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.

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.

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.

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.

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.

Circadian misalignment: A biological basis for mood vulnerability in shift work.

BACKGROUND: Approximately one in five workers perform night shift work. Epidemiological studies suggest that night shift workers are at a 25-30% higher risk for mental illnesses, including depression and anxiety, which is an increasingly important socioeconomic burden for the workforce. Thus, it is important to determine how shift work negatively affects mood, as it will help identify mechanisms that underlie a night shift worker's higher risk for developing mood disturbances. METHODS: This opinion discusses recently identified, potential biological mechanisms-including the role of the circadian system and circadian misalignment-underlying mood vulnerability in shift workers. Studies included are recent epidemiological, human laboratory studies and animal preclinical work on night shift work or circadian misalignment. Target biological mechanisms of interest discussed here include circadian misalignment effects on brain activity and brain-gut axis, essential for mood regulation. RESULTS: Circadian misalignment, which corresponds to the misalignment between biological (circadian) system and daily sleep-wake behaviours, can adversely affect mood levels and cortical activity underlying mood regulation. Furthermore, animal preclinical work shows that the brain-gut axis function is not only implicated in mood regulation but can disrupt specific metabolites essential for mood regulation when animals are exposed to circadian disruption. CONCLUSIONS: Circadian misalignment is a key mechanism underlying mood in e.g. shift workers. Therefore, understanding its role and applying sleep/circadian behavioural interventions to mitigate the adverse consequences of circadian misalignment on mood have the potential to improve quality of life, which is tightly associated with mood and sleep quality, in shift workers.

Exploring scoring methods for research studies: Accuracy and variability of visual and automated sleep scoring.

Sleep studies face new challenges in terms of data, objectives and metrics. This requires reappraising the adequacy of existing analysis methods, including scoring methods. Visual and automatic sleep scoring of healthy individuals were compared in terms of reliability (i.e., accuracy and stability) to find a scoring method capable of giving access to the actual data variability without adding exogenous variability. A first dataset (DS1, four recordings) scored by six experts plus an autoscoring algorithm was used to characterize inter-scoring variability. A second dataset (DS2, 88 recordings) scored a few weeks later was used to explore intra-expert variability. Percentage agreements and Conger's kappa were derived from epoch-by-epoch comparisons on pairwise and consensus scorings. On DS1 the number of epochs of agreement decreased when the number of experts increased, ranging from 86% (pairwise) to 69% (all experts). Adding autoscoring to visual scorings changed the kappa value from 0.81 to 0.79. Agreement between expert consensus and autoscoring was 93%. On DS2 the hypothesis of intra-expert variability was supported by a systematic decrease in kappa scores between autoscoring used as reference and each single expert between datasets (.75-.70). Although visual scoring induces inter- and intra-expert variability, autoscoring methods can cope with intra-scorer variability, making them a sensible option to reduce exogenous variability and give access to the endogenous variability in the data.

Seasonality in human cognitive brain responses.

Daily variations in the environment have shaped life on Earth, with circadian cycles identified in most living organisms. Likewise, seasons correspond to annual environmental fluctuations to which organisms have adapted. However, little is known about seasonal variations in human brain physiology. We investigated annual rhythms of brain activity in a cross-sectional study of healthy young participants. They were maintained in an environment free of seasonal cues for 4.5 d, after which brain responses were assessed using functional magnetic resonance imaging (fMRI) while they performed two different cognitive tasks. Brain responses to both tasks varied significantly across seasons, but the phase of these annual rhythms was strikingly different, speaking for a complex impact of season on human brain function. For the sustained attention task, the maximum and minimum responses were located around summer and winter solstices, respectively, whereas for the working memory task, maximum and minimum responses were observed around autumn and spring equinoxes. These findings reveal previously unappreciated process-specific seasonality in human cognitive brain function that could contribute to intraindividual cognitive changes at specific times of year and changes in affective control in vulnerable populations.

Evaluation of Visual Comfort and Mental Effort Under Different Light Conditions for Ultraviolet-Absorbing and Additional Blue-Filtering Intraocular Lenses for Cataract Surgery.

PATIENTS AND METHODS: Patients with an ultraviolet blocking lens (UV) (n = 5) or blue filter lens (BB) (n = 8) after intraocular lens (IOL) replacement for cataract and age-adjusted controls (AACs) (n = 16) underwent a balanced crossover within-subject design. After 1.5 h of dark adaptation, they were exposed to polychromatic light at 6500 K (blue-enriched) and 2500 K and 3000 K (non-blue-enriched) for 2 hours in the evening. Visual comfort and mental effort were repeatedly assessed by the Visual Analogue Scale (0 - 100) and the Visual Comfort and Mental Effort Rating Scale (0 - 100) for each light condition. The results were compared using mixed model analysis. RESULTS: The mean (± SD) age for AAC and patients with UV or BB was 69.8 ± 6.2 y, 70.8 ± 4 y, and 63.6 ± 5.6 y, respectively. Irrespective of the light condition, patients with UV and BB felt mentally more tired during the experiments compared to AACs (F = 6.15, p = 0.003). However, patients with BB were mentally more motivated to perform the exercises compared to patients with UV and AACs (F = 8.1, p < 0.001). Patients with BB perceived ambient light as less glary (F = 4.71, p = 0.01) than patients with UV. Blue ambient light was felt less intensely in patients with BB (F = 2.51, p = 0.042) compared to those with UV and the AACs. CONCLUSION: Lens replacement in older cataract patients may increase visual comfort and minimize mental effort. While subtle, the magnitude of these effects may depend on the type of intraocular lens. BB intraocular lenses may have potential benefits, as ambient light is perceived as having less glare and less visual tension.

Human fronto-parietal response scattering subserves vigilance at night.

Lack of sleep has a considerable impact on vigilance: we perform worse, we make more errors, particularly at night, when we should be sleeping. Measures of brain functional connectivity suggest that decrease in vigilance during sleep loss is associated with an impaired cross-talk within the fronto-parietal cortex. However, fronto-parietal effective connectivity, which is more closely related to the causal cross-talk between brain regions, remains unexplored during prolonged wakefulness. In addition, no study has simultaneously investigated brain effective connectivity and wake-related changes in vigilance, preventing the concurrent incorporation of the two aspects. Here, we used electroencephalography (EEG) to record responses evoked by Transcranial Magnetic Stimulation (TMS) applied over the frontal lobe in 23 healthy young men (18-30 yr.), while they simultaneously performed a vigilance task, during 8 sessions spread over 29 h of sustained wakefulness. We assessed Response Scattering (ReSc), an estimate of effective connectivity, as the propagation of TMS-evoked EEG responses over the fronto-parietal cortex. Results disclose a significant change in fronto-parietal ReSc with time spent awake. When focusing on the night-time period, when one should be sleeping, participants with lower fronto-parietal ReSc performed worse on the vigilance task. Conversely, no association was detected during the well-rested, daytime period. Night-time fronto-parietal ReSc also correlated with objective EEG measures of sleepiness and alertness. These changes were not accompanied by variations in fronto-parietal response complexity. These results suggest that decreased brain response propagation within the fronto-parietal cortex is associated to increased vigilance failure during night-time prolonged wakefulness. This study reveals a novel facet of the detrimental effect on brain function of extended night-time waking hours, which is increasingly common in our societies.

Eyes Open on Sleep and Wake: In Vivo to In Silico Neural Networks.

Functional and effective connectivity of cortical areas are essential for normal brain function under different behavioral states. Appropriate cortical activity during sleep and wakefulness is ensured by the balanced activity of excitatory and inhibitory circuits. Ultimately, fast, millisecond cortical rhythmic oscillations shape cortical function in time and space. On a much longer time scale, brain function also depends on prior sleep-wake history and circadian processes. However, much remains to be established on how the brain operates at the neuronal level in humans during sleep and wakefulness. A key limitation of human neuroscience is the difficulty in isolating neuronal excitation/inhibition drive in vivo. Therefore, computational models are noninvasive approaches of choice to indirectly access hidden neuronal states. In this review, we present a physiologically driven in silico approach, Dynamic Causal Modelling (DCM), as a means to comprehend brain function under different experimental paradigms. Importantly, DCM has allowed for the understanding of how brain dynamics underscore brain plasticity, cognition, and different states of consciousness. In a broader perspective, noninvasive computational approaches, such as DCM, may help to puzzle out the spatial and temporal dynamics of human brain function at different behavioural states.

A finite-element reciprocity solution for EEG forward modeling with realistic individual head models.

We present a finite element modeling (FEM) implementation for solving the forward problem in electroencephalography (EEG). The solution is based on Helmholtz's principle of reciprocity which allows for dramatically reduced computational time when constructing the leadfield matrix. The approach was validated using a 4-shell spherical model and shown to perform comparably with two current state-of-the-art alternatives (OpenMEEG for boundary element modeling and SimBio for finite element modeling). We applied the method to real human brain MRI data and created a model with five tissue types: white matter, gray matter, cerebrospinal fluid, skull, and scalp. By calculating conductivity tensors from diffusion-weighted MR images, we also demonstrate one of the main benefits of FEM: the ability to include anisotropic conductivities within the head model. Root-mean square deviation between the standard leadfield and the leadfield including white-matter anisotropy showed that ignoring the directional conductivity of white matter fiber tracts leads to orientation-specific errors in the forward model. Realistic head models are necessary for precise source localization in individuals. Our approach is fast, accurate, open-source and freely available online.

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.

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.

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.

Acute exposure to evening blue-enriched light impacts on human sleep.

Light in the short wavelength range (blue light: 446-483 nm) elicits direct effects on human melatonin secretion, alertness and cognitive performance via non-image-forming photoreceptors. However, the impact of blue-enriched polychromatic light on human sleep architecture and sleep electroencephalographic activity remains fairly unknown. In this study we investigated sleep structure and sleep electroencephalographic characteristics of 30 healthy young participants (16 men, 14 women; age range 20-31 years) following 2 h of evening light exposure to polychromatic light at 6500 K, 2500 K and 3000 K. Sleep structure across the first three non-rapid eye movement non-rapid eye movement - rapid eye movement sleep cycles did not differ significantly with respect to the light conditions. All-night non-rapid eye movement sleep electroencephalographic power density indicated that exposure to light at 6500 K resulted in a tendency for less frontal non-rapid eye movement electroencephalographic power density, compared to light at 2500 K and 3000 K. The dynamics of non-rapid eye movement electroencephalographic slow wave activity (2.0-4.0 Hz), a functional index of homeostatic sleep pressure, were such that slow wave activity was reduced significantly during the first sleep cycle after light at 6500 K compared to light at 2500 K and 3000 K, particularly in the frontal derivation. Our data suggest that exposure to blue-enriched polychromatic light at relatively low room light levels impacts upon homeostatic sleep regulation, as indexed by reduction in frontal slow wave activity during the first non-rapid eye movement episode.

Age effects on spectral electroencephalogram activity prior to dream recall.

Ageing is associated with marked changes in sleep timing, structure and electroencephalographic (EEG) activity. Older people exhibit less slow-wave and spindle activity during non-rapid eye movement (NREM) sleep, together with attenuated levels of rapid eye movement (REM) sleep as compared to young individuals. However, the extent to which these age-related changes in sleep impact on dream processing remains largely unknown. Here we investigated NREM and REM sleep EEG activity prior to dream recall and no recall in 17 young (20-31 years) and 15 older volunteers (57-74 years) during a 40 h multiple nap protocol. Dream recall was assessed immediately after each nap. During NREM sleep prior to dream recall, older participants displayed higher frontal EEG delta activity (1-3 Hz) and higher centro-parietal sigma activity (12-15 Hz) than the young volunteers. Conversely, before no recall, older participants had less frontal-central delta activity and less sigma activity in frontal, central and parietal derivations than the young participants. REM sleep was associated to age-related changes, such that older participants had less frontal-central alpha (10-12 Hz) and beta (16-19 Hz) activity, irrespective of dream recall and no recall. Our data indicate that age-related differences in dream recall seem to be directly coupled to specific frequency and topography EEG patterns, particularly during NREM sleep. Thus, the spectral correlates of dreaming can help to understand the cortical pathways of dreaming.

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.