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.

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.

Endogenous circadian rhythms in mood and well-being.

OBJECTIVES: We examined whether the endogenous circadian timing system modulates proxies of mood vulnerability and well-being. METHODS: Nineteen healthy participants (mean age: 26.6 years [23.0-30.2], seven females, body-mass index: 22.8 kg/m2 [21.1-25]) completed a laboratory protocol with a 32-hour Constant Routine, a stringently controlled protocol designed to isolate assessment of endogenous circadian rhythms. We assessed hourly anxiety- and depression-like mood (i.e., those typically observed in depression and anxiety) and well-being (i.e., associated with mental fatigue and physical comfort). RESULTS: Significant endogenous circadian rhythms were observed in anxiety-like and depression-like mood, as well as well-being (p values from the mixed-model analysis using false discovery rates < .001). Post-hoc comparisons revealed more anxiety-like and depression-like mood during the circadian phase 60°-75° (∼8-9 a.m.), and more mental fatigue and less physical comfort during the circadian phase 30°-60° (∼6-8 a.m.). CONCLUSIONS: Our data indicate endogenous circadian rhythms in anxiety-like and depression-like mood and well-being in healthy young adults. Future studies will help establish circadian-based therapeutics for individuals experiencing mood and anxiety disorders.

Spontaneous attentional failures reflect multiplicative interactions of chronic sleep loss with acute sleep loss and circadian misalignment.

OBJECTIVES: Acute and chronic sleep loss and circadian timing interact such that, depending on their combination, small or very large performance decrements are observed in tasks of attention. Here, we tested whether such nonlinear interactions extend to a physiological measure of spontaneous visual attentional failures, indicating a fundamental principle of sleep-wake regulation. METHODS: Nine healthy volunteers completed an in-laboratory 3-week forced desynchrony protocol consisting of 12 consecutive 42.85-hour cycles with a sleep-wake ratio of 1:3.3. The protocol induced increasing chronic sleep loss, while extended wake (32.85 hours) and sleep episodes (10 hours) occurred at multiple circadian phases. Attentional failure rate was quantified from continuous electrooculograms (number of 30-second epochs with slow eye movements/h of wakefulness) as a function of time since scheduled wake (acute sleep loss), week of study (chronic sleep loss), and circadian (melatonin) phase. RESULTS: During the first ∼8 hours awake, attentional failure rate was low, irrespective of the week. During the following wake hours, attentional failure rate increased steadily but at a faster rate in weeks 2 and 3 compared to week 1. The effects of acute and chronic sleep loss on attentional failure rate were magnified during the biological night compared to the biological day. CONCLUSIONS: A single extended sleep episode can only temporarily reverse attentional impairment associated with chronic sleep loss. Multiplicative effects of acute and chronic sleep loss-further amplified during the biological night-substantiate the interaction of 2 homeostatic response mechanisms and caution against underestimating their disproportionate combined impact on performance, health, and safety.

Association between sleep slow-wave activity and in-vivo estimates of myelin in healthy young men.

Sleep has been suggested to contribute to myelinogenesis and associated structural changes in the brain. As a principal hallmark of sleep, slow-wave activity (SWA) is homeostatically regulated but also differs between individuals. Besides its homeostatic function, SWA topography is suggested to reflect processes of brain maturation. Here, we assessed whether interindividual differences in sleep SWA and its homeostatic response to sleep manipulations are associated with in-vivo myelin estimates in a sample of healthy young men. Two hundred twenty-six participants (18-31 y.) underwent an in-lab protocol in which SWA was assessed at baseline (BAS), after sleep deprivation (high homeostatic sleep pressure, HSP) and after sleep saturation (low homeostatic sleep pressure, LSP). Early-night frontal SWA, the frontal-occipital SWA ratio, as well as the overnight exponential SWA decay were computed over sleep conditions. Semi-quantitative magnetization transfer saturation maps (MTsat), providing markers for myelin content, were acquired during a separate laboratory visit. Early-night frontal SWA was negatively associated with regional myelin estimates in the temporal portion of the inferior longitudinal fasciculus. By contrast, neither the responsiveness of SWA to sleep saturation or deprivation, its overnight dynamics, nor the frontal/occipital SWA ratio were associated with brain structural indices. Our results indicate that frontal SWA generation tracks inter-individual differences in continued structural brain re-organization during early adulthood. This stage of life is not only characterized by ongoing region-specific changes in myelin content, but also by a sharp decrease and a shift towards frontal predominance in SWA generation.

Late isocaloric eating increases hunger, decreases energy expenditure, and modifies metabolic pathways in adults with overweight and obesity.

Late eating has been linked to obesity risk. It is unclear whether this is caused by changes in hunger and appetite, energy expenditure, or both, and whether molecular pathways in adipose tissues are involved. Therefore, we conducted a randomized, controlled, crossover trial (ClinicalTrials.gov NCT02298790) to determine the effects of late versus early eating while rigorously controlling for nutrient intake, physical activity, sleep, and light exposure. Late eating increased hunger (p < 0.0001) and altered appetite-regulating hormones, increasing waketime and 24-h ghrelin:leptin ratio (p < 0.0001 and p = 0.006, respectively). Furthermore, late eating decreased waketime energy expenditure (p = 0.002) and 24-h core body temperature (p = 0.019). Adipose tissue gene expression analyses showed that late eating altered pathways involved in lipid metabolism, e.g., p38 MAPK signaling, TGF-ß signaling, modulation of receptor tyrosine kinases, and autophagy, in a direction consistent with decreased lipolysis/increased adipogenesis. These findings show converging mechanisms by which late eating may result in positive energy balance and increased obesity risk.

Daytime eating prevents mood vulnerability in night work.

Shift workers have a 25 to 40% higher risk of depression and anxiety partly due to a misalignment between the central circadian clock and daily environmental/behavioral cycles that may negatively affect mood and emotional well-being. Hence, evidence-based circadian interventions are required to prevent mood vulnerability in shift work settings. We used a stringently controlled 14-d circadian paradigm to assess mood vulnerability during simulated night work with either daytime and nighttime or daytime-only eating as compared with simulated day work (baseline). Simulated night work with daytime and nighttime eating increased depression-like mood levels by 26.2% (p-value adjusted using False Discovery Rates, pFDR = 0.001; effect-size r = 0.78) and anxiety-like mood levels by 16.1% (pFDR = 0.001; effect-size r = 0.47) compared to baseline, whereas this did not occur with simulated night work in the daytime-only eating group. Importantly, a larger degree of internal circadian misalignment was robustly associated with more depression-like (r = 0.77; P = 0.001) and anxiety-like (r = 0.67; P = 0.002) mood levels during simulated night work. These findings offer a proof-of-concept demonstration of an evidence-based meal timing intervention that may prevent mood vulnerability in shift work settings. Future studies are required to establish if changes in meal timing can prevent mood vulnerability in night workers.

Circadian and Sleep Modulation of Dreaming in Women with Major Depression.

Growing evidence indicates an association between reduced dream recall and depressive symptomatology. Here, we tested the prediction that reduced dream recall in individuals experiencing major depressive disorder (MDD) is due to alterations in circadian and sleep processes. Nine young healthy women (20−31 years) and eight young unmedicated women (20−31 years) diagnosed with MDD underwent a 40 h multiple nap protocol with ten alternating cycles of 150 min wake/75 min sleep under a stringently controlled circadian laboratory protocol. After each nap, we assessed dream recall, number of dreams and dream emotional load using the Sleep Mentation Questionnaire. Dream recall and the number of dreams did not significantly differ between groups (pFDR > 0.1). However, there was a significant difference for the dream emotional load (interaction of "Group" vs. "Time", pFDR = 0.01). Women with MDD had a two-fold higher (negative) emotional load as compared to healthy control women, particularly after naps during the circadian night (between ~22:00 h and ~05:00 h; Tukey−Kramer test, p = 0.009). Furthermore, higher (negative) dream emotional load was associated with impaired mood levels in both groups (R2 = 0.71; p < 0.001). Our findings suggest that the circadian and sleep modulation of dreaming may remain intact in unmedicated young women experiencing MDD.

Sleep and anxiety: From mechanisms to interventions.

Anxiety is the most common mental health problem worldwide. Epidemiological studies show that sleep disturbances, particularly insomnia, affect ∼50% of individuals with anxiety, and that insufficient sleep can instigate or further exacerbate it. This review outlines brain mechanisms underlying sleep and anxiety, by addressing recent human functional/structural imaging studies on brain networks underlying the anxiogenic impact of sleep loss, and the beneficial effect of sleep on these brain networks. We discuss recent developments from human molecular imaging studies that highlight the role of specific brain neurotransmitter mechanisms, such as the adenosinergic receptor system, on anxiety, arousal, and sleep. This review further discusses frontline sleep interventions aimed at enhancing sleep in individuals experiencing anxiety, such as nonbenzodiazepines/antidepressants, lifestyle and sleep interventions and cognitive behavioral therapy for insomnia. Notwithstanding therapeutic success, up to ∼30% of individuals with anxiety can be nonresponsive to frontline treatments. Thus, we address novel non-invasive brain stimulation techniques that can enhance electroencephalographic slow waves, and might help alleviate sleep and anxiety symptoms. Collectively, these findings contribute to an emerging biological framework that elucidates the interrelationship between sleep and anxiety, and highlight the prospect of slow wave sleep as a potential therapeutic target for reducing anxiety.

Cross-sectional study of intraocular cataract lens replacement, circadian rest-activity rhythms, and sleep quality in older adults.

STUDY OBJECTIVES: Age-related cataract decreases light transmission at the most sensitive spectrum for circadian photoentrainment, with negative ramifications for human health. Here, we assessed whether intraocular lens replacement (IOL) in older patients with previous cataract was associated with increased stability and amplitude of circadian rest-activity rhythms, and improved sleep quality. METHODS: Our cross-sectional study included sixteen healthy older individuals without ocular diseases (controls; 55-80 years; 63.6 ± 5.6y; 8 women) and 13 patients with previous cataract and bilateral IOL (eight with blue-blocking [BB] lens and five with ultraviolet-only [UV] blocking lens; 55-80 years; 69.9 ± 5.2y; 9 women). The study comprised three weeks of at home rest-activity assessments using wrist-worn actigraphs, and each week preceded a laboratory protocol. Primary outcomes were actigraphy-derived interdaily stability, intradaily variability, and relative amplitude of circadian rest-activity rhythms. Secondary outcomes were actigraphy-assessed sleep quality (i.e. time in bed, sleep duration, sleep efficiency, mean wake bout time and fragmentation index). RESULTS: Patients with IOL had significantly higher interdaily stability ("Group" effect: pFDR =.001), but not intradaily variability ("Group" effect: pFDR = n.s.), and significantly higher relative amplitude of rest-activity rhythms ("Group" effect: pFDR < .001). Moreover, patients with IOL had significantly higher activity levels during the day and lower levels during the evening, as compared to healthy older controls ("Group" effect: pFDR = .03). Analyses of actigraphy-derived sleep parameters yielded no significant differences across groups ("Group" effect: all pFDR > .1). CONCLUSIONS: Our cross-sectional study suggests that enhancing spectral lens transmission in patients with cataract may benefit their circadian health.

Proof-of-principle demonstration of endogenous circadian system and circadian misalignment effects on human oral microbiota.

Circadian misalignment-the misalignment between the central circadian "clock" and behavioral and environmental cycles (including sleep/wake, fasting/eating, dark/light)-results in adverse cardiovascular and metabolic effects. Potential underlying mechanisms for these adverse effects include alterations in the orogastrointestinal microbiota. However, it remains unknown whether human oral microbiota has endogenous circadian rhythms (i.e., independent of sleep/wake, fasting/eating, and dark/light cycles) and whether circadian misalignment influences oral microbiota community composition. Healthy young individuals [27.3 ± 2.3 years (18-35 years), 4 men and 2 women, body-mass index range: 18-28 kg/m2 ] were enrolled in a stringently controlled 14-day circadian laboratory protocol. This included a 32-h constant routine (CR) protocol (endogenous circadian baseline assessment), a forced desynchrony protocol with four 28-h "days" under ~3 lx to induce circadian misalignment, and a post-misalignment 40-h CR protocol. Microbiota assessments were performed on saliva samples collected every 4 h throughout both CR protocols. Total DNA was extracted and processed using high-throughput 16S ribosomal RNA gene amplicon sequencing. The relative abundance of specific oral microbiota populations, i.e., one of the five dominant phyla, and three of the fourteen dominant genera, exhibited significant endogenous circadian rhythms. Importantly, circadian misalignment dramatically altered the oral microbiota landscape, such that four of the five dominant phyla and eight of the fourteen dominant genera exhibited significant circadian misalignment effects. Moreover, circadian misalignment significantly affected the metagenome functional content of oral microbiota (inferred gene content analysis), as indicated by changes in specific functional pathways associated with metabolic control and immunity. Collectively, our proof-of-concept study provides evidence for endogenous circadian rhythms in human oral microbiota and show that even relatively short-term experimental circadian misalignment can dramatically affect microbiota community composition and functional pathways involved in metabolism and immune function. These proof-of-principle findings have translational relevance to individuals typically exposed to circadian misalignment, including night shift workers and frequent flyers.

Daytime eating prevents internal circadian misalignment and glucose intolerance in night work.

Night work increases diabetes risk. Misalignment between the central circadian "clock" and daily behaviors, typical in night workers, impairs glucose tolerance, likely due to internal misalignment between central and peripheral circadian rhythms. Whether appropriate circadian alignment of eating can prevent internal circadian misalignment and glucose intolerance is unknown. In a 14-day circadian paradigm, we assessed glycemic control during simulated night work with either nighttime or daytime eating. Assessment of central (body temperature) and peripheral (glucose and insulin) endogenous circadian rhythms happened during constant routine protocols before and after simulated night work. Nighttime eating led to misalignment between central and peripheral (glucose) endogenous circadian rhythms and impaired glucose tolerance, whereas restricting meals to daytime prevented it. These findings offer a behavioral approach to preventing glucose intolerance in shift workers.

Reply to Bracke et al. Comment on "Prayag et al. Light Modulation of Human Clocks, Wake, and Sleep. Clocks&Sleep 2019, 1, 193-208".

We thank Bracke and colleagues [...].

Age-related neuroendocrine and alerting responses to light.

Aging is associated with sleep and circadian alterations, which can negatively affect quality of life and longevity. Importantly, the age-related reduction in light sensitivity, particularly in the short-wavelength range, may underlie sleep and circadian alterations in older people. While evidence suggests that non-image-forming (NIF) light responses may diminish in older individuals, most laboratory studies have low sample sizes, use non-ecological light settings (e.g., monochromatic light), and typically focus on melatonin suppression by light. Here, we investigated whether NIF light effects on endogenous melatonin levels and sleep frontal slow-wave activity (primary outcomes), and subjective sleepiness and sustained attention (secondary outcomes) attenuate with aging. We conducted a stringently controlled within-subject study with 3 laboratory protocols separated by ~ 1 week in 31 young (18-30 years; 15 women) and 16 older individuals (55-80 years; eight women). Each protocol included 2 h of evening exposure to commercially available blue-enriched polychromatic light (6500 K) or non-blue-enriched light (3000 K or 2500 K) at low levels (~ 40 lx, habitual in evening indoor settings). Aging significantly affected the influence of light on endogenous melatonin levels, subjective sleepiness, sustained attention, and frontal slow-wave activity (interaction: P < 0.001, P = 0.004, P = 0.007, P = 0.001, respectively). In young individuals, light exposure at 6500 K significantly attenuated the increase in endogenous melatonin levels, improved subjective sleepiness and sustained attention performance, and decreased frontal slow-wave activity in the beginning of sleep. Conversely, older individuals did not exhibit signficant differential light sensitivity effects. Our findings provide evidence for an association of aging and reduced light sensitivity, with ramifications to sleep, cognition, and circadian health in older people.

Intraocular cataract lens replacement and light exposure potentially impact procedural learning in older adults.

Procedural learning declines with age and appropriately timed light exposure can improve cognitive performance in older individuals. Because cataract reduces light transmission and is associated with cognitive decline in older adults, we explored whether lens replacement (intraocular blue-blocking [BB] or UV-only blocking) in older patients with cataracts enhances the beneficial effects of light on procedural learning. Healthy older participants (n = 16) and older patients with post-cataract surgery (n = 13 with BB or UV lens replacement) underwent a randomized within-subject crossover laboratory design with three protocols. In each protocol, 3.5 hr dim-dark adaptation was followed by 2 hr evening blue-enriched (6,500K) or non-blue-enriched light exposure (3,000K or 2,500K), 30 min dim post-light, ~8 hr sleep and 2 hr morning dim light. Procedural learning was assessed by the alternating serial reaction time task (ASRT), as part of a larger test battery. Here, ASRT performance was indexed by type of trial (random or sequence) and sequence-specific (high or low probability) measures. During evening light exposure, we observed a significant effect of the interaction of "group" versus "light condition" on the type of trial (p = .04; p = .16; unadjusted and adjusted p-values, respectively) and sequence-specific learning (p = .04; p = .16; unadjusted and adjusted p-values, respectively), whereby patients with UV lens replacement performed better than patients with BB lens or non-cataract controls, during blue-enriched light exposure. Lens replacement in patients with cataracts may potentially be associated with beneficial effects of blue light on procedural learning. Thus, optimizing spectral lens transmission in patients with cataracts may help improve specific aspects of cognitive function, such as procedural learning.