Machine learning estimation of human body time using metabolomic profiling.

Circadian rhythms influence physiology, metabolism, and molecular processes in the human body. Estimation of individual body time (circadian phase) is therefore highly relevant for individual optimization of behavior (sleep, meals, sports), diagnostic sampling, medical treatment, and for treatment of circadian rhythm disorders. Here, we provide a partial least squares regression (PLSR) machine learning approach that uses plasma-derived metabolomics data in one or more samples to estimate dim light melatonin onset (DLMO) as a proxy for circadian phase of the human body. For this purpose, our protocol was aimed to stay close to real-life conditions. We found that a metabolomics approach optimized for either women or men under entrained conditions performed equally well or better than existing approaches using more labor-intensive RNA sequencing-based methods. Although estimation of circadian body time using blood-targeted metabolomics requires further validation in shift work and other real-world conditions, it currently may offer a robust, feasible technique with relatively high accuracy to aid personalized optimization of behavior and clinical treatment after appropriate validation in patient populations.

An independent comparison of the Novolytix salivary melatonin radioimmunoassay with the new Novolytix salivary melatonin enzyme-linked immunosorbent assay.

The dim light melatonin onset (DLMO) is the current gold standard biomarker of the timing of the central circadian clock in humans and is often assessed from saliva samples. To date, only one commercially available salivary melatonin assay is considered accurate at the low daytime levels required to accurately detect the DLMO (Novolytix RIA RK-DSM2). The aim of this study was to conduct the first independent evaluation of a newly improved enzyme-linked immunosorbent assay (ELISA; Novolytix MLTN-96) and compare it with the recommended radioimmunoassay (RIA)-both in terms of melatonin concentrations and derived DLMOs. Twenty participants (15 females, 18-59 years old) provided saliva samples every 30 min in dim light starting 6 h before their habitual bedtime, yielding a total of 260 saliva samples. Both the RIA and ELISA yielded daytime melatonin concentrations <2 pg/mL, indicating adequate accuracy to detect the DLMO. The melatonin concentrations from the two assays were highly correlated (r = .94, p < .001), although the RIA yielded lower levels of melatonin concentration than the ELISA, on average by 0.70 pg/mL (p = .006). Seventeen DLMOs were calculated from the melatonin profiles and the DLMOs from both assays were not statistically different (p = .36) and were highly correlated (r = .97, p < .001). Two DLMOs derived from the RIA occurred more than 30 min earlier than the DLMO derived from the ELISA. These results indicate that the new Novolytix ELISA is an appropriate assay to use if the Novolytix RIA is not feasible or available.

Exposure to real-ambient bedroom light at night delayed circadian rhythm in healthy Chinese young adults: A cross-sectional study.

BACKGROUND: Light at night (LAN) have attracted increased research attention on account of its widespread health hazards. However, the underlying mechanism remains unknown. The objective of this study was to investigate the effects of real-ambient bedroom LAN exposure on circadian rhythm among young adults and potential sex differences. METHODS: Bedroom LAN exposure was measured at 60-s intervals for 2 consecutive days using a portable illuminance meter. Circadian phase was determined by the dim light melatonin onset (DLMO) time in 7 time-series saliva samples. RESULTS: The mean age of the 142 participants was 20.7 ± 0.8 years, and 59.9% were women. The average DLMO time was 21:00 ± 1:11 h, with men (21:19 ± 1:12 h) later than women (20:48 ± 1:07 h). Higher level of LAN intensity (LANavg ≥ 3lx vs. LANavg < 3lx) was associated with an 81.0-min later in DLMO time (95% CI: 0.99, 1.72), and longer duration of nighttime light intensity ≥ 5lx (LAN5; LAN5 ≥ 45 min vs. LAN5 < 45 min) was associated with a 51.6-min later in DLMO time (95% CI: 0.46, 1.26). In addition, the delayed effect of LAN exposure on circadian phase was more pronounced in men than in women (all P-values <0.05). CONCLUSIONS: Overall, bedroom LAN exposure was significantly associated with delayed circadian rhythm. Additionally, the delayed effect is more significant in men. Keeping bedroom dark at night may be a practicable option to prevent circadian disruption and associated health implications. Future studies with more advanced light measurement instrument and consensus methodology for DLMO assessment are warranted.

Report from a randomized control trial: improved alignment between circadian biology and sleep-wake behavior as a mechanism of depression symptom improvement in evening-type adolescents with depressive symptoms.

STUDY OBJECTIVES: An evening circadian preference is common among adolescents. It is characterized by a behavioral predilection for later sleep and wake timing and is associated with higher rates of Major Depressive Disorder (MDD). The present study aims to (a) test the effectiveness of a cognitive behavioral sleep intervention (Transdiagnostic Sleep and Circadian Intervention; TranS-C) in a sample of adolescents with an evening circadian preference and clinically significant depressive symptoms and (b) evaluate improved alignment between circadian biology and sleep-wake behavior as a potential mechanism in the relationship between sleep and depression symptom improvement. METHODS: Adolescents with an evening circadian preference and clinically significant depressive symptoms were randomized to receive TranS-C (n = 24) or a psychoeducation condition (PE; n = 18). Alignment between circadian biology and sleep-wake behavior was measured using objective biological measurement. Measures of sleep and circadian rhythm were taken at pre- and posttreatment, and depression symptoms were measured at pre- and posttreatment and 6- and 12-month follow-up. RESULTS: Mixed effects modeling revealed that compared with an active control condition, TranS-C resulted in a significant reduction in MDD severity at 12-month follow-up. A MacArthur mediation analysis conducted to explore alignment between circadian biology and sleep-wake behavior as a mediator of depression severity reduction through 12-month follow-up revealed a significant interaction between change in alignment between circadian biology and sleep-wake behavior and treatment arm, indicating that improved alignment between circadian biology and sleep-wake behavior at posttreatment was associated with improvements in depression outcomes at 12-month follow-up under the treatment condition. CONCLUSIONS: These results provide novel evidence for improved alignment between circadian biology and sleep-wake behavior as a specific mechanism of depression improvement, provide key clues into the complex relationship between sleep and depression, and have significant clinical implications for adolescents with depression.

Single-item chronotype is associated with dim light melatonin onset in lymphoma survivors with fatigue.

Chronotype is frequently assessed in human observational studies using various morningness-eveningness questionnaires. An alternative single-item chronotype question has been proposed for its reduced administration time and its accessibility to all types of populations. We investigated whether this single-item chronotype is associated with dim light melatonin onset, the "gold standard" for estimating the endogenous circadian phase. We used data from a randomised trial in 166 (non-)Hodgkin lymphoma survivors with cancer-related fatigue. All participants completed a questionnaire, including a single-item chronotype question. A subsample of 47 participants also provided saliva samples before sleep onset for melatonin measurement. Using multiple linear regression, we examined whether chronotype based on a single question was associated with dim light melatonin onset. The subsample of 47 participants had a mean age of 44.6 years. The mean (SD) dim light melatonin onset was at 8:42 (1:19) p.m. and the most common chronotype was more evening than morning person (29.2%). A gradual increase in dim light melatonin onset with later chronotype (i.e. evening preference) was observed, with a mean ranging from 7:45 p.m. in definite morning persons to 9:16 p.m. in definite evening persons. Our study shows that single-item chronotype is associated with dim light melatonin onset as a marker of the endogenous circadian phase of fatigued lymphoma survivors. This type of chronotype assessment can therefore be a useful alternative for more extensive morningness-eveningness questionnaires.

The acute effects of sleep restriction therapy for insomnia on circadian timing and vigilance.

Sleep-restriction therapy (SRT) has been shown to improve insomnia symptoms by restricting sleep opportunity. Curtailment of time in bed affects the duration and consolidation of sleep, but also its timing. While recent work suggests that people with insomnia are characterised by misalignment between circadian and behavioural timing of sleep, no study has investigated if SRT modifies this relationship. The primary aim of the present study was to examine change in phase angle after 2 weeks of SRT. As a secondary aim, we also sought to assess the effect of SRT on psychomotor vigilance. Following a 1-week baseline phase, participants implemented SRT for 2 consecutive weeks. Phase angle was derived from the difference between the decimal clock time of dim light melatonin onset (DLMO) and attempted sleep time. Secondary outcomes included vigilance (assessed via hourly measurement during the DLMO laboratory protocol), sleep continuity (assessed via sleep diary and actigraphy), and insomnia severity. Eighteen participants meeting insomnia criteria (mean [SD] age 37.06 [8.99] years) took part in the study. Consistent with previous research, participants showed robust improvements in subjective and objective sleep continuity, as well as reductions in insomnia severity. The primary outcome (phase angle) was measurable in 15 participants and revealed an increase of 34.8 min (~0.58 hr; 95% confidence interval [CI] 0.01-1.15) from baseline to post-treatment (mean [SD] 2.27 [0.94] versus 2.85 [1.25] hr). DLMO remained relatively stable (20:49 versus 21:01 hours), while attempted sleep was 46.8 min later (~0.78 hr; 95%CI 0.41-1.15; 23:05 versus 23:52 hours). For psychomotor vigilance, reaction time was delayed (by 52.71 ms, 95% CI 34.44-70.97) and number of lapses increased (by 5.84, 95% CI 3.93-7.75) after SRT. We show that SRT increases phase angle during treatment, principally by delaying the timing of sleep attempt. Future studies are needed to test if an increase in phase angle is linked to clinical improvement. Finally, reduction in vigilance after SRT appears to be of similar magnitude to normal sleepers undergoing experimental sleep restriction, reinforcing the importance of appropriate safety advice during implementation.

The impact of the wake maintenance zone on attentional capacity, physiological drowsiness, and subjective task demands during sleep deprivation.

We aimed to investigate the impact of the Wake Maintenance Zone (WMZ) on measures of drowsiness, attention, and subjective performance under rested and sleep deprived conditions. We studied 23 healthy young adults (18 males; mean age = 25.41 ± 5.73 years) during 40 hr of total sleep deprivation under constant routine conditions. Participants completed assessments of physiological drowsiness (EEG-scored slow eye movements and microsleeps), sustained attention (PVT), and subjective task demands every two hours, and four-hourly ocular motor assessment of inhibitory control (inhibition of reflexive saccades on an anti-saccade task). Tests were analyzed relative to dim light melatonin onset (DLMO); the WMZ was defined as the 3 hr prior to DLMO, and the preceding 3 hr window was deemed the pre-WMZ. The WMZ did not mitigate the adverse impact of ~37 hr sleep deprivation on drowsiness, sustained attention, response inhibition, and self-rated concentration and difficulty, relative to rested WMZ performance (~13 hr of wakefulness). Compared to the pre-WMZ, though, the WMZ improved measures of sustained attention, and subjective concentration and task difficulty, during sleep deprivation. Cumulatively, these results expand on previous work by characterizing the beneficial effects of the WMZ on operationally-relevant indices of drowsiness, inhibitory attention control, and self-rated concentration and task difficulty relative to the pre-WMZ during sleep deprivation. These results may inform scheduling safety-critical tasks at more optimal circadian times to improve workplace performance and safety.

Home versus laboratory assessments of melatonin production and melatonin onset in young adults complaining of a delayed sleep schedule.

Recent evidence points toward an association between higher non-visual sensitivity to light and a later circadian phase in young adults complaining of a delayed sleep schedule. Light exposure in the evening may therefore induce a larger suppression of melatonin production in these individuals, which might: (a) bias home estimates of melatonin onset; and (b) decrease sleep propensity at bedtime. In this study, we compared home and laboratory melatonin onsets and production in sleep-delayed and control participants, using saliva samples collected in the 3 hr preceding habitual bedtime. The mean light intensity measured during saliva sampling at home was ~10 lux in both groups. Melatonin suppression at home was significant, averaging 31% and 24% in sleep-delayed and control individuals, respectively. Group difference in melatonin suppression was not significant. Estimates of melatonin onset were on average 27 min later at home than in laboratory conditions, with no group difference. Looking specifically at sleep-delayed participants, there was no correlation between non-visual sensitivity to light and home-laboratory differences in melatonin onsets. However, higher light sensitivity was associated with greater melatonin suppression in the hour before habitual bedtime. Greater melatonin suppression before bedtime was also associated with a later circadian phase. These results indicate that the validity of home estimates of melatonin onset is similar in sleep-delayed and in control individuals. Results also suggest that increased non-visual sensitivity to light could impact melatonin secretion in sleep-delayed individuals and contribute to a late bedtime by delaying circadian phase and decreasing sleep propensity.

Free-running circadian period in adolescents and adults.

Sleep timing shifts later during adolescence (second decade). This trend reverses at ~20 years and continues to shift earlier into adulthood. The current analysis examined the hypothesis that a longer free-running circadian period during late adolescence (14-17 years) compared with adulthood (30-45 years) accounts for sleep timing differences. Sex and ancestry were also examined because previous reports find that women and those with African-American ancestry have shorter free-running periods. Circadian period was measured using an ultradian dark-light protocol (2 hr dark/sleep, 2 hr dim room light [~20 lux]/wake) over 3.4 days. Dim light melatonin onsets were measured before and after the ultradian protocol, from which the circadian period was derived. In contrast to our hypothesis, we found that free-running circadian period was similar in adolescents and adults. African-American adults had shorter free-running circadian periods compared with adults of other ancestries. This ancestry difference was not seen in the adolescent group. Finally, we observed a non-significant trend for shorter free-running circadian periods in females compared with males. These data suggest that age-related changes in circadian period after late adolescence do not account for sleep timing differences. These data provide further support for ancestry-related differences in period, particularly in adults. Whether the large difference in circadian period between African-American and other ancestries emerges later in development should be explored.

A unified model of melatonin, 6-sulfatoxymelatonin, and sleep dynamics.

A biophysical model of the key aspects of melatonin synthesis and excretion has been developed, which is able to predict experimental dynamics of melatonin in plasma and saliva, and of its urinary metabolite 6-sulfatoxymelatonin (aMT6s). This new model is coupled to an established model of arousal dynamics, which predicts sleep and circadian dynamics based on light exposure and times of wakefulness. The combined model thus predicts melatonin levels over the sleep-wake/dark-light cycle and enables prediction of melatonin-based circadian phase markers, such as dim light melatonin onset (DLMO) and aMT6s acrophase under conditions of normal sleep and circadian misalignment. The model is calibrated and tested against group average data from 10 published experimental studies and is found to reproduce quantitatively the key dynamics of melatonin and aMT6s, including the timing of release and amplitude, as well as response to controlled lighting and shift work.

l-Serine Enhances Light-Induced Circadian Phase Resetting in Mice and Humans.

Background: The circadian clock is modulated by the timing of ingestion or food composition, but the effects of specific nutrients are poorly understood.Objective: We aimed to identify the amino acids that modulate the circadian clock and reset the light-induced circadian phase in mice and humans.Methods: Male CBA/N mice were orally administered 1 of 20 l-amino acids, and the circadian and light-induced phase shifts of wheel-running activity were analyzed. Antagonists of several neurotransmitter pathways were injected before l-serine administration, and light-induced phase shifts were analyzed. In addition, the effect of l-serine on the light-induced phase advance was investigated in healthy male students (mean ± SD age 22.2 ± 1.8 y) by using dim-light melatonin onset (DLMO) determined by saliva samples as an index of the circadian phase.Results: l-Serine administration enhanced light-induced phase shifts in mice (1.86-fold; P < 0.05). Both l-serine and its metabolite d-serine, a coagonist of N-methyl-d-aspartic acid (NMDA) receptors, exerted this effect, but d-serine concentrations in the hypothalamus did not increase after l-serine administration. The effect of l-serine was blocked by picrotoxin, an antagonist of γ-aminobutyric acid A receptors, but not by MK801, an antagonist of NMDA receptors. l-Serine administration altered the long-term expression patterns of clock genes in the suprachiasmatic nuclei. After advancing the light-dark cycle by 6 h, l-serine administration slightly accelerated re-entrainment to the shifted cycle. In humans, l-serine ingestion before bedtime induced significantly larger phase advances of DLMO after bright-light exposure during the morning (means ± SEMs-l-serine: 25.9 ± 6.6 min; placebo: 12.1 ± 7.0 min; P < 0.05).Conclusion: These results suggest that l-serine enhances light-induced phase resetting in mice and humans, and it may be useful for treating circadian disturbances.

An experimental study of adolescent sleep restriction during a simulated school week: changes in phase, sleep staging, performance and sleepiness.

This laboratory study investigated the impact of restricted sleep during a simulated school week on circadian phase, sleep stages and daytime functioning. Changes were examined across and within days and during a simulated weekend recovery. Participants were 12 healthy secondary school students (six male) aged 15-17 years [mean = 16.1 years, standard deviation (SD) = 0.9]. After 2 nights with 10 h (21:30-07:30 hours), time in bed was restricted to 5 h for 5 nights (02:30-07:30 hours), then returned to 10 h time in bed for 2 nights (21:30-07:30 hours). Saliva was collected in dim light on the first and last sleep restriction nights to measure melatonin onset phase. Sleep was recorded polysomnographically, and the Psychomotor Vigilance Task (PVT) and Karolinska Sleepiness Scale were undertaken 3-hourly while awake. Average phase delay measured by melatonin was 3 h (SD = 50 min). Compared to baseline, sleep during the restriction period contained a smaller percentage of Stages 1 and 2 and rapid eye movement (REM) and a greater percentage of Stage 4. PVT lapses increased significantly during sleep restriction and did not return to baseline levels during recovery. Subjective sleepiness showed a similar pattern during restriction, but returned to baseline levels during recovery. Results suggest that sustained attention in adolescents is affected negatively by sleep restriction, particularly in the early morning, and that a weekend of recovery sleep is insufficient to restore performance. The discrepancy between sleepiness ratings and performance may indicate a lack of perception of this residual impairment.

Salivary melatonin and cortisol and occupational injuries among Italian hospital workers.

Stress, circadian patterns, and sleep-related factors may have a role on occupational injuries. We investigated the association between occupational injuries among the workers of an Italian hospital and their secretion of salivary melatonin and cortisol. We used a case-control study design. 27 injured cases and 31 non-injured controls provided 5 salivary samples every 60 min from 9 pm to 1 am. Melatonin and cortisol concentrations were measured, and the Dim Light Melatonin Onset (DLMO) derived using two fixed thresholds (1 and 3 pg/mL). The associations between injury, melatonin, cortisol, and DLMO were assessed through univariate and multivariate analyses. Non-injured controls had higher melatonin (median 2.28 pg/mL) and lower cortisol concentrations (0.71 ng/mL), as well as earlier DLMO times (9:00 pm with the 1 pg/mL melatonin cutoff) than cases (1.01 pg/mL, 1.14 ng/mL and 9:12 pm, respectively), although only few results were statistically significant. Measuring these hormones might be helpful to characterize the risk of injury among hospital workers.

Chronotype is associated with the timing of the circadian clock and sleep in toddlers.

Chronotype is a construct reflecting individual differences in diurnal preference. Although chronotype has been studied extensively in school-age children, adolescents and adults, data on young children are scarce. This study describes chronotype and its relationship to the timing of the circadian clock and sleep in 48 healthy children aged 30-36 months (33.4 ± 2.1 months; 24 males). Parents completed the Children's Chronotype Questionnaire (CCTQ) ~2 weeks before the start of the study. The CCTQ provides three measures of chronotype: midsleep time on free days, a multi-item morningness/eveningness score and a single item chronotype score. After 5 days of sleeping on their habitual schedule (assessed with actigraphy and sleep diaries), children participated in an in-home salivary dim light melatonin onset assessment. Average midsleep time on free days was 1:47 ± 0:35, and the average morningness/eveningness score was 26.8 ± 4.3. Most toddlers (58.4%) were rated as 'definitely a morning type' or 'rather morning than evening type', while none (0%) were rated as 'definitely evening type'. More morning types (midsleep time on free days and morningness/eveningness score, respectively) had earlier melatonin onset times (r = 0.45, r = 0.26), earlier habitual bedtimes (r = 0.78, r = 0.54), sleep onset times (r = 0.80, r = 0.52), sleep midpoint times (r = 0.90, r = 0.53) and wake times (r = 0.74, r = 0.34). Parent ratings using the single-item chronotype score were associated with melatonin onset (r = 0.32) and habitual bedtimes (r = 0.27), sleep onset times (r = 0.33) and sleep midpoint times (r = 0.27). Morningness may best characterize circadian preference in early childhood. Associations between chronotype and circadian physiology and sleep timing suggest adequate validity for the CCTQ in this age group. These findings have important implications for understanding the marked variability in sleep timing during the early years of life.

Delayed melatonin circadian timing, lower melatonin output, and sleep disruptions in myopic, or short-sighted, children.

STUDY OBJECTIVES: This study investigated the differences in melatonin circadian timing and output, sleep characteristics, and cognitive function in myopic and non-myopic (or emmetropic) children, aged 8-15 years. METHODS: Twenty-six myopes (refractive error [mean ±â€…standard error mean] -2.06 ±â€…0.23 diopters) and 19 emmetropes (-0.06 ±â€…0.04 diopters), aged 11.74 ±â€…2.31 years were recruited. Circadian timing was assessed using salivary dim-light melatonin onset (DLMO), collected half-hourly for 7 hours, beginning 5 hours before and finishing 2 hours after individual average sleep onset in a sleep laboratory. Nocturnal melatonin output was assessed via aMT6s levels from urine voids collected from 05:30 pm to 8:00 am the following morning. Actigraphy-derived objective sleep timing were acquired for a week prior to the sleep laboratory visit. Cognitive assessments of sustained attention (using psychomotor vigilance task [PVT]) and working memory (using digit spans) were performed on the night of sleep laboratory. RESULTS: Myopic children (9:07 pm ±â€…14 minutes) exhibited a DLMO phase-delay of 1 hour 8 minutes compared to emmetropes (7:59 pm ±â€…13 minutes), p = 0.002. aMT6s melatonin levels were significantly lower among myopes (18.70 ±â€…2.38) than emmetropes (32.35 ±â€…6.93, p = 0.001). Myopes also exhibited significantly delayed sleep onset, delayed wake-up time, poor and reduced sleep, and more evening-type diurnal preference than emmetropes (all p < 0.05). Finally, myopes showed a slower reaction time in the PVT (p < 0.05), but not digit span tasks at night. CONCLUSIONS: These findings suggest a potential association between circadian rhythm dysfunction and myopia in children.

Estimating dim light melatonin onset time in children using delta changes in melatonin.

We aimed to establish a method for estimating dim light melatonin onset (DLMO) using mathematical slopes calculated from melatonin concentrations at three sampling points before and after sleep in children. The saliva of 30 children (mean age ± SD: 10.2 ± 1.3 years old) was collected under dim-light conditions up to six times every hour starting at 17:30 (t17), namely, 18:30 (t18), 19:30 (t19), 20:30 (t20), 21:30 (t21), 22:30 (t22), and 23:30 (t23), in the evening, and at 6:00 (t30) the following morning. We calculated SLOPEon (mathematical slope between melatonin concentrations at t18 and t20, t21 or t22), SLOPEoff (the slope between t20, t21 or t22, and t30), and ΔSLOPE, which is generated by subtracting SLOPEon from SLOPEoff. DLMO was estimated by multiple regression analysis with the leave-one-out cross-validation (LOOCV) method using SLOPEon and SLOPEoff, and ΔSLOPE. The intraclass correlation coefficient (ICC) between the estimated and measured DLMOs was used as the index of estimation accuracy. DLMOs estimated using multiple regression equations with SLOPEon and SLOPEoff yielded significant ICCs for the measured DLMOs, with the largest ICC at t20 (ICC = 0.634). Additionally, the ICC between the estimated and measured DLMOs using the equation with ΔSLOPE was significant, with a larger ICC at t20 (ICC = 0.726) than that of the equation with SLOPEon and SLOPEoff. Our results showed that DLMO could be estimated with a certain level of accuracy from salivary melatonin levels at three time points before and after sleep in children. Supplementary Information: The online version contains supplementary material available at 10.1007/s41105-023-00493-x.

Exploring the role of sex in the association of late chronotype on cardiorespiratory fitness.

Circadian rhythms differ between young adult males and females. For example, males tend to be later chronotypes, preferring later timing of sleep and activity, than females. Likewise, there are sex differences in body composition and cardiorespiratory fitness. Few studies have investigated the association between circadian rhythms, cardiorespiratory fitness, and body composition. We sought to determine whether chronotype and circadian phase were associated with cardiorespiratory fitness, body composition, and anthropometric measures in sedentary males and females. Fifty-nine adults participated in the study. Circadian phase and chronotype were measured using dim light melatonin onset (DLMO) and the Morningness-Eveningness Questionnaire (MEQ) score. We used peak oxygen uptake (VO2peak ) results from a maximal graded exercise test to assess cardiorespiratory fitness. Body composition, BMI, and circumferences were collected as markers of adiposity. We observed a sex difference in the association between DLMO and VO2peak . For males, a later DLMO was associated with a lower VO2peak . VO2peak did not vary based on DLMO in females. Later circadian phase was also associated with increased body fat percentage, fat mass index, and abdominal circumference in males, but not females. Collectively, these results suggest that males who are later chronotypes may be at risk of obesity and low cardiorespiratory fitness.

Correlation of Circadian Rhythms and Improvement of Depressive Symptoms in Acute Ischemic Stroke Patients

OBJECTIVES: To investigate the correlation between evening melatonin timing secretion, dim light melatonin onset (DLMO), and post-stroke depression (PSD) in acute ischemic stroke patients and their influence on the improvement of depressive symptoms. MATERIALS AND METHODS: 120 patients with a recent magnetic resonance imaging confirmed stroke were included. Salivary melatonin samples were collected at 5 time points within 1 week after hospitalization (7 p.m.-11 p.m., 1 sample per hour). The circadian phase was defined by calculating DLMO secretion. Post-stroke depressive symptoms were evaluated by the 17-item Hamilton Rating Scale for Depression (HRSD) both on day 7 of hospitalization and 3 months after stroke. Patients were divided into PSD and non-PSD groups based on whether the acute phase HRSD score was ≥8. Similarly, patients were divided into the improved depressive symptoms (IDS) and no improvement in depressive symptoms (non-IDS) groups based on whether the HRSD score at 3 months was lower than at baseline. Neurological recovery at 3 months was assessed using the modified Rankin Scale (mRS). RESULTS: The difference in DLMO between PSD and non-PSD patients was not statistically significant (p =0.173). In the non-IDS group, there was a significant decrease in melatonin secretion at 10 p.m. (p =0.012), and DLMO was significantly later than in the IDS group (p =0.017). Logistic regression analysis showed that DLMO (OR 1.91, 95%CI:1.13-3.23, p = 0.016) was an independent risk factor for persistent no improvement in depressive symptoms, which was associated with a markedly worse prognosis (p <.001). CONCLUSION: Our findings suggest possible interventions for the very early identification of non-IDS patients.

Low-dose exogenous melatonin plus evening dim light and time in bed scheduling advances circadian phase irrespective of measured or estimated dim light melatonin onset time: preliminary findings.

STUDY OBJECTIVES: The purpose of the present study was to preliminarily evaluate whether knowing the dim light melatonin onset (DLMO) time is advantageous when treating delayed sleep-wake phase disorder with low-dose melatonin treatment plus behavioral interventions (ie, evening dim light and time in bed scheduling). METHODS: In this randomized, controlled, double-blind trial, 40 adults with delayed sleep-wake phase disorder were randomly assigned to 4 weeks of 0.5 mg timed to be administered either 3 hours before the DLMO (measured DLMO group, n = 20) or 5 hours before sleep-onset time per actigraphy (estimated DLMO group, n = 20), in conjunction with behavioral interventions. The primary outcome was change in the DLMO (measured in-home). Secondary outcomes included sleep parameters per diary and actigraphy (sleep-onset and -offset times and total sleep time), Morningness-Eveningness Questionnaire, Multidimensional Fatigue Inventory, PROMIS-Sleep Disturbance, PROMIS-Sleep Related Impairment, and Pittsburgh Sleep Quality Index. Mixed-effects models tested for group differences in these outcome. RESULTS: After applying the Bonferroni correction for multiple comparisons (significant P value set at < .004), there were significant main effects for visit on all outcomes except for the Pittsburgh Sleep Quality Index and total sleep time per wrist actigraphy and diary. There were no group-by-visit interactions for any of the outcomes (P > .004). CONCLUSIONS: Scheduled low-dose melatonin plus behavioral interventions may improve many circadian and sleep parameters regardless of whether melatonin administration is scheduled based on estimated or measured DLMO. A larger-scale trial is needed to confirm these preliminary findings. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Name: The Clinical Utility of Measuring the Circadian Clock in Treatment of Delayed Sleep-Wake Phase Disorder; URL: https://clinicaltrials.gov/study/NCT03715465; Identifier: NCT03715465. CITATION: Swanson LM, de Sibour T, DuBuc K, et al. Low-dose exogenous melatonin plus evening dim light and time in bed scheduling advances circadian phase irrespective of measured or estimated dim light melatonin onset time: preliminary findings. J Clin Sleep Med. 2024;20(7):1131-1140.

Distribution of dim light melatonin offset (DLMOff) and phase relationship to waketime in healthy adults and associations with chronotype.

OBJECTIVES: Dim light melatonin onset, or the rise in melatonin levels representing the beginning of the biological night, is the gold standard indicator of circadian phase. Considerably less is known about dim light melatonin offset, or the decrease in melatonin to low daytime levels representing the end of the biological night. In the context of insufficient sleep, morning circadian misalignment, or energy intake after waketime but before dim light melatonin offset, is linked to impaired insulin sensitivity, suggesting the need to characterize dim light melatonin offset and identify risk for morning circadian misalignment. METHODS: We examined the distributions of dim light melatonin offset clock hour and the phase relationship between dim light melatonin offset and waketime, and associations between dim light melatonin offset, phase relationship, and chronotype in healthy adults (N = 62) who completed baseline protocols measuring components of the circadian melatonin rhythm and chronotype. RESULTS: 74.4% demonstrated dim light melatonin offset after waketime, indicating most healthy adults wake up before the end of biological night. Later chronotype (morningness-eveningness, mid-sleep on free days corrected, and average mid-sleep) was associated with later dim light melatonin offset clock hour. Later chronotype was also associated with a larger, positive phase relationship between dim light melatonin offset and waketime, except for morningness-eveningness. CONCLUSIONS: These findings suggest morning circadian misalignment risk among healthy adults, which would not be detected if only dim light melatonin onset were assessed. Chronotype measured by sleep timing may better predict this risk in healthy adults keeping a consistent sleep schedule than morningness-eveningness preferences. Additional research is needed to develop circadian biomarkers to predict dim light melatonin offset and evaluate appropriate dim light melatonin offset timing to promote health.