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.

Sleep ability mediates individual differences in the vulnerability to sleep loss: evidence from a PER3 polymorphism.

Sleep deprivation is highly prevalent in our 24/7 society with harmful consequences on daytime functioning on the individual level. Genetically determined, trait-like vulnerability contributes to prominent inter-individual variability in the behavioral responses to sleep loss and adverse circadian phase. We aimed at investigating the effects of differential sleep pressure levels (high vs low) on the circadian modulation of neurobehavioral performance, sleepiness correlates, and nap sleep in individuals genotyped for a polymorphism in the clock gene PERIOD3. Fourteen homozygous long (PER3(5/5)) and 15 homozygous short (PER3(4/4)) allele carriers underwent both a 40-h sleep deprivation and multiple nap protocol under controlled laboratory conditions. We compared genotypes regarding subjective and ocular correlates of sleepiness, unintentional sleep episodes as well as psychomotor vigilance during both protocols. Nap sleep was monitored by polysomnography and visually scored according to standard criteria. The detrimental effects of high sleep pressure on sleepiness correlates and psychomotor vigilance were more pronounced in PER3(5/5) than PER3(4/4) carriers. Under low sleep pressure, both groups showed similar circadian time courses. Concomitantly, nap sleep efficiency and subjective sleep quality across all naps tended to be higher in the more vulnerable PER3(5/5) carriers. In addition, PER3-dependent sleep-loss-related attentional lapses were mediated by sleep efficiency across the circadian cycle. Our data corroborate a greater detrimental impact of sleep deprivation in PER3(5/5) compared to PER3(4/4) carriers. They further suggest that the group with greater attentional performance impairment due to sleep deprivation (PER3(5/5) carriers) is superior at initiating sleep over the 24-h cycle. This higher sleep ability may mirror a faster sleep pressure build-up between the multiple sleep opportunities and thus a greater flexibility in sleep initiation. Finally, our data show that this higher nap sleep efficiency is positively related to attentional failures under sleep loss conditions and might thus be used as a marker for inter-individual vulnerability to elevated sleep pressure.

Challenging the sleep homeostat: sleep in depression is not premature aging.

OBJECTIVES: The close relationship between major depression and sleep disturbances led to the hypothesis of a deficiency in homeostatic sleep pressure in depression (S-deficiency hypothesis). Many observed changes of sleep characteristics in depression are also present in healthy aging, leading to the premise that sleep in depression resembles premature aging. In this study, we aimed at quantifying the homeostatic sleep-wake regulation in young women with major depression and healthy young and older controls under high sleep pressure conditions. METHODS: After an 8-h baseline night nine depressed women, eight healthy young, and eight healthy older women underwent a 40-h sustained wakefulness protocol followed by a recovery night under constant routine conditions. Polysomnographic recordings were carried out continuously. Sleep parameters as well as the time course of EEG slow-wave activity (SWA) (EEG spectra range: 0.75-4.5 Hz), as a marker of homeostatic sleep pressure, were analyzed during the recovery night. RESULTS: Young depressed women exhibited higher absolute mean SWA levels and a stronger response to sleep deprivation, particularly in frontal brain regions. In contrast, healthy older women exhibited not only attenuated SWA values compared to the other two groups, but also an absence of the frontal SWA predominance. CONCLUSIONS: Homeostatic sleep regulation and sleep architecture in young depressed women are not equal to premature aging. Moreover, our findings demonstrate that young moderately depressed women exhibit no deficiency in the sleep homeostatic process S as predicted by the S-deficiency hypothesis, but, rather, live on an elevated level of homeostatic sleep pressure.

[Sleep and circadian rhythms in ageing]. / Schlaf und zirkadiane Rhythmik im Alter.

With age, the consolidation of nocturnal sleep decreases, daytime napping increases, and sleep occurs earlier. Sleep regulation is dependent on the interaction between a circadian pacemaker (biological clock) and the sleep homeostat (sleep pressure increasing with duration of time awake). We have shown that in the healthy elderly, the amplitude of circadian rhythms (e. g. melatonin secretion) declines, as does slow wave sleep, parallel with an increase in afternoon sleepiness and a tendency to fall asleep in the early evening when younger subjects do not. Light is the major zeitgeber to stabilise the biological clock: older subjects require sufficient light exposure during daytime and in the evening, and should take no or only brief naps during the day to improve sleep.

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.

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.

Homeostatic control of slow-wave and spindle frequency activity during human sleep: effect of differential sleep pressure and brain topography.

The impact of a 40 h sleep deprivation versus a 40 h multiple nap paradigm on topographic and temporal aspects of electroencephalographic (EEG) activity during the subsequent recovery sleep was investigated in 10 young volunteers in a controlled 'constant posture' protocol. The accumulation of sleep pressure with extended wakefulness could be significantly attenuated by intermittent naps. The differential sleep pressure conditions induced frequency- and topographic-specific changes in the EEG slow wave range (0.5-5 Hz) and in the low (LSFA, 12.25-13.25 Hz) and high spindle frequency activity range (HSFA, 13.75-16.5 Hz) during non-REM sleep. The observed increase of EEG slow-wave activity (SWA) after high sleep pressure was significantly more pronounced in the fronto-central (Fz, Cz) than in the parieto-occipital (Pz, Oz) derivations. Low sleep pressure after the nap paradigm decreased SWA with an occipital predominance. Spindle frequency activity showed a dissimilar homeostatic regulation: HSFA was significantly decreased after high sleep pressure and increased after low sleep pressure, exclusively in the centro-parietal brain region (Cz, Pz). LSFA was significantly enhanced after both manipulations. The data indicate that EEG activity, in particular frontal SWA and centro-parietal HSFA, are under a clear sleep-wake-dependent homeostatic control and imply a reciprocal relationship in the homeostatic regulation of SWA and HSFA, which however shows different spatio-temporal aspects.

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.

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.

Cold feet and prolonged sleep-onset latency in vasospastic syndrome.

People with vasospastic syndrome have cold hands and feet and abnormal vasoconstriction after local cold exposure. Normally there is a circadian rhythm of distal vasodilation, with onset in the early evening, which directly influences ability to fall asleep. We gave a sleep questionnaire to 32 patients with primary vasospastic syndrome and 31 healthy controls. People with vasospasticity had significantly prolonged sleep-onset latency both at onset of night-time sleep and after nocturnal disturbance. This prolonged latency could be associated with impaired capacity for distal vasodilation.

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.

Phase advance after one or three simulated dawns in humans.

A specially designed apparatus that can simulate the waveform of the dawn or dusk signal at any latitude and any day of the year has been shown to phase shift the circadian pacemaker in rodents and primates at a fraction of the illuminance previously used. Until recently, it was considered that rather high illuminances or rather long exposure episodes to room light were necessary to phase shift human circadian rhythms. This experiment shows that, under controlled conditions of a modified constant routine protocol, a single dawn signal is sufficient to phase advance the timing of the onset of secretion of the pineal hormone melatonin. The significant phase advance of salivary melatonin of 20 minutes, which is enhanced to 34 minutes after three consecutive dawn signals, is small, but appears to be of sufficient magnitude to entrain the human circadian pacemaker, which has an endogenous period of about 24.2h.

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 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.

Functional link between distal vasodilation and sleep-onset latency?

Thermoregulatory processes have long been implicated in initiation of human sleep. The purpose of this study was to evaluate the role of heat loss in sleep initiation, under the controlled conditions of a constant-routine protocol modified to permit nocturnal sleep. Heat loss was indirectly measured by means of the distal-to-proximal skin temperature gradient (DPG). A stepwise regression analysis revealed that the DPG was the best predictor variable for sleep-onset latency (compared with core body temperature or its rate of change, heart rate, melatonin onset, and subjective sleepiness ratings). This study provides evidence that selective vasodilation of distal skin regions (and hence heat loss) promotes the rapid onset of sleep.

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.

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.