The Light-Dosimeter: A new device to help advance research on the non-visual responses to light.

This article describes the development of a device to investigate the non-visual responses to light: The Light-Dosimeter (lido). Its multidisciplinary team followed a user-centred approach throughout the project, that is, their design decisions focused on researchers' and participants' needs. Together with custom-made mountings and the software Lido Studio, the lidos provide researchers with a holistic solution to record participants' light exposure in the near-corneal plane in laboratory settings and under real-world conditions. Validation measurements with commercial equipment were deemed satisfying, as was the combining with data from other devices. The handling of the lidos and mountings and the use of the software Lido Studio during the trial period by various researchers and participants were successful. Despite some limitations, the lidos can help advance research on the non-visual responses to light over the coming years.

Dose-response relationship between light exposure and cycling performance.

Light has a stimulating effect on physical performance if scheduled according to the chronotype, but dose-dependent effects on performance have not yet been examined. Three groups of healthy men (25.1 ± 3.1 years) were exposed to light for different durations in a parallel group design before a 40-min time-trial. In each group, subjects were exposed to either bright light (BL, 4420 lx) or moderate light (ML, 230 lx) in a randomized order in a crossover design. The durations of light exposure were 120 min prior to and during exercise (2HEX; n = 16), 60 min prior to and during exercise (1HEX; n = 10), or only for 60 min prior to exercise (1H; n = 15). Total work performed during the time-trial in kJ in the 2HEX group was significantly higher in the BL setting (527 kJ) than in ML (512 kJ) (P = 0.002), but not in 1HEX (BL: 485 kJ; ML: 498 kJ) or 1H (BL: 519 kJ; ML: 514 kJ) (P = 0.770; P = 0.485). There was a significant (P = 0.006) positive dose-response relationship between the duration of light exposure and the work performed over the three doses of light exposure. A long duration light exposure is an effective tool to increase total work in a medium length time-trial in subjects normalized for their individual chronotype.

Neurology and psychiatry: waking up to opportunities of sleep. : State of the art and clinical/research priorities for the next decade.

In recent years, evidence has emerged for a bidirectional relationship between sleep and neurological and psychiatric disorders. First, sleep-wake disorders (SWDs) are very common and may be the first/main manifestation of underlying neurological and psychiatric disorders. Secondly, SWDs may represent an independent risk factor for neuropsychiatric morbidities. Thirdly, sleep-wake function (SWF) may influence the course and outcome of neurological and psychiatric disorders. This review summarizes the most important research and clinical findings in the fields of neuropsychiatric sleep and circadian research and medicine, and discusses the promise they bear for the next decade. The findings herein summarize discussions conducted in a workshop with 26 European experts in these fields, and formulate specific future priorities for clinical practice and translational research. More generally, the conclusion emerging from this workshop is the recognition of a tremendous opportunity offered by our knowledge of SWF and SWDs that has unfortunately not yet entered as an important key factor in clinical practice, particularly in Europe. Strengthening pre-graduate and postgraduate teaching, creating academic multidisciplinary sleep-wake centres and simplifying diagnostic approaches of SWDs coupled with targeted treatment strategies yield enormous clinical benefits for these diseases.

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, and REM sleep. There is a need for further studies using physiological 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.

The acute soporific action of daytime melatonin administration: effects on the EEG during wakefulness and subjective alertness.

Melatonin has been reported to have soporific effects; following daytime administration, it induces sleepiness and reduces sleep onset latency. However, subjective sleepiness is masked by a variety of stimuli and behaviors; thus, it is important to be able to delineate objective psychophysiological sequelae of melatonin administration. Alertness decrements during wakefulness are correlated with augmented theta/alpha power in the waking electroencephalogram (EEG). This has been validated in a constant routine protocol. In a variety of experiments with melatonin administration (5 mg), the authors have shown that the EEG changes can be measured immediately, before any subjective soporific effects are recognized. These increases in theta/alpha power occur when melatonin is administered during the day (1300 or 1800 h) but are less visible when near the endogenous melatonin rise in the evening (2040 h). Importantly, both subjective and objective measures of sleepiness are suppressed when subjects change posture from supine to standing.

A rapid-cycling bipolar patient treated with long nights, bedrest, and light.

BACKGROUND: Stabilization of rapid-cycling bipolar disorder is extremely difficult. METHODS: A refractory bipolar I rapid-cycling patient on valproate was treated with long "nights" (extended sleep in darkness) and daytime light therapy. RESULTS: Rapid cycling immediately stopped on initiation of a 10 hour dark/rest period. This was extended to 14 hours (plus a self-selected 1 hour midday nap) without problems. Depression gradually improved when midday light therapy was added; near-euthymia was attained after light therapy was shifted to the morning. CONCLUSIONS: Nonpharmacological chronobiological treatments may be a means to interrupt rapid cycling.

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.

Separation of circadian and wake duration-dependent modulation of EEG activation during wakefulness.

The separate contribution of circadian rhythmicity and elapsed time awake on electroencephalographic (EEG) activity during wakefulness was assessed. Seven men lived in an environmental scheduling facility for 4 weeks and completed fourteen 42.85-h 'days', each consisting of an extended (28.57-h) wake episode and a 14.28-h sleep opportunity. The circadian rhythm of plasma melatonin desynchronized from the 42.85-h day. This allowed quantification of the separate contribution of circadian phase and elapsed time awake to variation in EEG power spectra (1-32 Hz). EEG activity during standardized behavioral conditions was markedly affected by both circadian phase and elapsed time awake in an EEG frequency- and derivation-specific manner. The nadir of the circadian rhythm in alpha (8-12 Hz) activity in both fronto-central and occipito-parietal derivations occurred during the biological night, close to the crest of the melatonin rhythm. The nadir of the circadian rhythm of theta (4.5-8 Hz) and beta (20-32 Hz) activity in the fronto-central derivation was located close to the onset of melatonin secretion, i.e. during the wake maintenance zone. As time awake progressed, delta frequency (1-4.5 Hz) and beta (20-32 Hz) activity rose monotonically in frontal derivations. The interaction between the circadian and wake-dependent increase in frontal delta was such that the intrusion of delta was minimal when sustained wakefulness coincided with the biological day, but pronounced during the biological night. Our data imply that the circadian pacemaker facilitates frontal EEG activation during the wake maintenance zone, by generating an arousal signal that prevents the intrusion of low-frequency EEG components, the propensity for which increases progressively during wakefulness.

Dynamics of EEG slow-wave activity and core body temperature in human sleep after exposure to bright light.

In seven subjects sleep was recorded after a single 3-hour (2100-0000 hours) exposure to either bright light (BL, approx. 2,500 lux) or dim light (DL, approx. 6 lux) in a crossover design. The latency to sleep onset was increased after BL. Whereas rectal temperature before onset and during the first 4 hours of sleep was higher after BL than after DL, the time course of electroencephalographic (EEG) slow-wave activity (SWA, EEG power density in the range of 0.75-4.5 Hz) in nonrapid eye movement sleep (NREMS) differed only slightly between the conditions. After BL, SWA tended to be lower than after DL in the first NREMS-REMS cycle and was higher in the fourth cycle at the time when the rectal temperature did not differ. The differences in SWA may have been due to a minor sleep-disturbing aftereffect of BL, which was followed by a rebound. The data are not in support of a close relationship between SWA and core body temperature.

Sleep extension in humans: sleep stages, EEG power spectra and body temperature.

In eight male subjects the electroencephalogram (EEG) and core body temperature (Tcore) were recorded during long sleep episodes from 0000 to 1,500 hr. EEGs were visually scored and subjected to spectral analysis by fast Fourier transform. Slow-wave sleep [SWS, i.e. stages 3 + 4 of non-rapid eye movement (NREM) sleep and slow wave activity (SWA, mean EEG power density in the range of 0.75-4.5 Hz)] in NREM sleep attained highest values in the first 3 hr of sleep and lowest values in the morning hours when rapid eye movement (REM) sleep was at its maximum. Wakefulness was significantly enhanced in the last 3 hr of the recording period. Occasional NREM episodes containing SWS were observed in the late morning and early afternoon. However, no significant increase in SWS or SWA in the last 3 hr of the sleep episode over any of the preceding 3-hr intervals was present and SWA in this interval was significantly below the values observed at the beginning of sleep. The duration of NREM episodes varied significantly over the sleep episode. Analysis of the dynamics of SWA within NREM episodes revealed that SWA gradually rose during the episode. Consequently, SWA averaged per episode was positively correlated with episode duration. Tcore dropped in the initial part of sleep, rose during the morning hours and reached values in the afternoon that were higher than at the beginning of sleep. Thus the time course of Tcore dissociated from the time course of SWA. This indicates that SWA in NREM sleep is not directly related to the variation in core body temperature.

Power density in theta/alpha frequencies of the waking EEG progressively increases during sustained wakefulness.

Electroencephalogram (EEG) power density and self-rated fatigue were assessed in nine healthy women during a 40-hour period of sustained wakefulness under constant behavioral and environmental conditions (constant routine protocol). Waking EEG recordings were performed for 4 minutes after 3, 10, 27 and 34 hours of prior wakefulness. EEG power density in the 6.25- to 9.0-Hz frequency range progressively increased across the four recordings, suggesting an endogenous homeostatic component in the regulation of the theta/alpha frequencies under constant conditions. Subjective fatigue also exhibited an increasing component in the course of the constant routine protocol, with a clear circadian modulation. Fatigue ratings and the theta/ alpha power density of the waking EEG recorded at the same four time points during the constant routine protocol correlated significantly. Our data demonstrate the presence of a homeostatic component in the control of EEG power density in the 6.25- to 9.0-Hz range.

Role of melatonin in the regulation of human circadian rhythms and sleep.

The circadian rhythm of pineal melatonin is the best marker of internal time under low ambient light levels. The endogenous melatonin rhythm exhibits a close association with the endogenous circadian component of the sleep propensity rhythm. This has led to the idea that melatonin is an internal sleep "facilitator" in humans, and therefore useful in the treatment of insomnia and the readjustment of circadian rhythms. There is evidence that administration of melatonin is able: (i) to induce sleep when the homeostatic drive to sleep is insufficient; (ii) to inhibit the drive for wakefulness emanating from the circadian pacemaker; and (iii) induce phase shifts in the circadian clock such that the circadian phase of increased sleep propensity occurs at a new, desired time. Therefore, exogenous melatonin can act as soporific agent, a chronohypnotic, and/or a chronobiotic. We describe the role of melatonin in the regulation of sleep, and the use of exogenous melatonin to treat sleep or circadian rhythm disorders.

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.

Dynamics of frontal EEG activity, sleepiness and body temperature under high and low sleep pressure.

The impact of sleep deprivation (high sleep pressure) vs sleep satiation (low sleep pressure) on waking EEG dynamics, subjective sleepiness and core body temperature (CBT) was investigated in 10 young volunteers in a 40 h controlled constant posture protocol. The differential sleep pressure induced frequency-specific changes in the waking EEG from 1-7 Hz and 21-25 Hz. Frontal low EEG activity (FLA, 1-7 Hz) during sleep deprivation exhibited a prominent increase as time awake progressed, which could be significantly attenuated by sleep satiation attained with intermittent naps. Subjective sleepiness exhibited a prominent circadian regulation during sleep satiation, with virtually no homeostatic modulation. These extremely different sleep pressure conditions were not reflected in significant changes of the CBT rhythm. The data demonstrate that changes in FLA during wakefulness are to a large extent determined by the sleep-wake dependent process with little circadian modulation, and reflect differential levels of sleep pressure in the awake subject.

A relationship between heat loss and sleepiness: effects of postural change and melatonin administration.

Both the pineal hormone melatonin (Mel) and postural changes have thermoregulatory sequelae. The purpose of the study was to evaluate their relationship to subjective sleepiness. Eight healthy young men were investigated under the unmasking conditions of a constant routine protocol. Heart rate, rectal temperature (Tre), skin temperatures (foot, Tfo; and stomach), and subjective sleepiness ratings were continuously recorded from 1000 to 1700. Mel (5 mg po) was administered at 1300, a time when Mel should not phase shift the circadian system. Both the postural change at 1000 from upright to a supine position (lying down in bed) and Mel administration at 1300 reduced Tre and increased Tfo in parallel with increased sleepiness. These findings suggest that under comfortable ambient temperature conditions, heat loss via the distal skin regions (e.g., feet) is a key mechanism for induction of sleepiness as core body temperature declines.

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.

Early morning melatonin administration impairs psychomotor vigilance.

The acute soporific effect of melatonin in humans has been demonstrated in a range of studies. How alertness and performance are changed after melatonin given in the morning is not yet known. In a double-blind, placebo-controlled study of nine healthy young men, melatonin was given at 0700 h under controlled conditions of a modified constant routine protocol lasting 56 h (2 days, 3 nights with sleep). A clear decrement in neurobehavioral functions as measured by the Psychomotor Vigilance Test lasted for 6 h after melatonin administration (particularly in the lapse domain and median of the reaction time) without any effect on a letter cancellation task. A subjective soporific effect was present but less pronounced. Thus, melatonin taken in the morning requires caution in situations where high attention is needed.

Disturbed circadian rest-activity cycles in schizophrenia patients: an effect of drugs?

The circadian rest-activity cycle of schizophrenia patients stabilized for more than a year on monotherapy with a "classical" neuroleptic (haloperidol, flupentixol) or with the atypical neuroleptic clozapine was documented by continuous activity monitoring for 3-7 weeks. In this pilot study, the three patients treated with clozapine had remarkably highly ordered restactivity cycles, whereas the four patients on classical neuroleptics had minor to major circadian rhythm abnormalities. This is the first documentation of circadian rest-activity cycle disturbances in schizophrenia related to class of drug.

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.

The hypothermic effect of late evening melatonin does not block the phase delay induced by concurrent bright light in human subjects.

This constant routine study (n = 9 men) compared the phase delay of the circadian system induced by a single pulse of evening light (5000 lx at 2100-2400 h) in the presence or absence of exogenous melatonin (5 mg p.o. at 2040 h). On the treatment day, light and melatonin protracted and accelerated, respectively, the evening decline in core body temperature (CBT). Subjective sleepiness ratings showed parallel shifts, the earlier the decline in CBT, the sleepier. On the post-treatment day, light induced a phase delay in the mid-range crossing time of CBT decline independent of whether melatonin was co-administered or not. Subjective sleepiness was delayed in parallel. The phase delay of the circadian system by evening light appears to be independent of an immediate hyperthermic effect and is not mediated by melatonin.