Circadian free-running and temporal organization during 40 days of human group isolation in a cave without external time cues

To determine whether there was evidence of circadian or sleep-regulatory dysfunction in sighted individuals with non-24-hour sleep-wake rhythm disorder. Three sighted individuals with signs and/or symptoms of non-24-hour sleep-wake rhythm disorder were studied. Thirty-five- to 332-day laboratory and home-based assessments of sleep-wake and circadian timing, endogenous circadian period, photic input to the circadian pacemaker, and/or circadian and sleep-wake-dependent regulation of sleep were conducted. No evidence of circadian dysfunction was found in these individuals. Instead, sleep-wake timing appeared to dissociate from the circadian timing system, and/or self-selected sleep-wake and associated light/dark timing shifted the circadian pacemaker later, rather than the circadian pacemaker determining sleep-wake timing. These findings suggest that the etiology of this disorder may be light- and/or behaviorally induced in some sighted people, which has implications for the successful treatment of this disorder. Emens JS, St Hilaire MA, Klerman EB, etal. Behaviorally and environmentally induced non-24-hour sleep-wake rhythm disorder in sighted patients. J Clin Sleep Med. 2022;18(2):453-459.

An ingestible telemetric temperature sensor for measuring body core temperature (Tc) was first described 45 years ago, although the method has only recently gained widespread use for exercise applications. This...

Biological rhythms that recur approximately every 24 h (circadian) are driven by the internal biological clock located in the suprachiasmatic nuclei (SCN) of the hypothalamus. These circadian rhythms are intrinsically generated but also synchronized by external time cues—the daily light/dark cycle being the most important. Preferably under controlled conditions (constant routine or forced desynchrony), appropriately timed measurement of the 24-h variation in certain hormones (e.g., melatonin) or other relevant physiological variable (e.g., core body temperature) can be used to evaluate circadian phase. Interactions between circadian rhythms and sleep have a significant effect on multiple physiological processes. Human performance (cognitive and athletic) exhibits a circadian variation with minimal levels around time points close to the core body temperature minimum (shortly after the maximum melatonin secretion) while peak performance is observed around time points close to the core body temperature maximum (shortly before melatonin onset). Furthermore, misalignment of the internal clock with the external environment as seen in jet lag and shift work can negatively affect athletic performance and appropriately timed exposure to and avoidance of bright light can be used to mitigate the effects of jet lag. The circadian variation in performance can affect outcome of competitions and could be also important for choosing the optimal time to exercise.

Circadian rhythms are controlled by an endogenous time-keeping system oscillating approximately on a 24-h cycle under constant conditions. These rhythms depend on a network of interacting genes and proteins, including transcriptional activators such as CLOCK, NPAS2, and ARNTL (BMAL1), which induce transcription of the clock genes Period ( Per1 , Per2 , and Per3 ) and Cryptochrome ( Cry1 and Cry2 ). Human salivary cortisol and melatonin follow a clear circadian rhythm as well. Disruption of the circadian rhythm and sleep-wake cycles are considered risk factors for a variety of health problems, especially hypertension and other cardiovascular and metabolic diseases. Here we put together practical methods for assessing circadian rhythms in adult subjects conducted by each individual. This method is non-invasive, inexpensive and provides a predictive profile of an individual’s circadian rhythm related to clock-controlled gene expression in buccal cells, salivary cortisol, salivary melatonin, and subject’s activity or sleep. Subjects are instructed on how to obtain buccal cells using swabs (Whatman OmniSwab) from the inside of their cheeks and collect saliva using salivettes (Sarstedt) every 4 hours starting at 6am, for 2 consecutive days. Subjects also wear actigraphy watches (Phillips Respironics) during the 2 days, to record their activity, light exposure and estimates of sleep times. To monitor adherence to correct time point collections, each subject is given an electronic vial called eCAP (Information Mediary Corp) that records the exact time the container is opened to place samples once collected. We demonstrate feasibility to extract up to 150ng/μl of RNA (Ambion RNAqueous-Micro Total RNA Isolation Kit) from buccal cells swabs. Salivary melatonin and cortisol are measured by radioimmunoassay (Buhlmann Lab) with melatonin peak levels ranging from 14 to 23 pg/ml and cortisol peak levels ranging from 10 to 24 ng/ml. We suggest that buccal cell expression of clock-controlled genes, salivary melatonin, salivary cortisol, and actigraphy data are valuable in providing reliable assessment of human circadian rhythm profiles under a variety of conditions.

Circadian rest/activity rhythms (RARs) change across adulthood, and alterations in RARs have been associated with cognitive decline, Alzheimer's disease (AD), and dementia. Little is known, however, about associations of RARs with subsequent changes in brain structure. We investigated cross-sectional and longitudinal associations between RARs from wrist actigraphy and AD-relevant brain volumes from magnetic resonance imaging in cognitively unimpaired adults aged≥50 and whether age moderated these associations. In cross-sectional analyses, weaker and more fragmented RARs were associated with smaller medial temporal region volumes. Longitudinally, more regular and less fragmented RARs were associated with better maintenance of amygdala volume over time. Further, associations between RAR fragmentation and global atrophy were strongest among the oldest participants. Results link RARs with medial temporal lobe and global brain volumes and indicate that these associations may differ by age. Research is needed on the effects of RAR-focused interventions on brain health.

ABSTRACTChemotherapy administration may result in the disruption of circadian rhythms and impairment of quality of life (QoL) of cancer patients. Nevertheless, we have little knowledge on the long-term consequences of chemotherapy and the effects of hospitalization. In the present study, we employed the two-factor repeated-measure cross-sectional design to determine the effects of chemotherapy and hospitalization on rest-activity (RA) rhythm and QoL of breast cancer patients. Initially, we randomly selected 39 inpatients and 42 outpatients, scheduled to receive six cycles of chemotherapy, from the Regional Cancer Center (RCC), Raipur, India. Finally, 30 patients in each group were included in the current study. We monitored circadian RA rhythm and QoL using wrist actigraphy and QLQ-C30 and QLQ-BR23, respectively, during the 1st (C1), 3rd (C3) and 6th (C6) chemotherapy cycles. Results revealed that with the progression of chemotherapy cycles (from C1 to C6), all rhythm parameters, namely mesor, amplitude, acrophase, rhythm quotient (RQ), circadian quotient (CQ), peak activity (PA), dichotomy index and autocorrelation coefficient, significantly decreased in both cancer in- and outpatients. In both groups of patients and during C1–C6, all functional and global QoL measures of QLQ-C30 and QLQ-BR23 significantly decreased and the symptoms significantly increased, except constipation, body image, sexual functioning and future perspectives in outpatients. The hospitalization exacerbated the problems associated with the RA rhythm and the QoL of the patients. In conclusion, the current study highlighted the negative consequences of hospitalization among inpatients, irrespective of the stage of cancer. We, therefore, recommend that cancer patients should be administered with chemotherapy as outpatients. The proposed protocol might have a covert bearing on the expression of better physiological state leading to satisfactory treatment outcomes.

Introduction Characterizing 24-hour rest-activity rhythm (RAR) patterns in adolescents is critical, as this developmental period is marked by developmental and social changes that may impact circadian regulation. This study aimed to characterized 24-hour RAR patterns among adolescents transitioning from middle to high school, with a focus on variations across socio-demographic factors, pubertal status, and season of measurement. Methods Baseline and follow-up data in the Sleep and Growth Study were analyzed (N=107; 45.8% female; Mage 13.9 years [baseline] and 14.9 years [follow-up]). Wrist actigraphy (ranging from 3-14 days) was used to collect movement profiles (Philips Actiwatch 2) and proprietary count data were further processed using ActCR and GGIR (g.getM5L5) packages to derive RAR parameters. Non-parametric (i.e., interdaily stability [IS], intradaily variability [IV], relative amplitude [RA], most active 10-hour midpoint [M10], least active 5-hour midpoint [L5]), and parametric (i.e., mesor, amplitude, acrophase) RAR metrics were estimated. Data on socio-demographic factors (sex, race, parental education level, household income), and pubertal status were obtained through self/parental-report; and season of measurement was based on measurement (Nov-Apr, May-Oct). Linear mixed effect modeling was used to examine the impacts of grade, socio-demographic factors, and season. Results Compared to 8th grade, adolescents in 9th grade exhibited less stable RAR (IS: β=-0.03, p=0.001) and more fragmented patterns (IV: β=0.07, p=0.000). Male sex, compared to female, was associated with lower amplitude (β =-30.37, p=0.013) and earlier acrophase (β=-0.36, p=0.025). Adolescents in lowest household income category, compared to those in the highest, had earlier midpoint for the least active 5-hour period (L5 midpoint: β=-1.12, p=0.004). Post-pubertal, compared to pre-pubertal adolescents, exhibited lower IS (β=-0.03, p=0.024), lower amplitude (β=-40.89, p=0.000), lower mesor (β=-18.25, p=0.006), earlier acrophase (β=-0.36, p=0.025), and delayed daily activity midpoint (M10 midpoint: β=0.41, p=0.018). No associations were observed between any RAR metrics and sex, household income, parental education level, or season of measurement. Conclusion Advancing grade level, male, lower socioeconomic factors, and pubertal maturation were associated with less stable, more fragmented, reduced amplitude and mesor, and shifts in activity timing. These findings underscore the developmental and socio-demographic influences on circadian rhythms during adolescence. Support (if any) NIH/NHLBI K01HL123612 (Mitchell), NIH/NHLBI T32HL007953 (Kwon)

Interest in sleep and circadian research in inflammatory bowel disease (IBD) (Crohn's disease and ulcerative colitis) is growing; however, few studies have objectively measured sleep or circadian rhythms in people with these conditions. The purpose was to determine the feasibility of the use of wrist actigraphy, electronic sleep/activity diaries, and participant-collected saliva among adults with both active and inactive IBD. We conducted a 10-day feasibility study of adults aged 18 years to 60 years with IBD. We measured sleep and rest-activity rhythms with wrist actigraphy, self-reported sleep/activity using electronic diaries, and participant-collected saliva to compute salivary dim light melatonin onset. All 37 (100%) participants wore the wrist actigraphs, 91.8% (N = 34) participants completed at least 15 of the 18 electronic diaries, and 34 (91.9%) completed the saliva collection. It is feasible to use wrist actigraphy and electronic sleep/activity diaries in adult participants with inflammatory bowel disease.

Background: Intrinsically photosensitive retinal ganglion cells (ipRGCs) control non-visual light responses (e.g. pupillary light reflex and circadian entrainment). Patients with diabetic retinopathy (DR) show reduced ipRGC function, as inferred by abnormalities in the post illumination pupil response (PIPR). We explored whether ipRGC function in DR is associated with circadian outputs and sleep/wake behavior. Methods: Forty-five participants (15 without diabetes, 15 with type 2 diabetes (T2D) and no DR, 15 with T2D and DR) participated. ipRGC function was inferred from the PIPR (pupil size following stimulus offset). Circadian outputs were melatonin amplitude (overnight urinary 6-sulfatoxymelatonin (aMT6s)) and timing (dim light melatonin onset (DLMO)), and evening salivary cortisol levels. Sleep/wake patterns were measured with wrist actigraphy and insomnia symptoms were assessed subjectively. Results: Patients with T2D and DR had smaller PIPR and lower urinary aMT6s than other groups (p < 0.001). In adjusted regression models, smaller PIPR was associated with lower urinary aMT6s (β = 4.552, p = 0.005). Patients with DR were more likely to have no detectable DLMO (p = 0.049), higher evening salivary cortisol, greater insomnia symptoms and greater sleep variability compared to other groups. Sleep duration, efficiency and rest-activity rhythms were similar. Conclusion: Reduced ipRGC function in DR is associated with circadian dysregulation and sleep disturbances, although a causal relationship cannot be established in this cross-sectional study. Prospective mechanistic and intervention studies examining circadian and sleep health in these patients are warranted.

To characterize acute alterations of circadian and ultradian rest-activity rhythms in critically ill patients and their association with brain dysfunction, systemic multiple organ dysfunction, and melatonin rhythms. Prospective study observing a cohort for 48 hours beginning within the first day of ICU admission. ICUs within an academic medical center. Patients presenting from the community with acute onset of either intracerebral hemorrhage or sepsis as representative neurologic and systemic critical illnesses. Healthy control patients were studied in the community, during hospital bedrest, and during sleep deprivation. None. Circadian and ultradian characteristics of rest-activity patterns were measured by wrist actigraphy, severity of neurologic and systemic illness by Glasgow Coma Scale and Sequential Organ Failure Assessment, and central circadian rhythm by melatonin profile. We studied 112 critically ill patients, including 53 with sepsis and 59 with intracerebral hemorrhage, along with 53 control participants. Total daily activity was markedly reduced and rest-activity rhythmicity was undetectable, neither of which was replicated by hospital bedrest in healthy controls. Circadian rest-activity rhythm fragmentation and attenuation and ultradian disorganization was associated with Glasgow Coma Scale and Sequential Organ Failure Assessment in adjusted models. Rest-activity rhythms showed no detectable phase coherence with melatonin rhythms. Critically ill patients rapidly enter a state of behavioral quiescence proportionate to their illness severity with concomitant disturbance of circadian and ultradian rest-activity rhythms and loss of phase coherence with the melatonin rhythm. Quiescence characteristics in rest-activity rhythms were not different in patients with and without delirium, suggesting them to be distinct phenomena. Animal models of severe physiologic stress have shown that specific neural pathway separate from the sleep-wake regulatory pathway induce behavioral quiescence and rest-activity arrhythmia, and facilitate recovery of cellular homeostasis. Whether quiescence is a conserved protective response pathway in humans is not yet understood.

Following menopause, women are at a greater risk of becoming obese and suffering from associated cardiometabolic diseases 1,2. The transition towards greater visceral adiposity and metabolic dysregulation after menopause is likely to be a consequence of changes in energy metabolism, primarily mediated by a reduction in circulating sex hormones such as estrogen or progesterone 1,2. In the current issue of cardiovascular endocrinology, Neff et al.3 describe that core body temperature is lower in women who have reached menopause, reaching temperatures similar to that of men. Their observation that the lower core body temperatures in those women who had reached menopause raises the possibility that this little studied factor could itself play a role in the increase in disease risk after this time 1,2, although whether the associated higher BMI and adiposity is an effect of age or the menopause per se cannot be determined from their study. Although the researchers acknowledge that the study was an exploratory post-hoc analysis of data synthesized from temporally distinct studies, it is worth further consideration, given current interest in brown adipose tissue (BAT) as a therapeutic target to combat cardiometabolic diseases 4. BAT is a thermogenic organ located mainly in the supraclavicular regions and in much smaller amounts 5 in other locations such as surrounding the kidneys and heart. Most abundant at birth 6, BAT is responsible for nonshivering thermogenesis and the maintenance of thermal homeostasis. This is achieved through the uncoupling of oxidative metabolism from ATP production through mitochondrial uncoupling protein 1, which dissipates chemical energy as heat 7. We now know that a majority of adults retain metabolically active BAT into adulthood 8, in declining amounts with age, and that sex hormones such as estrogen are likely to play a key role in the development of brown adipocytes and their function 9,10. Preclinical research has long demonstrated that exogenous sex hormones play a key role in the metabolic activity of BAT, and more recently it has been shown that cerebroventricular estradiol administration stimulates BAT function, increasing core body and BAT temperatures 11–13. Another feature of the study by Neff and colleagues is the large variation in body temperatures within women irrespective of age, and this appears to be most marked in the group described as postmenopausal. Although the authors do not define how many of the so-called postmenopausal women in the study were still experiencing hot flushes, a stage already known to be associated with lower body temperature, 14,15 and a truly age-matched group of men is omitted, their observations fit with studies showing that women are more sensitive to cold compared with men 8,16. This is likely to be a primary factor contributing to their higher incidence of BAT 17. Moreover, a recent small study in premenopausal women demonstrated a potentially important relationship between salivary cortisol and basal temperature of BAT within the neck 18. A combination of differences in the hypothalamic–pituitary–adrenal axis, BAT abundance, stress and thermal sensitivity could explain the large variation in body temperatures of healthy women. These relationships may shift after menopause as BAT activity declines. However, whether a decline in BAT after menopause occurs in humans and, therefore, contributes to greater BMI and fat mass remains to be determined. Given the role of BAT in metabolic homeostasis 19,20 and the recent associations between BAT activity and cardiovascular events 21, investigation of changes in BAT around the menopause and any effects of hormone replacement therapy are warranted. Maintenance of active BAT after the menopause has potential to attenuate the development of adiposity. Future investigations would require well-matched groups as differences in age, body mass and seasonality can all have a significant impact on BAT functionality as highlighted by the authors. Future studies should use additional methods as core body temperature measurements to determine thermal homeostasis and should include supraclavicular skin temperature 22–25 and thermal imaging 22,25 to assess BAT function (Fig. 1).Fig. 1: Overview of phenotypic differences between premenopausal/postmenopausal women and possible mechanisms involved. Histological image adapted from Ravussin and Galgani 26.

Primary open-angle glaucoma as a causal factor for circadian disruption: Living by the clock, in alignment with external time cues is an important condition for human health and well-being. Periodic changes in the ambient light serve as a key factor to synchronize the endogenously generated circadian rhythms. The retina perceives the photic signals and transmits them to the central body clock, the suprachiasmatic nuclei (SCN), via the retinohypothalamic tract. Primary open angle glaucoma (POAG) is an optic neuropathy, in which disease progression can be monitored by assessing damage to the retinal ganglion cells (RGCs) (Pérez-Rico et al., 2010; Feigl et al., 2011; Kankipati et al., 2011). Damage of retinal ganglion cells, particularly of intrinsically photosensitive RGCs (ipRGCs), is also one of the causes of circadian disruption. Pathophysiological mechanisms of POAG are complex, including elevated intraocular pressure (IOP), which adds mechanical stress, causing damage, dysfunction, and death of the RGCs (Figure 1). Glaucoma progression affects both image-forming and non-image-forming visual functions of RGCs. A central role of ipRGCs is to convey non-image-forming photic information to the clock. Their damage reduces light signaling to the SCN. Already in early stages of glaucoma, ipRGCs are dysfunctional (Pérez-Rico et al., 2010; Feigl et al., 2011; Kankipati et al., 2011).Figure 1: Melatonin potential to counteract complex circadian alterations with aging, neurodegeneration, specifically in glaucoma.ipRGCs: Intrinsically photosensitive retinal ganglion cells; SNPs: single nucleotide polymorphisms.As RGCs are progressively altered, and non-image-forming function is affected, circadian rhythms are disrupted, sleep is impaired, and mood is altered (Graticelli et al., 2015; Gubin et al., 2019, 2021). Circadian rhythm alterations are found in POAG as compared to age-matched healthy peers (Gubin et al., 2019). Circadian disruption worsens in advanced POAG (Gubin et al., 2019, Neroev et al., 2020), correlating to the increasing loss of ipRGCs with disease progression (Obara et al., 2016). Circadian rhythms also change with increasing age. Age-dependent circadian alterations are not necessarily related to retinal damage, as photic transduction to the central clock is not always compromised. When they are related to retinal damage, they can be due to either neurodegenerative ipRGCs damage, or to ipRGC damage caused by increased mean or deregulated circadian IOP. The intriguing principal difference between the presence or absence of retinal damage in aging is that the reduced light transmitted to the SCN by damaged ipRGCs phase-delays circadian rhythms, but ipRGC-uncompromised aging is commonly associated with phase-advanced circadian rhythms (Gubin et al., 2019). Since individual differences in sensitivity to light, and/or in endogenous melatonin production may interfere with this theoretical modeling, the search for specific genetic factors that may determine such individual differences constitutes a promising approach. In conditions where photic entrainment is compromised, not only is the alignment with external time cues altered, so can be the variability of overt physiologic functions. We showed that large inter-individual variability obscured the circadian IOP rhythm in POAG (Neroev et al., 2020). Circadian IOP rhythms had specific alterations manifested in advanced, but not in mild POAG, which were associated with the progressive damage and dysfunction of RGCs. In patients with RGCs' global loss volume above 15%, as assessed by high-definition optical coherence tomography, the 24-hour IOP rhythm peaked during the night, whereas in patients with stable POAG and a two-eye mean RGCs' global loss volume less than 10%, the IOP peaked predominantly during the daytime. Misalignment between circadian rhythms in body temperature and IOP increased as a function of global loss volume loss. Higher nocturnal IOP in POAG may adversely affect the disease state, fostering damage to RGCs (Neroev et al., 2020). Depending on individual genetic factors, these changes may manifest themselves to a different degree. Individual clock properties depend on numerous genetic factors, comprising clock genes and melatonin receptor genes, melatonin nuclear receptor 1b (MTNR1b) in particular, which may account for large individual differences in light sensitivity. Our pilot study of gene polymorphisms in POAG showed that the D-allele of the Angiotensin-converting enzyme holding a deletion of the 16th intron Alu repeat was significantly associated with alterations of the circadian IOP rhythm. It may also account for the resistance to IOP-lowering therapy (Neroev et al., 2020). Endogenous melatonin production in primary open-angle glaucoma: Glaucoma patients experienced reduced post-illumination pupil response (Kankipati et al., 2011) and reduced nocturnal melatonin suppression by light (Pérez-Rico et al., 2010). Clinical evidence for changes in the timing and mean values of endogenous melatonin production in POAG was also evident (reviewed in Gubin et al., 2021): in POAG, salivary melatonin can be lower than in age-matched controls without POAG; even greater alterations were observed In advanced stages of the disease. The main alteration concerned the time of maximal secretion of melatonin. Such altered melatonin production in POAG and other neurodegenerative pathologies can stem from different factors, including diminished light signaling due to a reduced sensitivity to light. The presence of certain gene polymorphisms can increase the susceptibility of carriers to these factors. We investigated 24-hour profiles of salivary melatonin under controlled lighting conditions and analyzed several clock genes and polymorphisms of the melatonin receptor gene MTNR1b (Gubin et al., 2021). Patients diagnosed with stable POAG had unaltered circadian rhythms of salivary melatonin and body temperature, which peaked at the anticipated time. Circadian rhythms of both variables were delayed, however, in patients diagnosed with advanced POAG (Gubin et al., 2019, 2021). Their 24-hour mean value and circadian amplitude of melatonin were also reduced (Gubin et al., 2021). Analysis of selected polymorphisms in clock and melatonin receptor genes revealed that these changes were observed specifically in carriers of the MTNR1B rs10830963 G-allele with advanced POAG. Overt changes of circadian phenotypes in POAG patients occur when several factors are present in combination: for example, when RGC loss exceeds a certain threshold in carriers of those genotypes, known to be associated with a prolonged duration of melatonin production. The MTNR1B rs10830963 G-allele is mainly known for its association with an elevated fasting glucose and the risk of type 2 diabetes, but it is also listed as a factor predicting POAG independently of diabetes (Shen et al., 2016), a fact supporting the assumption that melatonin may have pleiotropic physiological functions in the development of POAG. Melatonin to counteract non-image-forming visual function deterioration in primary open-angle glaucoma: To enhance circadian entrainment, morning light therapy and evening melatonin administration can both be effective. While studies aimed at estimating the merit of morning light therapy or outdoor light exposure in POAG are lacking, some studies provide evidence for a beneficial effect of exogenously administered melatonin in glaucoma and neurodegenerative pathologies (González Fleitas et al., 2021; Gubin et al., 2021). Melatonin transmits environmental light signals, thus facilitating the synchronization of peripheral clocks. It can thus mitigate several conditions such as glaucoma and its progression: disruption of circadian rhythms, compromised sleep, and mood (Tosini et al., 2012; Gubin et al., 2021) (Figure 1). Melatonin improves internal synchronization, ameliorating circadian alignment between local (IOP) and systemic (temperature) circadian rhythms (Gubin et al., 2021), which were progressively desynchronized with greater RGCs loss in POAG (Neroev et al., 2020). Melatonin is produced endogenously with a pronounced 24-hour rhythm governed by the SCN. Peak production occurs at night. Its specific timing may differ among individuals. Exact endogenous factors that predetermine these differences are not known but may include single nucleotide polymorphisms within candidate genes or melatonin receptors that influence sensitivity to light. Melatonin receptors (MTNR1B) are widespread in numerous brain regions. Their structure may determine the specific response to (both endogenous and exogenous) melatonin. We investigated the effect of oral melatonin administration (daily at 10:30 p.m. for 90 days) on the circadian rhythms of IOP, body temperature, and the pattern electroretinogram in patients diagnosed with stable or advanced POAG, also assessing effects on sleep and mood (Gubin et al., 2021). Melatonin administration increased the stability of the circadian body temperature rhythm, improving its alignment with the circadian IOP rhythm. Melatonin decreased IOP to a different extent at different times of the day and decreased the standard deviation of IOP with statistical significance. Larger changes were found in patients with initially higher 24-hour mean values of IOP. Melatonin improved RGCs function in patients with advanced POAG by increasing the amplitude of pattern electroretinogram that correlated positively with the degree of RGCs loss. Melatonin had more pronounced positive effects on sleep and mood in patients with advanced POAG, who had greater damage of their RGCs. Taken together melatonin has the potential to restore disrupted circadian rhythms in POAG. Its systemic effect is distinct from its local effect on the retinal circadian rhythms. Similar to light exposure, physiological effects of melatonin depend on the time of its administration. Personalizing melatonin administration in terms of its timing and dosing, accounting for the genetic profile, is expected to further refine its multiple benefits. Melatonin may provide beneficial effects in POAG stemming from both its ability to reduce IOP and its potential to prevent RGC damage derived from mechanisms of neurodegeneration (Hardeland, 2021) (Figure 1). These effects may not only mitigate circadian disruption but also improve other aspects of health and well-being. Circadian alignment may strengthen human physiological functions and help slow neurodegeneration. The choice of an optimal melatonin dosing, however, is not yet clear (Hardeland, 2021). Consideration of the best timing should be based on internal circadian parameters and on genes that may account for personal differences in melatonin efficacy. Concluding remarks: In assessing disruptions in the non-image-forming visual system in POAG patients, one needs to discriminate between different situations. There may be complex, non-specific changes in circadian rhythms with age. Changes related to neurogenerative disease, including Alzheimer's disease, Parkinson's disease, and POAG, might promote alterations in neural structures: SCN, pineal, retina. Changes specific to POAG include additional RGC damage caused by the elevated IOP, together with abnormal circadian patterns of physiological variables such as IOP, body temperature, pattern electroretinogram, and melatonin (Figure 1). The circadian IOP pattern with relatively higher values during the resting span may foster harmful effects of IOP on RGCs, since tissue sensitivity may vary depending on circadian time (Neroev et al., 2020). Numerous candidate gene polymorphisms may play a role, alone or in combination with others, affecting the susceptibility to POAG itself (as a primary pathology of vision), or POAG-associated alterations of circadian rhythms, sleep, and mood, linked to non-visual pathways. To answer this question, clinical data combined with circadian profiles of melatonin and other physiological variables, chronotype questionnaires, sleep and mood information, to be checked against single nucleotide polymorphisms databases, should be collected on large cohorts. Constructive collaboration among ophthalmologists, chronobiologists, and geneticists is therefore advocated. The present work was supported by the Russian Foundation for Basic Research (grant No. 19-015-00329) (to DG), and by Government of Tyumen District, Decree of 20.11.2020 No. 928-rp (to DG). The authors have no proprietary or commercial interest in any materials discussed in this article.

Introduction Rest-activity rhythms (RARs) reflecting sleep-wake cycles, rest-activity patterns, and circadian influences are a measure of circadian rhythmicity in naturalistic settings. Robust RARs are associated with lower office blood pressure (BP) and hypertension risk, but there is limited data on their association with out-of-office BP. This study examined associations of RARs with home BP monitoring (HBPM) and 24-h ambulatory BP monitoring (ABPM) outcomes. Methods A community-based sample of 201 middle-aged to older adults was recruited across New York City (mean age(SD): 55±11y, 70% female, 26% Black, 22% Hispanic). Participants completed seven consecutive days of wrist actigraphy concurrent with HBPM and ABPM. Wrist actigraphy was used to estimate non-parametric RAR variables. Morning and evening BP were measured daily using HBPM for 7 days and used to estimate daily averages; mean 24-h, sleep, and wake BP were derived from 24-h ABPM. Linear regression models, adjusted for age, sex, education, and BP medications, examined associations of RARs with BP outcomes. Results Greater relative amplitude, indicating more robust RARs (greater circadian rhythmicity), was associated with lower 24-h SBP and DBP, wake SBP, sleep SBP and DBP, and lower mean home SBP and DBP (β ranges:-14mmHg to -37mmHg, p&amp;lt; 0.01). Higher most active 10-h period counts, reflecting greater waketime activity, were associated with lower levels of all ABPM and HBPM measurements, while higher least active 5-hour period timing, reflecting later sleep timing, was related to higher sleep SBP and DBP from ABPM (p&amp;lt; 0.05 for all). Greater interdaily stability, reflecting more day-to-day sleep-wake and rest-activity pattern regularity, was associated with lower 24-h and sleep SBP and DBP from ABPM and with lower evening SBP from HBPM (β ranges:-12mmHg to -27mmHg, p&amp;lt; 0.05). Greater intradaily variability, reflecting higher rhythm fragmentation and sleep inefficiency, was associated with higher levels of all ABPM and HBPM outcomes (β ranges: 6mmHg to 11mmHg, p&amp;lt; 0.05). Conclusion Greater circadian rhythmicity across the 24-h behavioral cycle is associated with lower out-of-office BP. The timing, regularity, and magnitude of RARs in the 24-h day and across days may represent an important target for optimizing BP, but findings warrant confirmation in larger longitudinal studies. Support (if any) NHLBI:HL148511; PI: Makarem.

Introduction:The propensity for sleep shifts later as puberty progresses. The present analysis examines whether the circadian-dependent wake maintenance zone, or forbidden zone for sleep observed in the evening just before habitual bedtime is more pronounced in late to post-pubertal adolescents compared to adults and may partly explain late sleep onset in maturing adolescents.Methods:Forty four healthy late/post-pubertal adolescents (aged 14.3–17.8 years, 23 female) and 44 healthy adults (aged 30.8–45.8 years, 21 female) participated in an ultradian light/dark protocol for 3 days cycling between 2-h wake periods (~20 lux) and 2-h nap periods (~0 lux) without external time cues. The dim light melatonin onset (DLMO), a measure of circadian phase, was measured immediately before the ultradian protocol by sampling saliva every 30 min in dim light. Wrist actigraphs were used to assess sleep onset latency and total sleep time during the naps that occurred during the ultradian sleep/wake schedule. Sleep episodes were grouped into 2-h bins relative to individual DLMOs (28–56 naps/bin). Sleep onset and total sleep time were compared between adolescents and adults as well as between males and females within each age group.Results:Adolescents took significantly longer to fall asleep compared to adults during naps that occurred in the 4 h window surrounding the DLMO [2h before DLMO t(50) = 2.13, p = 0.04; 2 h after DLMO t(33) = 3.25, p = 0.003]. Adolescents also slept significantly less than adults during naps that occurred in the 4-h window surrounding DLMO [2 h before DLMO t(51) = −2.91, p = 0.01; 2 h after DLMO t(33) = −1.99, p = 0.05]. Adolescent males slept less than adolescent females in naps that occurred in the 2 h window after the DLMO [t(14) = −2.24, p = 0.04].Discussion:Compared to adults, late/post-pubertal adolescents showed greater difficulty falling asleep and maintaining sleep around the time of their DLMO, which usually occurs a few hours before habitual sleep onset. A greater amplitude in the circadian-driven forbidden zone for sleep could be an additional physiological mechanism explaining why maturing adolescents find it difficult to fall asleep early, increasing the risk for restricted sleep in the context of early school start times.

There is limited information regarding the physiological and psychological demands of the racing environment, and the subsequent effect on the performance of pit crew athletes. The purpose of this study was to evaluate heart rates (HRs) and core body temperatures (CTs) of pit crew athletes in the race environment. The HR and CT of pit crew athletes (n = 7) and control subjects were measured during 6 National Association for Stock Car Automobile Racing Sprint Cup races using ingestible sensors (HQ Inc, Palmetto, FL, USA). The HR and CT were measured before each race, at 15-minute intervals during the race, and upon completion of each pit stop. Compared to the control subject at each race, the pit crew athletes had significantly (p = 0.014) lower core temperatures (CTs). The pit crew athletes displayed higher HRs on the asphalt tracks than on concrete tracks (p = 0.011), and HR responses of the crew members were significantly (p = 0.012) different between pit crew positions, with the tire changers and jackman exhibiting higher HRs than the tire carriers. Unexpectedly, the CTs of the pit crew athletes were not elevated in the race environment, despite high ambient temperatures and the extensive fire-protection equipment (e.g., helmet, suit, gloves) each pit crew athlete wore. The lack of CT change is possibly the result of the increased HR more efficiently shunting blood to the skin and dissipating heat as a consequence of the athletes' extensive training regimen and ensuing heat acclimation. Additionally, it is possible that psychological stress unique to several of the tracks provided an additive effect resulting in increased heart rates.