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Melatonin is produced in the pineal gland under very tight control through the influences of light and the suprachiasmatic nucleus. As such, melatonin circulates in the blood at levels <3 pg/ml during the day and is only actively secreted at night reaching levels of approximately 100 pg/ml. As a consequence of binding to plasma proteins, free melatonin appears in saliva at approximately one third the plasma concentration. Measurement of melatonin is technically challenging because of these very low concentrations and while a number of commercial immunoassay kits are available and mass spectrometry assay methods have been published, not all are fit for purpose and can lead to unreliable conclusions. In this review I discuss the aspects of pineal melatonin production that saliva melatonin reflects, the factors influencing melatonin production or metabolism, saliva collection and analysis methods. Examples are provided of the appropriate use of saliva melatonin measurements; Dim Light Melatonin Onset (DLMO) assessment, impact of light on melatonin and the monitoring of rhythms prior to specific treatments. Examples of inappropriate use of saliva melatonin measurements are also provided including the use of poorly validated assays, morning saliva collections, attempts to stimulate melatonin, and linking specific illnesses to saliva melatonin levels. [ABSTRACT FROM AUTHOR]

There is growing interest in developing artificial lighting that stimulates intrinsically photosensitive retinal ganglion cells (ipRGCs) to entrain circadian rhythms to improve mood, sleep, and health. Efforts have focused on stimulating the intrinsic photopigment, melanopsin; however, specialized color vision circuits have been elucidated in the primate retina that transmit blue-yellow cone-opponent signals to ipRGCs. We designed a light that stimulates color-opponent inputs to ipRGCs by temporally alternating short- and long-wavelength components that strongly modulate short-wavelength sensitive (S) cones. Two-hour exposure to this S-cone modulating light produced an average circadian phase advance of 1 h and 20 min in 6 subjects (mean age = 30 years) compared to no phase advance for the subjects after exposure to a 500 lux white light equated for melanopsin effectiveness. These results are promising for developing artificial lighting that is highly effective in controlling circadian rhythms by invisibly modulating cone-opponent circuits. [ABSTRACT FROM AUTHOR]

Internal circadian phase assessment is increasingly acknowledged as a critical clinical tool for the diagnosis, monitoring, and treatment of circadian rhythm sleep−wake disorders and for investigating circadian timing in other medical disorders. The widespread use of in‐laboratory circadian phase assessments in routine practice has been limited, most likely because circadian phase assessment is not required by formal diagnostic nosologies, and is not generally covered by insurance. At‐home assessment of salivary dim light melatonin onset (DLMO, a validated circadian phase marker) is an increasingly accepted approach to assess circadian phase. This approach may help meet the increased demand for assessments and has the advantages of lower cost and greater patient convenience. We reviewed the literature describing at‐home salivary DLMO assessment methods and identified factors deemed to be important to successful implementation. Here, we provide specific protocol recommendations for conducting at‐home salivary DLMO assessments to facilitate a standardized approach for clinical and research purposes. Key factors include control of lighting, sampling rate, and timing, and measures of patient compliance. We include findings from implementation of an optimization algorithm to determine the most efficient number and timing of samples in patients with Delayed Sleep−Wake Phase Disorder. We also provide recommendations for assay methods and interpretation. Providing definitive criteria for each factor, along with detailed instructions for protocol implementation, will enable more widespread adoption of at‐home circadian phase assessments as a standardized clinical diagnostic, monitoring, and treatment tool. [ABSTRACT FROM AUTHOR]

Idiopathic/isolated REM sleep behavior disorder (iRBD) is widely regarded as an early sign of neurodegeneration leading to synucleinopathies. While circadian rhythm alterations in iRBD have been preliminarily demonstrated, evidence on melatonin secretion patterns in this clinical condition is limited. To address this knowledge gap, this exploratory study aimed to integrate salivary melatonin measurement with actigraphic monitoring in individuals with iRBD and age-matched healthy controls (HC) under real-life conditions. Participants diagnosed with iRBD and HC underwent clinical evaluation and wore an actigraph for seven days and nights. Salivary melatonin concentrations were measured at five time points during the last night of recording. Comparative analyses were conducted on clinical data, actigraphic parameters, and melatonin levels between the two groups. iRBD participants (n = 18) showed greater motor (p < 0.01) and non-motor symptoms (p < 0.001), alongside disruptions in circadian sleep-wake rhythm compared to HC (n = 10). Specifically, actigraphy revealed a delayed central phase measurement (p < 0.05), reduced activity during the most active hours (p < 0.001), and decreased relative amplitude (p < 0.05). Total salivary melatonin concentration was significantly lower in iRBD (p < 0.05), with a slight but non-significant phase delay in dim light melatonin onset. This exploratory study highlights a dysregulation of circadian sleep-wake rhythm coupled with reduced melatonin secretion in iRBD. Future research could add to these preliminary findings to evaluate novel treatment approaches to regulate the sleep-wake cycle and elucidate the implications of circadian dysregulation in the conversion from iRBD to neurodegeneration. • Combined use of actigraphy and salivary melatonin sampling in iRBD patients was tested. • Disrupted sleep-wake rhythms were found in iRBD compared to healthy controls. • Reduced melatonin secretion was observed in iRBD in dim light hours. [ABSTRACT FROM AUTHOR]

IntroductionAspects of circadian sleep health including circadian alignment, circadian phase, or chronotype may be related to mental health outcomes in adolescents. Using novel and robust data collection methods, this study explored the relationship between adolescents' circadian sleep health and traits related to depression, anxiety, stress, and emotional regulation.MethodsFifty-two healthy 14–18-year-olds (58% female; 94% European American) participated in this study. Across a 10-day period, participants completed wrist-worn actigraphy. Next, participants completed a dim-light melatonin onset (DLMO) protocol where 12 saliva samples were collected over a 6-h period to measure circadian phase. Circadian phase was calculated as the duration of time between DMLO to average sleep onset time across the monitoring period. Social jetlag was measured as the discrepancy between sleep times from weekday to weekend. Participants completed the Depression Anxiety Stress Scales (DASS-21), Emotion Regulation Questionnaire (ERQ), and the Morningness-Eveningness Questionnaire for Adolescents (MEQ). Following dichotomizing sleep outcomes into clinically relevant groups (late vs. early circadian phase, aligned vs. misaligned circadian rhythms, minimal social jetlag vs. presence of social jetlag, intermediate to morningness vs. eveningness chronotype), we conducted general linear models to determine circadian group differences in mental health outcomes (depression, anxiety, stress, expressive suppression, and cognitive reappraisal) while controlling for gender and pubertal development.ResultsCircadian phase had a large effect on depression symptoms in adolescents, with adolescents with later DLMO having significantly higher depression scores than those with earlier DLMO (p = 0.031). Chronotype had a medium but non-significant effect on anxiety and stress symptoms in adolescents, with adolescents with eveningness-tendencies having higher anxiety and stress symptoms than those with intermediate to morningness-tendencies (p's = 0.140 and 0.111, respectively).ConclusionsIn the first ever study using gold-standard methodologies to examine the relationship between mental health and circadian sleep health in healthy adolescents, we observed that adolescents with later circadian phase had increased depressive symptoms compared to earlier circadian phase. Furthermore, adolescents who endorsed behaviors that suggest eveningness tendencies may have heightened stress/anxiety. These conclusions encourage future experimental research regarding this topic and may help inform interventions aimed to decrease depression, anxiety, and stress in adolescents.

Circadian rhythm disruption is a core symptom of bipolar disorder (BD), also reflected in altered patterns of melatonin release. Reductions of grey matter (GM) volumes are well documented in BD. We hypothesized that levels and timing of melatonin secretion in bipolar depression could be associated with depressive psychopathology and brain GM integrity. The onset of melatonin secretion under dim light conditions (DLMO) and the amount of time between DLMO and midsleep (i.e. phase angle difference; PAD) were used as circadian rhythm markers. To study the time course of melatonin secretion, an exponential curve fitting the melatonin values was calculated, and the slope coefficients (SLP) were obtained for each participant. Significant differences were found between HC and BD in PAD measures and melatonin profiles. Correlations between PAD and depressive psychopathology were identified. Melatonin secretion patterns were found to be associated with GM volumes in the Striatum and Supramarginal Gyrus in BD. Our findings emphasized the role of melatonin secretion role as a biological marker of circadian synchronization in bipolar depression and provided a novel insight for a link between melatonin release and brain structure. [ABSTRACT FROM AUTHOR]

Due to time zones, sun time and local time rarely match. The difference between local and sun time, which we designate by Solar Jet Lag (SoJL), depends on location within a time zone and can range from zero to several hours. Daylight saving time (DST) simply adds 1 h to SoJL, independently of the location. We hypothesised that the impact of DST is particularly problematic in patients with delayed sleep‐wake phase disorder (DSWPD), worsening their sleep debt. DSWPD is characterised by a chronic misalignment between the internal and social timing, reflected by an inability to fall asleep and wake‐up at conventional or socially acceptable times. We analysed the clinical records of 162 DSWPD patients from a sleep medicine centre in Lisbon, Portugal (GMTzone), and separated them into two groups: the ones diagnosed across DST or across Standard Time (ST). We included 82 patients (54.9% male; age: median [Q1, Q3] 34.5 [25.0, 45.3]; range 16–92; 54 in DST and 28 in ST) who had Dim Light Melatonin Onset (DLMO) measured as a marker for the circadian phase and sleep timing (onset, SO, mid‐point, MS and end, SE) self‐reported separately for work‐ and work‐free days. Differences between ST and DST were compared using Mann–Whitney or Student's t‐tests. On a weekly average, patients in DST slept less (difference between medians of 37 min. p <.01), mainly due to sleep on workdays (SDw,p <.01), which also correlated with SoJL (rsp =.38, p <.01). While the time from DLMO to SO was similar in those in ST or those in DST, the time from DLMO to SE was significantly shorter for those in DST. The average duration between DLMO and sleep end was close to 10.5 h in ST, the biological night length described in the literature. Our results favour perennial ST and suggest assigning time‐zones close to sun time to prevent social jetlag and sleep deprivation. [ABSTRACT FROM AUTHOR]

Dim light melatonin onset (DLMO) is considered the most reliable circadian phase marker in humans. However, the methods to calculate it are diverse, which limits the comparability between studies. Given the key role of DLMO to diagnose circadian rhythm sleep-wake disorders and determine the optimal timing of chronotherapies, the establishment of clear and validated guidelines on the methodology to assess DLMO is very important. We performed a repeatability study (n = 31) and an agreement study (n = 62) in healthy young adults with hourly blood samples collected under dim light conditions (<8 lux) during a chronobiological protocol. We assessed the repeatability of DLMO with three different methods (fixed threshold, dynamic threshold and hockey stick) across two nights and assessed agreement of each method with the mean visual estimation made by four chronobiologists. Analyses included Bland-Altman diagrams, intraclass correlation coefficients and equivalence tests. The repeatability of the four methods across two nights ranged from good to perfect. The agreement study highlighted that the hockey stick showed equivalent or superior performance (ICC: 0.95, mean difference with visual estimation: 5 min) in healthy subjects compared to the dynamic and fixed thresholds. Thanks to its objective nature, the hockey stick method may provide better estimates than the mean of the visual estimations of several raters. These findings suggest that the hockey stick method provides the most reliable estimate of DLMO within the tested methods and should be considered for use in future studies. [ABSTRACT FROM AUTHOR]

Abstract Background Sleep dysfunction is a core symptom in bipolar disorder (BD), especially during major mood episodes. This study investigated the possible link between subjective and objective sleep disturbances in inter-episode BD, changes in melatonin and cortisol levels, and circadian melatonin alignment. The study included 21 euthymic BD patients and 24 healthy controls. Participants had to wear an actigraphy device, keep a weekly sleep diary and take salivary samples: five samples on the last evening to determine the dim light melatonin onset (DLMO) and one the following morning to measure rising cortisol. Sleep quality was assessed by the Pittsburgh Sleep Quality Index (PSQI) and Regensburg Insomnia Scale (RIS), and circadian alignment by the phase angle difference (PAD). Results In comparison to healthy controls, BD patients had: (1) higher PSQI (5.52 ± 3.14 vs. 3.63 ± 2.18; p = 0.022) (significant after controlling for age and gender), and higher RIS scores (8.91 ± 5.43 vs. 5.83 ± 3.76; p = 0.031); (2) subjective a longer mean TST (p = 0.024) and TIB (p = 0.002) (both significant after controlling for age and gender), longer WASO (p = 0.019), and worse SE (p = 0.036) (significant after controlling for gender); (3) actigraphically validated earlier sleep onset (p = 0.002), less variation in sleep onset time (p = 0.005) and no longer TST (p = 0.176); (4) no differing melatonin levels (4.06 ± 2.77 vs. 3.35 ± 2.23 p = 0.352), an 1.65 h earlier DLMO (20.17 ± 1.63 vs. 21.82 ± 1.50; p = 0. 001) (significant after controlling for gender), and a phase advance of melatonin (6.35 ± 1.40 vs. 7.48 ± 1.53; p = 0.017) (significant after controlling for gender); and (5) no differing cortisol awakening response (16.97 ± 10.22 vs 17.06 ± 5.37 p = 0.969). Conclusions Patients with BD, even in euthymic phase, have a significantly worse perception of their sleep. Advanced sleep phases in BD might be worth further investigation and could help to explain the therapeutic effects of mood stabilizers such as lithium and valproate.

Light environment in the Arctic differs widely with the seasons. Studies of relationships between objectively measured circadian phase and amplitude of light exposure and melatonin in community-dwelling Arctic residents are lacking. This investigation combines cross-sectional (n = 24-62) and longitudinal (n = 13-27) data from week-long actigraphy (with light sensor), 24-h salivary melatonin profiles, and proxies of metabolic health. Data were collected within the same week bracketing spring equinox (SE), and winter/summer solstices (WS/SS). Drastic seasonal differences in blue light exposure (BLE) corresponded to seasonal changes in the 24-h pattern of melatonin, which was phase delayed and reduced in normalized amplitude (NA) during WS/SS compared to SE. The extent of individual melatonin's acrophase and Dim Light Melatonin Onset (DLMO) change from SE to WS correlated with that from SE to SS. Although similar in extent and direction, melatonin phase changes versus SE were linked to morning BLE deficit in WS, contrasting to evening BLE excess in SS. Seasonal changes in sleep characteristics were closely associated with changes in the phases of BLE and melatonin. Proxies of metabolic health included triglycerides (TG), high-density lipoprotein cholesterol (HDL), TG/HDL ratio, and cortisol. Adverse seasonal changes in these proxies were associated with delayed acrophases of BLE and melatonin during WS and SS. TG and TG/HDL were higher in WS and SS than in SE, and cross-sectionally correlated with later melatonin and BLE acrophases, while lower HDL was associated with later BLE onset and later melatonin acrophase. Overall, this study shows that optimal 24-h patterns of light exposure during SE is associated with an earlier acrophase and a larger 24-h amplitude of melatonin, and that both features are linked to better metabolic health. Improving light hygiene, in particular correcting winter morning light deficit and summer evening light excess may help maintain metabolic health at high latitudes. Novel solutions for introducing proper circadian light hygiene such as human-centric light technologies should be investigated to address these issues in future studies., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The study’s aim was to examine the effect of chronotype on cognitive performance during a single night shift. Data were collected from 72 (36f) young, healthy adults in a laboratory study. Participants had a 9 h sleep period (03:00–12:00) followed by an 8 h night shift (23:00–07:00). During the night shift, participants completed five test sessions, which included measures of subjective sleepiness, subjective alertness, and sustained attention (i.e., psychomotor vigilance task; PVT). Dim light melatonin onset (DLMO) was derived from saliva samples taken during the evening preceding the night shift. A tertile split of DLMO was used to determine three chronotype categories: earlier (DLMO = 20:22 ± 0:42), intermediate (DLMO = 21:31 ± 0:13), and later (DLMO = 22:54 ± 0:54). There were (a) significant main effects of test session (all p < 0.001); (b) no main effects of chronotype; and (c) no interaction effects between chronotype and test session on sleepiness, alertness, PVT response time, and PVT lapses. The results indicate that under controlled sleeping conditions, chronotype based on dim light melatonin onset did not affect nighttime performance. Differences in performance during night shift between chronotypes reported by field studies may be related to differences in the amount and/or timing of sleep before or between night shifts, rather than circadian timing.

Chronotype reflects circadian timing and can be determined from biological markers (e.g., dim light melatonin onset; DLMO), or questionnaires (e.g., Morningness-Eveningness Questionnaire; MEQ, or Munich Chronotype Questionnaire; MCTQ). The study’s aim was to quantify concordance between chronotype categorisations based on these measures. A total of 72 (36f) young, healthy adults completed the MEQ and MCTQ and provided saliva samples hourly in dim light during the evening in a laboratory. The corrected midpoint of sleep on free days (MSFsc) was derived from MCTQ, and tertile splits were used to define early, intermediate and late DLMO-CT, MEQ-CT and MSFsc-CT chronotype categories. DLMO correlated with MEQ score (r = −0.25, p = 0.035) and MSFsc (r = 0.32, p = 0.015). For early, intermediate and late DLMO-CT categories, mean(SD) DLMO were 20:25(0:46), 21:33(0:10) and 23:03(0:53). For early, intermediate and late MEQ-CT categories, mean(SD) MEQ scores were 60.5(5.3), 51.4(2.9) and 40.8 (5.0). For early, intermediate and late MSFsc-CT categories, mean(SD) MSFsc were 03:23(0:34), 04:37(0:12) and 05:55(0:48). Low concordance of categorisations between DLMO-CT and MEQ-CT (37%), and between DLMO-CT and MSFsc-CT (37%), suggests chronotype categorisations depend on the measure used. To enable valid comparisons with previous results and reduce the likelihood of misleading conclusions, researchers should select measures and statistical techniques appropriate to the construct of interest and research question.

Background: Sleep dysfunction is a core symptom in bipolar disorder (BD), especially during major mood episodes. This study investigated the possible link between subjective and objective sleep disturbances in inter-episode BD, changes in melatonin and cortisol levels, and circadian melatonin alignment. The study included 21 euthymic BD patients and 24 healthy controls. Participants had to wear an actigraphy device, keep a weekly sleep diary and take salivary samples: five samples on the last evening to determine the dim light melatonin onset (DLMO) and one the following morning to measure rising cortisol. Sleep quality was assessed by the Pittsburgh Sleep Quality Index (PSQI) and Regensburg Insomnia Scale (RIS), and circadian alignment by the phase angle difference (PAD). Results: In comparison to healthy controls, BD patients had: (1) higher PSQI (5.52 ± 3.14 vs. 3.63 ± 2.18; p = 0.022) (significant after controlling for age and gender), and higher RIS scores (8.91 ± 5.43 vs. 5.83 ± 3.76; p = 0.031); (2) subjective a longer mean TST (p = 0.024) and TIB (p = 0.002) (both significant after controlling for age and gender), longer WASO (p = 0.019), and worse SE (p = 0.036) (significant after controlling for gender); (3) actigraphically validated earlier sleep onset (p = 0.002), less variation in sleep onset time (p = 0.005) and no longer TST (p = 0.176); (4) no differing melatonin levels (4.06 ± 2.77 vs. 3.35 ± 2.23 p = 0.352), an 1.65 h earlier DLMO (20.17 ± 1.63 vs. 21.82 ± 1.50; p = 0. 001) (significant after controlling for gender), and a phase advance of melatonin (6.35 ± 1.40 vs. 7.48 ± 1.53; p = 0.017) (significant after controlling for gender); and (5) no differing cortisol awakening response (16.97 ± 10.22 vs 17.06 ± 5.37 p = 0.969). Conclusions: Patients with BD, even in euthymic phase, have a significantly worse perception of their sleep. Advanced sleep phases in BD might be worth further investigation and could help to explain the therapeutic effects of mood stabilizers such as lithium and valproate. [ABSTRACT FROM AUTHOR]

Study Objectives: Our sleep extension intervention in adolescents showed that gradually shifting weekday bedtime earlier plus one weekend of morning bright light advanced circadian phase and increased weeknight sleep duration. Here, we examine at-home maintenance of these changes., Methods: Fourteen adolescents (15.3-17.9 years; 7 female) completed a 7-week study. After usual sleep at home (2-week baseline), intervention participants ( n  = 8) gradually advanced weekday bedtime (1 hour earlier than baseline during week 3; 2 hours earlier in week 4) and received bright light (~6000 lux; 2.5 hours) on both mornings of the intervening weekend. During three maintenance weeks, intervention participants were instructed to maintain their school-day wake-up time on all days, keep their early week four bedtimes, except on weekends when they could go to bed up to 1 hour later, and get a 2.5-hour light box exposure within 5 minutes of waking on one morning (Saturday or Sunday) of both weekends at home. Control participants ( n  = 6) slept as usual at home and did not receive weekend bright light. Dim light melatonin onset (DLMO) was measured after the 2-week baseline, 2-week intervention, and 3-week maintenance in all participants. Actigraphic sleep-wake was collected throughout., Results: After the 2-week intervention, DLMOs advanced more compared to control (37.0 ± 40.0 minutes vs. -14.7 ± 16.6 minutes), weekday sleep duration increased by 69.7 ± 27.8 minutes and sleep onset was 103.7 ± 14.2 minutes earlier compared to baseline. After three maintenance weeks, intervention participants showed negligible DLMO delays (-4.9 ± 22.9 minutes); weekday fall-asleep times and sleep durations also remained stable., Conclusions: Early circadian phase and extended sleep can be maintained with at-home weekend bright light., (© The Author(s) 2024. Published by Oxford University Press on behalf of Sleep Research Society.)

The study's aim was to examine the effect of chronotype on cognitive performance during a single night shift. Data were collected from 72 (36f) young, healthy adults in a laboratory study. Participants had a 9 h sleep period (03:00-12:00) followed by an 8 h night shift (23:00-07:00). During the night shift, participants completed five test sessions, which included measures of subjective sleepiness, subjective alertness, and sustained attention (i.e., psychomotor vigilance task; PVT). Dim light melatonin onset (DLMO) was derived from saliva samples taken during the evening preceding the night shift. A tertile split of DLMO was used to determine three chronotype categories: earlier (DLMO = 20:22 ± 0:42), intermediate (DLMO = 21:31 ± 0:13), and later (DLMO = 22:54 ± 0:54). There were (a) significant main effects of test session (all p < 0.001); (b) no main effects of chronotype; and (c) no interaction effects between chronotype and test session on sleepiness, alertness, PVT response time, and PVT lapses. The results indicate that under controlled sleeping conditions, chronotype based on dim light melatonin onset did not affect nighttime performance. Differences in performance during night shift between chronotypes reported by field studies may be related to differences in the amount and/or timing of sleep before or between night shifts, rather than circadian timing. [ABSTRACT FROM AUTHOR]

Chronotype reflects circadian timing and can be determined from biological markers (e.g., dim light melatonin onset; DLMO), or questionnaires (e.g., Morningness-Eveningness Questionnaire; MEQ, or Munich Chronotype Questionnaire; MCTQ). The study's aim was to quantify concordance between chronotype categorisations based on these measures. A total of 72 (36f) young, healthy adults completed the MEQ and MCTQ and provided saliva samples hourly in dim light during the evening in a laboratory. The corrected midpoint of sleep on free days (MSFsc) was derived from MCTQ, and tertile splits were used to define early, intermediate and late DLMO-CT, MEQ-CT and MSFsc-CT chronotype categories. DLMO correlated with MEQ score (r = -0.25, p = 0.035) and MSFsc (r = 0.32, p = 0.015). For early, intermediate and late DLMO-CT categories, mean(SD) DLMO were 20:25(0:46), 21:33(0:10) and 23:03(0:53). For early, intermediate and late MEQ-CT categories, mean(SD) MEQ scores were 60.5(5.3), 51.4(2.9) and 40.8 (5.0). For early, intermediate and late MSFsc-CT categories, mean(SD) MSFsc were 03:23(0:34), 04:37(0:12) and 05:55(0:48). Low concordance of categorisations between DLMO-CT and MEQ-CT (37%), and between DLMO-CT and MSFsc-CT (37%), suggests chronotype categorisations depend on the measure used. To enable valid comparisons with previous results and reduce the likelihood of misleading conclusions, researchers should select measures and statistical techniques appropriate to the construct of interest and research question. [ABSTRACT FROM AUTHOR]

Circadian misalignment remains a distinct challenge for night shift workers. Variability in individual sleep-wake/light-dark patterns might contribute to individual differences in circadian alignment in night shift workers. In this simulation study, we compared the predicted phase shift from a mathematical model of the effect of light on the human circadian pacemaker to the observed melatonin phase shift among individuals who completed one of four interventions during simulated night shift work. Two inputs to the model were used to simulate circadian phase: sleep-wake/light-dark patterns measured from a wrist monitor (Simulation 1) and sleep-wake/light-dark patterns measured from a wrist monitor enhanced by known light levels measured at the level of the eye during simulated night shifts (Simulation 2). The estimated phase shift from the model was within 2 hours of the observed phase shift in ~80% of night shift workers for both simulations; none of the model-predicted phase shifts was more than ~3 hours from the observed phase shift. Overall, the root-mean-square error between observed and predicted phase shifts was better for Simulation 1. The light input from the wrist monitor informed by actual light level measured at the eye performed better in the sub-group exposed to bright light during their night shifts. The findings from this simulation study suggest that using a mathematical model combined with sleep-wake and light exposure data from a wrist monitor can facilitate the design of shift work schedules to enhance circadian alignment, which is expected to improve sleep, alertness, and performance. [ABSTRACT FROM AUTHOR]

Determination of circadian phase is required to diagnose and treat circadian abnormalities, but the measurement of dim light melatonin onset (DLMO), the most common phase marker, is laborious. As sleep timing reflects circadian phase, measurement of sleep markers (e.g., sleep onset, sleep midpoint, sleep offset) provides a simple way to estimate DLMO. The study aim was to compare methods to estimate DLMO from markers derived from the Pittsburgh Sleep Quality Index (PSQI), Munich Chronotype Questionnaire (MCTQ), sleep diaries, and actigraphy. PSQI, MCTQ, and 1 week of diary and actigraphy data were collected from 72 (36 f, 36 m) healthy adults aged 23.1 (± 3.6) y prior to a laboratory sleep study. Saliva samples were collected hourly in dim light during the second evening of the study. The sleep markers most strongly associated with DLMO from each source were PSQI onset, MCTQ average midpoint, 7-d diary midpoint, and 7-d actigraphy midpoint. Estimates of DLMO as a fixed interval before the sleep marker exhibited proportional bias. DLMO estimated from regression models based on sleep midpoint from 7 d of diary or 7 d of actigraphy showed the narrowest limits of agreement with measured DLMO without proportional bias (±1.8 h and ±1.9 h, respectively). Our findings indicate none of the methods provided precise estimates of DLMO from sleep markers. The best estimates were from linear regressions on sleep midpoints from 7 d of diary or actigraphy, and these estimates of DLMO may be suitable for limited research purposes. [ABSTRACT FROM AUTHOR]

Individuals vary in how their circadian system synchronizes with the cyclic environment (zeitgeber). Assessing these differences in "phase of entrainment"—often referred to as chronotype—is an important procedure in laboratory experiments and epidemiological studies but is also increasingly applied in circadian medicine, both in diagnosis and therapy. While biochemical measurements (e.g., dim-light melatonin onset [DLMO]) of internal time are still the gold standard, they are laborious, expensive, and mostly rely on special conditions (e.g., dim light). Chronotype estimation in the form of questionnaires is useful in approximating the timing of an individual's circadian clock. They are simple, inexpensive, and location independent (e.g., administrable on- and offline) and can therefore be easily administered to many individuals. The Munich ChronoType Questionnaire (MCTQ) is an established instrument to assess chronotype by asking subjects about their sleep-wake-behavior. Here we present a shortened version of the MCTQ, the µMCTQ, for use in situations in which instrument length is critical, such as in large cohort studies. The µMCTQ contains only the core chronotype module of the standard MCTQ (stdMCTQ), which was shortened and adapted from 17 to 6 essential questions, allowing for a quick assessment of chronotype and other related parameters such as social jetlag and sleep duration. µMCTQ results correspond well to the ones collected by the stdMCTQ and are externally validated by actimetry and DLMO, assessed at home (no measure of compliance). Sleep onset, midpoint of sleep, and the µMCTQ-derived marker of chronotype showed slight deviations toward earlier times in the µMCTQ when compared with the stdMCTQ (<35 min). The µMCTQ assessment of chronotype showed good test-retest reliability and correlated significantly with phase markers from actimetry and melatonin (DLMO), especially with measurements taken on work-free days. Because of its brevity, the µMCTQ represents an ideal tool to estimate individual internal time in time-critical contexts, from large cohort studies to individualized medicine. [ABSTRACT FROM AUTHOR]

Background: Circadian dysfunction is thought to take part in the pathogenesis of sleep disorders in Alzheimer's disease (AD) and in AD pathophysiology itself.Objective: Our study aims to calculate dim light melatonin onset (DLMO) secretion in order to define the circadian phase in patients with AD at an early stage of the disease.Methods: Twenty-one patients (M/F: 11/10; mean age 74.1 ± 5.4 years; mean disease duration 3.4 ± 1.6 years) with a diagnosis of AD and 17 healthy controls (HC; M/F: 10/7; mean age 67.47 ± 3.8 years) were investigated for subjective nocturnal sleep quality and chronotype, for DLMO and quantitative aspects of the evening melatonin secretion by means of a 5-point in-home evening melatonin saliva test.Results: Subjective sleep quality score on the Pittsburgh Sleep Quality Index questionnaire (PSQI) above 5 (p = 0.24), insomnia frequency as measured by Sleep Condition Indicator Questionnaire (p = 0.823) and the subjective chronotype according to Morning Evening Questionnaire (MEQ) scores distribution (p = 0.464) did not differ between AD and HC. However, DLMO occurred significantly later (55 min; p = 0.028), and melatonin secretion following DLMO was significantly decreased in AD patients compared to HC.Conclusion: Initial evening secretion of melatonin proves to be delayed and mildly impaired in patients with a mild/moderate form of Alzheimer disease while patients' subjective sleep parameters and chronotype are reported to be similar to those of HC. These results indicate that subclinical altered patterns of melatonin secretion occur in subjects with AD at an early stage of the disease. [ABSTRACT FROM AUTHOR]

Studies on circadian timing in depression have produced variable results, with some investigations suggesting phase advances and others phase delays. This variability may be attributable to differences in participant diagnosis, medication use, and methodology between studies. This study examined circadian timing in a sample of unmedicated women with and without unipolar major depressive disorder. Participants were aged 18–28 years, had no comorbid medical conditions, and were not taking medications. Eight women were experiencing a major depressive episode, nine had previously experienced an episode, and 31 were control participants with no history of mental illness. Following at least one week of actigraphic sleep monitoring, timing of salivary dim light melatonin onset (DLMO) was assessed in light of <1 lux. In currently depressed participants, melatonin onset occurred significantly earlier relative to sleep than in controls, with a large effect size. Earlier melatonin onset relative to sleep was also correlated with poorer mood for all participants. Our results indicate that during a unipolar major depressive episode, endogenous circadian phase is advanced relative to sleep time. This is consistent with the early-morning awakenings often seen in depression. Circadian misalignment may represent a precipitating or perpetuating factor that could be targeted for personalized treatment of major depression. [ABSTRACT FROM AUTHOR]

Light exposure and sleep timing are two factors that influence inter-individual variability in the timing of the human circadian clock. The aim of this study was to quantify the degree to which evening light exposure predicts variance in circadian timing over and above bedtime alone in preschool children. Participants were 21 children ages 4.5–5.0 years (4.7±0.2 years; 9 females). Children followed their typical sleep schedules for 4 days during which time they wore a wrist actigraph to assess sleep timing and a pendant light meter to measure minute-by-minute illuminance levels in lux. On the 5th day, children participated in an in-home dim-light melatonin onset (DLMO) assessment. Light exposure in the 2 h before bedtime was averaged and aggregated across the 4 nights preceding the DLMO assessment. Mean DLMO and bedtime were 19:22±01:04 and 20:07±00:46, respectively. Average evening light exposure was 710.1±1418.2 lux. Children with later bedtimes (lights-off time) had more delayed melatonin onset times (r=0.61, p=0.002). Evening light exposure was not independently associated with DLMO (r=0.32, p=0.08); however, a partial correlation between evening light exposure and DLMO when controlling for bedtime yielded a positive correlation (r=0.46, p=0.02). Bedtime explained 37.3% of the variance in the timing of DLMO, and evening light exposure accounted for an additional 13.3% of the variance. These findings represent an important step in understanding factors that influence circadian phase in preschool-age children and have implications for understanding a modifiable pathway that may underlie late sleep timing and the development of evening settling problems in early childhood.

We examined phase shifts to bright morning light when sleep was restricted by delaying bedtimes. Adolescents (n = 6) had 10-h sleep/dark opportunities for 6 days. For the next 2 days, half were put to bed 4.5 h later and then allowed to sleep for 5.5 h (evening room light + sleep restriction). The others continued the 10-h sleep opportunities (sleep satiation). Then, sleep schedules were gradually shifted earlier and participants received bright light (90 min, ~6000 lux) after waking for 3 days. As expected, sleep satiation participants advanced (~2 h). Evening room light + sleep restriction participants did not shift or delayed by 2-4 h. Abbreviations: DLMO: dim light melatonin onset. [ABSTRACT FROM AUTHOR]

In mammals, daily physiological events are regulated by the circadian rhythm, which comprises two types of internal clocks: the central clock and peripheral clocks. Circadian rhythm plays an important role in maintaining physiological functions including the sleep-wake cycle, body temperature, metabolism and organ functions. Circadian rhythm disorder, which is caused, for example, by an irregular lifestyle or long-haul travel, increases the risk of developing disease; therefore, it is important to properly maintain the rhythm of the circadian clock. Food and the circadian clock system are known to be closely linked. Studies on rodents suggest that ingesting specific food ingredients, such as the flavonoid nobiletin, fish oil, the polyphenol resveratrol and the amino acid L-ornithine affects the circadian clock. However, there are few reports on the foods that affect these circadian clocks in humans. In this study, therefore, we examined whether L-ornithine affects the human central clock in a crossover design placebo-controlled human trial. In total, 28 healthy adults (i.e. ≥20 years) were randomly divided into two groups and completed the study protocol. In the 1st intake period, participants were asked to take either L-ornithine (400 mg) capsules or placebo capsules for 7 days. After 7 days’ interval, they then took the alternative test capsules for 7 days in the 2nd intake period. On the final day of each intake period, saliva was sampled at various time points in the dim light condition, and the concentration of melatonin was quantified to evaluate the phase of the central clock. The results revealed that dim light melatonin onset, a recognized marker of central circadian phase, was delayed by 15 min after ingestion of L-ornithine. Not only is this finding an indication that L-ornithine affects the human central clock, but it also demonstrates that the human central clock can be regulated by food ingredients. [ABSTRACT FROM AUTHOR]

The purpose of this review is to provide an overview of the research regarding circadian rhythms in Alzheimer disease (AD). Furthermore, this paper explores the role of melatonin in the pathogenesis of AD and the limitation of trials addressing circadian rhythms disturbances in the AD population. A literature search using Medline with PubMed and Embase was carried out identifying papers focusing on circadian rhythms in AD. Sleep disorders and especially circadian rhythm disturbances are very common in the elderly population but definitely more pronounced in patients with AD. The lack of trials evaluating the management of circadian rhythms disorders in the elderly population and especially in AD should be considered of the utmost importance. Although there is a better understanding about the pathophysiology of AD and its relationship with circadian disorders, further studies in human models need to be conducted. [ABSTRACT FROM AUTHOR]

Dim Light Melatonin Onset (DLMO) is a reliable marker of the endogenous circadian rhythm. To determine if sleep timing can predict DLMO, we investigated the relationship between sleep timing and DLMO in patients in various circadian sleep-wake rhythm disorders (CSWRDs), ages and genders. We found that correlations were only moderate between DLMO and sleep-onset in the complete data-set, but they increased in patients with delayed sleep-wake phase disorder (DSWPD), DSWPD patients with a regular sleep pattern and patients with advanced sleep-wake phase disorder (ASWPD); the levels of correlation werer = 0.542, 0.657, 0.728 and 0.814, respectively. In DSWPD patients with a regular sleep pattern, mid-sleep strongly correlated (r = 0.839) with DLMO. Correlation in other CSRWDs was not significant. DLMO, sleep-onset and age were most discriminated factors between the various CSRWDs. Estimation of DLMO is only possible in patients with ASWPD and in DSWPD patients with a regular sleep pattern. [ABSTRACT FROM PUBLISHER]

This study assessed melatonin levels and the dim light melatonin onset (DLMO) in adults with Autism Spectrum Disorder (ASD) and also investigated the relationships between melatonin and objectively measured sleep parameters. Sixteen adults with ASD (ASD-Only), 12 adults with ASD medicated for comorbid diagnoses of anxiety and/or depression (ASD-Med) and 32 controls participated in the study. Although, the timing of the DLMO did not differ between the two groups, advances and delays of the melatonin rhythm were observed in individual profiles. Overall mean melatonin levels were lower in the ASD-Med group compared to the two other groups. Lastly, greater increases in melatonin in the hour prior to sleep were associated with greater sleep efficiency in the ASD groups. [ABSTRACT FROM AUTHOR]

Light is the most potent time cue that synchronizes (entrains) the circadian pacemaker to the 24-h solar cycle. This entrainment process is an interplay between an individual’s daily light perception and intrinsic pacemaker period under free-running conditions. Establishing individual estimates of circadian phase and period can be time-consuming. We show that circadian phase can be accurately predicted (SD = 1.1 h for dim light melatonin onset, DLMO) using 9 days of ambulatory light and activity data as an input to Kronauer’s limit-cycle model for the human circadian system. This approach also yields an estimated circadian period of 24.2 h (SD = 0.2 h), with longer periods resulting in later DLMOs. A larger amount of daylight exposure resulted in an earlier DLMO. Individuals with a long circadian period also showed shorter intervals between DLMO and sleep timing. When a field-based estimation of tau can be validated under laboratory studies in a wide variety of individuals, the proposed methods may prove to be essential tools for individualized chronotherapy and light treatment for shift work and jetlag applications. These methods may improve our understanding of fundamental properties of human circadian rhythms under daily living conditions. [ABSTRACT FROM AUTHOR]

In circadian rhythm sleep-wake disorders precision medicine is less developed than in other medical disciplines mainly because homeostatic sleep and circadian timing have a very complex phenotype with multiple genetic regulation mechanisms. However, biomarkers, phenotyping and psychosocial characteristics are increasingly used. Devices for polysomnography, actigraphy and sleep-tracking applications in mobile phones and other consumer devices with eHealth technologies are increasingly used. Also sleep-related questionnaires and the assessment of co-morbidities influencing sleep in circadian rhythm sleep-wake disorders are major contributors to precision sleep medicine. To further strengthen the (pharmaco-)genetic and biomarker pillar, technology needs to be evolved further. Routinely measuring treatment results using patient-reported outcome measures and clinical neurophysiological instruments will boost precision sleep medicine. [ABSTRACT FROM AUTHOR]

Associations amongst personality, diurnal preference, and circadian phase were investigated using a constant routine laboratory protocol. One hundred and sixty-eight healthy participants aged 18–30 years (Women n = 68) completed either a 30- or 50-hour constant routine under dim-light conditions (< 3 lx), during which circadian phase was measured from core body temperature and melatonin. Prior to laboratory admission, self-report measures of personality and diurnal preference were also obtained. The personality trait of Constraint correlated positively with morning diurnal preference and earlier circadian phase, with circadian phase partially mediating the relationship between Constraint and diurnal preference. No other personality variables correlated with circadian phase. Sex was an important covariate in several of the relationships investigated due to lower levels of Constraint and later CBT phase amongst men and was thus controlled for in all relevant analyses. Findings from this highly controlled study are consistent with previous field research in suggesting that earlier circadian phase is associated with the personality trait of Constraint. [ABSTRACT FROM AUTHOR]

Objective/background It has been debated in the literature whether patients with idiopathic generalized epilepsy (IGE) have a distinctive, evening-oriented chronotype. The few questionnaire-based studies that are available in the literature have conflicting results. The aim of our study was to define chronotype in patients with IGE by determining dim light melatonin onset (DLMO). Patients/methods Twenty adults diagnosed with IGE (grand mal on awakening [GM] in 7 cases and juvenile myoclonic epilepsy in 13 cases) were investigated by means of a face-to-face semistructured sleep interview, Morningness–Eveningness Questionnaire (MEQ), Pittsburgh Sleep Quality Index (PSQI) questionnaire, and a melatonin salivary test with DLMO determination. Eighteen healthy subjects (HC) and 28 patients affected with cryptogenic focal epilepsy (FE) served as controls. Results The mean MEQ score was significantly lower in patients with IGE than that in patients with FE (49.1 ± 5.9 versus 56.1 ± 8.7 P < 0.01) but not significantly lower than that in HC (49.1 ± 5.9 versus 49.3 ± 8.6). Midsleep on free days corrected for sleep duration did not differ significantly between the three subject groups (04:59 ± 01:21 h, 04:37 ± 01:17 h, 04:29 ± 00:52 h). The mean DLMO time in patients with IGE (22:13 ± 01:34 h) occurred 49 min later than that in HC (21.24 ± 1 h), and the melatonin surge within the 30-minute time interval after DLMO in patients with IGE was significantly lower than that in HC (1.51 ± 2.7 versus 3.8 ± 3.6 pg/mL P = 0.045). Conclusions Subjective measures of chronotype do not indicate a definite evening-oriented chronotype in patients with IGE. However, the data concerning endogenous melatonin secretion indicate that patients with IGE tend to have a late circadian phase. Further studies are warranted in order to better define the late pattern of endogenous melatonin secretion in patients with IGE and to ascertain the role of this pattern in influencing behavioral chronotype in these subjects. [ABSTRACT FROM AUTHOR]

Objective/background: Circadian rhythm sleep-wake disorders (CRSWDs) often manifest during the adolescent years. Measurement of circadian phase such as the dim light melatonin onset (DLMO) improves diagnosis and treatment of these disorders, but financial and time costs limit the use of DLMO phase assessments in clinic. The current analysis aims to inform a cost-effective and efficient protocol to measure the DLMO in older adolescents by reducing the number of samples and total sampling duration.Patients/methods: A total of 66 healthy adolescents (26 males) aged 14.8-17.8 years participated in a study; they were required to sleep on a fixed baseline schedule for a week before which they visited the laboratory for saliva collection in dim light (<20 lux). Two partial 6-h salivary melatonin profiles were derived for each participant. Both profiles began 5 h before bedtime and ended 1 h after bedtime, but one profile was derived from samples taken every 30 min (13 samples) and the other from samples taken every 60 min (seven samples). Three standard thresholds (first three melatonin values mean + 2 SDs, 3 pg/mL, and 4 pg/mL) were used to compute the DLMO. An agreement between DLMOs derived from 30-min and 60-min sampling rates was determined using Bland-Altman analysis; agreement between the sampling rate DLMOs was defined as ± 1 h.Results and Conclusions: Within a 6-h sampling window, 60-min sampling provided DLMO estimates within ± 1 h of DLMO from 30-min sampling, but only when an absolute threshold (3 or 4 pg/mL) was used to compute the DLMO. Future analyses should be extended to include adolescents with CRSWDs. [ABSTRACT FROM AUTHOR]

Studies based on self-administered questionnaires indicate that most patients with epilepsy are morning-oriented. We aimed to investigate chronotype in patients with epilepsy with late-onset focal epilepsy by combining subjective data with dim light melatonin onset (DLMO) as an objective marker of the circadian phase. Sixty adult patients (mean age 46.5 ± 13.8; 27 males) with late-onset focal epilepsy under pharmacological treatment were prospectively studied. Subjective chronotype was determined using the Morningness–Eveningness Questionnaire (MEQ) and circadian phase through analysis of salivary melatonin secretion, considering 3 pg/ml as the dim light melatonin onset (DLMO) threshold. The mean MEQ score was significantly higher in the patients with epilepsy than in the controls, and significantly, more patients had a MEQ score indicative of the morning type (50.0% vs 30.0%, p = 0.02). However, no significant differences were found in mean time of DLMO (21:38 ± 01:21 vs 21:26 ± 01:03; p = ns), and DLMO time was in the range indicative of an intermediate chronotype in both patients and controls. Sleep onset and sleep offset phase angles were significantly shorter in the patients. Patients whose global MEQ score identified them as morning types were significantly older than those with an intermediate or evening chronotype, and they had less social jet lag. No difference in epilepsy features and treatments was found between morning-oriented and nonmorning-oriented patients. Our analyses showed that the patients with epilepsy tended to be morning-oriented and to perceive themselves as morning types, even though this was not reflected in their DLMO values which did not differ significantly from those of controls and mostly fell within the intermediate chronotype range. Several factors may considerably influence subjective chronotype. We speculate that, in patients with epilepsy, the disease itself, prompting certain lifestyle choices, including a regular sleep schedule and early bedtime, may induce morning orientation and a morning-type self-perception. [ABSTRACT FROM AUTHOR]

Since there is less movement during sleep than during wake, the recording of body movements by actigraphy has been used to indirectly evaluate the sleep-wake cycle. In general, most actigraphic devices are placed on the wrist and their measures are based on acceleration detection. Here, we propose an alternative way of measuring actigraphy at the level of the arm for joint evaluation of activity and body position. This method analyzes the tilt of three axes, scoring activity as the cumulative change of degrees per minute with respect to the previous sampling, and measuring arm tilt for the body position inference. In this study, subjects ( N = 13) went about their daily routine for 7 days, kept daily sleep logs, wore three ambulatory monitoring devices and collected sequential saliva samples during evenings for the measurement of dim light melatonin onset (DLMO). These devices measured motor activity (arm activity, AA) and body position (P) using the tilt sensing of the arm, with acceleration (wrist acceleration, WA) and skin temperature at wrist level (WT). Cosinor, Fourier and non-parametric rhythmic analyses were performed for the different variables, and the results were compared by the ANOVA test. Linear correlations were also performed between actimetry methods (AA and WA) and WT. The AA and WA suitability for circadian phase prediction and for evaluating the sleep-wake cycle was assessed by comparison with the DLMO and sleep logs, respectively. All correlations between rhythmic parameters obtained from AA and WA were highly significant. Only parameters related to activity levels, such as mesor, RA (relative amplitude), VL5 and VM10 (value for the 5 and 10 consecutive hours of minimum and maximum activity, respectively) showed significant differences between AA and WA records. However, when a correlation analysis was performed on the phase markers acrophase, mid-time for the 10 consecutive hours of highest (M10) and mid-time for the five consecutive hours of lowest activity (L5) with DLMO, all of them showed a significant correlation for AA ( R = 0.607, p = 0.028; R = 0.582, p = 0.037; R = 0.620, p = 0.031, respectively), while for WA, only acrophase did ( R = 0.621, p = 0.031). Regarding sleep detection, WA showed higher specificity than AA (0.95 ± 0.01 versus 0.86 ± 0.02), while the agreement rate and sensitivity were higher for AA (0.76 ± 0.02 versus 0.66 ± 0.02 and 0.71 ± 0.03 versus 0.53 ± 0.03, respectively). Cohen's kappa coefficient also presented the highest values for AA (0.49 ± 0.04) and AP (0.64 ± 0.04), followed by WT (0.45 ± 0.06) and WA (0.37 ± 0.04). The findings demonstrate that this alternative actigraphy method (AA), based on tilt sensing of the arm, can be used to reliably evaluate the activity and sleep-wake rhythm, since it presents a higher agreement rate and sensitivity for detecting sleep, at the same time allows the detection of body position and improves circadian phase assessment compared to the classical actigraphic method based on wrist acceleration. [ABSTRACT FROM AUTHOR]

The objective of the current study was to determine if night-shift workers carrying the five-repeat variant of the Period 3 gene show elevated levels of nocturnal sleepiness and earlier circadian phase compared with homozygotes for the four-repeat allele. Twenty-four permanent night-shift workers were randomly selected from a larger study. Participants took part in an observational laboratory protocol including an overnight multiple sleep latency test and half-hourly saliva collection for calculation of dim-light melatonin onset. Period 3-/5 shift workers had significantly lower multiple sleep latency test during overnight work hours compared with Period 34/4 workers (3.52 ± 23.44 min versus 10.39 ± 6.41 min, P = 0.003). We observed no significant difference in sleepiness during early morning hours following acute sleep deprivation. Long-allele carriers indicated significantly higher sleepiness on the Epworth Sleepiness Scale administered at 17:00 hours (12.08 ± 2.55 versus 8.00 ± 1.94, P < 0.001). We observed a significantly earlier melatonin onset in Period 3-/5 individuals compared with Period 34/4 shift workers (20:44 ± 6:37 versus 02:46 ± 4:58, P = 0.021). Regression analysis suggests that Period 3 genotype independently predicts sleepiness even after controlling for variations in circadian phase, but we were unable to link Period 3 to circadian phase when controlling for sleepiness. Period 3-/5 shift workers showed both subjective and objective sleepiness in the pathological range, while their Period 34/4 counterparts showed sleepiness within normal limits. Period 3-/5 night workers also show a mean circadian phase 6 h earlier (i.e. less adapted) than Period 34/4 workers. Because Period 3-/5 workers have maladaptive circadian phase as well as pathological levels of sleepiness, they may be at greater risk for occupational and automotive accidents. We interpret these findings as a call for future research on the role of Period 3 in sleepiness and circadian phase, especially as they relate to night work. [ABSTRACT FROM AUTHOR]

Objective Efficient treatments to phase-advance human circadian rhythms are needed to attenuate circadian misalignment and the associated negative health outcomes that accompany early-morning shift work, early school start times, jet lag, and delayed sleep phase disorder. This study compared three morning bright-light exposure patterns from a single light box (to mimic home treatment) in combination with afternoon melatonin. Methods Fifty adults (27 males) aged 25.9 ± 5.1 years participated. Sleep/dark was advanced 1 h/day for three treatment days. Participants took 0.5 mg of melatonin 5 h before the baseline bedtime on treatment day 1, and an hour earlier each treatment day. They were exposed to one of three bright-light (~5000 lux) patterns upon waking each morning: four 30-min exposures separated by 30 min of room light (2-h group), four 15-min exposures separated by 45 min of room light (1-h group), and one 30-min exposure (0.5-h group). Dim-light melatonin onsets (DLMOs) before and after treatment determined the phase advance. Results Compared to the 2-h group (phase shift = 2.4 ± 0.8 h), smaller phase-advance shifts were seen in the 1-h (1.7 ± 0.7 h) and 0.5-h (1.8 ± 0.8 h) groups. The 2-h pattern produced the largest phase advance; however, the single 30-min bright-light exposure was as effective as 1 h of bright light spread over 3.25 h, and it produced 75% of the phase shift observed with 2 h of bright light. Conclusions A 30-min morning bright-light exposure with afternoon melatonin is an efficient treatment to phase-advance human circadian rhythms. [ABSTRACT FROM AUTHOR]

Study Objectives: Shift sleep onset earlier and extend school-night sleep duration of adolescents., Methods: Forty-six adolescents (14.5-17.9 years; 24 females) with habitual short sleep (≤7 h) and late bedtimes (≥23:00) on school nights slept as usual for 2 weeks (baseline). Then, there were three weekends and two sets of five weekdays in between. Circadian phase (Dim Light Melatonin Onset, DLMO) was measured in the laboratory on the first and third weekend. On weekdays, the "Intervention" group gradually advanced school-night bedtime (1 h earlier than baseline during week 1; 2 h earlier than baseline during week 2). Individualized evening time management plans ("Sleep RouTeen") were developed to facilitate earlier bedtimes. On the second weekend, Intervention participants received bright light (~6000 lux; 2.5 h) on both mornings. A control group completed the first and third weekend but not the second. They slept as usual and had no evening time management plan. Weekday sleep onset time and duration were derived from actigraphy., Results: Dim light melatonin onset (DLMO) advanced more in the Intervention (0.6 ± 0.8 h) compared to the Control (-0.1 ± 0.8 h) group. By week 2, the Intervention group fell asleep 1.5 ± 0.7 h earlier and sleep duration increased by 1.2 ± 0.7 h; sleep did not systematically change in the Control group., Conclusions: This multi-pronged circadian-based intervention effectively increased school-night sleep duration for adolescents reporting chronic sleep restriction. Adolescents with early circadian phases may only need a time management plan, whereas those with later phases probably need both time management and morning bright light., Clinical Trials: Teen School-Night Sleep Extension: An Intervention Targeting the Circadian System (#NCT04087603): https://clinicaltrials.gov/ct2/show/NCT04087603., (© The Author(s) 2022. Published by Oxford University Press on behalf of Sleep Research Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The onset of melatonin secretion in the evening is the most reliable and most widely used index of circadian timing in humans. Saliva (or plasma) is usually sampled every 0.5-1 hours under dim-light conditions in the evening 5-6 hours before usual bedtime to assess the dim-light melatonin onset (DLMO). For many years, attempts have been made to find a reliable objective determination of melatonin onset time either by fixed or dynamic threshold approaches. The here-developed hockey-stick algorithm, used as an interactive computer-based approach, fits the evening melatonin profile by a piecewise linear-parabolic function represented as a straight line switching to the branch of a parabola. The switch point is considered to reliably estimate melatonin rise time. We applied the hockey-stick method to 109 half-hourly melatonin profiles to assess the DLMOs and compared these estimates to visual ratings from three experts in the field. The DLMOs of 103 profiles were considered to be clearly quantifiable. The hockey-stick DLMO estimates were on average 4 minutes earlier than the experts' estimates, with a range of −27 to +13 minutes; in 47% of the cases the difference fell within ±5 minutes, in 98% within −20 to +13 minutes. The raters' and hockey-stick estimates showed poor accordance with DLMOs defined by threshold methods. Thus, the hockey-stick algorithm is a reliable objective method to estimate melatonin rise time, which does not depend on a threshold value and is free from errors arising from differences in subjective circadian phase estimates. The method is available as a computerized program that can be easily used in research settings and clinical practice either for salivary or plasma melatonin values. [ABSTRACT FROM AUTHOR]

The increased prevalence of circadian disruptions due to abnormal coupling between internal and external time makes the detection of circadian phase in humans by ambulatory recordings a compelling need. Here, we propose an accurate practical procedure to estimate circadian phase with the least possible burden for the subject, that is, without the restraints of a constant routine protocol or laboratory techniques such as melatonin quantification, both of which are standard procedures. In this validation study, subjects ( N = 13) wore ambulatory monitoring devices, kept daily sleep diaries and went about their daily routine for 10 days. The devices measured skin temperature at wrist level (WT), motor activity and body position on the arm, and light exposure by means of a sensor placed on the chest. Dim light melatonin onset (DLMO) was used to compare and evaluate the accuracy of the ambulatory variables in assessing circadian phase. An evening increase in WT: WTOnset (WTOn) and 'WT increase onset' (WTiO) was found to anticipate the evening increase in melatonin, while decreases in motor activity (Activity Offset or AcOff), body position (Position Offset (POff)), integrative TAP (a combination of WT, activity and body position) (TAPOffset or TAPOff) and an increase in declared sleep propensity were phase delayed with respect to DLMO. The phase markers obtained from subjective sleep ( R = 0.811), WT ( R = 0.756) and the composite variable TAP ( R = 0.720) were highly and significantly correlated with DLMO. The findings strongly support a new method to calculate circadian phase based on WT (WTiO) that accurately predicts and shows a temporal association with DLMO. WTiO is especially recommended due to its simplicity and applicability to clinical use under conditions where knowing endogenous circadian phase is important, such as in cancer chronotherapy and light therapy. [ABSTRACT FROM AUTHOR]

While much research has investigated the effects of exogenous melatonin on sleep, less is known about the relationship between the timing of the endogenous melatonin rhythm and the sleep-wake cycle. Significant inter-individual variability in the phase relationship between sleep and melatonin rhythms has been reported although the extent to which the variability reflects intrinsic and/or environmental differences is unknown. We examined the effects of different sleeping schedules on the time of dim light melatonin onset (DLMO) in 28 young, healthy adults. Participants chose to maintain either an early (22:30 – 06:30 h) or a late (00:30 – 08:30 h) sleep schedule for at least three weeks prior to an overnight laboratory visit. Saliva samples were collected under dim light (

Circadian phase and its relation to sleep are increasingly recognized as fundamental factors influencing human physiology and behavior. Dim light melatonin onset (DLMO) is a reliable marker of the timing of the circadian clock, which has been used in experimental, clinical, and descriptive studies in the past few decades. Although DLMO and its relationship to sleep have been well documented in school-aged children, adolescents, and adults, very little is known about these processes in early childhood. The purpose of this study was 1) to describe circadian phase and phase angles of entrainment in toddlers and 2) to examine associations between DLMO and actigraphic measures of children’s nighttime sleep. Participants were 45 healthy toddlers aged 30 to 36 months (33.5 ± 2.2 months; 21 females). After sleeping on a parent-selected schedule for 5 days (assessed with actigraphy and diaries), children participated in an in-home DLMO assessment involving the collection of saliva samples every 30 minutes for 6 hours. Average bedtime was 2015 ± 0036 h, average sleep onset time was 2043 ± 0043 h, average midsleep time was 0143 ± 0038 h, and average wake time was 0644 ± 0042 h. Average DLMO was 1929 ± 0051 h, with a 3.5-hour range. DLMO was normally distributed; however, the distribution of the bedtime, sleep onset time, and midsleep phase angles of entrainment were skewed. On average, DLMO occurred 47.8 ± 47.6 minutes (median = 39.4 minutes) before bedtime, 74.6 ± 48.0 minutes (median = 65.4 minutes) before sleep onset time, 6.2 ± 0.7 hours (median = 6.1 hours) before midsleep time, and 11.3 ± 0.7 hours before wake time. Toddlers with later DLMOs had later bedtimes (r = 0.46), sleep onset times (r = 0.51), midsleep times (r = 0.66), and wake times (r = 0.65) (all p < 0.001). Interindividual differences in toddlers’ circadian phase are large and associated with their sleep timing. The early DLMOs of toddlers indicate a maturational delay in the circadian timing system between early childhood and adolescence. These findings are a first step in describing the fundamental properties of the circadian system in toddlers and have important implications for understanding the emergence of sleep problems and the consequences of circadian misalignment in early childhood. [ABSTRACT FROM PUBLISHER]

Background: Perinatal changes in maternal sleep patterns may modify circadian phase. Our objectives were to (a) measure changes in circadian phase and phase angle between salivary dim light melatonin onset (DLMO) and sleep onset across the perinatal period; and (b) prospectively examine associations between circadian measures and depressed mood in women with a history of major depressive disorder (MDD). Methods: Twelve women (age±SD=26.9±5 years) who fulfilled DSM-IV criteria for history of MDD (but not in a mood episode at enrollment) were studied from third trimester of pregnancy through postpartum week 6. Participants completed sleep diaries, wore wrist actigraphs and light sensors, and had mood assessed with the Hamilton Depression Rating Scale (HAMD-17) during 3 separate weeks of the perinatal period; they gave saliva samples at 33 weeks gestation and 6 weeks postpartum to determine DLMO phase. Results: Nine women had DLMO phase shifts ≥30min. On average±SD, new mothers phase delayed 42±80min (range=163min phase delay to 144min phase advance). The time interval between average actigraphic sleep onset and DLMO was shorter at 6 weeks postpartum compared to 3rd trimester in 9 of 12 women, indicating that most new mothers were going to bed closer to the onset of endogenous melatonin secretion. Circadian measures were associated with depressed mood at postpartum weeks 2 and 6. Limitations: These data are preliminary findings from a small sample and require replication. Conclusions: We observed individual differences in magnitude and direction of circadian phase shifts and their timing relative to sleep across the perinatal period. These measures were correlated with postpartum depressive symptoms. These preliminary data indicate that changes in perinatal circadian rhythms may contribute to the development of postpartum mood disorders. [ABSTRACT FROM AUTHOR]

Approximately one-third of patients with epilepsy continue to have seizures despite antiepileptic therapy. Many seizures occur in diurnal, sleep/wake, circadian, or even monthly patterns. The relationship between biomarkers and state changes is still being investigated, but early results suggest that some of these patterns may be related to endogenous circadian patterns whereas others may be related to wakefulness and sleep or both. Chronotherapy, the application of treatment at times of greatest seizure susceptibility, is a technique that may optimize seizure control in selected patients. It may be used in the form of differential dosing, as preparations designed to deliver sustained or pulsatile drug delivery or in the form of 'zeitgebers' that shift endogenous rhythms. Early trials in epilepsy suggest that chronopharmacology may provide improved seizure control compared with conventional treatment in some patients. The present article reviews chronopharmacology in the treatment of epilepsy as well as future treatment avenues. [ABSTRACT FROM AUTHOR]

Dim light melatonin onset (DLMO) is defined as the start of the melatonin production in the evening during dim light conditions and has become a reliable phase marker of the circadian clock. The aim of the study was to investigate DLMO and its association with sleep timing and diurnal preferences in healthy working adults during real-life conditions. Fourteen adults were investigated. A sleep diary was kept during the preceding week, but no fixed sleep–wake schedule was implemented. Diurnal preferences were measured with the Horne–Östberg Morningness–Eveningness Questionnaire. DLMO was defined as the time point when melatonin in saliva exceeded a threshold of 3 ng/L. Results showed that DLMO appeared in the expected time interval but was not significantly associated with sleep timing or diurnal preference. The results illustrate the complexity of monitoring sleep patterns in real-life settings. [ABSTRACT FROM PUBLISHER]

Abstract: Objective: To determine whether an accurate circadian phase assessment could be obtained from saliva samples collected by patients in their home. Methods: Twenty-four individuals with a complaint of sleep initiation or sleep maintenance difficulty were studied for two evenings. Each participant received instructions for collecting eighthourly saliva samples in dim light at home. On the following evening they spent 9h in a laboratory room with controlled dim (<20lux) light where hourly saliva samples were collected. Circadian phase of dim light melatonin onset (DLMO) was determined using both an absolute threshold (3pgml−1) and a relative threshold (two standard deviations above the mean of three baseline values). Results: Neither threshold method worked well for one participant who was a “low-secretor”. In four cases the participants’ in-lab melatonin levels rose much earlier or were much higher than their at-home levels, and one participant appeared to take the at home samples out of order. Overall, the at-home and in-lab DLMO values were significantly correlated using both methods, and differed on average by 37 (±19)min using the absolute threshold and by 54 (±36)min using the relative threshold. Conclusions: The at-home assessment procedure was able to determine an accurate DLMO using an absolute threshold in 62.5% of the participants. Thus, an at-home procedure for assessing circadian phase could be practical for evaluating patients for circadian rhythm sleep disorders. [Copyright &y& Elsevier]