac rhythmicity, as well as a significant interaction between these processes. Turning the lights off was associated with a rapid increase in mean RR interval and cardiac parasympathetic modulation (high-frequency [HF] power), whereas low-frequency (LF) power and sympathovagal balance (LF:HF ratio) were reduced (p ≤ .001). A significant circadian rhythm in mean RR interval and HRV components was observed throughout the wake and nap episodes (p ≤ .001). Sleep-to-wake transitions occurring in the morning were associated with maximal shifts towards sympathetic autonomic activation as compared to those occurring during the rest of the day. Namely, peak LF:HF ratio was observed in the morning, coincidental with peak salivary cortisol levels. These results contribute to our understanding of the observed increase in cardiovascular vulnerability after awakening in the morning. (Author correspondence: diane.boivin@douglas.mcgill.ca)

Circadian Adaptation to Night Shift Work Influences Sleep, Performance, Mood and the Autonomic Modulation of the Heart

Our aim was to investigate how circadian adaptation to night shift work affects psychomotor performance, sleep, subjective alertness and mood, melatonin levels, and heart rate variability (HRV). Fifteen healthy police officers on patrol working rotating shifts participated to a bright light intervention study with 2 participants studied under two conditions. The participants entered the laboratory for 48 h before and after a series of 7 consecutive night shifts in the field. The nighttime and daytime sleep periods were scheduled during the first and second laboratory visit, respectively. The subjects were considered “adapted” to night shifts if their peak salivary melatonin occurred during their daytime sleep period during the second visit. The sleep duration and quality were comparable between laboratory visits in the adapted group, whereas they were reduced during visit 2 in the non-adapted group. Reaction speed was higher at the end of the waking period during the second laboratory visit in the adapted compared to the non-adapted group. Sleep onset latency (SOL) and subjective mood levels were significantly reduced and the LF∶HF ratio during daytime sleep was significantly increased in the non-adapted group compared to the adapted group. Circadian adaptation to night shift work led to better performance, alertness and mood levels, longer daytime sleep, and lower sympathetic dominance during daytime sleep. These results suggest that the degree of circadian adaptation to night shift work is associated to different health indices. Longitudinal studies are required to investigate long-term clinical implications of circadian misalignment to atypical work schedules.

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. (Author correspondence: diane.boivin@douglas.mcgill.ca)

Photic Resetting in Night-Shift Work: Impact on Nurses' Sleep

The objective of this study was to quantify daytime sleep in night-shift workers with and without an intervention designed to recover the normal relationship between the endogenous circadian pacemaker and the sleep/wake cycle. Workers of the treatment group received intermittent exposure to full-spectrum bright light during night shifts and wore dark goggles during the morning commute home. All workers maintained stable 8-h daytime sleep/darkness schedules. The authors found that workers of the treatment group had daytime sleep episodes that lasted 7.1 ± .1 h (mean ± SEM) versus 6.6 ± .2 h for workers in the control group (p = .04). The increase in total sleep time co-occurred with a larger proportion of the melatonin secretory episode during daytime sleep in workers of the treatment group. The results of this study showed reestablishment of a phase angle that is comparable to that observed on a day-oriented schedule favors longer daytime sleep episodes in night-shift workers. (Author correspondence: diane.boivin@douglas.mcgill.ca)

Simulated Night Shift Disrupts Circadian Rhythms of Immune Functions in Humans

Recent research unveiled a circadian regulation of the immune system in rodents, yet little is known about rhythms of immune functions in humans and how they are affected by circadian disruption. In this study, we assessed rhythms of cytokine secretion by immune cells and tested their response to simulated night shifts. PBMCs were collected from nine participants kept in constant posture over 24 h under a day-oriented schedule (baseline) and after 3 d under a night-oriented schedule. Monocytes and T lymphocytes were stimulated with LPS and PHA, respectively. At baseline, a bimodal rhythmic secretion was detected for IL-1β, IL-6, and TNF-α: a night peak was primarily due to a higher responsiveness of monocytes, and a day peak was partly due to a higher proportion of monocytes. A rhythmic release was also observed for IL-2 and IFN-γ, with a nighttime peak due to a higher cell count and responsiveness of T lymphocytes. Following night shifts, with the exception of IL-2, cytokine secretion was still rhythmic but with peak levels phase advanced by 4.5–6 h, whereas the rhythm in monocyte and T lymphocyte numbers was not shifted. This suggests distinct mechanisms of regulation between responsiveness to stimuli and cell numbers of the human immune system. Under a night-oriented schedule, only cytokine release was partly shifted in response to the change in the sleep–wake cycle. This led to a desynchronization of rhythmic immune parameters, which might contribute to the increased risk for infection, autoimmune diseases, cardiovascular and metabolic disorders, and cancer reported in shift workers.

Correlation of heart rate variability and circadian markers in humans

The frequency of adverse cardiovascular events is greater in the morning compared to its 24-hour average. A circadian variation in the regulation of the cardiovascular system could contribute to this increased cardiovascular risk in the morning. Indeed, circadian rhythms have been shown for a wide array of physiological processes. Using an ultradian sleep-wake cycle (USW) procedure, we sought to determine how heart rate (HR) and heart rate variability (HRV) correlate with the well-characterized circadian rhythms of cortisol and melatonin secretion. Specific HRV components, namely the low frequency (LF) power, high frequency (HF) power, and the LF:HF ratio can be used as markers of the autonomic modulation of the heart. Cross-correlation between HRV parameters and hormonal rhythms demonstrated that mean RR interval is significantly phase-advanced relative to salivary cortisol and urinary 6-sulfatoxy-melatonin (UaMt6s). Parasympathetic modulation of the heart (HF power) was phase-advanced relative to cortisol, but was in-phase with UaMt6s levels. Maximal correlation of the sympathovagal balance (the LF:HF ratio) had no significant lag compared to cortisol secretion and UaMt6s excretion. The protective effect of the parasympathetic nervous system at night, combined with the putative risk associated with the sympathetic nervous system peaking in the morning, could be associated with the increased cardiovascular risk observed in the morning hours.

Predominance of Distal Skin Temperature Changes at Sleep Onset across Menstrual and Circadian Phases

Menstrual cycle—associated changes in reproductive hormones affect body temperature in women. We aimed to characterize the interaction between the menstrual, circadian, and scheduled sleep-wake cycles on body temperature regulation. Eight females entered the laboratory during the midfollicular (MF) and midluteal (ML) phases of their menstrual cycle for an ultradian sleep-wake cycle procedure, consisting of 36 cycles of 60-minute wake episodes alternating with 60-minute nap opportunities, in constant bed-rest conditions. Core body temperature (CBT) and distal skin temperature (DT) were recorded and used to calculate a distal-core gradient (DCG). Melatonin, sleep, and subjective sleepiness were also recorded. The circadian variation of DT and DCG was not affected by menstrual phase. DT and DCG showed rapid, large nap episode—dependent increases, whereas CBT showed slower, smaller nap episode—dependent decreases. DCG values were significantly reduced for most of the wake episode in an overall 60-minute wake/60-minute nap cycle during ML compared to MF, but these differences were eliminated at the wake-to-nap lights-out transition. Nap episode—dependent decreases in CBT were further modulated as a function of both circadian and menstrual factors, with nap episode—dependent deceases occurring more prominently during the late afternoon/evening in ML, whereas nap episode—dependent DT and DCG increases were not significantly affected by menstrual phase but only circadian phase. Circadian rhythms of melatonin secretion, DT, and DCG were significantly phase-advanced relative to CBT and sleep propensity rhythms. This study explored how the thermoregulatory system is influenced by an interaction between circadian phase and vigilance state and how this is further modulated by the menstrual cycle. Current results agree with the thermophysiological cascade model of sleep and indicate that despite increased CBT during ML, heat loss mechanisms are maintained at a similar level during nap episodes, which may allow for comparable circadian sleep propensity rhythms between menstrual phases.

Diurnal and circadian variation of sleep and alertness in men vs. naturally cycling women

Significance This study quantifies sex differences in the diurnal and circadian variation of sleep and waking while carefully controlling for menstrual cycle phase and hormonal contraceptive use. Compared to men, rhythms of core body temperature, sleep, and subjective alertness are advanced in women during both the midfollicular and midluteal phases. Our study also reveals lower alertness levels at night in women. These sex differences are important for understanding the increased female susceptibility to sleep and wake disturbances. This study quantifies sex differences in the diurnal and circadian variation of sleep and waking while controlling for menstrual cycle phase and hormonal contraceptive use. We compared the diurnal and circadian variation of sleep and alertness of 8 women studied during two phases of the menstrual cycle and 3 women studied during their midfollicular phase with that of 15 men. Participants underwent an ultradian sleep–wake cycle (USW) procedure consisting of 36 cycles of 60-min wake episodes alternating with 60-min nap opportunities. Core body temperature (CBT), salivary melatonin, subjective alertness, and polysomnographically recorded sleep were measured throughout this procedure. All analyzed measures showed a significant diurnal and circadian variation throughout the USW procedure. Compared with men, women demonstrated a significant phase advance of the CBT but not melatonin rhythms, as well as an advance in the diurnal and circadian variation of sleep measures and subjective alertness. Furthermore, women experienced an increased amplitude of the diurnal and circadian variation of alertness, mainly due to a larger decline in the nocturnal nadir. Our results indicate that women are likely initiating sleep at a later circadian phase than men, which may be one factor contributing to the increased susceptibility to sleep disturbances reported in women. Lower nighttime alertness is also observed, suggesting a physiological basis for a greater susceptibility to maladaptation to night shift work in women.