Andrew W. McHill

Entrainment of the Human Circadian Clock to the Natural Light-Dark Cycle

The electric light is one of the most important human inventions. Sleep and other daily rhythms in physiology and behavior, however, evolved in the natural light-dark cycle [1], and electrical lighting is thought to have disrupted these rhythms. Yet how much the age of electrical lighting has altered the human circadian clock is unknown. Here we show that electrical lighting and the constructed environment is associated with reduced exposure to sunlight during the day, increased light exposure after sunset, and a delayed timing of the circadian clock as compared to a summer natural 14 hr 40 min:9 hr 20 min light-dark cycle camping. Furthermore, we find that after exposure to only natural light, the internal circadian clock synchronizes to solar time such that the beginning of the internal biological night occurs at sunset and the end of the internal biological night occurs before wake time just after sunrise. In addition, we find that later chronotypes show larger circadian advances when exposed to only natural light, making the timing of their internal clocks in relation to the light-dark cycle more similar to earlier chronotypes. These findings have important implications for understanding how modern light exposure patterns contribute to late sleep schedules and may disrupt sleep and circadian clocks.

Impact of circadian misalignment on energy metabolism during simulated nightshift work.

Significance Demands of modern society force many work operations into the night, when the intrinsic circadian timing system promotes sleep. Overnight shiftwork is associated with increased risk for adverse metabolic health and sleep disruption. Uncovering potential physiological mechanisms that contribute to metabolic dysregulation when work and eating occur at inappropriate circadian times is vital to the development of effective treatment strategies. In this study, healthy volunteers underwent a commonly used simulated shiftwork protocol to quantify changes in metabolic, sleep, and circadian physiology when working and eating during the night as compared with a traditional day work schedule. We demonstrate that nightshift work reduces total daily energy expenditure, representing a contributing mechanism for unwanted weight gain and obesity. Eating at a time when the internal circadian clock promotes sleep is a novel risk factor for weight gain and obesity, yet little is known about mechanisms by which circadian misalignment leads to metabolic dysregulation in humans. We studied 14 adults in a 6-d inpatient simulated shiftwork protocol and quantified changes in energy expenditure, macronutrient utilization, appetitive hormones, sleep, and circadian phase during day versus nightshift work. We found that total daily energy expenditure increased by ∼4% on the transition day to the first nightshift, which consisted of an afternoon nap and extended wakefulness, whereas total daily energy expenditure decreased by ∼3% on each of the second and third nightshift days, which consisted of daytime sleep followed by afternoon and nighttime wakefulness. Contrary to expectations, energy expenditure decreased by ∼12–16% during scheduled daytime sleep opportunities despite disturbed sleep. The thermic effect of feeding also decreased in response to a late dinner on the first nightshift. Total daily fat utilization increased on the first and second nightshift days, contrary to expectations, and carbohydrate and protein utilization were reduced on the second nightshift day. Ratings of hunger were decreased during nightshift days despite decreases in 24-h levels of the satiety hormones leptin and peptide-YY. Findings suggest that reduced total daily energy expenditure during nightshift schedules and reduced energy expenditure in response to dinner represent contributing mechanisms by which humans working and eating during the biological night, when the circadian clock is promoting sleep, may increase the risk of weight gain and obesity.

Effects of caffeine on the human circadian clock in vivo and in vitro

Caffeine delays the human circadian clock and affects cellular timekeeping through an adenosine receptor–dependent mechanism. Your daily drug resets your clock Your morning cup of coffee may be shifting your circadian clock. Burke et al. show that caffeine—widely available, legal, and psychoactive—inserts a delay into the ~24-hour metabolic rhythm that keeps your body running in time with the world. In a sensitive, within-subject experimental design, five people were kept under highly controlled conditions for 49 days. Before bedtime, they were given various treatments: either a double-espresso caffeine dose, exposure to bright or dim light, or a placebo. The caffeine delayed their internal clock by 40 min, a shift about half as long as bright light, a stimulus known to robustly lengthen the circadian phase. The authors used cultured cells to determine that the drug acted directly on the adenosine receptor, which increases the intracellular messenger molecule cyclic AMP. The fact that cyclic AMP forms a key cog in the inner workings of the clock links caffeine’s biochemical effects to its delay of the circadian rhythm. Not only do these results reinforce the common advice to avoid caffeine in the evening, but they also raise the intriguing possibility that caffeine may be useful for resetting the circadian clock to treat jet lag induced by international time zone travel. Caffeine’s wakefulness-promoting and sleep-disrupting effects are well established, yet whether caffeine affects human circadian timing is unknown. We show that evening caffeine consumption delays the human circadian melatonin rhythm in vivo and that chronic application of caffeine lengthens the circadian period of molecular oscillations in vitro, primarily with an adenosine receptor/cyclic adenosine monophosphate (AMP)–dependent mechanism. In a double-blind, placebo-controlled, ~49-day long, within-subject study, we found that consumption of a caffeine dose equivalent to that in a double espresso 3 hours before habitual bedtime induced a ~40-min phase delay of the circadian melatonin rhythm in humans. This magnitude of delay was nearly half of the magnitude of the phase-delaying response induced by exposure to 3 hours of evening bright light (~3000 lux, ~7 W/m2) that began at habitual bedtime. Furthermore, using human osteosarcoma U2OS cells expressing clock gene luciferase reporters, we found a dose-dependent lengthening of the circadian period by caffeine. By pharmacological dissection and small interfering RNA knockdown, we established that perturbation of adenosine receptor signaling, but not ryanodine receptor or phosphodiesterase activity, was sufficient to account for caffeine’s effects on cellular timekeeping. We also used a cyclic AMP biosensor to show that caffeine increased cyclic AMP levels, indicating that caffeine influenced a core component of the cellular circadian clock. Together, our findings demonstrate that caffeine influences human circadian timing, showing one way that the world’s most widely consumed psychoactive drug affects human physiology.

Morning Circadian Misalignment during Short Sleep Duration Impacts Insulin Sensitivity

Short sleep duration and circadian misalignment are hypothesized to causally contribute to health problems including obesity, diabetes, metabolic syndrome, heart disease, mood disorders, cognitive impairment, and accidents. Here, we investigated the influence of morning circadian misalignment induced by an imposed short nighttime sleep schedule on impaired insulin sensitivity, a precursor to diabetes. Imposed short sleep duration resulted in morning wakefulness occurring during the biological night (i.e., circadian misalignment)-a time when endogenous melatonin levels were still high indicating the internal circadian clock was still promoting sleep and related functions. We show the longer melatonin levels remained high after wake time, insulin sensitivity worsened. Overall, we find a simulated 5-day work week of 5-hr-per-night sleep opportunities and ad libitum food intake resulted in ∼20% reduced oral and intravenous insulin sensitivity in otherwise healthy men and women. Reduced insulin sensitivity was compensated by an increased insulin response to glucose, which may reflect an initial physiological adaptation to maintain normal blood sugar levels during sleep loss. Furthermore, we find that transitioning from the imposed short sleep schedule to 9-hr sleep opportunities for 3 days restored oral insulin sensitivity to baseline, but 5 days with 9-hr sleep opportunities was insufficient to restore intravenous insulin sensitivity to baseline. These findings indicate morning wakefulness and eating during the biological night is a novel mechanism by which short sleep duration contributes to metabolic dysregulation and suggests food intake during the biological night may contribute to other health problems associated with short sleep duration.

Role of sleep and circadian disruption on energy expenditure and in metabolic predisposition to human obesity and metabolic disease

Weight gain, obesity and diabetes have reached alarming levels in the developed world. Traditional risk factors such as over‐eating, poor nutritional choices and lack of exercise cannot fully account for the high prevalence of metabolic disease. This review paper examines the scientific evidence on two novel risk factors that contribute to dys‐regulated metabolic physiology: sleep disruption and circadian misalignment. Specifically, fundamental relationships between energy metabolism and sleep and circadian rhythms and the impact of sleep and circadian disruption on metabolic physiology are examined. Millions of individuals worldwide do not obtain sufficient sleep for healthy metabolic function, and many participate in shift work and social activities at times when the internal physiological clock is promoting sleep. These behaviours predispose an individual for poor metabolic health by promoting excess caloric intake in response to reduced sleep, food intake at internal biological times when metabolic physiology is not prepared, decreased energy expenditure when wakefulness and sleep are initiated at incorrect internal biological times, and disrupted glucose metabolism during short sleep and circadian misalignment. In addition to the traditional risk factors of poor diet and exercise, disturbed sleep and circadian rhythms represent modifiable risk factors for prevention and treatment of metabolic disease and for promotion of healthy metabolism.

Recognizing academic performance, sleep quality, stress level, and mental health using personality traits, wearable sensors and mobile phones

What can wearable sensors and usage of smart phones tell us about academic performance, self-reported sleep quality, stress and mental health condition? To answer this question, we collected extensive subjective and objective data using mobile phones, surveys, and wearable sensors worn day and night from 66 participants, for 30 days each, totaling 1,980 days of data. We analyzed daily and monthly behavioral and physiological patterns and identified factors that affect academic performance (GPA), Pittsburg Sleep Quality Index (PSQI) score, perceived stress scale (PSS), and mental health composite score (MCS) from SF-12, using these month-long data. We also examined how accurately the collected data classified the participants into groups of high/low GPA, good/poor sleep quality, high/low self-reported stress, high/low MCS using feature selection and machine learning techniques. We found associations among PSQI, PSS, MCS, and GPA and personality types. Classification accuracies using the objective data from wearable sensors and mobile phones ranged from 67-92%.

Later circadian timing of food intake is associated with increased body fat

Background: Weight gain and obesity have reached alarming levels. Eating at a later clock hour is a newly described risk factor for adverse metabolic health; yet, how eating at a later circadian time influences body composition is unknown. Using clock hour to document eating times may be misleading owing to individual differences in circadian timing relative to clock hour.Objective: This study examined the relations between the timing of food consumption relative to clock hour and endogenous circadian time, content of food intake, and body composition.Design: We enrolled 110 participants, aged 18-22 y, in a 30-d cross-sectional study to document sleep and circadian behaviors within their regular daily routines. We used a time-stamped-picture mobile phone application to record all food intake across 7 consecutive days during a participants regular daily routines and assessed their body composition and timing of melatonin release during an in-laboratory assessment.Results: Nonlean individuals (high body fat) consumed most of their calories 1.1 h closer to melatonin onset, which heralds the beginning of the biological night, than did lean individuals (low body fat) (log-rank P = 0.009). In contrast, there were no differences between lean and nonlean individuals in the clock hour of food consumption (P = 0.72). Multiple regression analysis showed that the timing of food intake relative to melatonin onset was significantly associated with the percentage of body fat and body mass index (both P < 0.05) while controlling for sex, whereas no relations were found between the clock hour of food intake, caloric amount, meal macronutrient composition, activity or exercise level, or sleep duration and either of these body composition measures (all P > 0.72).Conclusions: These results provide evidence that the consumption of food during the circadian evening and/or night, independent of more traditional risk factors such as amount or content of food intake and activity level, plays an important role in body composition. This trial was registered at clinicaltrials.gov as NCT02846077.

Effects of Caffeine on Skin and Core Temperatures, Alertness, and Recovery Sleep During Circadian Misalignment:

Caffeine promotes wakefulness during night shift work, although it also disturbs subsequent daytime sleep. Increased alertness by caffeine is associated with a higher core body temperature (CBT). A lower CBT and a narrow distal-to-proximal skin temperature gradient (DPG) have been reported to be associated with improved sleep, yet whether caffeine influences the DPG is unknown. We tested the hypothesis that the use caffeine during nighttime total sleep deprivation would reduce the DPG, increase CBT and alertness, and disturb subsequent daytime recovery sleep. We also expected that a greater widening of the DPG prior to sleep would be associated with a greater degree of sleep disturbance. Thirty healthy adults (9 females) aged 21.6 ± 3.5 years participated in a double-blind, 28-h modified constant routine protocol. At 23 h of wakefulness, participants in the treatment condition (n = 10) were given 2.9 mg/kg caffeine, equivalent to ~200 mg (or 2 espressos) for a 70-kg adult, 5 h before a daytime recovery sleep episode. Throughout the protocol, core and skin body temperatures, DPG, sleep architecture, and subjective alertness and mood were measured. Prior to sleep, caffeine significantly widened the DPG and increased CBT, alertness, and clear-headedness (p < 0.05). Caffeine also disturbed daytime recovery sleep (p < 0.05). Increased CBT and a wider DPG prior to sleep were associated with a longer latency to sleep, and a wider DPG was associated with disturbed recovery sleep (i.e., increased wakefulness after sleep onset, increased stage 1 sleep, decreased sleep efficiency, and decreased slow wave sleep) (p < 0.05). A widening of the DPG following nighttime caffeine may represent a component of the integrated physiological response by which caffeine improves alertness and disturbs subsequent daytime recovery sleep. Furthermore, our findings highlight that sleep disturbances associated with caffeine consumed near the circadian trough of alertness are still present when daytime recovery sleep occurs 5 h or approximately 1 half-life later.

Prediction of Happy-Sad mood from daily behaviors and previous sleep history.

We collected and analyzed subjective and objective data using surveys and wearable sensors worn day and night from 68 participants for ~30 days each, to address questions related to the relationships among sleep duration, sleep irregularity, self-reported Happy-Sad mood and other daily behavioral factors in college students. We analyzed this behavioral and physiological data to (i) identify factors that classified the participants into Happy-Sad mood using support vector machines (SVMs); and (ii) analyze how accurately sleep duration and sleep regularity for the past 1-5 days classified morning Happy-Sad mood. We found statistically significant associations amongst Sad mood and poor health-related factors. Behavioral factors including the frequency of negative social interactions, and negative emails, and total academic activity hours showed the best performance in separating the Happy-Sad mood groups. Sleep regularity and sleep duration predicted daily Happy-Sad mood with 65-80% accuracy. The number of nights giving the best prediction of Happy-Sad mood varied for different individuals.

Multimodal ambulatory sleep detection

Inadequate sleep affects health in multiple ways. Unobtrusive ambulatory methods to monitor long-term sleep patterns in large populations could be useful for health and policy decisions. This paper presents an algorithm that uses multimodal data from smartphones and wearable technologies to detect sleep/wake state and sleep episode on/offset. We collected 5580 days of multimodal data and applied recurrent neural networks for sleep/wake classification, followed by cross-correlation-based template matching for sleep episode on/offset detection. The method achieved a sleep/wake classification accuracy of 96.5%, and sleep episode on/offset detection F1 scores of 0.85 and 0.82, respectively, with mean errors of 5.3 and 5.5 min, respectively, when compared with sleep/wake state and sleep episode on/offset assessed using actigraphy and sleep diaries.