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Mental health is independently influenced by the inclination to sleep at specific times (chronotype) and the actual sleep timing (behavior). Chronotype and timing of actual sleep are, however, often misaligned. This study aims to determine how chronotype, sleep timing, and the alignment between the two impact mental health. In a community-dwelling cohort of middle- and older-aged adults (UK Biobank, n = 73,888), we examined the impact of chronotype (questionnaire-based), the timing of behavior (determined with 7-day accelerometry), and the alignment between the two on mental, behavioral, neurodevelopmental disorders (MBN), depression, and anxiety, as assessed through ICD-10 codes. As compared to morning types with early behavior (aligned), morning types with late behavior (misaligned) had an increased risk of having MBN, depression, and anxiety (p's<0.001). As compared to evening-types with late behavior (aligned), however, evening-types with early behavior (misaligned) had a decreased risk of depression (p < 0.01), with a trend for MBN (p = 0.04) and anxiety (p = 0.05). Longitudinal analyses, in which the likelihood of developing de novo mental health disorders was associated with chronotype, behavioral timing, and alignment between the two, confirmed cross-sectional findings. To age healthily, individuals should start sleeping before 1AM, despite chronobiological preferences., Competing Interests: Declaration of competing interest None., (Published by Elsevier B.V.)

Objectives: To explore how the blood plasma proteome fluctuates across the 24-hour day and identify a subset of proteins that show endogenous circadian rhythmicity., Methods: Plasma samples from 17 healthy adults were collected hourly under controlled conditions designed to unmask endogenous circadian rhythmicity; in a subset of 8 participants, we also collected samples across a day on a typical sleep-wake schedule. A total of 6916 proteins were analyzed from each sample using the SomaScan aptamer-based multiplexed platform. We used differential rhythmicity analysis based on a cosinor model with mixed effects to identify a subset of proteins that showed circadian rhythmicity in their abundance., Results: One thousand and sixty-three (15%) proteins exhibited significant daily rhythmicity. Of those, 431 (6.2%) proteins displayed consistent endogenous circadian rhythms on both a sleep-wake schedule and under controlled conditions: it included both known and novel proteins. When models were fitted with two harmonics, an additional 259 (3.7%) proteins exhibited significant endogenous circadian rhythmicity, indicating that some rhythmic proteins cannot be solely captured by a simple sinusoidal model. Overall, we found that the largest number of proteins had their peak levels in the late afternoon/evening, with another smaller group peaking in the early morning., Conclusions: This study reveals that hundreds of plasma proteins exhibit endogenous circadian rhythmicity in humans. Future analyses will likely reveal novel physiological pathways regulated by circadian clocks and pave the way for improved diagnosis and treatment for patients with circadian disorders and other pathologies. It will also advance efforts to include knowledge about time-of-day, thereby incorporating circadian medicine into personalized medicine., Competing Interests: Declaration of conflicts of interest Mr. Specht and Mr. Kolosov, and Drs. Arrona-Palacios, Bueno, Cederberg, Duffy, Pardilla-Delgado, Ruiz-Herrera, Zeitzer, and Zitting, declare no conflict of interest. Dr. Pardilla-Delgado is currently employed by Vanda Pharmaceuticals, but this work is unrelated to his position there. Dr. Kramer’s institution has issued patents (PCT/EP2018/066771) related to biomarkers for detecting the clock. This intellectual property has been licensed by BodyClock Technologies GmbH, in which Dr. Kramer is a shareholder. Dr. Mignot occasionally consults and has received contracts from Jazz Pharmaceuticals, Orexia/Centessa, Takeda and ActiGraph; has received grant/clinical trial funding from Harmony, Takeda, Apple, Huami, Sunovion, Idorsia, Eisai; is and has been a Principal Investigator on clinical trials using oxybate salts, orexin agonists and Solriamfetol, Pharmaceutical products, for the treatment of Type 1 narcolepsy; all outside the scope of this work. Dr. Czeisler serves as the incumbent of an endowed professorship provided to Harvard Medical School by Cephalon, Inc., and reports institutional support for a Quality Improvement Initiative from Delta Airlines and Puget Sound Pilots; education support to Harvard Medical School Division of Sleep Medicine and support to Brigham and Women’s Hospital from: Jazz Pharmaceuticals PLC, Inc, Philips Respironics, Inc., Optum, and ResMed, Inc.; research support to Brigham and Women’s Hospital from Axome Therapeutics, Inc., Dayzz Ltd., Peter Brown and Margaret Hamburg, Regeneron Pharmaceuticals, Sanofi SA, Casey Feldman Foundation, Summus, Inc., Takeda Pharmaceutical Co., LTD, Abbaszadeh Foundation, CDC Foundation; educational funding to the Sleep and Health Education Program of the Harvard Medical School Division of Sleep Medicine from ResMed, Inc., Teva Pharmaceuticals Industries, Ltd., and Vanda Pharmaceuticals; personal royalty payments on sales of the Actiwatch-2 and Actiwatch-Spectrum devices from Philips Respironics, Inc; personal consulting fees from Axsome, Inc., Bryte Foundation, With Deep, Inc., and Vanda Pharmaceuticals, the Institute of Digital Media and Child Development, the Klarman Family Foundation, and the UK Biotechnology and Biological Sciences Research Council; honoraria from the Associated Professional Sleep Societies, the Massachusetts Medical Society, the National Council for Mental Wellbeing, and the National Sleep Foundation; lecture fees from Teva Pharma Australia PTY Ltd. and Emory University. Dr. Czeisler has received personal fees for serving as an expert witness on a number of civil matters, criminal matters, and arbitration cases, including those involving the following commercial and government entities: Amtrak; Bombardier, Inc.; C&J Energy Services; Dallas Police Association; Delta Airlines/Comair; Enterprise Rent-A-Car; FedEx; Greyhound Lines, Inc./Motor Coach Industries/FirstGroup America; PAR Electrical Contractors, Inc.; Puget Sound Pilots; and the San Francisco Sheriff’s Department; Schlumberger Technology Corp.; Union Pacific Railroad; United Parcel Service; Vanda Pharmaceuticals. Dr. Czeisler has received travel support from the Stanley Ho Medical Development Foundation, Merck Sharpe and Dohme; equity interest in Vanda Pharmaceuticals, With Deep, Inc, and Signos, Inc.; and institutional educational gifts to Brigham and Women’s Hospital from Johnson & Johnson, Mary Ann and Stanley Snider via Combined Jewish Philanthropies, Alexandra Drane, DR Capital, Harmony Biosciences, LLC, San Francisco Bar Pilots, Whoop, Inc., Harmony Biosciences LLC, Eisai Co., LTD, Idorsia Pharmaceuticals LTD, Sleep Number Corp., Apnimed, Inc., Avadel Pharmaceuticals, Bryte Foundation, f.lux Software, LLC, and the Stuart F. and Diana L. Quan Charitable Fund. Dr Czeisler's interests, which are all outside the scope of this work, were reviewed and are managed by the Brigham and Women's Hospital and Mass General Brigham in accordance with their conflict-of interest policies., (Copyright © 2024 National Sleep Foundation. Published by Elsevier Inc. All rights reserved.)

Light at night can improve alertness and cognition. Exposure to daytime light, however, has yielded less conclusive results. In addition to direct effects, daytime light may also mitigate the impact of nocturnal light exposure on alertness. To examine the impact of daytime lighting on daytime cognitive performance, and evening alertness, we studied nine healthy individuals using a within subject crossover design. On four visits, participants were exposed to one of four lighting conditions for 10 h (dim fluorescent, room fluorescent, broad-spectrum LED, standard white LED; the latter three conditions were matched for 100 lx) followed by an exposure to bright evening light. Cognitive performance, subjective and objective measures of alertness were regularly obtained. While daytime alertness was not impacted by light exposure, the broad-spectrum LED light improved several aspects of daytime cognition. The impact of evening light on alertness was not mitigated by the pre-exposure to different daytime lighting conditions. Results suggest that daytime exposure to white light with high melanopic efficacy has the potential to improve daytime cognitive function and that such improvements are likely to be direct rather than a consequence of light-induced changes in alertness., (Published by Elsevier B.V.)

The central pacemaker of flies, rodents, and humans generates less robust circadian output signals across normative aging. It is not well understood how changes in light sensitivity might contribute to this phenomenon. In the present study, we summarize results from an extended data series (n = 5681) showing that the locomotor activity rhythm of aged Drosophila can phase-shift normally to intermittently spaced episodes of bright polychromatic light exposure (600 lx) but that deficits emerge in response to 8, 16, and 120-millisecond flashes of narrowband blue (λ m , 452 nm) and green (λ m , 525 nm) LED light. For blue, phase-resetting of the activity rhythm of older flies is not as energy efficient as it is in younger flies at the fastest flash-exposures tested (8 milliseconds), suggesting there might be different floors of light duration necessary to incur photohabituation in each age group. For green, the responses of older flies are universally crippled relative to those of younger flies across the slate of protocols we tested. The difference in green flash photosensitivity is one of the most salient age-related phenotypes that has been documented in the circadian phase-shifting literature thus far. These data provide further impetus for investigations on pacemaker aging and how it might relate to changes in the circadian system's responses to particular sequences of light exposure tuned for wavelength, intensity, duration, and tempo., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Altered 24-hour rest-activity rhythms may be associated with cognitive impairment in older adults, but evidence from prospective studies is limited. Nonparametric methods were used to assess actigraphy-based activity patterns in 2 496 older men. Incident cognitive impairment was assessed 4 times over 12 years using the Modified Mini-Mental State Examination (3MS) and Trails B tests, self-reported medication use, and clinical diagnosis. The highest quartile (vs the lowest) of intradaily variability and the lowest quartiles (vs the highest) of interdaily stability and relative amplitude were associated with incident cognitive impairment (hazard ratio [95% confidence interval]: 1.82 [1.31-2.53], 1.36 [0.99-1.86], and 1.85 [1.33-2.56], respectively). A larger increase in intradaily variability over 7.5 years was associated with a greater subsequent decline in 3MS scores but not in Trails B performance. In conclusion, less stable and more variable rest-activity rhythms may represent early biomarkers of cognitive impairment in older men., (© The Author(s) 2021. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Light is the preeminent external influence in determining the position of the internal circadian clock relative to the outside world. In this chapter, we discuss the different parameters of light that impact how it influences the human circadian clock. We detail how the timing (phase), intensity, duration and temporal structure, and spectral composition all can modulate the impact of light on both the timing of the circadian clock as well as its amplitude. The neurobiological underpinnings of the system are briefly discussed in the context of understanding how light can evoke its observed effects on the circadian clock., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The circadian wake drive is a mathematic representation of the observed increased propensity to stay awake late in the day, peaking in the hours just before anticipated bed time. It has been called the "forbidden zone" due to the difficulty in initiating sleep during this time and is responsible for the problems initiating sleep when traveling eastward, for maintaining daytime sleep in shift workers, and for initiating sleep in some individuals with insomnia. Evidence culled from studies in individuals with narcolepsy, who lack production of hypocretin (orexin) neuropeptides, as well as a primate model of human wake consolidation and pharmacologic studies of hypocretin antagonists indicate that hypocretin-1 may be the physiologic instantiation of the circadian wake drive. This review will discuss the evidence in support of this hypothesis., (Published by Elsevier Inc.)

Background: Flattened diurnal salivary cortisol patterns predict shorter subsequent survival with breast, lung, and renal cell carcinomas. The underlying cause of this flattened slope is undetermined, though it has been hypothesized to be secondary to a deficit in the amplitude of the circadian clock. To gain greater insight into the portions of the diurnal salivary curve that are associated with cancer survival, we examined (1) which points in the diurnal curve are predictive of the slope of the curve and (2) whether elevated evening cortisol levels alone are associated with reduced HPA-axis feedback inhibition (i.e., decreased sensitivity to the dexamethasone suppression test)., Method: We examined study hypotheses on adult women with advanced breast cancer (age = 54.3 ± 9.58 years; n = 99) using non-parametric Wilcoxon's rank-sum tests, Spearman correlation coefficients and an accuracy formula based on a confusion matrix. Cortisol was sampled five times per day for three consecutive days, with dexamethasone administered late on the second day., Results: Salivary cortisol concentrations did not vary between those with flat and steep slopes during the morning (p's > .05), but did vary in the evening (p's < 0.05). Furthermore, the concentration of the 2100h alone was 86% accurate in discriminating between individuals classified as having "flat" or "steep" slopes. Dexamethasone suppression was only associated with diurnal salivary cortisol slope (p = .0042)., Conclusions: Evening cortisol levels are a sensitive indicator flattened diurnal cortisol slope, suggesting evening cortisol may also be a useful predictor of breast cancer survival. Future research should focus on determining the causes of abnormally increased evening cortisol., Competing Interests: Declaration of Competing Interest No authors on this manuscript have any conflicts of interest., (Copyright © 2020. Published by Elsevier Ltd.)

The human circadian pacemaker entrains to the 24-h day, but interindividual differences in properties of the pacemaker, such as intrinsic period, affect chronotype and mediate responses to challenges to the circadian system, such as shift work and jet lag, and the efficacy of therapeutic interventions such as light therapy. Robust characterization of circadian properties requires desynchronization of the circadian system from the rest-activity cycle, and these forced desynchrony protocols are very time and resource intensive. However, circadian protocols designed to derive the relationship between light intensity and phase shift, which is inherently affected by intrinsic period, may be applied more broadly. To exploit this relationship, we applied a mathematical model of the human circadian pacemaker with a Markov-Chain Monte Carlo parameter estimation algorithm to estimate the representative group intrinsic period for a group of participants using their collective illuminance-response curve data. We first validated this methodology using simulated illuminance-response curve data in which the intrinsic period was known. Over a physiological range of intrinsic periods, this method accurately estimated the representative intrinsic period of the group. We also applied the method to previously published experimental data describing the illuminance-response curve for a group of healthy adult participants. We estimated the study participants' representative group intrinsic period to be 24.26 and 24.27 h using uniform and normal priors, respectively, consistent with estimates of the average intrinsic period of healthy adults determined using forced desynchrony protocols. Our results establish an approach to estimate a population's representative intrinsic period from illuminance-response curve data, thereby facilitating the characterization of intrinsic period across a broader range of participant populations than could be studied using forced desynchrony protocols. Future applications of this approach may improve the understanding of demographic differences in the intrinsic circadian period.

Recent work suggests that the circadian pacemaker responds optimally to millisecond flashes of light, not continuous light exposure as has been historically believed. It is unclear whether these responses are influenced by the physical characteristics of the pulsing. In the present study, Drosophila (n = 2199) were stimulated with 8, 16 or 120 ms flashes. For each duration, the energy content of the exposure was systematically varied by changing the pulse irradiance and the number of stimuli delivered over a fixed 15 min administration window (64 protocols surveyed in all). Results showed that per microjoule invested, 8 ms flashes were more effective at resetting the circadian activity rhythm than 16- and 120 ms flashes (i.e. left shift of the dose-response curve, as well as a higher estimated maximal response). These data suggest that the circadian pacemaker's photosensitivity declines within milliseconds of light contact. Further introduction of light beyond a floor of (at least) 8 ms leads to diminishing returns on phase-shifting.

Introduction: Chronotype (morningness/eveningness) is associated with preference for the timing of many types of behavior, most notably sleep. Chronotype is also associated with differences in the timing of various physiologic events as well as aspects of personality. One aspect linked to personality, prosocial behavior, has not been studied before in the context of chronotype. There are many variables contributing to who, when, and why one human might help another and some of these factors appear fixed, while some change over time or with the environment. It was our intent to examine prosocial behavior in the context of chronotype and environment., Methods: Randomly selected adults (N = 100, ages 18-72) were approached in a public space and asked to participate in a study. If the participants consented (n = 81), they completed the reduced Morning-Eveningness Questionnaire and the Stanford Sleepiness Scale, then prosocial behavior was assessed., Results/conclusions: We found that people exhibited greater prosocial behavior when they were studied further from their preferred time of day. This did not appear to be associated with subjective sleepiness or other environmental variables, such as ambient illumination. This suggests the importance of appreciating the differentiation between the same individual's prosocial behavior at different times of day. Future studies should aim at replicating this result in larger samples and across other measures of prosocial behavior., Competing Interests: The authors have declared that no competing interests exist.

Background: Bipolar disorder (BD) is associated with later sleep and daily activity (evening rather than morning chronotype). Objective chronotype identification (e.g., based on actigraphs/smartphones) has potential utility, but to date, chronotype has mostly been assessed by questionnaires. Given the ubiquity of accelerometer-based devices (e.g. actigraphs/smartphones) worn/used during daytime and tendency to recharge rather than wear at night, we assessed chronotype using daytime (rather than sleep) interval midpoints., Methods: Sixty-one participants with BD type I (BD-I) or II (BD-II) and 61 healthy controls completed 25-50 days of continuous actigraphy. The Composite Scale of Morningness (CSM) was completed by a subset of this group. Daytime activity midpoint was calculated for each daytime interval, excluding naps. Evening chronotype was defined as having a daytime interval midpoint at or after 16:15:00 (4:15:00 PM)., Results: BD versus controls had delayed daytime midpoint (mean ± standard deviation) (16:49:07 ± 01:26:19 versus 16:12:51 ± 01:02:14, p < 0.01), and greater midpoint variability (73.3 ± 33.9 min versus 58.1 ± 18.3 min, p < 0.01). Stratifying by gender and age, females and adolescents with BD had delayed and more variable daytime midpoints versus controls. Adults with BD had greater midpoint variability than controls. Within-person mean and standard deviations of daytime midpoints were highly correlated with sleep midpoints (r = 0.99, p < 0.01 and r = 0.86, p < 0.01, respectively). Daytime midpoint mean was also significantly correlated with the CSM (r = -0.56, p < 0.01)., Limitations: Small sample size; analyses not fully accounting for daytime napping., Conclusions: Wrist actigraphy for determination of daytime midpoints is a potential tool to identify objective chronotype. Exploration of the use of consumer devices (wearables/smartphones) is needed., (Copyright © 2018 Elsevier B.V. All rights reserved.)

While a relationship between disruption of circadian rhythms and the progression of cancer has been hypothesized in field and epidemiologic studies, it has never been unequivocally demonstrated. We determined the circadian rhythm of cortisol and sleep in women with advanced breast cancer (ABC) under the conditions necessary to allow for the precise measurement of these variables. Women with ABC (n = 97) and age-matched controls (n = 24) took part in a 24-h intensive physiological monitoring study involving polysomnographic sleep measures and high-density plasma sampling. Sleep was scored using both standard clinical metrics and power spectral analysis. Three-harmonic regression analysis and functional data analysis were used to assess the 24-h and sleep-associated patterns of plasma cortisol, respectively. The circadian pattern of plasma cortisol as described by its timing, timing relative to sleep, or amplitude was indistinguishable between women with ABC and age-matched controls (p's > 0.11, t-tests). There was, however, an aberrant spike of cortisol during the sleep of a subset of women, during which there was an eightfold increase in the amount of objectively measured wake time (p < 0.004, Wilcoxon Signed-Rank). This cortisol aberration was associated with cancer progression such that the larger the aberration, the shorter the disease-free interval (time from initial diagnosis to metastasis; r = -0.30, p = 0.004; linear regression). The same aberrant spike was present in a similar percent of women without ABC and associated with concomitant sleep disruption. A greater understanding of this sleep-related cortisol abnormality, possibly a vulnerability trait, is likely important in our understanding of individual variation in the progression of cancer.

Background: Beyond image formation, the light that is detected by retinal photoreceptors influences subcortical functions, including circadian timing, sleep, and arousal. The physiology of nonimage-forming (NIF) photoresponses in humans is not well understood; therefore, the development of therapeutic interventions based on this physiology, such as bright light therapy to treat chronobiological disorders, remains challenging., Methods: Thirty-nine participants were exposed to 60 minutes of either continuous light (n = 8) or sequences of 2-millisecond light flashes (n = 31) with different interstimulus intervals (ISIs; ranging from 2.5 to 240 seconds). Melatonin phase shift and suppression, along with changes in alertness and sleepiness, were assessed., Results: We determined that the human circadian system integrates flash sequences in a nonlinear fashion with a linear rise to a peak response (ISI = 7.6 ± 0.53 seconds) and a power function decrease following the peak of responsivity. At peak ISI, flashes were at least 2-fold more effective in phase delaying the circadian system as compared with exposure to equiluminous continuous light 3,800 times the duration. Flashes did not change melatonin concentrations or alertness in an ISI-dependent manner., Conclusion: We have demonstrated that intermittent light is more effective than continuous light at eliciting circadian changes. These findings cast light on the phenomenology of photic integration and suggest a dichotomous retinohypothalamic network leading to circadian phase shifting and other NIF photoresponses. Further clinical trials are required to judge the practicality of light flash protocols., Trial Registration: Clinicaltrials.gov NCT01119365., Funding: National Heart, Lung, and Blood Institute (1R01HL108441-01A1) and Department of Veterans Affairs Sierra Pacific Mental Illness Research, Education, and Clinical Center.

The human circadian timing system is most sensitive to the phase-shifting effects of light during the biological nighttime, a time at which humans are most typically asleep. The overlap of sleep with peak sensitivity to the phase-shifting effects of light minimizes the effectiveness of using light as a countermeasure to circadian misalignment in humans. Most current light exposure treatments for such misalignment are mostly ineffective due to poor compliance and secondary changes that cause sleep deprivation. Using a 16-day, parallel group design, we examined whether a novel sequence of light flashes delivered during sleep could evoke phase changes in the circadian system without disrupting sleep. Healthy volunteers participated in a 2-week circadian stabilization protocol followed by a 2-night laboratory stay. During the laboratory session, they were exposed during sleep to either darkness (n = 7) or a sequence of 2-msec light flashes given every 30 sec (n = 6) from hours 2 to 3 after habitual bedtime. Changes in circadian timing (phase) and micro- and macroarchitecture of sleep were assessed. Subjects exposed to the flash sequence during sleep exhibited a delay in the timing of their circadian salivary melatonin rhythm compared with the control dark condition (p < 0.05). Confirmation that the flashes penetrated the eyelids is presented by the occurrence of an evoked response in the EEG. Despite the robust effect on circadian timing, there were no large changes in either the amount or spectral content of sleep (p values > 0.30) during the flash stimulus. Exposing sleeping individuals to 0.24 sec of light spread over an hour shifted the timing of the circadian clock and did so without major alterations to sleep itself. While a greater number of matched subjects and more research will be necessary to ascertain whether these light flashes affect sleep, our data suggest that this type of passive phototherapy might be developed as a useful treatment for circadian misalignment in humans., (© 2014 The Author(s).)

Disruption of circadian rhythms, which frequently occurs during night shift work, may be associated with cancer progression. The effect of chronotype (preference for behaviors such as sleep, work, or exercise to occur at particular times of day, with an associated difference in circadian physiology) and alignment of bedtime (preferred vs. habitual), however, have not yet been studied in the context of cancer progression in women with breast cancer. Chronotype and alignment of actual bedtime with preferred chronotype were examined using the Morningness-Eveningness Scale (MEQ) and sleep-wake log among 85 women with metastatic breast cancer. Their association with disease-free interval (DFI) was retrospectively examined using the Cox proportional hazards model. Median DFI was 81.9 months for women with aligned bedtimes ("going to bed at preferred bedtime") (n = 72), and 46.9 months for women with misaligned bedtimes ("going to bed later or earlier than the preferred bedtime") (n = 13) (log rank p = 0.001). In a multivariate Cox proportional hazard model, after controlling for other significant predictors of DFI, including chronotype (morning type/longer DFI; HR = 0.539, 95% CI = 0.320-0.906, p = 0.021), estrogen receptor (ER) status at initial diagnosis (negative/shorter DFI; HR = 2.169, 95% CI = 1.124-4.187, p = 0.028) and level of natural-killer cell count (lower levels/shorter DFI; HR = 1.641, 95% CI = 1.000-2.695, p = 0.050), misaligned bedtimes was associated with shorter DFI, compared to aligned bedtimes (HR = 3.180, 95% CI = 1.327-7.616, p = 0.018). Our data indicate that a misalignment of bedtime on a daily basis, an indication of circadian disruption, is associated with more rapid breast cancer progression as measured by DFI. Considering the limitations of small sample size and study design, a prospective study with a larger sample is necessary to explore their causal relationship and underlying mechanisms.

Introduction: The 'diurnal slope' of salivary cortisol has been used as a measure of stress and circadian function in a variety of reports with several detailing its association with cancer progression. The relationship of this slope, typically a negative value from high morning concentrations to low evening concentrations, to the underlying daily variation in total plasma cortisol throughout the 24-hour cycle, however, has never been reported., Methods: To examine the relationship between the diurnal salivary cortisol slope and the underlying pattern of plasma cortisol in individuals with cancer, we examined a cohort of women with advanced breast cancer (n = 97) who had saliva and plasma collected during a modified 24-hour, constant posture protocol., Results: We found that the steepness of the diurnal slope of salivary cortisol was correlated with the amplitude of plasma cortisol rhythm when the slope was calculated from samples taken at wake + 30 min and 9 PM (r = -0.29, p > 0.05). Other variants of salivary slope calculations were not significantly correlated with the amplitude of the plasma cortisol rhythm. Diurnal salivary cortisol slope steepness was not correlated with the time between habitual waking and the computed circadian peak of cortisol, but there was a correlation between diurnal slope steepness and the time between habitual waking and the time of the awakening spike of morning cortisol (r values <-0.23, p values <0.05)., Conclusion: It therefore appears that in women with advanced breast cancer, diurnal salivary cortisol slope primarily represents aspects of the cortisol awakening response in relation to evening levels more than the circadian rhythm of total plasma cortisol., (© 2014 S. Karger AG, Basel.)

Objective: To examine the validity of a novel caffeine intake questionnaire and to examine the effects of caffeine on sleep in college students., Methods: One-week, ad libitum behavior of 50 university students (28 female, 22 male; aged 20.9 ± 1.78 years) was examined with sleep logs, wrist actigraphy, and a novel daily questionnaire assessing caffeine intake at different times of day. Saliva samples were collected for caffeine assessment (questionnaire validation) and DNA extraction, and for analysis of a single nucleotide polymorphism in the adenosine receptor 2A (ADORA2A) gene., Results: The caffeine questionnaire was able to accurately predict salivary concentrations of caffeine (R(2) = 0.41, P<0.001). Estimations of integrated salivary caffeine concentration during sleep were correlated with wake after sleep onset (WASO) most strongly in morning-type individuals (R(2) = 0.49; P<0.001, ANOVA), less so in intermediate chronotypes (R(2) = 0.16; P<0.001, ANOVA), and not significantly in evening-types (R(2) = 0.00098; P = 0.13, ANOVA). Using multivariate modeling methods we found that the ADORA2A genotype did not moderate the effects of caffeine on WASO, but did independently alter WASO such that those with the CC genotype had nearly three-times as much WASO as those with CT or TT., Conclusions: Our questionnaire was able to accurately predict salivary caffeine concentrations and helped to describe a novel relationship between the effects of caffeine on sleep and genotype and chronotype., (Published by Elsevier B.V.)

Ocular light sensitivity is the primary mechanism by which the central circadian clock, located in the suprachiasmatic nucleus (SCN), remains synchronized with the external geophysical day. This process is dependent on both the intensity and timing of the light exposure. Little is known about the impact of the duration of light exposure on the synchronization process in humans. In vitro and behavioral data, however, indicate the circadian clock in rodents can respond to sequences of millisecond light flashes. In a cross-over design, we tested the capacity of humans (n = 7) to respond to a sequence of 60 2-msec pulses of moderately bright light (473 lux) given over an hour during the night. Compared to a control dark exposure, after which there was a 3.5±7.3 min circadian phase delay, the millisecond light flashes delayed the circadian clock by 45±13 min (p<0.01). These light flashes also concomitantly increased subjective and objective alertness while suppressing delta and sigma activity (p<0.05) in the electroencephalogram (EEG). Our data indicate that phase shifting of the human circadian clock and immediate alerting effects can be observed in response to brief flashes of light. These data are consistent with the hypothesis that the circadian system can temporally integrate extraordinarily brief light exposures.

Studies of sex differences in the timing of human circadian rhythms have reported conflicting results. This may be because the studies conducted to date have not controlled for the masking effects of the rest activity cycle on the circadian rhythms being assessed. In the present analysis of data collected under controlled conditions, we examined sex differences in the timing of circadian rhythms while minimizing masking from behavioral and environmental factors using a constant routine (CR) protocol. All participants (28 women and 28 men paired by habitual wake time; age range, 18 30 years) maintained a regular self selected sleep wake schedule at home prior to the study. After 3 baseline days in the laboratory, participants began a CR. Women were found to have a significantly higher melatonin amplitude and lower temperature amplitude than men. While sleep timing was the same between the 2 groups, the timing of the circadian rhythms of core body temperature and pineal melatonin secretion was earlier relative to sleep time in women as compared to men. Sleep therefore occurred at a later biological time for women than men, despite being at the same clock time. Given that sleep propensity and structure vary with circadian phase and are impacted by circulating melatonin, these findings may have important implications for understanding sex differences in sleep timing and duration, diurnal preference, and the prevalence of sleep disorders such as insomnia.

Objectives: To determine whether bright light can improve sleep in older individuals with insomnia., Design: Single-blind, placebo-controlled, 12-week, parallel-group randomized design comparing four treatment groups representing a factorial combination of two lighting conditions and two times of light administration., Setting: At-home light treatment; eight office therapy sessions., Participants: Thirty-six women and fifteen men (aged 63.6+/-7.1) meeting primary insomnia criteria recruited from the community., Intervention: A 12-week program of sleep hygiene and exposure to bright ( approximately 4,000 lux) or dim light ( approximately 65 lux) scheduled daily in the morning or evening for 45 minutes., Measurements: Within-group changes were observed for subjective (sleep logs, questionnaires) and objective (actigraphy, polysomnography) sleep measures after morning or evening bright light., Results: Within-group changes for subjective sleep measures after morning or evening bright light were not significantly different from those observed after exposure to scheduled dim light. Objective sleep changes (actigraphy, polysomnography) after treatment were not significantly different between the bright and dim light groups. Scheduled light exposure was able to shift the circadian phase predictably but was unrelated to changes in objective or subjective sleep measures. A polymorphism in CLOCK predicted morningness but did not moderate the effects of light on sleep. The phase angle between the circadian system (melatonin midpoint) and sleep (darkness) predicted the magnitude of phase delays, but not phase advances, engendered by bright light., Conclusion: Except for one subjective measure, scheduled morning or evening bright light effects were not different from those of scheduled dim light. Thus, support was not found for bright light treatment of older individuals with primary insomnia.

Study Objectives: To determine the effects of sleep and sleep deprivation on plasma melatonin concentrations in humans and whether these effects are age-dependent., Design: At least 2 weeks of regular at-home, sleep/wake schedule followed by 3 baseline days in the laboratory and at least one constant routine (sleep deprivation)., Setting: General Clinical Research Center (GCRC), Brigham and Women's Hospital, Boston, MA., Participants: In Study 1, one group (<10 lux when awake) of 19 young men (18-30 y) plus a second group (<2 lux when awake) of 15 young men (20-28 y) and 10 young women (19-27 y); in Study 2, 90 young men (18-30 y), 18 older women (65-81 y), and 11 older men (64-75 y). All participants were in good health, as determined by medical and psychological screening., Interventions: One to three constant routines with interspersed inversion of the sleep/wake cycle in those with multiple constant routines., Measurements and Results: Examination of plasma melatonin concentrations and core body temperature. Study 1. There was a small, but significant effect of sleep deprivation of up to 50 hours on melatonin concentrations (increase of 9.81 +/- 3.73%, P <0.05, compared to normally timed melatonin). There was also an effect of circadian phase angle with the prior sleep episode, such that if melatonin onset occurred <8 hours after wake time, the amplitude was significantly lower (22.4% +/- 4.79%, P <0.001). Study 2. In comparing melatonin concentrations during sleep to the same hours during constant wakefulness, in young men, melatonin amplitude was 6.7% +/- 2.1% higher(P <0.001) during the sleep episode. In older men, melatonin amplitude was 37.0% +/- 12.5% lower (P <0.05) during the sleep episode and in older women, melatonin amplitude was non-significantly 10.9% +/- 8.38% lower (P = 0.13) during the sleep episode., Conclusions: Both sleep and sleep deprivation likely influence melatonin amplitude, and the effect of sleep on melatonin appears to be age dependent.

The rhythm of plasma melatonin concentration is currently the most accurate marker of the endogenous human circadian pacemaker. A number of methods exist to estimate circadian phase and amplitude from the observed melatonin rhythm. However, almost all these methods are limited because they depend on the shape and amplitude of the melatonin pulse, which vary among individuals and can be affected by environmental influences, especially light. Furthermore, these methods are not based on the underlying known physiology of melatonin secretion and clearance, and therefore cannot accurately quantify changes in secretion and clearance observed under different experimental conditions. A published physiologically-based mathematical model of plasma melatonin can estimate synthesis onset and offset of melatonin under dim light conditions. We amended this model to include the known effect of melatonin suppression by ocular light exposure and to include a new compartment to model salivary melatonin concentration, which is widely used in clinical settings to determine circadian phase. This updated model has been incorporated into an existing mathematical model of the human circadian pacemaker and can be used to simulate experimental protocols under a number of conditions.

Aging is associated with a change in the relationship between the timing of sleep and circadian rhythms, such that the rhythms occur later with respect to sleep than in younger adults. To investigate whether a difference in the phase-delaying response to evening light contributes to this, we conducted a 9-day inpatient study in 10 healthy older (> or =65 y.o.) subjects. We assessed circadian phase in a constant routine, exposed each subject to a 6.5h broad-spectrum light stimulus beginning in the early biological night, and reassessed circadian phase. The stimuli spanned a range from very dim (approximately 2 lx) to very bright (approximately 8000 lx) indoor light. We found a significant dose-response relationship between illuminance and the phase shift of the melatonin rhythm, with evidence that sensitivity, but not the maximal response to light, differed from that of younger adults. These findings suggest an age-related reduction in the phase-delaying response to moderate light levels. However, our findings alone do not explain the altered phase relationship between sleep and circadian rhythms associated with aging.

The light-dark cycle is the primary synchronizing factor that keeps the internal circadian pacemaker appropriately aligned with the environmental 24-h day. Although it is known that ocular light exposure can effectively shift the human circadian pacemaker and do so in an intensity-dependent manner, the curve that describes the relationship between light intensity and pacemaker response has not been fully characterized for light exposure in the late biological night. We exposed subjects to 3 consecutive days of 5 h of experimental light, centered 1.5 h after the timing of the fitted minimum of core body temperature, and show that such light can phase advance shift the human circadian pacemaker in an intensity-dependent manner, with a logistic model best describing the relationship between light intensity and phase shift. A similar sigmoidal relationship is also observed between light intensity and the suppression of plasma melatonin concentrations that occurs during the experimental light exposure. As with a simpler, 1-day light exposure during the early biological night, our data indicate that the human circadian pacemaker is highly sensitive even to typical room light intensities during the late biological night, with approximately 100 lux evoking half of the effects observed with light 10 times as bright.

Study Objectives: Hypocretins (orexins) are involved in the sleep disorder narcolepsy. While hypocretin-1 has a daily oscillation, little is known regarding the relative contribution of circadian and homeostatic components on hypocretin release. The effect of lesions of the suprachiasmatic nucleus (SCN) on hypocretin-1 in the cerebrospinal fluid (CSF) was examined., Design: SCN-ablated (SCNx) and sham-operated control rats were implanted with activity-temperature transmitters. Animals were housed individually under 1 of 3 lighting conditions: 12-hour:12-hour light:dark cycle (LD), constant light (LL), and constant darkness (DD). Lesions were verified histologically and shown not to affect hypocretin-containing cells. Hypocretin-1 concentrations in the CSF were determined every 4 hours using radioimmunoassays., Measurements and Results: Control animals displayed robust circadian (LL, DD) and diurnal (LD) fluctuations in CSF hypocretin-1, locomotor activity, and temperature. Peak CSF hypocretin-1 was at the end of the active period. Activity, temperature, and CSF hypocretin-1 were arrhythmic in SCNx animals in LL and DD. In LD, a weak but significant fluctuation in activity and temperature but not CSF hypocretin-1 was observed in SCNx animals. We also explored correlations between CSF hypocretin-1, CSF corticosterone, and locomotor activity occurring prior to CSF sampling in arrhythmic SCNx rats under constant conditions. Significant correlations between hypocretin-1 and activity were observed both across and within animals, suggesting that interindividual and time-of-the-day differences in activity have significant effects on hypocretin release in arrhythmic animals. No correlation was found between CSF hypocretin-1 and corticosterone., Conclusions: Hypocretin-1 release is under SCN control. Locomotor activity influences the activity of the hypocretin neurons.

Background: Hypocretins, excitatory neuropeptides at monoaminergic synapses, appear to regulate human sleep-wake cycles. Undetectable cerebrospinal fluid hypocretin-1 levels are seen in narcolepsy, which is frequently associated with secondary depression. Shortened rapid eye movement latency is observed in both narcolepsy and depression. Cerebrospinal fluid hypocretin-1 levels have not been reported in mood disorders., Methods: We examined hypocretin-1 levels in 14 control and 15 depressed subjects. Cerebrospinal fluid was drawn continuously in supine subjects for 24 hours with an indwelling intrathecal catheter under entrained light-dark conditions. Depressed subjects were studied before and after 5 weeks of sertraline (n=10, three nonresponders) or bupropion (n=5, two nonresponders)., Results: Hypocretin-1 levels varied slightly (amplitude 10%) but significantly across the diurnal cycle in control subjects, with amplitude significantly reduced in depression (3%). Levels were lowest at midday, surprising for a hypothetically wake-promoting peptide. Mean hypocretin levels trended higher in depressive than in control subjects. Hypocretin-1 levels decreased modestly but significantly after sertraline (-14%) but not bupropion., Conclusions: Our results are consistent with previous physiologic findings in depression indicating dampened diurnal variations in hypocretin-1. The finding that sertraline but not bupropion slightly decreased cerebrospinal fluid hypocretin-1 indicates a serotoninergic influence on hypocretin tone.

In humans, consolidation of wakefulness into a single episode can be modeled as the interaction of two processes, a homeostatic "hour-glass" wake signal that declines throughout the daytime and a circadian wake-promoting signal that peaks in the evening. Hypocretins, novel hypothalamic neuropeptides that are dysfunctional in the sleep disorder narcolepsy, may be involved in the expression of the circadian wake-promoting signal. Hypocretins (orexins) are wake-promoting peptides, but their role in normal human sleep physiology has yet to be determined. We examined the daily temporal pattern of hypocretin-1 in the cisternal CSF of the squirrel monkey, a New World primate with a pattern of wake similar to that of humans. Hypocretin-1 levels peaked in the latter third of the day, consistent with the premise that hypocretin-1 is involved in wake regulation. When we lengthened the wake period by 4 hr, hypocretin-1 concentrations remained elevated, indicating a circadian-independent component to hypocretin-1 regulation. Changes in the stress hormone cortisol were not correlated with hypocretin-1 changes. Although hypocretin-1 is at least partially activated by a reactive homeostatic mechanism, it is likely also regulated by the circadian pacemaker. In the squirrel monkey, hypocretin-1 works in opposition to the accumulating sleep drive during the day to maintain a constant level of wake.

We investigated the relationship between sleep timing and the timing of the circadian rhythm of plasma melatonin secretion in a group of healthy young and older subjects without sleep complaints. The timing of sleep and the phase of the circadian melatonin rhythm were earlier in the older subjects. The relationship between the plasma melatonin rhythm and the timing of sleep was such that the older subjects were sleeping and waking earlier relative to their nightly melatonin secretory episode. Consequently, the older subjects were waking at a time when they had higher relative melatonin levels, in contrast with younger subjects, whose melatonin levels were relatively lower by wake time. Our findings indicate that aging is associated not only with an advance of sleep timing and the timing of circadian rhythms but also with a change in the internal phase relationship between the sleep-wake cycle and the output of the circadian pacemaker. In healthy older subjects, the relative timing of the melatonin rhythm with respect to sleep may not play a causal role in sleep disruption.

The daily rhythm of melatonin influences multiple physiological measures, including sleep tendency, circadian rhythms, and reproductive function in seasonally breeding mammals. The biological signal for photoperiodic changes in seasonally breeding mammals is a change in the duration of melatonin secretion, which in a natural environment reflects the different durations of daylight across the year, with longer nights leading to a longer duration of melatonin secretion. These seasonal changes in the duration of melatonin secretion do not simply reflect the known acute suppression of melatonin secretion by ocular light exposure, but also represent long-term changes in the endogenous nocturnal melatonin episode that persist in constant conditions. As the eyes of totally blind individuals do not transmit ocular light information, we hypothesized that the duration of the melatonin secretory episode in blind subjects would be longer than those in sighted individuals, who are exposed to light for all their waking hours in an urban environment. We assessed the melatonin secretory profile during constant posture, dim light conditions in 17 blind and 157 sighted adults, all of whom were healthy and using no prescription or nonprescription medications. The duration of melatonin secretion was not significantly different between blind and sighted individuals. Healthy blind individuals after years without ocular light exposure do not have a longer duration of melatonin secretion than healthy sighted individuals.

Ocular exposure to early morning room light can significantly advance the timing of the human circadian pacemaker. The resetting response to such light has a non-linear relationship to illuminance. The dose-response relationship of the human circadian pacemaker to late evening light of dim to moderate intensity has not been well established. Twenty-three healthy young male and female volunteers took part in a 9 day protocol in which a single experimental light exposure6.5 h in duration was given in the early biological night. The effects of the light exposure on the endogenous circadian phase of the melatonin rhythm and the acute effects of the light exposure on plasma melatonin concentration were calculated. We demonstrate that humans are highly responsive to the phase-delaying effects of light during the early biological night and that both the phase resetting response to light and the acute suppressive effects of light on plasma melatonin follow a logistic dose-response curve, as do many circadian responses to light in mammals. Contrary to expectations, we found that half of the maximal phase-delaying response achieved in response to a single episode of evening bright light ( approximately 9000 lux (lx)) can be obtained with just over 1 % of this light (dim room light of approximately 100 lx). The same held true for the acute suppressive effects of light on plasma melatonin concentrations. This indicates that even small changes in ordinary light exposure during the late evening hours can significantly affect both plasma melatonin concentrations and the entrained phase of the human circadian pacemaker.

The human circadian timing system regulates the temporal organization of several endocrine functions, including the production of melatonin (via a neural pathway that includes the spinal cord), TSH, and cortisol. In traumatic spinal cord injury, afferent and efferent circuits that influence the basal production of these hormones may be disrupted. We studied five subjects with chronic spinal cord injury (three tetraplegic and two paraplegic, all neurologically complete injuries) under stringent conditions in which the underlying circadian rhythmicity of these hormones could be examined. Melatonin production was absent in the three tetraplegic subjects with injury to their lower cervical spinal cord and was of normal amplitude and timing in the two paraplegic subjects with injury to their upper thoracic spinal cord. The amplitude and the timing of TSH and cortisol rhythms were robust in the paraplegics and in the tetraplegics. Our results indicate that neurologically complete cervical spinal injury results in the complete loss of pineal melatonin production and that neither the loss of melatonin nor the loss of spinal afferent information disrupts the rhythmicity of cortisol or TSH secretion.

Despite the preeminence of light as the synchronizer of the circadian timing system, the phototransductive machinery in mammals which transmits photic information from the retina to the hypothalamic circadian pacemaker remains largely undefined. To determine the class of photopigments which this phototransductive system uses, we exposed a group (n = 7) of human subjects to red light below the sensitivity threshold of a scotopic (i.e. rhodopsin/rod-based) system, yet of sufficient strength to activate a photopic (i.e. cone-based) system. Exposure to this light stimulus was sufficient to reset significantly the human circadian pacemaker, indicating that the cone pigments which mediate color vision can also mediate circadian vision.