Dr Eva Winnebeck

Early school times clash with the late sleep of adolescents, leading to wide-spread sleep restriction in students. Evidence suggests that delaying school starts is beneficial for sleep and recent studies investigated whether this also translates into improved academic achievement. We thus conducted a systematic review of the literature on school start times, grades and test scores in middle and high-school students. We reviewed 21 studies following the PRISMA guidelines and assessed the evidence quality using a pre-defined risk of bias tool. Nine studies reported no association of later starts with achievement, while the remaining reported mixed (5), positive (5), negative (1) or unclear (1) results. Considering the heterogeneity in academic outcomes, study types, amount of delay and exposure, and the substantial risk of bias, a meta-analysis was not warranted - instead we provide grouped reviews and discussion. Overall, no generalisable improvements in achievement with later starts emerge beyond the level of single studies. This does not necessarily preclude improvements in students’ learning but highlights shortcomings of the literature and the challenges of using grades and test scores to operationalise academic achievement. Given other previously reported positive outcomes, our results suggest that schools could start later while achievement is likely maintained.

Sleep and wake represent two profoundly different states of physiology that arise within the brain from a complex interaction between multiple neural circuits and neurotransmitter systems. These neural networks are, in turn, adjusted by three key drivers that collectively determine the duration, quality, and efficiency of sleep. Two of these drivers are endogenous, namely, the circadian system and a homeostatic hourglass oscillator, while the third is exogenous-our societal structure (social time). In this chapter, we outline the neuroscience of sleep and highlight the links between sleep, mood, cognition, and mental health. We emphasize that the complexity of sleep/wake generation and regulation makes this behavioral cycle very vulnerable to disruption and then explore this concept by examining sleep and circadian rhythm disruption (SCRD) when the exogenous and endogenous drivers of sleep are in conflict. SCRD can be particularly severe when social timing forces an abnormal pattern of sleep and wake upon our endogenous sleep biology. SCRD is also very common in mental illness, and although well known, this association is poorly understood or treated. Recent studies suggest that the generation of sleep and mental health shares overlapping neural mechanisms such that defects in these endogenous pathways result in pathologies to both behaviors. The evidence for this association is examined in some detail. We conclude this review by suggesting that the emerging understanding of the neurobiology of sleep/wake behavior, and of the health consequences of sleep disruption, will provide new ways to decrease the conflict between biological and societal timing in both the healthy and individuals with mental illness.

The temporal dynamics that characterize sleep are difficult to capture outside the sleep laboratory. Therefore, longitudinal studies and big-data approaches assessing sleep dynamics are lacking. Here, we present the first large-scale analysis of human sleep dynamics in real life by making use of longitudinal wrist movement recordings of > 16,000 sleep bouts from 573 subjects. Through non-linear conversion of locomotor activity to "Locomotor Inactivity During Sleep'' (LIDS), movement patterns are exposed that directly reflect ultradian sleep cycles and replicate the dynamics of laboratory sleep parameters. Our current analyses indicate no sex differences in LIDS-derived sleep dynamics, whereas especially age but also shift work have pronounced effects, specifically on decline rates and ultradian amplitude. In contrast, ultradian period and phase emerged as remarkably stable across the tested variables. Our approach and results provide the necessary quantitative sleep phenotypes for large field studies and outcome assessments in clinical trials.

Our lives are structured by the daily alternation of activity and rest, of wake and sleep. Despite significant advances in circadian and sleep research, we still lack answers to many of the most fundamental questions about this conspicuous behavioral pattern. We strongly believe that investigating this pattern in entrained conditions, real-life and daily contexts-in situ-will help the field to elucidate some of these central questions. Here, we present two common approaches for in situ investigation of human activity and rest: the Munich ChronoType Questionnaire (MCTQ) and actimetry. In the first half of this chapter, we provide detailed instructions on how to use and interpret the MCTQ. In addition, we give an overview of the main insights gained with this instrument over the past 10 years, including some new findings on the interaction of light and age on sleep timing. In the second half of this chapter, we introduce the reader to the method of actimetry and share our experience in basic analysis techniques, including visualization, smoothing, and cosine model fitting of in situ recorded data. Additionally, we describe our new approach to automatically detect sleep from activity recordings. Our vision is that the broad use of such easy techniques in real-life settings combined with automated analyses will lead to the creation of large databases. The resulting power of big numbers will promote our understanding of such fundamental biological phenomena as sleep.

After a flight across multiple time zones, most people show a transient state of circadian misalignment causing temporary malaise known as jetlag disorder. The severity of the elicited symptoms is postulated to depend mostly on circadian factors such as the number of time zones crossed and the direction of travel. Here, we examined the influence of prior expectation on symptom severity, compared to said 'classic' determinants, in order to gauge potential psychosocial effects in jetlag disorder. To this end, we monitored jetlag symptoms in travel-inexperienced individuals (n=90, 18-37y) via detailed questionnaires twice daily for one week before and after flights crossing >3 time zones. We found pronounced differences in individual symptom load that could be grouped into 4 basic symptom trajectories. Both traditional and newly devised metrics of jetlag symptom intensity and duration (accounting for individual symptom trajectories) recapitulated previous results of jetlag prevalence at about 50-60% as well as general symptom dynamics. Surprisingly, however, regression models showed very low predictive power for any of the jetlag outcomes. The classic circadian determinants, including number of time zones crossed and direction of travel, exhibited little to no link with jetlag symptom intensity and duration. Only expectation emerged as a parameter with systematic, albeit small, predictive value. These results suggest expectation as a relevant factor in jetlag experience - hinting at potential placebo effects and new treatment options. Our findings also caution against jetlag recommendations based on circadian principles but insufficient evidence linking circadian re-synchronization dynamics with ensuing symptom intensity and duration. Competing Interest Statement The authors have declared no competing interest.

Periods of sleep and wakefulness can be estimated from wrist-locomotor activity recordings via algorithms that identify periods of relative activity and inactivity. Here, we evaluated the performance of our Munich Actimetry Sleep Detection Algorithm. The Munich Actimetry Sleep Detection Algorithm uses a moving 24-h threshold and correlation procedure estimating relatively consolidated periods of sleep and wake. The Munich Actimetry Sleep Detection Algorithm was validated against sleep logs and polysomnography. Sleep-log validation was performed on two field samples collected over 54 and 34 days (median) in 34 adolescents and 28 young adults. Polysomnographic validation was performed on a clinical sample of 23 individuals undergoing one night of polysomnography. Epoch-by-epoch analyses were conducted and comparisons of sleep measures carried out via Bland-Altman plots and correlations. Compared with sleep logs, the Munich Actimetry Sleep Detection Algorithm classified sleep with a median sensitivity of 80% (interquartile range [IQR] = 75%-86%) and specificity of 91% (87%-92%). Mean onset and offset times were highly correlated (r = .86-.91). Compared with polysomnography, the Munich Actimetry Sleep Detection Algorithm reached a median sensitivity of 92% (85%-100%) but low specificity of 33% (10%-98%), owing to the low frequency of wake episodes in the night-time polysomnographic recordings. The Munich Actimetry Sleep Detection Algorithm overestimated sleep onset (similar to 21 min) and underestimated wake after sleep onset (similar to 26 min), while not performing systematically differently from polysomnography in other sleep parameters. These results demonstrate the validity of the Munich Actimetry Sleep Detection Algorithm in faithfully estimating sleep-wake patterns in field studies. With its good performance across daytime and night-time, it enables analyses of sleep-wake patterns in long recordings performed to assess circadian and sleep regularity and is therefore an excellent objective alternative to sleep logs in field settings.

Internal clocks driving rhythms of about a day (circadian) are ubiquitous in animals, allowing them to anticipate environmental changes. Genetic or environmental disturbances to circadian clocks or the rhythms they produce are commonly associated with illness, compromised performance or reduced survival. Nevertheless, some animals including Arctic mammals, open sea fish and social insects such as honeybees are active around-the-clock with no apparent ill effects. The mechanisms allowing this remarkable natural plasticity are unknown. We generated and validated a new and specific antibody against the clock protein PERIOD of the honeybee Apis mellifera (amPER) and used it to characterize the circadian network in the honeybee brain. We found many similarities to Drosophila melanogaster and other insects, suggesting common anatomical organization principles in the insect clock that have not been appreciated before. Time course analyses revealed strong daily oscillations in amPER levels in foragers, which show circadian rhythms, and also in nurses that do not, although the latter have attenuated oscillations in brain mRNA clock gene levels. The oscillations in nurses show that activity can be uncoupled from the circadian network and support the hypothesis that a ticking circadian clock is essential even in around-the-clock active animals in a constant physical environment.

The integrity of extracted ribonucleic acid (RNA) is commonly assessed by gel electrophoresis and subsequent analysis of the ribosomal RNA (rRNA) bands. Using the honey bee, Apis mellifera (Hymenoptera: Apidae), as an example, the electrophoretic rRNA profile of insects is explained. This profile differs significantly from the standard benchmark since the 28S rRNA of most insects contains an endogenous "hidden break."Upon denaturation, the masking hydrogen bonds are hydrolyzed, releasing two similar sized fragments that both migrate closely with 18S rRNA. The resulting rRNA profile thus reflects the endogenous composition of insect rRNA and should not be misinterpreted as degradation.

Abstract Sleep deprivation in teenage students is pervasive and a public health concern, but evidence is accumulating that delaying school start times may be an effective countermeasure. Most studies so far assessed static changes in schools start time, using cross-sectional comparisons and one-off sleep measures. When a high school in Germany introduced flexible start times for their senior students—allowing them to choose daily between an 8 am or 9 am start (≥08:50)—we monitored students’ sleep longitudinally using subjective and objective measures. Students (10–12th grade, 14–19 y) were followed 3 weeks prior and 6 weeks into the flexible system via daily sleep diaries (n = 65) and a subcohort via continuous wrist-actimetry (n = 37). Satisfaction and perceived cognitive outcomes were surveyed at study end. Comparisons between 8 am and ≥9 am-starts within the flexible system demonstrated that students slept 1.1 h longer when starting school later—independent of gender, grade, chronotype, and frequency of later starts; sleep offsets were delayed but, importantly, onsets remained unchanged. Sleep quality was increased and alarm-driven waking reduced. However, overall sleep duration in the flexible system was not extended compared to baseline—likely because students did not start later frequently enough. Nonetheless, students were highly satisfied with the flexible system and reported cognitive and sleep improvements. Therefore, flexible systems may present a viable alternative for implementing later school starts to improve teenage sleep if students can be encouraged to use the late-option frequently enough. Flexibility may increase acceptance of school start changes and speculatively even prevent delays in sleep onsets through occasional early starts.

With the emergence of big data science, the question how we can easily collect meaningful information about circadian clock phenotypes in large human cohorts imposes itself. Here, we describe potentials and limitations of using questionnaires, specifically the Munich ChronoType Questionnaire (MCTQ), to characterize such circadian phenotypes. We also discuss scenarios when alternative methods might be more appropriate.

Earlier human activity relative to sunrise and sunset, the very essence of DST, is linked with health and safety detriments in humans. A new study predicts that deer, at least, may benefit from earlier human activity through reduced deer-vehicle collisions. Daylight saving time (DST) regulations are under debate again in many countries around the world. The US and the EU are considering abolishing the biannual switches into and out of DST but have yet to decide if they will settle for permanent Standard Time or permanent DST. The public and political debates are ripe with personal anecdotes, wrong assumptions and strong convictions, so empirical evidence on the advantages of either timing system are all the more important to encourage evidence-based policy – and highlight unintended side effects that may require tailored mitigation measures. In this issue, Cunningham et al. 1 investigated one of these potential side effects by analyzing the likelihood of deer-vehicle collisions in the US under different timing regimes, finding that the timing of humans on the road to and from work significantly adds to the risks of wildlife encounters and collisions. Chronobiology, the study of biological rhythms, has long recognized that, for each animal, there is a time and a place to be active, rest, eat or reproduce. This timing is not random but heavily influenced by endogenous timing mechanisms that interpret and synchronize to Earth's timing signals, like day and night and the seasons. Deer, as crepuscular animals, lock their activity to the hours before and after sunrise and sunset, which means that the clock times at which they are most active changes throughout the year together with the increase and decrease in daylength over the seasons. Their seasonal program will also lock their breeding to fall, in white-tailed deer in North America even to a very narrow window of 2-3 weeks 2,3 (Fig. 1). In contrast, humans are day active mammals, who have introduced artificial conditions into their lives that reduce the connection with natural light to the detriment of their daily and seasonal rhythms 4. We shield from the sun by hiding indoors, turn on light when it is dark outside and live to rigid work schedules that do not reflect local solar time but are the same across an entire time zone-often too wide or ill-placed, ignoring the fact that even under these conditions our biology will seek to respond to the sun 4-8. DST is another factor in this chronobiological problem humans are facing, shifting around the timing of entire societies twice a year or even permanently as currently under proposition. DST brings human activity forward by one hour by moving clocks and thus schedules one hour earlier. This leads to an abrupt advance of human activity in relation to the timing of sunlight (Fig. 1), with acute health and safety detriments 9-12. The long-term effects are much harder to quantify. However, theory and indirect data clearly indicate that what might still resonate with our biology during midsummer when daylight

Following general anesthesia, people are often confused about the time of day and experience sleep disruption and fatigue. It has been hypothesized that these symptoms may be caused by general anesthesia affecting the circadian clock. The circadian clock is fundamental to our well-being because it regulates almost all aspects of our daily biochemistry, physiology, and behavior. Here, we investigated the effects of the most common general anesthetic, isoflurane, on time perception and the circadian clock using the honeybee (Apis mellifera) as a model. A 6-h daytime anesthetic systematically altered the time-compensated sun compass orientation of the bees, with a mean anticlockwise shift in vanishing bearing of 87 in the Southern Hemisphere and a clockwise shift in flight direction of 58 in the Northern Hemisphere. Using the same 6-h anesthetic treatment, time-trained bees showed a delay in the start of foraging of 3.3 h, and whole-hive locomotor-activity rhythms were delayed by an average of 4.3 h. We show that these effects are all attributable to a phase delay in the core molecular clockwork. mRNA oscillations of the central clock genes cryptochrome-m and period were delayed by 4.9 and 4.3 h, respectively. However, this effect is dependent on the time of day of administration, as is common for clock effects, and nighttime anesthesia did not shift the clock. Taken together, our results suggest that general anesthesia during the day causes a persistent and marked shift of the clock effectively inducing "jet lag" and causing impaired time perception. Managing this effect in humans is likely to help expedite postoperative recovery.

Early school times fundamentally clash with the late sleep of teenagers. This mismatch results in chronic sleep deprivation posing acute and long-term health risks and impairing students' learning. Despite immediate short-term benefits for sleep, the long-term effects of later starts remain unresolved. In a pre-post design over 1 year, we studied a unique flexible school start system, in which 10-12th grade students chose daily between an 8:00 or 8:50AM-start. Missed study time (8:00-8:50) was compensated for during gap periods or after classes. Based on 2 waves (6-9 weeks of sleep diary each), we found that students maintained their ~ 1-h-sleep gain on later days, longitudinally (n = 28) and cross-sectionally (n = 79). This gain was independent of chronotype and frequency of later starts but attenuated for boys after 1 year. Students showed persistently better sleep quality and reduced alarm-driven waking and reported psychological benefits (n = 93) like improved motivation, concentration, and study quality on later days. Nonetheless, students chose later starts only infrequently (median 2 days/week), precluding detectable sleep extensions in the flexible system overall. Reasons for not choosing late starts were the need to make up lost study time, preference for extra study time and transport issues. Whether flexible systems constitute an appealing alternative to fixed delays given possible circadian and psychological advantages warrants further investigation.

Background Melatonin modulates circadian rhythms in physiology and sleep initiation. Genetic variants of the MTNR1B locus, encoding the melatonin MT2 receptor, have been associated with increased type 2 diabetes (T2D) risk. Carriers of the common intronic MTNR1B rs10830963 T2D risk variant have modified sleep and circadian traits such as changes of the melatonin profile. However, it is currently unknown whether rare variants in the MT2 coding region are also associated with altered sleep and circadian phenotypes, including meal timing. Materials and Methods In this pilot study, 28 individuals [50% male; 46-82 years old; 50% with rare MT2 mutations (T2D MT2)] wore actigraphy devices and filled out daily food logs for 4 weeks. We computed circadian, sleep, and caloric intake phenotypes, including sleep duration, timing, and regularity [assessed by the Sleep Regularity Index (SRI)]; composite phase deviations (CPD) as well a sleep timing-based proxy for circadian misalignment; and caloric intake patterns throughout the day. Using regression analyses, we estimated age- and sex-adjusted mean differences (MD) and 95% confidence intervals (95%CI) between the two patient groups. Secondary analyses also compare T2D MT2 to 15 healthy controls. Results Patients with rare MT2 mutations had a later sleep onset (MD = 1.23, 95%CI = 0.42;2.04), and midsleep time (MD = 0.91, 95%CI = 0.12;1.70), slept more irregularly (MD in SRI = -8.98, 95%CI = -16.36;-1.60), had higher levels of behavioral circadian misalignment (MD in CPD = 1.21, 95%CI = 0.51;1.92), were more variable in regard to duration between first caloric intake and average sleep offset (MD = 1.08, 95%CI = 0.07;2.08), and had more caloric episodes in a 24 h day (MD = 1.08, 95%CI = 0.26;1.90), in comparison to T2D controls. Secondary analyses showed similar patterns between T2D MT2 and non-diabetic controls. Conclusion This pilot study suggests that compared to diabetic controls, T2D MT2 patients display a number of adverse sleep, circadian, and caloric intake phenotypes, including more irregular behavioral timing. A prospective study is needed to determine the role of these behavioral phenotypes in T2D onset and severity, especially in view of rare MT2 mutations.

The mismatch between teenagers’ late sleep phase and early school start times results in acute and chronic sleep reductions. This is not only harmful for learning but may reduce career prospects and widen social inequalities. Delaying school start times has been shown to improve sleep at least short-term but whether this translates to better achievement is unresolved. Here, we studied whether 0.5–1.5 years of exposure to a flexible school start system, with the daily choice of an 8 AM or 8:50 AM-start, allowed secondary school students (n = 63–157, 14–21 years) to improve their quarterly school grades in a 4-year longitudinal pre-post design. We investigated whether sleep, changes in sleep or frequency of later starts predicted grade improvements. Mixed model regressions with 5111–16,724 official grades as outcomes did not indicate grade improvements in the flexible system per se or with observed sleep variables nor their changes—the covariates academic quarter, discipline and grade level had a greater effect in our sample. Importantly, our finding that intermittent sleep benefits did not translate into detectable grade changes does not preclude improvements in learning and cognition in our sample. However, it highlights that grades are likely suboptimal to evaluate timetabling interventions despite their importance for future success.

The Munich ChronoType Questionnaire (MCTQ) has now been available for more than 15 years and its original publication has been cited 1240 times (Google Scholar, May 2019). Additionally, its online version, which was available until July 2017, produced almost 300,000 entries from all over the world (MCTQ database). The MCTQ has gone through several versions, has been translated into 13 languages, and has been validated against other more objective measures of daily timing in several independent studies. Besides being used as a method to correlate circadian features of human biology with other factors-ranging from health issues to geographical factors-the MCTQ gave rise to the quantification of old wisdoms, like "teenagers are late", and has produced new concepts, like social jetlag. Some like the MCTQ's simplicity and some view it critically. Therefore, it is time to present a self-critical view on the MCTQ, to address some misunderstandings, and give some definitions of the MCTQ-derived chronotype and the concept of social jetlag.

This chapter summarizes epidemiological insights into sleep and wake behaviour and covers the limited knowledge about its disorders, with special emphasis on psychiatry. The chapter systematically refers to the interdependencies of four different aspects in both sleep and wake: timing, duration, structure, and quality. It provides an overview of the current methods used in the field for studying this behaviour and predicts that longterm actimetry monitoring in everyday life will revolutionize research into both sleep and the circadian clock. The chapter argues that a stronger alliance between sleep research and circadian biology will help to better understand the different aetiologies of sleep disorders, as well as the relationships between sleep and disease. It is predicted that strengthening our consideration of sleep’s circadian regulation versus its societal constraints—together with improved light environments—will ameliorate many sleep problems. There is also a need to improve public education about sleep and the circadian clock to increase selfawareness of sleep, activity, and light behaviour on an individual level to prevent false selfdiagnoses due to misconceptions about sleep.

Many regions and countries are reconsidering their use of Daylight Saving Time (DST) but their approaches differ. Some, like Japan, that have not used DST over the past decades are thinking about introducing this twice-a-year change in clock time, while others want to abolish the switch between DST and Standard Time, but don't agree which to use: California has proposed keeping perennial DST (i.e., all year round), and the EU debates between perennial Standard Time and perennial DST. Related to the discussion about DST is the discussion to which time zone a country, state or region should belong: the state of Massachusetts in the United States is considering switching to Atlantic Standard Time, i.e., moving the timing of its social clock (local time) 1 h further east (which is equivalent to perennial DST), and Spain is considering leaving the Central European Time to join Greenwich Mean Time (GMT), i.e., moving its social timing 1 h further west. A wave of DST discussions seems to periodically sweep across the world. Although DST has always been a political issue, we need to discuss the biology associated with these decisions because the circadian clock plays a crucial role in how the outcome of these discussions potentially impacts our health and performance. Here, we give the necessary background to understand how the circadian clock, the social clock, the sun clock, time zones, and DST interact. We address numerous fallacies that are propagated by lay people, politicians, and scientists, and we make suggestions of how problems associated with DST and time-zones can be solved based on circadian biology.

The shift from solitary to social behavior is one of the major evolutionary transitions. Primitively eusocial bumblebees are uniquely placed to illuminate the evolution of highly eusocial insect societies. Bumblebees are also invaluable natural and agricultural pollinators, and there is widespread concern over recent population declines in some species. High-quality genomic data will inform key aspects of bumblebee biology, including susceptibility to implicated population viability threats. We report the high quality draft genome sequences of Bombus terrestris and Bombus impatiens, two ecologically dominant bumblebees and widely utilized study species. Comparing these new genomes to those of the highly eusocial honeybee Apis mellifera and other Hymenoptera, we identify deeply conserved similarities, as well as novelties key to the biology of these organisms. Some honeybee genome features thought to underpin advanced eusociality are also present in bumblebees, indicating an earlier evolution in the bee lineage. Xenobiotic detoxification and immune genes are similarly depauperate in bumblebees and honeybees, and multiple categories of genes linked to social organization, including development and behavior, show high conservation. Key differences identified include a bias in bumblebee chemoreception towards gustation from olfaction, and striking differences in microRNAs, potentially responsible for gene regulation underlying social and other traits. These two bumblebee genomes provide a foundation for post-genomic research on these key pollinators and insect societies. Overall, gene repertoires suggest that the route to advanced eusociality in bees was mediated by many small changes in many genes and processes, and not by notable expansion or depauperation.