Running on Empty: Of Hypopinealism and Human Seasonality.

The pineal hormone melatonin is the natural transducer of the environmental light-dark signal to the body. Although the responsiveness to photoperiod is well-conserved in humans, only about 25 percent of the human population experiences seasonal changes in behavior. As a consequence, humans seem to have adapted-at least partly-to the seasonal changes in day length. The aim of the study was to demonstrate that the individual melatonin deficit marker DOC (degree of pineal calcification) is related to variation of seasonal phenomena in humans. Out of 3,011 patients in which cranial computer tomography (cCT) was performed for diagnostic reasons, 97 consecutive "healthy" subjects (43 female, 54 male; age 18-68 yrs, mean ± SD: 35.0 ± 13.1) were included. Exclusion criteria were pathological finding in cCT, acute/chronic illness including alcohol/drug abuse, shift work, and medication, which are known to influence melatonin excretion. The degree of pineal calcification (DOC) was semiquantitatively determined using the previously validated method. The Seasonal Pattern Assessment Questionnaire (SPAQ) was performed in a telephone interview. Twenty-six subjects fulfilled the criteria for seasonal affective disorder (SAD) or subsyndromal (S) SAD. Seasonality was more pronounced in women than in men (SPAQ seasonality score: 7.8 ± 4.0 vs. 4.9 ± 4.5; p = 0.001) and negatively and significantly associated with age (r = -0.178; p = 0.04). The subjective sleep length significantly varied between seasons (one-way repeated measures ANOVA: F = 45.75; p < 0.0001), with sleep during winter being 53 min (±70 min) longer than during summer. Controlling for age, the total seasonality score was negatively and significantly associated with DOC (r94 = -0.214; p = 0.036). Data confirm earlier studies with respect to distribution of seasonality with sex and age. The survival of seasonality in the sleep length of people living in an urban environment underlines functionality of the circadian timing system in modern societies. Moreover, data confirm for the first time that diminished experience of seasonality in behavior is associated with a reduced individual capacity to produce melatonin.

The alerting effect of the wake maintenance zone during 40 hours of sleep deprivation.

Under entrained conditions, the accumulation of homeostatic sleep pressure in the evening is opposed by a strong circadian arousal signal prior to the dim light melatonin onset, called the Wake Maintenance Zone (WMZ). This study aimed at investigating the impact of the WMZ on different cognitive performance tests, as well as on subjective and objective sleepiness. Twelve young male participants completed a constant routine protocol with 40 h of extended wakefulness that included two WMZs. Cognitive tests and saliva samples were assessed hourly, while the electroencephalogram (EEG) was recorded continuously. Participants improved in cognitive response inhibition during WMZ1 (13.5 h awake) and sustained attention during WMZ2 (37.5 h awake), but not in higher executive function tests. There were significant EEG power density reductions in the delta/theta frequency range during WMZ1 and in delta/theta, alpha, and sigma/beta ranges during WMZ2, with a greater change in the sigma/beta range during WMZ2 compared to WMZ1. EEG power reductions coincided during WMZ1 with stable subjective sleepiness and sustained attention. During WMZ2, EEG power reductions were more pronounced and coincided with improved sustained attention. Our results suggest the circadian arousal signal in the evening differently modulates cognitive functions and EEG power depending on the duration of prior wakefulness.

High-accuracy determination of internal circadian time from a single blood sample.

BACKGROUND: The circadian clock is a fundamental and pervasive biological program that coordinates 24-hour rhythms in physiology, metabolism, and behavior, and it is essential to health. Whereas therapy adapted to time of day is increasingly reported to be highly successful, it needs to be personalized, since internal circadian time is different for each individual. In addition, internal time is not a stable trait, but is influenced by many factors, including genetic predisposition, age, sex, environmental light levels, and season. An easy and convenient diagnostic tool is currently missing. METHODS: To establish a validated test, we followed a 3-stage biomarker development strategy: (a) using circadian transcriptomics of blood monocytes from 12 individuals in a constant routine protocol combined with machine learning approaches, we identified biomarkers for internal time; and these biomarkers (b) were migrated to a clinically relevant gene expression profiling platform (NanoString) and (c) were externally validated using an independent study with 28 early or late chronotypes. RESULTS: We developed a highly accurate and simple assay (BodyTime) to estimate the internal circadian time in humans from a single blood sample. Our assay needs only a small set of blood-based transcript biomarkers and is as accurate as the current gold standard method, dim-light melatonin onset, at smaller monetary, time, and sample-number cost. CONCLUSION: The BodyTime assay provides a new diagnostic tool for personalization of health care according to the patient's circadian clock. FUNDING: This study was supported by the Bundesministerium für Bildung und Forschung, Germany (FKZ: 13N13160 and 13N13162) and Intellux GmbH, Germany.

Night-time activity forecast by season and weather in a longitudinal design - natural light effects on three years' rest-activity cycles in nursing home residents with dementia.

Backround: Night-time agitation is a frequent symptom of dementia. It often causes nursing home admission and has been linked to circadian rhythm disturbances. A positive influence of light interventions on night-time agitation was shown in several studies. The aim of our study was to investigate whether there is a long-term association between regional weather data (as indicator for daylight availability) and 24-hour variations of motor activity. METHODS: Motor activity of 20 elderly nursing home residents living with dementia was analyzed using recordings of continuously worn wrist activity monitors over a three-year period. The average recording duration was 479 ± 206 days per participant (mean ± SD). Regional cloud amount and day length data from the local weather station (latitude: 52°56'N) were included in the analysis to investigate their effects on several activity variables. RESULTS: Nocturnal rest, here defined as the five consecutive hours with the least motor activity during 24 hours (L5), was the most predictable activity variable per participant. There was a significant interaction of night-time activity with day length and cloud amount (F 1,1174 = 4.39; p = 0.036). Night-time activity was higher on cloudy short days than on clear short days (p = 0.007), and it was also higher on cloudy short days than on cloudy long days (p = 0.032). CONCLUSIONS: The need for sufficient zeitgeber (time cue) strength during winter time, especially when days are short and skies are cloudy, is crucial for elderly people living with dementia. Activity forecast by season and weather might be a valuable approach to anticipate adequately complementary use of electrical light and thereby foster lower night-time activity.

Implementation of Dynamic Lighting in a Nursing Home: Impact on Agitation but not on Rest-Activity Patterns.

OBJECTIVE: Disturbances of circadian rest-activity rhythms in demented patients often culminate in the clinical problem of evening and nighttime agitation. The aim of the current study was to test the impact of a dynamic lighting system on agitation and rest-activity cycles in patients with dementia. METHODS: From midwinter on, a ceiling mounted dynamic lighting system was installed in the common room of a nursing home and programmed to produce high illuminance with higher blue light proportions during the day and lower illuminance without blue light in the evening. Fifteen residents with dementia were regularly assessed with the Cohen Mansfield Agitation Index (CMAI) before and after the lighting intervention. Additionally rest-activity cycles were continuously monitored for 6 months by a wrist worn activity watch. Analysis of CMAI data was performed by using the Wilcoxon-Test for matched pairs (before vs. after the lighting installation). Rest-activity data was compared with t-tests for dependent samples. The dynamic lighting significantly reduced the CMAI sum-scores from 30.2±5.1 to 27.9±2.6 (mean ± SD; N = 12; p<0.05). Analysis of the CMAI subscores revealed that under the dynamic lighting mainly non-physically aggressive behaviors were reduced. RESULTS: Results from the rest-activity analysis did not show differences of circadian amplitude and other circadian variables before and after the lighting installation. The dynamic lighting in the living room significantly reduced agitated behavior in demented patients, indicating short-term benefits from higher daily light exposures. Whether such lighting also impacts long-term (circadian) rest-activity cycles needs to be further investigated.

Applying Melanopic Lux to Measure Biological Light Effects on Melatonin Suppression and Subjective Sleepiness.

OBJECTIVE: At the beginning of this century, a novel photopigment, melanopsin, was discovered in a sub-class of retinal ganglion cells and its action spectrum was described. Shortly after, it became evident that melanopsin is a major contributor to non-visual eye-mediated effects of light on e.g. the circadian, neuroendocrine and neurobehavioral systems. First applied studies pointed out that these non-visual effects of light are relevant for wellbeing, performance and general health. A standardized measurement metric for these nonvisual effects does not exist, but would ease application. Such a metric termed as 'melanopic lux' has been recently introduced and was shown to be superior to describe non-visual effects in animal studies compared to standard metrics. METHODS: We aimed at showing some validity of melanopic lux in humans using a seminaturalistic setting. Therefore, we analyzed the impact of different lighting conditions on melatonin suppression and subjective sleepiness by calculating effective illuminance based on single photopigment sensitivities. We retrospectively analyzed data from our laboratory, where young participants were exposed to a total of 19 different polychromatic lighting conditions, for 30 minutes in the evening, one hour prior to habitual bedtime. Saliva samples for melatonin concentration measures and subjective sleepiness were regularly assessed. The photopic illuminance of all lighting conditions ranged from 3 to 604 lx. Stepwise for- and backward regression analyses showed that melanopic lux was the best predictor for changes in melatonin concentrations (but not subjective sleepiness); R²=0.16 (p<0.05). In addition, we found a significant dose-response relationship between melanopic lux and changes in melatonin concentrations for 18 different lighting conditions (adjusted R²=0.52; p=0.004), similarly to what was previously reported for photopic lux. RESULTS: Our results indicate some new relevance for the application of melanopic lux as an additional metric to predict non-visual light effects of electrical light sources for nursing homes, work places, and homes.

Blue-Enriched Morning Light as a Countermeasure to Light at the Wrong Time: Effects on Cognition, Sleepiness, Sleep, and Circadian Phase.

Light during the day and darkness at night are crucial factors for proper entrainment of the human circadian system to the solar 24-h day. However, modern life and work styles have led to much more time spent indoors, often with lower daytime and higher evening/nighttime light intensity from electrical lighting than outdoors. Whether this has long-term consequences for human health is being currently investigated. We tested if bright blue-enriched morning light over several days could counteract the detrimental effects of inadequate daytime and evening lighting. In a seminaturalistic, within-between subject study design, 18 young participants were exposed to different lighting conditions on 3 evenings (blue-enriched, bright orange, or dim light), after exposure to 2 lighting conditions (mixed blue-enriched light and control light, for 3 days each) in the mornings. Subjective sleepiness, reaction times, salivary melatonin concentrations, and nighttime sleep were assessed. Exposure to the blue-enriched morning lighting showed acute wake-promoting effects and faster reaction times than with control lighting. Some of these effects persisted until the evening, and performance improved over several days. The magnitude of circadian phase shifts induced by combinations of 3 different evening and 2 morning lighting conditions were significantly smaller with the blue-enriched morning light. During the night, participants had longer total sleep times after orange light exposure than after blue light exposure in the evening. Our results indicate that bright blue-enriched morning light stabilizes circadian phase, and it could be an effective counterstrategy for poor lighting during the day and also light exposure at the wrong time, such as in the late evening.

Out of the lab and into the bathroom: evening short-term exposure to conventional light suppresses melatonin and increases alertness perception.

Life in 24-h society relies on the use of artificial light at night that might disrupt synchronization of the endogenous circadian timing system to the solar day. This could have a negative impact on sleep-wake patterns and psychiatric symptoms. The aim of the study was to investigate the influence of evening light emitted by domestic and work place lamps in a naturalistic setting on melatonin levels and alertness in humans. Healthy subjects (6 male, 3 female, 22-33 years) were exposed to constant dim light (<10 lx) for six evenings from 7:00 p.m. to midnight. On evenings 2 through 6, 1 h before habitual bedtime, they were also exposed to light emitted by 5 different conventional lamps for 30 min. Exposure to yellow light did not alter the increase of melatonin in saliva compared to dim light baseline during (38 ± 27 pg/mL vs. 39 ± 23 pg/mL) and after light exposure (39 ± 22 pg/mL vs. 44 ± 26 pg/mL). In contrast, lighting conditions including blue components reduced melatonin increase significantly both during (office daylight white: 25 ± 16 pg/mL, bathroom daylight white: 24 ± 10 pg/mL, Planon warm white: 26 ± 14 pg/mL, hall daylight white: 22 ± 14 pg/mL) and after light exposure (office daylight white: 25 ± 15 pg/mL, bathroom daylight white: 23 ± 9 pg/mL, Planon warm white: 24 ± 13 pg/mL, hall daylight white: 22 ± 26 pg/mL). Subjective alertness was significantly increased after exposure to three of the lighting conditions which included blue spectral components in their spectra. Evening exposure to conventional lamps in an everyday setting influences melatonin excretion and alertness perception within 30 min.

Molecular insights into human daily behavior.

Human beings exhibit wide variation in their timing of daily behavior. We and others have suggested previously that such differences might arise because of alterations in the period length of the endogenous human circadian oscillator. Using dermal fibroblast cells from skin biopsies of 28 subjects of early and late chronotype (11 "larks" and 17 "owls"), we have studied the circadian period lengths of these two groups, as well as their ability to phase-shift and entrain to environmental and chemical signals. We find not only period length differences between the two classes, but also significant changes in the amplitude and phase-shifting properties of the circadian oscillator among individuals with identical "normal" period lengths. Mathematical modeling shows that these alterations could also account for the extreme behavioral phenotypes of these subjects. We conclude that human chronotype may be influenced not only by the period length of the circadian oscillator, but also by cellular components that affect its amplitude and phase. In many instances, these changes can be studied at the molecular level in primary dermal cells.