Endogenous Circadian Pacemaker Research Articles

Circadian aspects in the aetiology and pathophysiology of insomnia.

Because the endogenous circadian pacemaker is a very strong determinant of alertness/sleep propensity across the 24 h period, its mistiming may contribute to symptoms of insomnia (e.g., difficulties initiating sleep and maintaining sleep) and to the development of insomnia disorder. Despite the separation of insomnia and circadian rhythm disorders in diagnostic nosology implying independent pathophysiology, there is considerable evidence of co-morbidity and interaction between them. Sleep onset insomnia is associated with later timed circadian rhythms and can be treated with morning bright light to shift rhythms to an earlier timing. It is also possible that the causal link may go in both directions and that having a delayed circadian rhythm can result in enough experiences of delayed sleep onset to lead to some conditioned insomnia or insomnia disorder further exacerbating a delayed circadian rhythm. Early morning awakening insomnia is associated with an advanced circadian phase (early timing) and can be treated with evening bright light resulting in a delay of rhythms and an improved ability to sleep later in the morning and to obtain more sleep. There is some evidence suggesting that sleep maintenance insomnia is associated with a blunted amplitude of circadian rhythm that may be treated with increased regularity of sleep and light exposure timing. However, this is an insomnia phenotype that requires considerably more circadian research as well as further insomnia clinical research with the other insomnia phenotypes incorporating circadian timing measures and treatments.

Circadian misalignment increases mood vulnerability in simulated shift work

Night shift work can associate with an increased risk for depression. As night workers experience a ‘misalignment’ between their circadian system and daily sleep–wake behaviors, with negative health consequences, we investigated whether exposure to circadian misalignment underpins mood vulnerability in simulated shift work. We performed randomized within-subject crossover laboratory studies in non-shift workers and shift workers. Simulated night shifts were used to induce a misalignment between the endogenous circadian pacemaker and sleep/wake cycles (circadian misalignment), while environmental conditions and food intake were controlled. Circadian misalignment adversely impacted emotional state, such that mood and well-being levels were significantly decreased throughout 4 days of continuous exposure to circadian misalignment in non-shift workers, as compared to when they were under circadian alignment (interaction of “circadian alignment condition” vs. “day”, mood: p < 0.001; well-being: p < 0.001; adjusted p-values). Similarly, in shift workers, mood and well-being levels were significantly reduced throughout days of misalignment, as compared to circadian alignment (interaction of “circadian alignment condition” vs. “day”, mood: p = 0.002; well-being: p = 0.002; adjusted p-values). Our findings indicate that circadian misalignment is an important biological component for mood vulnerability, and that individuals who engage in shift work are susceptible to its deleterious mood effects.

Social stress and glucocorticoids alter PERIOD2 rhythmicity in the liver, but not in the suprachiasmatic nucleus

Circadian (~24 h) rhythms in behavior and physiological functions are under control of an endogenous circadian pacemaker in the suprachiasmatic nucleus (SCN) of the hypothalamus. The SCN directly drives some of these rhythms or serves as a coordinator of peripheral oscillators residing in other tissues and organs. Disruption of the circadian organization may contribute to disease, including stress-related disorders. Previous research indicates that the master clock in the SCN is resistant to stress, although it is unclear whether stress affects rhythmicity in other tissues, possibly mediated by glucocorticoids, released in stressful situations. In the present study, we examined the effect of uncontrollable social defeat stress and glucocorticoid hormones on the central and peripheral clocks, respectively in the SCN and liver. Transgenic PERIOD2::LUCIFERASE knock-in mice were used to assess the rhythm of the clock protein PERIOD2 (PER2) in SCN slices and liver tissue collected after 10 consecutive days of social defeat stress. The rhythmicity of PER2 expression in the SCN was not affected by stress exposure, whereas in the liver the expression showed a delayed phase in defeated compared to non-defeated control mice. In a second experiment, brain slices and liver samples were collected from transgenic mice and exposed to different doses of corticosterone. Corticosterone did not affect PER2 rhythm of the SCN samples, but caused a phase shift in PER2 expression in liver samples. This study confirms earlier findings that the SCN is resistant to stress and shows that clocks in the liver are affected by social stress, which might be due to the direct influence of glucocorticoids released from the adrenal gland.

Circadian signaling in the Northern krill Meganyctiphanes norvegica: In silico prediction of the protein components of a putative clock system using a publicly accessible transcriptome

The Northern krill Meganyctiphanes norvegica is a significant component of the zooplankton community in many regions of the North Atlantic Ocean. In the areas it inhabits, M. norvegica is of great importance ecologically, as it is both a major consumer of phytoplankton/small zooplankton and is a primary food source for higher-level consumers. One behavior of significance for both feeding and predator avoidance in Meganyctiphanes is diel vertical migration (DVM), i.e., a rising from depth at dusk and a return to depth at dawn. In this and other euphausiids, an endogenous circadian pacemaker is thought, at least in part, to control DVM. Currently, there is no information concerning the identity of the genes/proteins that comprise the M. norvegica circadian system. In fact, there is little information concerning the molecular underpinnings of circadian rhythmicity in crustaceans generally. Here, a publicly accessible transcriptome was used to identify the molecular components of a putative Meganyctiphanes circadian system. A complete set of core clock proteins was deduced from the M. norvegica transcriptome (clock, cryptochrome 2, cycle, period and timeless), as was a large suite of proteins that likely function as modulators of the core clock (e.g., doubletime), or serves as inputs to it (cryptochrome 1) or outputs from it (pigment dispersing hormone). This is the first description of a “complete” (core clock through putative output pathway signals) euphausiid clock system, and as such, provides a foundation for initiating molecular investigations of circadian signaling in M. norvegica and other krill species, including how clock systems may regulate DVM and other behaviors.

Reduced Tolerance to Night Shift in Chronic Shift Workers: Insight From Fractal Regulation.

Healthy physiology is characterized by fractal regulation (FR) that generates similar structures in the fluctuations of physiological outputs at different time scales. Perturbed FR is associated with aging and age-related pathological conditions. Shift work, involving repeated and chronic exposure to misaligned environmental and behavioral cycles, disrupts circadian coordination. We tested whether night shifts perturb FR in motor activity and whether night shifts affect FR in chronic shift workers and non-shift workers differently. We studied 13 chronic shift workers and 14 non-shift workers as controls using both field and in-laboratory experiments. In the in-laboratory study, simulated night shifts were used to induce a misalignment between the endogenous circadian pacemaker and the sleep-wake cycles (ie, circadian misalignment) while environmental conditions and food intake were controlled. In the field study, we found that FR was robust in controls but broke down in shift workers during night shifts, leading to more random activity fluctuations as observed in patients with dementia. The night shift effect was present even 2 days after ending night shifts. The in-laboratory study confirmed that night shifts perturbed FR in chronic shift workers and showed that FR in controls was more resilience to the circadian misalignment. Moreover, FR during real and simulated night shifts was more perturbed in those who started shift work at older ages. Chronic shift work causes night shift intolerance, which is probably linked to the degraded plasticity of the circadian control system.

Influence of blue-enriched classroom lighting on students׳ cognitive performance

Abstract Light is a powerful zeitgeber that synchronizes our endogenous circadian pacemaker with the environment and has been previously described as an agent in improving cognitive performance. With that in mind, this study was designed to explore the influence of exposure to blue-enriched white light in the morning on the performance of adolescent students. 58 High school students were recruited from four classes in two schools. In each school, one classroom was equipped with blue-enriched white lighting while the classroom next door served as a control setting. The effects of classroom lighting on cognitive performance were assessed using standardized psychological tests. Results show beneficial effects of blue-enriched white light on students׳ performance. In comparison to standard lighting conditions, students showed faster cognitive processing speed and better concentration. The blue-enriched white lighting seems to influence very basic information processing primarily, as no effects on short-term encoding and retrieval of memories were found.

The Role of Circadian Rhythms, Light and Melatonin in SAD and Nonseasonal Affective and Anxiety Disorders

More than three decades ago, bright light was found to be able to suppress melatonin production in humans, a finding which quickly led to identification of seasonal affective disorder (SAD) and its treatment with light. However, current thinking supports a phase shift hypothesis (PSH), according to which SAD is a disorder primarily of phasedelayed circadian misalignment {best assessed by the time interval [or phase angle difference (PAD)]} between the dim light melatonin onset (DLMO) and the midpoint of the sleep bout. It has been heuristically useful to use PAD 6 (a time interval of six hours) as the “sweet spot” for SAD: most patients with SAD have phase-delayed circadian misalignment (that is, have PADs ≤ 6), which explains why bright light exposure scheduled at waketime is the optimal treatment for most patients with SAD. Low-dose melatonin taken in the afternoon/evening also provides a corrective phase advance and is therefore an alternative or “add-on” treatment for these patients. The other SAD patients appear to be phase advanced (with PADs > 6) and respond to evening light and morning melatonin. Other hypotheses have not stood the test of time, including the two-oscillator dawn/dusk model of the endogenous circadian pacemaker which has been at least heuristically useful in rodents. However, recent research on multiple oscillators in the SCN and brain, as well as in other tissues and organs, may yet yield a more refined understanding of circadian misalignment. The salivary home DLMO may soon be the first laboratory test for a psychiatric disorder.

Circadian Rhythm Disorders and Melatonin Production in 127 Blind Women with and without Light Perception.

Light is the major environmental time cue that synchronizes the endogenous central circadian pacemaker, located in the suprachiasmatic nuclei of the hypothalamus, and is detected exclusively by the eyes primarily via specialized non-rod, non-cone ganglion cell photoreceptors. Consequently, most blind people with no perception of light (NPL) have either nonentrained or abnormally phased circadian rhythms due to this inability to detect light. Conversely, most visually impaired participants with some degree of light perception (LP) exhibit normal entrainment, emphasizing the functional separation of visual and "nonvisual" photoreception. The aims of the study were to identify the prevalence of circadian disorders in blind women, with the further aim of examining how eye disease may relate to the type of circadian disorder. Participants (n = 127, age 50.8 ± 13.4 years) completed an 8-week field study including daily sleep diaries and sequential 4 to 8 hourly urine collections over 48 h on 2 to 3 occasions separated by at least 2 weeks. Circadian type was determined from the timing and time course of the melatonin rhythm measured by cosinor-derived urinary 6-sulfatoxymelatonin rhythm peak. Of the participants with NPL (n = 41), the majority were abnormally phased (24%) or nonentrained (39%), with 37% classified as normally entrained. Of the participants with LP (n = 86), the majority were normally entrained (69%). Eighteen LP participants (21%) were abnormally phased (8 advanced, 10 delayed). Nine LP participants (10%) were nonentrained. The eye conditions most associated with abnormal phase and/or nonentrained circadian rhythms were bilateral enucleation (67%) and retinopathy of prematurity (57%). By contrast, 84% of participants with retinitis pigmentosa and 83% of those with age-related macular degeneration were normally entrained. These findings suggest that the etiology of blindness in addition to LP status is related to an individual's ability to process the circadian light signal.

Neurobiologic Mechanisms of Sleep and Wakefulness

Neurobiologic Mechanisms of Sleep and Wakefulness

Erratum to: Why does Sleep Stop Migraine?

Our comprehension of the physiology of the daily cycles of sleep and wakefulness, as well as the neuronal circuitry and molecular basis of the biological clock that underpins human circadian rhythms (daily sleep-wake cycles), has increased substantially in recent years. The wake promotion systems and the sleep promotion system are temporally controlled by the endogenous circadian pacemaker contained within the suprachiasmatic nuclei (SCN) that functions autonomously as the brain’s master clock. The SCN receives information about light and dark periods from melanopsin expressing retinal ganglion cells during the day (the light entrainment system) and melatonin from the pineal gland at night to reset the human 24.5 hour circadian rhythm to our 24 hour day length. The molecular basis of the clock function involves transcriptional and translational regulation of the expression of genes such as period, clock, Bmal and cryptochrome that when mutated or deleted disrupt circadian rhythm cycles [49]. Daily oscillations in SCN activity signal through the subparaventricular zone and the dorsal medial hypothalamus to both GABA-ergic neurons of the ventrolateral pre-optic area of the hypothalamus (VLPO) and the wake promoting orexinergic neurons of the lateral hypothalamus. GABA-ergic neurons promote sleep by sending inhibitory projections both to orexin neurons as well as brain stem nuclei such as locus ceruleus (norepinephrine), Raphe nucleus (serotonin) and tuberomamillary nucleus (histamine) that together with cholinergic projections from the basal forebrain form the ascending arousal systems. Attenuation of this inhibitory signal and increased excitatory input from the SCN to orexin secreting neurons that innervate these monoaminergic brain stem arousal nuclei promotes waking and somatosensory function. [50]. Increasing evidence suggests that human circadian rhythms are regulated by a thalamic switch that can be activated or deactivated to regulate sensory information reaching the cerebral cortex and the degree of consciousness [51]. The transition from sleep to wakefulness comes as thalamocortical pathways activate the cortex that has been primed by neurotransmitters (serotonin, histamine, norepinephrine) released from ascending pathways originating in the brain stem. The extent of information passing to the cortex through the thalamus is “gated” based on the arousal level of the central nervous system that is in turn set by outputs from the reticulo-activating systems (RAS) of the brain stem and hypothalamus. Migraine is often triggered by stimuli that activate the RAS such as environmental stimuli, exercise, changes in levels of stress, fatigue, sleep deprivation or poor sleep hygiene [52, 53] suggesting that the propensity to sleep during migraine could be an endogenous homeostatic response that can reduce the intensity or frequency of migraine headaches. The mechanisms through which physiological sleep achieves an antimigraine effect are likely to be diverse. It is well known that sleep influences output from the cardiovascular, sensory, The online version of the original article can be found at doi:http:// dx.doi.org/10.1007/s11916-013-0369-0.

The influence of break timing on the sleep quantity and quality of fly-in, fly-out shiftworkers.

Although shift and break timing is known to affect the sleep of shiftworkers, this has not been demonstrated in Fly-in, Fly-out (FIFO) settings which, compared to residential based settings, may be favourable for sleep. This study investigated the sleep quantity and quality of shiftworkers working a FIFO operation comprising of shifts, and therefore breaks, across the 24-h day. The sleep of 24 males (50.43 ± 8.57 yr) was measured using actigraphy and sleep diaries. Morning breaks were associated with less sleep (09:00–12:00 h; 4.4 ± 1.3 h) and a poorer sleep quality (06:00–09:00 h; 3.1 ± 1.0, “average”) compared to breaks beginning between 00:00 h and 03:00 h (6.8 ± 1.7 h; 2.2 ± 0.9, “good”). Sleep efficiency remained constant regardless of break timing (85.9 ± 5.0% to 89.9 ± 3.5%). Results indicate that even in operations such as FIFO where sleeping conditions are near-optimal and the break duration is held constant, the influence of the endogenous circadian pacemaker on sleep duration is evident.

Sleeping disorders related with alterations of melatonine secretion circadian rhythm

Introduction Several circadian rhythms have been used as indicators of the endogenous circadian pacemaker phase, but circadian rhythm of pineal melatonin secretion has been proved to be the indicator that most exactly describes the function of the suprachiasmatic nucleus. Dim Light Melatonin Onset (DLMO) determination is the only marker available of circadian rhythm pacemaker phase. This determination requires 5 blood, saliva or urine samples. DLMO test is a precise tool used to distinguish between sleep disorder patients with or without a subjacent alteration of circadian rhythm. Materials and methods A sample (N = 146) of 6–11 year old patients (65.75% men and 34.25% women) was selected. 730 determinations of salivary melatonin were carried out (5 per subject). Suitable samples were centrifuged 10 min to remove particulate material and frozen at −70°C until analysis. Quantitative determination of melatonin was performed by a direct non-extraction ELISA assay using DSX analyser. DMLO levels for each patient were determined and were then classified as normal o altered. Patients were also subjected to the Paediatric Sleep Questionnaire of Chervin for Sleep disorder diagnosis. Statistical analysis was carried to evaluate the null hypothesis against the alternative hypothesis (H0: DLMO is not related with sleeping disorders; H1: a relation exists between DLMO and sleeping disorders). Results Statistical analysis of DLMO difference between patients with and without sleeping disorders led the following results: Excessive daytime sleepiness (p-value 0.5789), Respiratory disorder related with sleep (p-value 0.8649), Bruxism (p-value 0.5866), Enuresis (p-value 0.0138), sleepwalking (p-value 0.7443), nightmares (p-value 0.4822), night terrors (p-value 0.9695), rhythmic movement disorders (p-value 0.5951), Insomnia (p-value 0.0014), Somniloquy (p-value 0.0178), Arousals (p-value 0.0001), Sleep start delay (p- value 0.0166), Sleep latency (p-value 0.0123), Bed- time resistance (p-value 0.4209), Awakening and Bedtime irregularity (p-value 0.5138). Conclusion The following sleeping disorders proved to have a significant relation with DLMO levels (p 0.05): enuresis, somniloquy, insomnia, arousals, sleep start delay and sleep latency. Acknowledgements Hospital Universitario de la Ribera for the trust placed in researchers and in the present study.

Circadian regulation of oviposition rhythm in Drosophilaagumbensis and Drosophila nagarholensis (Diptera)

The oviposition rhythm of two species of montium, namely Drosophila agumbensis and Drosophila nagarholensis was analysed under constant conditions such as constant light (LL), constant dark (DD) and 12 light/12 dark (LD). The members of the montium are the largest, wide spread and heterogeneous, and the intricacies of their wide spread nature may lie in their adaptability to diverse environment. An endogenous circadian pacemaker controls the timing of many events such as oviposition, hatching and eclosion occurring at a particular time of the day, which enhances the survival of an organism. This study is an attempt to understand the timing of oviposition at different light conditions. Over 80% of the egg laying occurred during scotophase for both the species. The peak of oviposition was observed at six hours after the lights were turned off. Shorter period was observed in LL and LD, and it was ∼24 h in DD condition. The number of eggs laid in LD was more compared to LL and DD.

Circadian entrainment and its role in depression: a mechanistic review

The natural rotation of the earth generates an environmental day-night cycle that repeats every 24h. This daily transition from dawn to dusk provides one of the most important time cues to which the majority of organisms synchronise their activity. Under these conditions, natural light, a photic stimulus, provides the principal entraining cue. In mammals, an endogenous circadian pacemaker located within the suprachiasmatic nucleus (SCN) of the hypothalamus acts as a coordinating centre to align physiological activity with the environmental light-dark cycle. However, the SCN also receives regulatory input from a number of behavioural, non-photic, cues such as physical activity, social interactions and feeding routines. The unique ability of the SCN to integrate both photic and non-photic cues allows it to generate a rhythm that is tailored to the individual and entrained to the environment. Here, we review the key neurotransmitter systems involved in both photic and non-photic transmission to the SCN and their interactions that assist in generating an entrained output rhythm. We also consider the impact on health of a desynchronised circadian system with a focus on depressive affective disorders and current therapies aimed at manipulating the relationship between photic and non-photic SCN regulators.

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)

Short-Day Response in Djungarian Hamsters of Different Circadian Phenotypes

In Djungarian hamsters (Phodopus sungorus) bred at the authors' institute, a certain number of animals show activity patterns incompatible with proper entrainment of their endogenous circadian pacemaker to the environmental light-dark (LD) cycle. Even though the activity-offset in these animals is stably coupled to “light-on,” activity-onset is increasingly delayed, leading to a compression of the activity time (α). If α falls below a critical value, the circadian rhythm in these so called delayed activity-onset (DAO) hamsters starts to free-run and finally breaks down. Animals then show an arrhythmic activity pattern (AR hamsters). Previous studies revealed the mechanisms of photic entrainment have deteriorated (DAO) or the suprachiasmatic nucleus (SCN) does not generate a rhythmic signal (AR). The aim of the present study was to investigate the consequences that these deteriorations have upon photoperiodic time measurement. Animals were bred and kept under standardized housing conditions with food and water ad libitum and a 14L/10D (long day, LD) regimen. Locomotor activity was recorded continuously using passive infrared motion detectors. Body mass, testes size, and fur coloration were measured weekly or biweekly to further quantify the photoperiodic reaction. In a first experiment, adult male wild-type (WT), DAO, and AR hamsters were transferred initially to a 16L/8D cycle. After 3–4 wks, the light period was shortened symmetrically by 8 h. After 14 wks, none of the DAO and AR hamsters, and only 1 of 8 WT hamsters showed short-day (SD) traits. Therefore, in a second experiment, hamsters were transferred to SD conditions (8L/16D cycle) for 8 wks directly from standard LD conditions. In 6 of 7 WT hamsters, activity time expanded, body mass and testes size decreased, and fur coloration changed from summer to winter pelage. In contrast, none of the DAO and AR hamsters displayed an SD response. In a third experiment, DAO and AR hamsters were kept in constant darkness (DD) for 8 and 14 wks. After 8 wks, DAO hamsters showed a similar photoperiodic reaction to WT hamsters that had been kept for 8 wks under SD conditions. However, the level of adaptation was still less compared to WT hamsters, but this difference was not apparent after 14 wks. In contrast, AR animals did not display any photoperiodic reaction, even after 14 wks in DD. Type VI phase response curves (PRCs) were constructed to better understand the mechanism behind the SD response. In WT hamsters, the photosensitive phase, where light pulses induce phase shifts, was lengthened in SD condition. In DAO hamsters, in contrast, the PRCs were similar under LD and SD conditions with a compressed photosensitive phase corresponding to α. Also, “light-on” induced only weak phase advances of activity-onset, insufficient to compensate for the long endogenous period. The results show that physiological mechanisms necessary for seasonal adaptation are working in DAO hamsters and that it is the inadequate interaction of the LD cycle with the SCN that prevents the photoperiodic reaction. AR hamsters, on the other hand, are incapable of measuring photoperiodic time due to a complete disruption of circadian rhythmicity.

Effects of prior light exposure on early evening performance, subjective sleepiness, and hormonal secretion.

In sighted humans, light intensity, timing, exposure duration, and spectral composition of light are important to entrain the endogenous circadian pacemaker to the 24-h day-night cycle. We tested the impact of two realistic office lighting conditions during the afternoon on subjective sleepiness, hormonal secretion, and cognitive performance in the early evening hours. Twenty-nine young subjects came twice and spent 8 h (12:00-20:00) in our laboratory, where they were exposed for 6 h to either artificial light (AL) or to mainly daylight (DL). In the early evening, we assessed their salivary cortisol and melatonin secretion, subjective sleepiness, and cognitive performance (n-back test) under dim light conditions. Subjects felt significantly more alert at the beginning of the evening after the DL condition, and they became sleepier at the end of the evening after the AL condition. For cognitive performance we found a significant interaction between light conditions, mental load (2- or 3-back task) and the order of light administration. On their first evening, subjects performed with similar accuracy after both light conditions, but on their second evening, subjects performed significantly more accurately after the DL in both n-back versions and committed fewer false alarms in the 2-back task compared to the AL group. Lower sleepiness in the evening was significantly correlated with better cognitive performance (p < .05). In summary, even short-term lighting conditions during the afternoon had an impact on cognitive task performance in the evening. This rapid effect was only distinguishable on the second day of training, when a difficult task had been sufficiently practiced.

The Validity of Temperature-Sensitive Ingestible Capsules for Measuring Core Body Temperature in Laboratory Protocols

The human core body temperature (CBT) rhythm is tightly coupled to an endogenous circadian pacemaker located in the suprachiasmatic nucleus of the anterior hypothalamus. The standard method for assessing the status of this pacemaker is by continuous sampling of CBT using rectal thermometry. This research sought to validate the use of ingestible, temperature-sensitive capsules to measure CBT as an alternative to rectal thermometry. Participants were 11 young adult males who had volunteered to complete a laboratory protocol that extended across 12 consecutive days. A total of 87 functional capsules were ingested and eliminated by participants during the laboratory internment. Core body temperature samples were collected in 1-min epochs and compared to paired samples collected concurrently via rectal thermistors. Agreement between samples that were collected using ingestible sensors and rectal thermistors was assessed using the gold-standard limits of agreement method. Across all valid paired samples collected during the study (n = 120,126), the mean difference was 0.06°C, whereas the 95% CI (confidence interval) for differences was less than ±0.35°C. Despite the overall acceptable limits of agreement, systematic measurement bias was noted across the initial 5 h of sensor-transit periods and attributed to temperature gradations across the alimentary canal. (Author correspondence: david.darwent@unisa.edu.au)

Dim Nighttime Illumination Interacts With Parametric Effects of Bright Light to Increase the Stability of Circadian Rhythm Bifurcation in Hamsters

The endogenous circadian pacemaker of mammals is synchronized to the environmental day by the ambient cycle of relative light and dark. The present studies assessed the actions of light in a novel circadian entrainment paradigm where activity rhythms are bifurcated following exposure to a 24-h light:dark:light:dark (LDLD) cycle. Bifurcated entrainment under LDLD reflects the temporal dissociation of component oscillators that comprise the circadian system and is facilitated when daily scotophases are dimly lit rather than completely dark. Although bifurcation can be stably maintained in LDLD, it is quickly reversed under constant conditions. Here the authors examine whether dim scotophase illumination acts to maintain bifurcated entrainment under LDLD through potential interactions with the parametric actions of bright light during the two daily photophases. In three experiments, wheel-running rhythms of Syrian hamsters were bifurcated under LDLD with dimly lit scotophases, and after several weeks, dim scotophase illumination was either retained or extinguished. Additionally, “full” and “skeleton” photophases were employed under LDLD cycles with dimly lit or completely dark scotophases to distinguish parametric from nonparametric effects of bright light. Rhythm bifurcation was more stable in full versus skeleton LDLD cycles. Dim light facilitated the maintenance of bifurcated entrainment under full LDLD cycles but did not prevent the loss of rhythm bifurcation in skeleton LDLD cycles. These studies indicate that parametric actions of bright light maintain the bifurcated entrainment state; that dim scotophase illumination increases the stability of the bifurcated state; and that dim light interacts with the parametric effects of bright light to increase the stability of rhythm bifurcation under full LDLD cycles. A further understanding of the novel actions of dim light may lead to new strategies for understanding, preventing, and treating chronobiological disturbances. (Author correspondence: jevans@msm.edu)

The stress hormone system in various sleep disorders

Hypothalamic-pituitary-adrenal (HPA)-system activity is regulated by the suprachiasmatic nucleus, the primary endogenous circadian pacemaker. In addition, sleep plays an important modulatory role. However, data on HPA-system activity in sleep disorders are quite conflicting. A sensitive challenge test to assess negative feedback sensitivity of the HPA-system like the dexamethasone/corticotropin-releasing-hormone (DEX/CRH)-test has never been used so far in sleep disorders. Therefore we studied 25 obstructive sleep apnea (OSA) patients, 18 restless legs syndrome (RLS) patients, 21 patients with primary insomnia and compared them to 33 healthy controls. The dynamic response of the HPA-system was assessed by the DEX/CRH-test which combines suppression (dexamethasone) and stimulation (CRH) of the stress hormone system. After HPA-axis suppression the number of non-suppressors did not differ among groups indicating normal negative feedback sensitivity. In RLS patients ACTH levels were slightly lower compared to controls while cortisol levels were similar between groups. Following CRH stimulation we did not detect differences in ACTH- or cortisol levels and adrenocortical responsitivity to ACTH was comparable between groups. These results for the first time document normal HPA-system feedback sensitivity in various sleep disorders and suggest that abnormalities of the stress hormone system in affective disorders are unlikely due to concomitant sleep problems.