Sex differences in sleep, circadian rhythms, and metabolism: Implications for precision medicine.

The number of individuals experiencing sleep loss has exponentially risen over the past decades. Extrapolation of laboratory findings to the real world suggests that females are more affected by extended wakefulness and circadian misalignment than males are. Therefore, long-term effects such as sleep and metabolic disorders are likely to be more prevalent in females than in males. Despite emerging evidence for sex differences in key aspects of sleep-wake and circadian regulation, much remains unknown, as females are often underrepresented in sleep and circadian research. This narrative review aims at highlighting 1) how sex differences systematically impinge on the sleep-wake and circadian regulation in humans, 2) how sex differences in sleep and circadian factors modulate metabolic control, and 3) the relevance of these differences for precision medicine. Ultimately, the findings justify factoring in sex differences when optimizing individually targeted sleep and circadian interventions in humans.

Fatigued but not sleepy? An empirical investigation of the differentiation between fatigue and sleepiness in sleep disorder patients in a cross-sectional study.

OBJECTIVE: Sleepiness and fatigue are common complaints among individuals with sleep disorders. The two concepts are often used interchangeably, causing difficulty with differential diagnosis and treatment decisions. The current study investigated sleep disorder patients to determine which factors best differentiated sleepiness from fatigue. METHODS: The study used a subset of participants from a multi-site study (n = 606), using a cross-sectional study design. We selected 60 variables associated with either sleepiness or fatigue, including demographic, mental health, and lifestyle factors, medical history, sleep questionnaires, rest-activity rhythms (actigraphy), polysomnographic (PSG) variables, and sleep diaries. Fatigue was measured with the Fatigue Severity Scale and sleepiness was measured with the Epworth Sleepiness Scale. A Random Forest machine learning approach was utilized for analysis. RESULTS: Participants' average age was 47.5 years (SD 14.0), 54.6% female, and the most common sleep disorder diagnosis was obstructive sleep apnea (67.4%). Sleepiness and fatigue were moderately correlated (r = 0.334). The model for fatigue (explained variance 49.5%) indicated depression was the strongest predictor (relative explained variance 42.7%), followed by insomnia severity (12.3%). The model for sleepiness (explained variance 17.9%), indicated insomnia symptoms was the strongest predictor (relative explained variance 17.6%). A post hoc receiver operating characteristic analysis indicated depression could be used to discriminate fatigue (AUC = 0.856) but not sleepiness (AUC = 0.643). CONCLUSIONS: The moderate correlation between fatigue and sleepiness supports previous literature that the two concepts are overlapping yet distinct. Importantly, depression played a more prominent role in characterizing fatigue than sleepiness, suggesting depression could be used to differentiate the two concepts.

The sleep-circadian interface: A window into mental disorders.

Sleep, circadian rhythms, and mental health are reciprocally interlinked. Disruption to the quality, continuity, and timing of sleep can precipitate or exacerbate psychiatric symptoms in susceptible individuals, while treatments that target sleep-circadian disturbances can alleviate psychopathology. Conversely, psychiatric symptoms can reciprocally exacerbate poor sleep and disrupt clock-controlled processes. Despite progress in elucidating underlying mechanisms, a cohesive approach that integrates the dynamic interactions between psychiatric disorder with both sleep and circadian processes is lacking. This review synthesizes recent evidence for sleep-circadian dysfunction as a transdiagnostic contributor to a range of psychiatric disorders, with an emphasis on biological mechanisms. We highlight observations from adolescent and young adults, who are at greatest risk of developing mental disorders, and for whom early detection and intervention promise the greatest benefit. In particular, we aim to a) integrate sleep and circadian factors implicated in the pathophysiology and treatment of mood, anxiety, and psychosis spectrum disorders, with a transdiagnostic perspective; b) highlight the need to reframe existing knowledge and adopt an integrated approach which recognizes the interaction between sleep and circadian factors; and c) identify important gaps and opportunities for further research.

Impaired 24-h activity patterns are associated with an increased risk of Alzheimer's disease, Parkinson's disease, and cognitive decline.

BACKGROUND: Sleep-wake regulating circuits are affected during prodromal stages in the pathological progression of both Alzheimer's disease (AD) and Parkinson's disease (PD), and this disturbance can be measured passively using wearable devices. Our objective was to determine whether accelerometer-based measures of 24-h activity are associated with subsequent development of AD, PD, and cognitive decline. METHODS: This study obtained UK Biobank data from 82,829 individuals with wrist-worn accelerometer data aged 40 to 79 years with a mean (± SD) follow-up of 6.8 (± 0.9) years. Outcomes were accelerometer-derived measures of 24-h activity (derived by cosinor, nonparametric, and functional principal component methods), incident AD and PD diagnosis (obtained through hospitalization or primary care records), and prospective longitudinal cognitive testing. RESULTS: One hundred eighty-seven individuals progressed to AD and 265 to PD. Interdaily stability (a measure of regularity, hazard ratio [HR] per SD increase 1.25, 95% confidence interval [CI] 1.05-1.48), diurnal amplitude (HR 0.79, CI 0.65-0.96), mesor (mean activity; HR 0.77, CI 0.59-0.998), and activity during most active 10 h (HR 0.75, CI 0.61-0.94), were associated with risk of AD. Diurnal amplitude (HR 0.28, CI 0.23-0.34), mesor (HR 0.13, CI 0.10-0.16), activity during least active 5 h (HR 0.24, CI 0.08-0.69), and activity during most active 10 h (HR 0.20, CI 0.16-0.25) were associated with risk of PD. Several measures were additionally predictive of longitudinal cognitive test performance. CONCLUSIONS: In this community-based longitudinal study, accelerometer-derived metrics were associated with elevated risk of AD, PD, and accelerated cognitive decline. These findings suggest 24-h rhythm integrity, as measured by affordable, non-invasive wearable devices, may serve as a scalable early marker of neurodegenerative disease.

ENLIGHT: A consensus checklist for reporting laboratory-based studies on the non-visual effects of light in humans.

BACKGROUND: There is no consensus on reporting light characteristics in studies investigating non-visual responses to light. This project aimed to develop a reporting checklist for laboratory-based investigations on the impact of light on non-visual physiology. METHODS: A four-step modified Delphi process (three questionnaire-based feedback rounds and one face-to-face group discussion) involving international experts was conducted to reach consensus on the items to be included in the checklist. Following the consensus process, the resulting checklist was tested in a pilot phase with independent experts. FINDINGS: An initial list of 61 items related to reporting light-based interventions was condensed to a final checklist containing 25 items, based upon consensus among experts (final n = 60). Nine items were deemed necessary to report regardless of research question or context. A description of each item is provided in the accompanying Explanation and Elaboration (E&E) document. The independent pilot testing phase led to minor textual clarifications in the checklist and E&E document. INTERPRETATION: The ENLIGHT Checklist is the first consensus-based checklist for documenting and reporting ocular light-based interventions for human studies. The implementation of the checklist will enhance the impact of light-based research by ensuring comprehensive documentation, enhancing reproducibility, and enabling data aggregation across studies. FUNDING: Network of European Institutes for Advanced Study (NETIAS) Constructive Advanced Thinking (CAT) programme; Sir Henry Wellcome Postdoctoral Fellowship (Wellcome Trust, 204686/Z/16/Z); Netherlands Organisation for Health Research and Development VENI fellowship (2020-09150161910128); U.S. Department of Defense Grant (W81XWH-16-1-0223); National University of Singapore (NUHSRO/2022/038/Startup/08); and National Research Foundation Singapore (NRF2022-THE004-0002).

Moving time zones in a flash with light therapy during sleep.

In humans, exposure to continuous light is typically used to change the timing of the circadian clock. This study examines the efficiency of a sequence of light flashes ("flash therapy") applied during sleep to shift the clock. Healthy participants (n = 10) took part in two 36-h laboratory stays, receiving a placebo (goggles, no light) during one visit and the intervention (goggles, 2-ms flashes broad-spectrum light for 60 min, delivered every 15 s, starting 30 min after habitual sleep onset) during the other. Circadian phase shift was assessed with changes in salivary dim light melatonin onset (DLMO). Sleep, measured with polysomnography, was analyzed to assess changes in sleep architecture and spectral power. After 1 h of flashes, DLMO showed a substantial delay (1.13 ± 1.27 h) compared to placebo (12 ± 20 min). Two individuals exhibited very large shifts of 6.4 and 3.1 h. There were no substantive differences in sleep architecture, but some evidence for greater instability in sleep. 1 h of flash therapy during sleep evokes large changes in circadian timing, up to 6 h, and does so with only minimal, if any, impact on sleep. Flash therapy may offer a practical option to delay the circadian clock in shift workers and jet travelers.

The Impact of Missing Data and Imputation Methods on the Analysis of 24-Hour Activity Patterns.

The purpose of this study is to characterize the impact of the timing and duration of missing actigraphy data on interdaily stability (IS) and intradaily variability (IV) calculation. The performance of three missing data imputation methods (linear interpolation, mean time of day (ToD), and median ToD imputation) for estimating IV and IS was also tested. Week-long actigraphy records with no non-wear or missing timeseries data were masked with zeros or 'Not a Number' (NaN) across a range of timings and durations for single and multiple missing data bouts. IV and IS were calculated for true, masked, and imputed (i.e., linear interpolation, mean ToD and, median ToD imputation) timeseries data and used to generate Bland-Alman plots for each condition. Heatmaps were used to analyze the impact of timings and durations of and between bouts. Simulated missing data produced deviations in IV and IS for longer durations, midday crossings, and during similar timing on consecutive days. Median ToD imputation produced the least deviation among the imputation methods. Median ToD imputation is recommended to recapitulate IV and IS under missing data conditions for less than 24 h.

Circadian photoreception: The impact of light on human circadian rhythms.

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

Impact of daytime spectral tuning on cognitive function.

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

Objective underpinnings of self-reported sleep quality in middle-aged and older adults: The importance of N2 and wakefulness.

STUDY OBJECTIVES: The measurable aspects of brain function (polysomnography, PSG) that are correlated with sleep satisfaction are poorly understood. Using recent developments in automated sleep scoring, which remove the within- and between-rater error associated with human scoring, we examine whether PSG measures are associated with sleep satisfaction. DESIGN AND SETTING: A single night of PSG data was compared to contemporaneously collected measures of sleep satisfaction with Random Forest regressions. Whole and partial night PSG data were scored using a novel machine learning algorithm. PARTICIPANTS: Community-dwelling adults (N = 3165) who participated in the Sleep Heart Health Study. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: Models explained 30% of sleep depth and 27% of sleep restfulness, with a similar top four predictors: minutes of N2 sleep, sleep efficiency, age, and minutes of wake after sleep onset (WASO). With increasing self-reported sleep quality, there was a progressive increase in N2 and decrease in WASO of similar magnitude, without systematic changes in N1, N3 or REM sleep. In comparing those with the best and worst self-reported sleep satisfaction, there was a range of approximately 30 min more N2, 30 min less WASO, an improvement of sleep efficiency of 7-8%, and an age span of 3-5 years. Examination of sleep most proximal to morning awakening revealed no greater explanatory power than the whole-night data set. CONCLUSIONS: Higher N2 and concomitant lower wake is associated with improved sleep satisfaction. Interventions that specifically target these may be suitable for improving the self-reported sleep experience.

Physiological correlates of the Epworth Sleepiness Scale reveal different dimensions of daytime sleepiness.

The Epworth Sleepiness Scale is commonly used to examine self-reported daytime sleepiness in clinical populations; the physiologic correlates of this scale, however, are not well understood. Furthermore, how well this scale correlates with parallel objective and self-reported concepts of daytime sleepiness is not well described. As such, we used machine learning algorithms to examine the association between Epworth Sleepiness Scale scores and 55 sleep and medical variables in the Sleep Heart Health Study (N = 2105). Secondary analyses examined data stratified by age and gender and the relationship between the Epworth and other measures of daytime sleepiness. Analyses of the main data set resulted in low explained variance (7.15%-10.0%), with self-reported frequency of not getting enough sleep as most important predictor (10.3%-13.9% of the model variance). Stratification by neither age nor gender significantly improved explained variance. Cross-correlational analysis revealed low correlation of other daytime sleepiness measures to Epworth scores. We find that Epworth scores are not well explained by habitual or polysomnographic sleep values, or other biomedical characteristics. These analyses indicate that there are different, potentially orthogonal dimensions of the concept of "daytime sleepiness" that may be driven by different aspects of sleep physiology. As the physiologic correlates of the Epworth Sleepiness Scale remain to be elucidated, interpretation of the clinical meaning of these scores should be done with caution.

A Temporal Threshold for Distinguishing Off-Wrist from Inactivity Periods: A Retrospective Actigraphy Analysis.

(1) Background. To facilitate accurate actigraphy data analysis, inactive periods have to be distinguished from periods during which the device is not being worn. The current analysis investigates the degree to which off-wrist and inactive periods can be automatically identified. (2) Methods. In total, 125 actigraphy records were manually scored for 'off-wrist' and 'inactivity' (99 collected with the Motionlogger AMI, 26 (sampling frequency of 60 (n = 20) and 120 (n = 6) s) with the Philips Actiwatch 2.) Data were plotted with cumulative frequency percentage and analyzed with receiver operating characteristic curves. To confirm findings, the thresholds determined in a subset of the Motionlogger dataset (n = 74) were tested in the remaining dataset (n = 25). (3) Results. Inactivity data lasted shorter than off-wrist periods, with 95% of inactive events being shorter than 11 min (Motionlogger), 20 min (Actiwatch 2; 60 s epochs) or 30 min (Actiwatch 2; 120 s epochs), correctly identifying 35, 92 or 66% of the off-wrist periods. The optimal accurate detection of both inactive and off-wrist periods for the Motionlogger was 3 min (Youden's Index (J) = 0.37), while it was 18 (J = 0.89) and 16 min (J = 0.81) for the Actiwatch 2 (60 and 120 s epochs, respectively). The thresholds as determined in the subset of the Motionlogger dataset showed similar results in the remaining dataset. (4) Conclusion. Off-wrist periods can be automatically identified from inactivity data based on a temporal threshold. Depending on the goal of the analysis, a threshold can be chosen to favor inactivity data's inclusion or accurate off-wrist detection.

Deep Brain Stimulation in the Nucleus Accumbens for Binge Eating Disorder: a Study in Rats.

Binge eating disorder (BED), with its compulsive and addictive components, may often underlie weight regain after gastrointestinal bariatric surgeries. BED is therefore considered an exclusion criterion for these surgeries. Anecdotal reports suggest that deep brain stimulation (DBS) is an effective treatment for addictive disorders with, similar to BED, pathological changes in cerebral reward circuitry. We therefore assessed effect of DBS of the nucleus accumbens (NAC) in a rat model of BED. Twenty-one male obesity prone Wistar rats with DBS electrodes placed in NAC subregions were subjected to a binge eating protocol. Binge eating was significantly reduced with DBS during (NAC core) or before (NAC lateral shell) the binge. These outcomes provide a base to further explore the potential of DBS in the treatment of BED.

Daytime melatonin and light independently affect human alertness and body temperature.

Light significantly improves alertness during the night (Cajochen, Sleep Med Rev, 11, 2007 and 453; Ruger et al., AJP Regul Integr Comp Physiol, 290, 2005 and R1413), but results are less conclusive at daytime (Lok et al., J Biol Rhythms, 33, 2018 and 589). Melatonin and core body temperature levels at those times of day may contribute to differences in alerting effects of light. In this experiment, the combined effect of daytime exogenous melatonin administration and light intensity on alertness, body temperature, and skin temperature was studied. The goal was to assess whether (a) alerting effects of light are melatonin dependent, (b) soporific effects of melatonin are mediated via the thermoregulatory system, and (c) light can improve alertness after melatonin-induced sleepiness during daytime. 10 subjects (5 females, 5 males) received melatonin (5 mg) in dim (10 lux) and, on a separate occasion, in bright polychromatic white light (2000 lux). In addition, they received placebo both under dim and bright light conditions. Subjects participated in all four conditions in a balanced order, yielding a balanced within-subject design, lasting from noon to 04:00 pm. Alertness and performance were assessed half hourly, while body temperature and skin temperature were measured continuously. Saliva samples to detect melatonin concentrations were collected half hourly. Melatonin administration increased melatonin concentrations in all subjects. Subjective sleepiness and distal skin temperature increased after melatonin ingestion. Bright light exposure after melatonin administration did not change subjective alertness scores, but body temperature and proximal skin temperature increased, while distal skin temperature decreased. Light exposure did not significantly affect these parameters in the placebo condition. These results indicate that (a) exogenous melatonin administration during daytime increases subjective sleepiness, confirming a role for melatonin in sleepiness regulation, (b) bright light exposure after melatonin ingestion significantly affected thermoregulatory parameters without altering subjective sleepiness, therefore temperature changes seem nonessential for melatonin-induced sleepiness, (c) subjective sleepiness was increased by melatonin ingestion, but bright light administration was not able to improve melatonin-induced sleepiness feelings nor performance. Other (physiological) factors may therefore contribute to differences in alerting effects of light during daytime and nighttime.

Light, Alertness, and Alerting Effects of White Light: A Literature Overview.

Light is known to elicit non-image-forming responses, such as effects on alertness. This has been reported especially during light exposure at night. Nighttime results might not be translatable to the day. This article aims to provide an overview of (1) neural mechanisms regulating alertness, (2) ways of measuring and quantifying alertness, and (3) the current literature specifically regarding effects of different intensities of white light on various measures and correlates of alertness during the daytime. In general, the present literature provides inconclusive results on alerting effects of the intensity of white light during daytime, particularly for objective measures and correlates of alertness. However, the various research paradigms employed in earlier studies differed substantially, and most studies tested only a limited set of lighting conditions. Therefore, the alerting potential of exposure to more intense white light should be investigated in a systematic, dose-dependent manner with multiple correlates of alertness and within one experimental paradigm over the course of day.

White Light During Daytime Does Not Improve Alertness in Well-rested Individuals.

Broad-spectrum light applied during the night has been shown to affect alertness in a dose-dependent manner. The goal of this experiment was to investigate whether a similar relationship could be established for light exposure during daytime. Fifty healthy participants were subjected to a paradigm (0730-1730 h) in which they were intermittently exposed to 1.5 h of dim light (<10 lux) and 1 h of experimental light (24-2000 lux). The same intensity of experimental light was used throughout the day, resulting in groups of 10 subjects per intensity. Alertness was assessed with subjective and multiple objective measures. A significant effect of time of day was found in all parameters of alertness ( p < 0.05). Significant dose-response relationships between light intensity and alertness during the day could be determined in a few of the parameters of alertness at some times of the day; however, none survived correction for multiple testing. We conclude that artificial light applied during daytime at intensities up to 2000 lux does not elicit significant improvements in alertness in non-sleep-deprived subjects.