Christian Cajochen

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.

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.

EEG and ocular correlates of circadian melatonin phase and human performance decrements during sleep loss.

The aim of this study was to quantify the associations between slow eye movements (SEMs), eye blink rate, waking electroencephalogram (EEG) power density, neurobehavioral performance, and the circadian rhythm of plasma melatonin in a cohort of 10 healthy men during up to 32 h of sustained wakefulness. The time course of neurobehavioral performance was characterized by fairly stable levels throughout the first 16 h of wakefulness followed by deterioration during the phase of melatonin secretion. This deterioration was closely associated with an increase in SEMs. Frontal low-frequency EEG activity (1-7 Hz) exhibited a prominent increase with time awake and little circadian modulation. EEG alpha activity exhibited circadian modulation. The dynamics of SEMs and EEG activity were phase locked to changes in neurobehavioral performance and lagged the plasma melatonin rhythm. The data indicate that frontal areas of the brain are more susceptible to sleep loss than occipital areas. Frontal EEG activity and ocular parameters may be used to monitor and predict changes in neurobehavioral performance associated with sleep loss and circadian misalignment.

Melatonin and the circadian regulation of sleep initiation, consolidation, structure, and the sleep EEG.

The endogenous circadian rhythm of melatonin, driven by the suprachiasmatic nucleus, exhibits a close association with the endogenous circadian component of the sleep propensity rhythm and the endogenous circadian component of the variation in electroencephalogram (EEG) oscillations such as sleep spindles and slow waves. This association is maintained even when the sleep-wake cycle is desynchronized from the endogenous circadian rhythm of melatonin. Administration of melatonin during the day increases daytime sleep propensity as indexed by both the latency to sleep onset and sleep consolidation. The EEG during daytime sleep after melatonin administration exhibits characteristics reminiscent of the nocturnal sleep EEG, that is, increased sleep spindle activity and reduced slow-wave sleep and slow-wave activity as detected by quantitative EEG analysis. Administration of higher doses of melatonin (5 mg or more) prior to nocturnal sleep results in an increase in rapid eye movement (REM) sleep. These data demonstrate that melatonin exerts effects on the main characteristics of human sleep, that is, latency to sleep onset, sleep consolidation, slow waves, sleep spindles, an M sleep. There is a need for further studies using physioloRical doses and delivery systems that generate physiological plasma melatonin profiles to firmly establish the role of the endogenous circadian rhythm of melatonin in the circadian regulation of sleep.

Effect of a single 3-hour exposure to bright light on core body temperature and sleep in humans.

Seven human subjects were exposed to bright light (BL, approx. 2500 lux) and dim light (DL, approx. 6 lux) during 3 h prior to nocturnal sleep, in a cross-over design. At the end of the BL exposure period core body temperature was significantly higher than at the end of the DL exposure period. The difference in core body temperature persisted during the first 4 h of sleep. The latency to sleep onset was increased after BL exposure. Rapid-eye movement sleep (REMS) and slow-wave sleep (SWS; stage 3 + 4 of non-REMS) were not significantly changed. Eight subjects were exposed to BL from 20.30 to 23.30 h while their eyes were covered or uncovered. During BL exposure with uncovered eyes, core body temperature decreased significantly less than during exposure with covered eyes. We conclude that bright light immediately affects core body temperature and that this effect is mediated via the eyes.

EEG and subjective sleepiness during extended wakefulness in seasonal affective disorder: circadian and homeostatic influences

BACKGROUND Seasonal affective disorder (SAD) may reflect a disturbance of circadian phase relationships or a disturbance of sleep-wake dependent processes, both of which change daytime energy and sleepiness levels. METHODS Under the unmasking conditions of a 40-hour constant routine protocol (CR), self-rated sleepiness and waking electroencephalogram (EEG) power density were assessed in women with SAD (n = 8) and in age-matched healthy control subjects (n = 9). RESULTS There was no significant effect of season or light treatment in any of the measures. The time course of subjective sleepiness was characterized by a circadian modulation and an overall increase during extended wakefulness in both SAD patients and control subjects. A prominent circadian rhythm of subjective sleepiness was not different in SAD patients and control subjects; however, the progressive buildup of sleepiness, as quantified by nonlinear regression analysis, was significantly reduced in SAD patients, mainly because they were sleepier than control subjects during the first 12 hours of the CR. The time course of waking EEG theta-alpha activity showed a more rapid increase during the first 10 hours of the CR in SAD patients. In contrast to control subjects who showed a progressive increase in the course of the 40-hour episode of extended wakefulness, EEG theta-alpha activity in SAD patients did not further increase over the remainder of the CR. CONCLUSIONS The data suggest that SAD patients may have a trait (rather than state) deficiency in the homeostatic buildup of sleep pressure during extended wakefulness as indexed by subjective sleepiness and EEG theta-alpha activity.

Heart rate dynamics during human sleep

To investigate the dynamics of heart rate in the course of sleep and to relate cardiac activity to sleep intensity, the electrocardiogram was recorded concomitantly with the polysomnogram in healthy young males. Heart rate was assessed across consecutive non-REM sleep (NREMS)-REM sleep (REMS) cycles as well as within individual episodes of NREMS and REMS. Within a sleep cycle, heart rate was lower in the NREMS episode than in the subsequent REMS episode. A global declining trend was present over successive NREMS episodes and over successive REMS episodes. A rapid increase of heart rate at the NREMS-REMS transitions was followed by a slow decline that started within the REMS episodes. Heart rate variability was higher in REMS than in NREMS and showed an increasing trend over successive REMS episodes but not over successive NREMS episodes. EEG slow-wave activity (spectral power density in the 0.75-4.5 Hz band), an intensity measure of NREMS, declined across NREMS episodes and was not correlated with heart rate. The global trends and ultradian variations of heart rate may represent sleep state-dependent modulations and circadian variations of the autonomic nervous system, which are not fully reflected in the sleep EEG.

Human circadian melatonin rhythm phase delay during a fixed sleep–wake schedule interspersed with nights of sleep deprivation

Abstract:  The human circadian pacemaker, with an intrinsic period between 23.9 and 24.5 hr, can be reset by low levels of light. Biomathematical models of the human clock predict that light–dark cycles consisting of only ∼3.5 lux during 16 hr of wakefulness and 0 lux during 8 hr of sleep should entrain ∼45% of the population. However, under real‐life conditions, sleep–wake schedules and the associated light–dark exposures are often irregular. It remains unclear whether the phase of the pacemaker would remain stable under such conditions. We investigated the stability of the circadian phase in dim light by assessing the plasma melatonin rhythm during nine consecutive circadian cycles. Ten subjects were scheduled to sleep for 8 hr (0.03 lux) and to be awake for 16 hr (5–13 lux) during all days except on days 4 and 8, during which the subjects were sleep deprived for 40 hr (5–13 lux), either in a sitting/standing or supine body posture. In all subjects, the phase of the melatonin rhythm occurred at a later clock time on day 9 than on day 2 (average delay: 1.4 hr). Largest delays in the melatonin onset were observed in subjects with low amplitude melatonin rhythms. The area under the curve during active melatonin secretion was significantly reduced when subjects were sleep deprived in the 40‐hr supine body posture condition compared with either the 40‐hr sitting/standing sleep deprivation (SD) or the ambulatory condition under non‐SD conditions. Posture differences did not significantly affect the relative phase position of the melatonin profiles. The data indicate that under conditions of reduced zeitgeber strength, the phase of the human circadian pacemaker, using plasma melatonin as a marker, can be phase delayed by one night of SD and the associated dim light exposure.

Sleep in a sitting position: effect of triazolam on sleep stages and EEG power spectra

The effect of triazolam (0.25 mg) and placebo was investigated in healthy, male subjects who slept in a sitting position. After the intake of placebo, sleep efficiency, rapid eye movement (REM) sleep and subjective sleep quality were lower than in the preceding sleep episode in bed, while stage 1 and REM sleep latency were higher. Triazolam did not prevent this impairment of sleep. However, in comparison with the placebo condition, the percentage of slow wave sleep was higher in the first third of the night, and in the morning sleep was rated as more quite. EEG power density in nonREM sleep was reduced in the frequency range of 1.25–10.0 Hz and enhanced in the range of sleep spindles (12.25–13.0 Hz). These changes were still present in the last third of the night. In REM sleep, triazolam reduced spectral activity in some frequency bins between 4.25 and 10.0 Hz. The sitting position itself affected the nonREM sleep spectra, since the placebo level in the 2.25–21.0-Hz range exceeded the baseline level. We conclude that a 0.25 mg dose of triazolam does not effectively counteract a posture-induced sleep disturbance, but induces changes in the EEG spectra which are typical for benzodiazepine receptor agonists.