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Effects of caffeine on the human circadian clock in vivo and in vitro
Abstract
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.
... Chronic caffeine or coffee consumption dose-dependently extends the period of the circadian locomotor rhythm under conditions of constant darkness, but not under a light-dark cycle in mice 13,14 . A prolonged circadian period by caffeine was also found in mammalian cell lines, mouse liver or SCN explants, and Neurospora, and the effect was mediated by adenosine receptor [13][14][15][16] . Caffeine administration during the active phase of mice inhibits or promotes the phase change of behavioral rhythm by light-pulse treatment depending on the caffeine concentration [17][18][19] . ...
... Intraperitoneal administration of caffeine at the end of the active period for three consecutive days delayed the peripheral clock phase. In humans, similar to mice, consuming two cups of espresso 3 h before their usual bedtime delays the circadian secretion of melatonin 15 . Taken together, these results indicate that caffeine modifies photic entrainment in the SCN, lengthens the circadian clock period, and causes a transient phase shift in the peripheral circadian clock. ...
... In fact, the caffeine drinking increased at around ZT0, similar as the behavioral increase (Fig. S2). In contrast, the decrease in activity at the beginning of the dark phase following caffeine consumption or injection may be attributed to phase delays in the circadian clock 14,15 and the impact of sleep deprivation due to increased arousal during the light phase 34,35 . In fact, the presence of residual activity around ZT0 even after caffeine withdrawal (Fig. 3) suggests that it is not just a result of acute masking but rather a high likelihood of phase delays in the circadian rhythm. ...
Caffeine consumption is associated with the evening chronotype, and caffeine administration in mice results in prolonged period of the circadian rhythm in locomotor activity. However, as caffeine is bitter, sweetened caffeine is preferred by humans and mice; yet, its impact on the circadian clock has not been explored. In this study, mice were provided with freely available sweetened caffeine to investigate its effects on behavioral rhythms and peripheral clocks. Mice that freely consumed sweetened caffeine shifted from nocturnal to diurnal activity rhythms. In addition to the light-dark entrained behavioral rhythm component, some animals exhibited free-running period longer than 24-h. Intraperitoneal administration of caffeine at the beginning of the light phase also acutely induced diurnal behavior. The behavioral rhythms with long period (26–30 h) due to sweetened caffeine were observed even in mice housed under constant light or with a lesioned central circadian clock located in the suprachiasmatic nucleus of the hypothalamus; however, the rhythmicity was unstable. PER2::LUCIFERASE rhythms in peripheral tissues, such as the kidney, as measured via in vivo whole-body imaging during caffeine consumption, showed reduced amplitude and desynchronized phases among individuals. These results indicate that consumption of sweetened caffeine induces diurnal and long-period behavioral rhythms irrespective of the central clock, causing desynchronization of the clock in the body.
... Studies investigating the effects of dietary components on cognitive performance using ANS responses as outcome measures have resulted in mixed findings (Table 3). While there appears to be an association between caffeine consumption and cognitive function, several factors may influence this relationship, including the timing of consumption, dosage, experimental conditions, expectancy bias, population demographics, and habitual intake of caffeine [53][54][55]. In the study conducted by Pomportes and colleagues [52], a decrease in parasympathetic modulation was observed following caffeine (100 mg) ingestion. ...
... The results from the above-mentioned studies suggest that gum chewing induces variations in arousal that relate to changes in cognitive performance according to an inverted U-shaped function [56]. However, the experimental ECG setup used by Allen AP, Jacob TJ and Smith AP [51] can be discussed as it may have biased the rating of alertness, which was quite high at baseline [53][54][55]. ...
... One factor contributing to this complexity is that different mood states sharing similar valence and arousal can lead to similar ANS responses [59]. Moreover, individual differences, such as daily consumption of the tested component or age, body weight and sex, can significantly complicate the relationship between ANS responses, mood states, and cognitive function [53,54,60]. Another challenge is achieving comprehensive results across ANS responses, cognitive tasks, and subjective ratings, as they reflect different aspects of an individual's physiological and psychological states [61]. ...
A growing body of literature suggests dietary components can support mood and cognitive function through the impact of their bioactive or sensorial properties on neural pathways. Of interest, objective measures of the autonomic nervous system—such as those regulating bodily functions related to heartbeat and sweating—can be used to assess the acute effects of dietary components on mood and cognitive function. Technological advancements in the development of portable and wearable devices have made it possible to collect autonomic responses in real-world settings, creating an opportunity to study how the intake of dietary components impacts mood and cognitive function at an individual level, day-to-day. In this paper, we aimed to review the use of autonomic nervous system responses such as heart rate or skin galvanic response to investigate the acute effects of dietary components on mood and cognitive performance in healthy adult populations. In addition to examining the existing methodologies, we also propose new state-of-the-art techniques that use autonomic nervous system responses to detect changes in proxy patterns for the automatic detection of stress, alertness, and cognitive performance. These methodologies have potential applications for home-based nutrition interventions and personalized nutrition, enabling individuals to recognize the specific dietary components that impact their mental and cognitive health and tailor their nutrition accordingly.
... Second, to improve compliance with TRE, we allowed low-energy drinks, including coffee, during fasting hours. Although these drinks have no caloric impact, the caffeine content may affect circadian rhythms [72], which is one of the principles of TRE. Specifically, caffeine can delay the phase of the human circadian clock by altering the melatonin rhythm [72]. ...
... Although these drinks have no caloric impact, the caffeine content may affect circadian rhythms [72], which is one of the principles of TRE. Specifically, caffeine can delay the phase of the human circadian clock by altering the melatonin rhythm [72]. Since melatonin is a hormone that regulates sleep-wake cycles and influences various metabolic processes [73], disruption in its secretion may negatively affect energy balance and fat storage, potentially impacting body composition. ...
Background
Time-restricted eating (TRE) is a dietary regimen that limits food intake for at least 12 h daily. Unlike other fasting protocols, TRE does not dictate what or how much to eat but rather focuses on the timing of meals. This approach has been previously demonstrated to improve body composition in individuals with obesity or metabolic impairments. However, its impact on body composition and cardiometabolic factors in healthy individuals remains unclear. Furthermore, the optimal fasting duration is still debated. Thus, we aimed to compare the effects of 8 weeks of different fasting durations on body composition and biochemical parameters in metabolically healthy, non-trained individuals using a parallel randomized controlled trial.
Methods
Forty-one volunteers were randomly assigned to one of the four experimental groups: TRE 16:8 (16 h of fasting,8 h of eating), TRE 14:10 (14 h of fasting,10 h of eating), TRE 12:12 (12 h of fasting,12 h of eating) or a normal diet group (ND; no dietary restriction). Participants underwent body composition measurements and blood tests for lipid profiles (i.e., total cholesterol, LDL, HDL, and triglycerides), fasting glucose, leptin, and anabolic hormones (i.e., insulin and testosterone) levels. Data were analyzed using both intention-to-treat (ITT) and per-protocol (PP) analysis to account for compliance. A two-way ANOVA for repeated measures was employed to assess interactions between time and group.
Results
In the ITT analysis, TRE 16:8 reduced body mass (-2.46%, p = 0.003) and absolute fat mass (-8.65%, p = 0.001) with no changes in lean soft tissue and in calorie intake. These results were consistent with the PP analysis which included 8 participants in TRE 16:8, 5 in TRE 14:10, 9 in TRE 12:12, and the entire ND group. Participants in the TRE 16:8 group spontaneously reduced their total caloric intake, although this reduction was not statistically significant. None of the other measurements significantly changed after 8 weeks.
Conclusions
Our results suggest that a 16-hour fasting window, even without caloric restriction, may be a viable strategy for improving body composition in healthy and non-trained individuals, whereas a shorter fasting period may be insufficient to produce significant changes in a healthy population.
Trial registration
NCT, NCT04503005. Registered 4 August 2020, https://clinicaltrials.gov/study/NCT04503005.
... There are four core clock components: the transcription activators circadian locomotor output cycles protein kaput (CLOCK) and brain and muscle arnt-like 1 (BMAL1), and the transcription repressors cryptochrome (CRY) and period circadian protein (PER) (10). Caffeine delays the human circadian clock in vivo and in vitro, altering circadian rhythm phases (11) and affecting the sleep-wake cycle in preterm infants (12). CLOCK gene polymorphisms have been found to influence preterm infant response to caffeine citrate. ...
... At the molecular level, at the beginning of a circadian rhythm cycle, CLOCK and BMAL1 form heterodimers in the cell nucleus and bind to the enhancer box elements (E-boxes) of the upstream promoter of the PER and CRY genes, initiating their transcription and translation. PER and CRY (11). Circadian rhythms can influence the metabolic processes of drugs and affect the efficacy and toxicity of drugs based on the timing of administration (24). ...
Background
Circadian rhythms impact metabolism and the therapeutic effects of drugs. The purpose of this study was to determine the association between PER and CRY polymorphisms and caffeine citrate treatment response in infants with apnea of prematurity.
Methods
A total of 221 preterm infants of gestational age <34 weeks were included in this study (160 in the response group and 61 in the non-response group). The propensity score matching method was used to perform a 1:1 matching for all premature infants, and the general characteristics and clinical outcomes of the two groups were compared. The association between polymorphisms of the circadian transcription repressors PER and CRY and caffeine citrate treatment response in infants with apnea of prematurity was analyzed with co-dominant, dominant, recessive, and over-dominant models, as well as analysis of alleles. Generalized multifactor dimensionality reduction (GMDR) analysis was used to analyze the interaction between the PER and CRY genes.
Results
After propensity score matching, 45 preterm infants were included in each of the response and non-response groups, and there were no statistically significant differences in general characteristics between the two groups (P > 0.05). Infants in the non-response groups had a higher incidence of moderate and severe bronchopulmonary dysplasia (BPD) (P = 0.043), retinopathy of prematurity (ROP) (P = 0.035), and invasive ventilation (P = 0.027), and their duration of oxygen use (P = 0.041) was longer. When corrected for false discovery rate, the PER3 rs228669 recessive model (PFDR = 0.045) and the over-dominant model (PFDR = 0.045) were both associated with caffeine citrate treatment response. Preterm infants with the rs228669 CC genotype had a significantly lower rate of caffeine citrate non-response in the recessive model (OR = 0.28, 95% CI = 0.12–0.66), which was significantly higher in preterm infants with the CT genotype in the over-dominant model (OR = 4.18, 95% CI = 1.64–10.66). GMDR analysis revealed an interaction between the PER and CRY genes (P < 0.05).
Conclusions
Circadian rhythms may play a role in the response of premature infants to caffeine citrate, and polymorphisms of the PER and CRY genes may influence the effectiveness of caffeine citrate treatment for apnea of prematurity.
... Caffeine is one of the most common naturally occurring psychoactive stimulant drugs in use worldwide, and it has a robust effect on the circadian period of molecular oscillations [13,14]. Caffeine acts as an adenosine receptor antagonist and exerts its effect in a dose-dependent manner [15]. ...
The effect of caffeine on the behavior and sleep patterns of zebrafish larvae, as well as its underlying mechanisms, has been a topic of great interest. This study aimed to investigate the impact of caffeine on zebrafish larval sleep/wake behavior and the expression of key regulatory genes such as cAMP-response element binding protein (CREB) and adenosine (ADA) in the sleep pathway. To begin, the study determined the optimal dose and duration of caffeine exposure, with the optimal doses found to be 31.25 μM, 62.5 μM, and 120 μM. Similarly, the optimal exposure time was established as no more than 120 h, ensuring a mortality rate of less than 10%. The confirmation of these conditions was achieved through the assessment of angiogenesis and the inflammatory reaction. As a result, the treatment time point of 24 h post-fertilization (hpf) was selected to examine the effects of caffeine on zebrafish larval sleep rhythm (48 h, with a light cycle of 14:10). Furthermore, the study analyzed the expression of clock genes (bmal1a, per1b, per2, per3, cry2), adenosine receptor genes (adora1a, adora1b, adora2aa, adora2ab, adora2b), and key regulatory factors (CREB and ADA). The research confirmed that caffeine could induce sleep pattern disorders, significantly upregulate adenosine receptor genes (adora1a, adora1b, adora2a, adora2ab, adora2b) (p < 0.05), and markedly decrease the total sleep time and sleep efficiency of the larvae. Additionally, the activity of ADA significantly increased during the exposure (p < 0.001), and the tissue-specific expression of CREB was also significantly increased, as assessed by immunofluorescence. Caffeine may regulate circadian clock genes through the ADA/ADORA/CREB pathway. These findings not only enhance our understanding of the effects of caffeine on zebrafish larvae but also provide valuable insights into the potential impact of caffeine on human behavior and sleep.
... Participants perceived a significantly longer sleep onset latency when consuming the 400 mg dose of theacrine 12 h prior to bedtime compared to the placebo, despite no significant effect when assessed objectively. There is evidence to suggest that the time of day of at which theacrine is consumed may alter the perceived effect of the substance [36][37][38] . Previous studies investigating theacrine have shown mixed effects on self-reported level of arousal. ...
Psychostimulants can be employed as a countermeasure to cognitive declines resulting from insufficient sleep. Although caffeine is the most consumed psychostimulant, consumption can cause adverse side-effects, including sleep disturbance. Therefore, there is interest in identifying alternative supplements that improve cognitive performance without compromising subsequent sleep. Here we investigate the influence of the dose and timing of theacrine consumption on cognitive performance and subsequent sleep using conditions that replicate a low (100 mg) and high (400 mg) dose consumed in the morning (12 h prior to bedtime), afternoon (eight hours prior to bedtime), and evening (four hours prior to bedtime). We found no significant effect of the low or high theacrine dose on subsequent sleep although the high dose showed small non-significant effects on sleep efficiency and wake after sleep onset at each timepoint of consumption. However, consuming theacrine within eight hours of bedtime improved next-morning cognitive performance, with the 400 mg dose reducing the number of lapses on the Psychomotor Vigilance Task, although there were no significant effects on reaction time. Our findings provide initial scientific evidence suggesting that theacrine consumption may improve some aspects of next-morning cognitive performance but not others, with small non-significant effects on nighttime sleep.
... Some studies suggest benefits [12,13], while others find no impact [14] or even potential harm [15,16]. In fact, there are abundant bioactive substances in coffee and tea, such as caffeine, catechin, chlorogenic acid, theobromine, lysine, and etc., and several animal studies indicated that these substances can entrain biological rhythm by regulating various circadian clock genes associated with blood glucose homeostasis [17,18]. Therefore, compared with daily coffee and tea consumption, consumption timing may be a more important aspect in terms of long-term survival among diabetic patients. ...
Background
Previous observational studies have suggested diabetic patients should synchronize their foods and nutrient intake with their biological rhythm; however, the optimal intake time of coffee and tea for reducing all-cause and disease-specific mortality in diabetes is still unknown. This study aims to examine by investigating the association of timing for coffee and tea consumption with long-term survival in people with diabetes.
Methods
A total of 5378 people with diabetes who enrolled in the National Health and Nutrition Examination Survey from 2003 to 2014 were recruited for this study. Coffee and tea intakes were measured by a 24-h dietary recall, which were divided by different time intervals across the day, including dawn to forenoon, forenoon to noon, noon to evening, and evening to dawn. Weighted cox proportional hazards regression models were developed to evaluate the survival-relationship of coffee and tea consumption with mortality of all-cause, cardiovascular disease (CVD), stroke, and diabetes.
Results
During 47,361 person-year follow up, total 1639 death cases were documented, including 731 CVD deaths, 467 heart disease deaths, 99 stroke deaths, and 462 diabetes deaths. After adjustment for potential confounders, compared with participants without drinking coffee during dawn to forenoon, drinking coffee at this period was associated with increased mortality risk of all-cause (HR 1.25, 95% CI 1.05–1.50), CVD (HR 1.41, 95% CI 1.07–1.86), heart-disease (HR 1.47, 95% CI 1.05–2.07), and diabetes (HR 1.50, 95% CI 1.10–2.04). In contrast, drinking coffee during forenoon to noon had lower mortality risk of all-cause (HR 0.80, 95% CI 0.69–0.92), CVD (HR 0.79, 95% CI 0.63–0.99), and heart disease (HR 0.70, 95% CI 0.52–0.94). Similarly, drinking tea during forenoon to noon had lower risk of CVD mortality (HR = 0.62, 95% CI 0.44–0.87).
Conclusions
This study suggests that drinking coffee in dawn to forenoon is linked to a higher risk of death, but having coffee and tea from forenoon to noon is linked to a lower risk of overall mortality, CVD, and heart disease in individuals with diabetes.
Graphical Abstract
... A few animal studies have indicated that bioactive substances in coffee can entrain the biological rhythm by regulating various circadian clock genes related with metabolic and inflammatory homeostasis. 26,27 Also, due to the disrupted circadian rhythms of blood glucose, blood pressure, and inflammation in diabetes patients, [28][29][30][31] an optimal intake time of coffee may prevent the natural course of CKD by regulating the physiological rhythm process. 32,33 However, limited studies have examined the association between timing of coffee consumption and incidence risk of CKD in diabetes. ...
Logistic regression models were used to assess the association between the amount and timing of coffee consumption and the prevalence of CKD in 8564 diabetic patients from the NHANES 2003–2018 cohort.
... Sophisticated modeling techniques such as those outlined in the paper could be used to develop and validate commonsense heuristics to support those who need to better manage alertness. For example, a current limitation of the guidelines is the failure to consider the impact of caffeine on subsequent sleep or potentially on the circadian phase [14]. Moreover, the current guidelines fail to account for individual differences in the psycho-pharmacokinetics of sleep and caffeine. ...
... Caffeine has been shown to impact circadian rhythms and sleep behaviour in human and animal studies [5][6][7][8]. Previous research has shown that caffeine may potentiate non-image-forming effects of light in animals and humans, for instance, on the timing of rest-activity cycles or on melatonin secretion [9][10][11][12][13]. Therefore, caffeine may represent a tool to enhance light effects on the biological clock. ...
Caffeine is a widely used drug that broadly affects human cognition and brain function. Caffeine acts as an antagonist to the adenosine receptors in the brain. Previous anecdotal reports have also linked caffeine intake with changes in pupil diameter. By modifying the retinal irradiance, pupil diameter modulates all ocular light exposure relevant for visual (i.e., perception, detection and discrimination of visual stimuli) and non-visual (i.e., circadian) functions. To date, the extent of the influence of caffeine on pupillary outcomes, including pupil diameter, has not been examined in a systematic review. We implemented a systematic review laid out in a pre-registered protocol following PRISMA-P guidelines. We only included original research articles written in English reporting studies with human participants, in which caffeine was administered, and pupil diameter was measured using objective methods. Using broad search strategies, we consulted various databases (PsycINFO, Medline, Embase, Cochrane Library, bioRxiv and medRxiv) and used the Covidence platform to screen, review and extract data from studies. After importing studies identified through database search (n = 517 imported, n = 46 duplicates), we screened the title and abstracts (n = 471), finding 14 studies meeting our eligibility criteria. After full-text review, we excluded seven studies, leaving only a very modest number of included studies (n = 7). Extraction of information revealed that the existing literature on the effect of caffeine on pupil parameters is very heterogeneous, differing in pupil assessment methods, time of day of caffeine administration, dose, and protocol timing and design. The evidence available in the literature does not provide consistent results but studies rated as valid by quality assessment suggest a small effect of caffeine on pupil parameters. We summarize the numeric results as both differences in absolute pupil diameter and in terms of effect sizes. More studies are needed using modern pupil assessment methods, robust study design, and caffeine dose–response methodology.
... Although beyond the scope of this review, macro-and micronutrients including fat, cholesterol, sugars, amino acids, vitamins, polyphenols, and phytosterols can all shift circadian clocks in the body and brain, including potentially in the SCN (reviewed in 46,102,115). Among these, caffeine is notable for its potent phase-shifting effect in both mice and humans (25,99). Most circadian nutritional studies have been completed in preclinical models, and far less is known about how diet composition impacts the clock in humans (but see 113). ...
The time of day that we eat is increasingly recognized as contributing as importantly to overall health as the amount or quality of the food we eat. The endogenous circadian clock has evolved to promote intake at optimal times when an organism is intended to be awake and active; but electric lights and abundant food allow eating around the clock with deleterious health outcomes. In this review, we highlight literature pertaining to the effects of food timing on health, beginning with animal models and then translation into human experiments. We emphasize the pitfalls and opportunities that technological advances bring in bettering understanding of eating behaviors and their association with health and disease. There is great promise for restricting the timing of food intake both in clinical interventions and in public health campaigns for improving health via nonpharmacological therapies.
... In clinical studies with positive outcomes, coffee has been found to have various benefits, such as promoting physical activity (7), lowering the risk of depression (8), reducing the risk of Parkinson's disease (9), and lowering the risk of type 2 diabetes (10). However, Burke et al. also reported that excessive coffee consumption disrupts the body's circadian rhythm (11). ...
Objective
Existing studies have reported sustained changes in the cortical structure of rats due to coffee-related factors, which are speculated to occur in the human body. However, there is a lack of research on this topic. Additionally, previous observational studies have found the impact of diseases on cortical structure and the potential therapeutic effects of coffee on these diseases. Our aim was to study the causal effects of coffee-related factors on the human brain using SNPs (single nucleotide polymorphisms). We will connect these discovered causal effects to the impact of diseases on the brain. Through triangulating evidence, we will reveal the potential active areas of coffee in preventing diseases.
Methods
We utilized GWAS data from multiple cohorts and their databases, selecting instrumental variables for genetic prediction of coffee intake and plasma levels of caffeine and its direct metabolites. We applied these instrumental variables to individual data on cortical thickness and surface area, as well as hippocampal volume, from the ENIGMA and CHARGE consortium for Mendelian randomization analysis (MR). Triangular evidence was obtained by integrating existing evidence through a specified retrieval strategy, calculating the overlap between coffee's effects on brain regions and disease-related brain regions to identify potential regions of action.
Results
The MR analysis yielded 93 positive results for 9 exposures, among which theobromine, a metabolite in the caffeine pathway, was found to be associated with increased hippocampal volume. For cortical structure, theobromine in the caffeine pathway was associated with a decrease in total surface area, while theobromine and caffeine in the pathway were associated with an increase in total thickness. The overlap rate of triangular evidence showed no difference in both overall and subgroup analyses, indicating a high overlap between the effects of coffee on brain regions and disease.
Conclusions
From predicted outcomes from causal effects, coffee intake-related factors may have lasting effects on cortical structure. Additionally, theobromine and theophylline have the greatest impact on certain brain gyri, rather than caffeine. Triangulation evidence indicates that disease and coffee intake-related factors act on the same cortical regions, suggesting the presence of potential shared or antagonistic pathways.
... For example, caffeine, flavonoids, amino acids (such as L-serine), ω3 fatty acids, and triterpenoids have been reported as circadian clock-modulating agents [3]. Caffeine treatment before the sleep phase was found to delay mice and human circadian clocks; however, treatment in the early morning showed phase advancement [4,5]. Thus, the timing of the intake of clock-modulating supplements should be examined for translational research. ...
Polymethoxyflavonoids, such as nobiletin (abundant in Citrus depressa), have been reported to have antioxidant, anti-inflammatory, anticancer, and anti-dementia effects, and are also a circadian clock modulator through retinoic acid receptor-related orphan receptor (ROR) α/γ. However, the optimal timing of nobiletin intake has not yet been determined. Here, we explored the time-dependent treatment effects of nobiletin and a possible novel mechanistic idea for nobiletin-induced circadian clock regulation in mice. In vivo imaging showed that the PER2::LUC rhythm in the peripheral organs was altered in accordance with the timing of nobiletin administration (100 mg/kg). Administration at ZT4 (middle of the light period) caused an advance in the peripheral clock, whereas administration at ZT16 (middle of the dark period) caused an increase in amplitude. In addition, the intraperitoneal injection of nobiletin significantly and potently stimulated corticosterone and adrenaline secretion and caused an increase in Per1 expression in the peripheral tissues. Nobiletin inhibited phosphodiesterase (PDE) 4A1A, 4B1, and 10A2. Nobiletin or rolipram (PDE4 inhibitor) injection, but not SR1078 (RORα/γ agonist), caused acute Per1 expression in the peripheral tissues. Thus, the present study demonstrated a novel function of nobiletin and the regulation of the peripheral circadian clock.
... Studies indicate that caffeine can disrupt pineal gland function, leading to inhibition of melatonin secretion. Consequently, caffeine consumption markedly diminishes melatonin levels on the day of intake and triggers early gene expression in the SCN, the central circadian pacemaker [133]. ...
Caffeine has attracted significant attention from researchers in the sports field due to its well-documented ergogenic effects across various athletic disciplines. As research on caffeine continues to progress, there has been a growing emphasis on evaluating caffeine dosage and administration methods. However, investigations into the optimal timing of caffeine intake remain limited. Therefore, this narrative review aimed to assess the ergogenic effects of caffeine administration at different times during the morning (06:00 to 10:00) and evening (16:00 to 21:00). The review findings suggest that circadian rhythms play a substantial role in influencing sports performance, potentially contributing to a decline in morning performance. Caffeine administration has demonstrated effectiveness in mitigating this phenomenon, resulting in ergogenic effects and performance enhancement, even comparable to nighttime levels. While the specific mechanisms by which caffeine regulates circadian rhythms and influences sports performance remain unclear, this review also explores the mechanisms underlying caffeine’s ergogenic effects, including the adenosine receptor blockade, increased muscle calcium release, and modulation of catecholamines. Additionally, the narrative review underscores caffeine’s indirect impact on circadian rhythms by enhancing responsiveness to light-induced phase shifts. Although the precise mechanisms through which caffeine improves morning performance declines via circadian rhythm regulation necessitate further investigations, it is noteworthy that the timing of caffeine administration significantly affects its ergogenic effects during exercise. This emphasizes the importance of considering caffeine intake timing in future research endeavors to optimize its ergogenic potential and elucidate its mechanisms.
... For example, foods that are rich in tryptophan, an amino acid that is a precursor of melatonin and serotonin, may promote sleepiness and help induce sleep [88]. On the other hand, foods that are high in caffeine, sugar, or alcohol may disrupt sleep by stimulating the central nervous system or interfering with the circadian system [89,90]. Likewise, dietary patterns may relate to increased or decreased low-grade subclinical inflammation, which may lead to neuro-inflammation [91]. ...
We aimed to systematically review and synthesize the available evidence regarding the link between dietary patterns and insomnia symptoms among the general population using observational studies. We reviewed 16,455 references, of which 37 studies met inclusion criteria with a total sample size of 591,223. There was a significant association of the Mediterranean diet (OR: 0.86; 95 % CI, 0.79, 0.93; P < 0.001; I2 = 32.68 %), a high-quality diet (OR: 0.66; 95 % CI, 0.48, 0.90; P = 0.010; I2 = 84.62 %), and an empirically-derived healthy dietary pattern (OR: 0.91; 95 % CI, 0.85, 0.98; P = 0.010; I2 = 57.14 %) with a decreased risk of insomnia symptoms. Moreover, the dietary glycemic index (OR: 1.16; 95 % CI, 1.08, 1.25; P < 0.001; I2 = 0.0 %), the dietary glycemic load (OR: 1.10; 95 % CI, 1.01, 1.20; P = 0.032; I2 = 74.36 %), and an empirically-derived unhealthy dietary pattern (OR: 1.20; 95 % CI, 1.01, 1.42; P = 0.040; I2 = 68.38 %) were linked with a higher risk of insomnia symptoms. Most individual studies were of good quality (NOS) but provided very low certainty of evidence (GRADE). Consistent data reveals that following healthy diets is associated with decreased insomnia symptoms prevalence, while adherence to an unhealthy pattern is associated with an increased prevalence of insomnia symptoms.
... Specific nutrients and meal times can also modulate the circadian timing system [15]. For instance, research by Wright et al. [17] demonstrated that evening caffeine consumption delays the human circadian melatonin rhythm and lengthens the circadian period of molecular oscillations [in vitro/in vivo]. In a recent population-based study involving over 20,000 participants, we observed a link between later meal times and increased obesity risk [18]. ...
There are several determinants of mental health symptoms, ranging from individual characteristics to social factors. Consistent with patterns in the general population, students with evening characteristics tend to exhibit more anxiety symptoms and poorer sleep quality compared to morning students. Meal timing also appears to affect sleep and may be associated with mental health symptoms. In this context, the aim of the present study was to investigate the association of the timing of the main and last meals of the day with sleep quality and anxiety levels, according to the chronotype of university students. This study was conducted in colleges in São Paulo, Brazil, and involved application of a questionnaire to 162 university students. The questionnaire collected sociodemographic information meal and study times, and included scales assessing eveningness and morningness, sleep quality, and anxiety. Students demonstrating a phase delay in both chronotype and dinner timing exhibited higher levels of anxiety compared to morning-type students. Although no associations were observed between meal timing and sleep quality, sleeping later was associated with poorer sleep quality. The study suggests that evening students and those who eat late at night are more prone to presenting mental health symptoms. More studies are needed to further investigate this association.
... Sleep is facilitated by MEL but inhibited by CA, and it is well known that CA intake leads to disturbances in sleep rhythms [5,6]. Many studies have investigated the effect of CA on MEL and found that it increases MEL plasma levels [7,8]. ...
Melatonin (MEL) and caffeine (CA) are mediated by cytochrome P450 1A2 (CYP1A2), and the plasma concentration of MEL is reportedly affected by CA intake and CYP1A2 activity. Because the plasma concentrations of MEL and CA or paraxanthine (PX) differ by approximately 10⁶, MEL, CA, and PX (a metabolite of CYP1A2) have not been quantified in a single-sample preparation. This study aimed to evaluate a liquid chromatography-tandem mass spectrometry method for quantification of MEL, CA, and PX in the same sample preparation. Initially, an injection volume of 10 µL produced a sharp peak for MEL, but the peaks for CA and PX were not suitable for quantification due to their asymmetric peaks. Therefore, CA and PX were separately quantified using 0.1 μL sample, which enabled measurement of both compounds with good peak symmetry. Under these conditions, the relative error for MEL, CA, and PX ranged from − 9.62% to 1.01%, 0.96% to 9.39%, and − 2.77% to 5.67%, with relative standard deviations of 7.23%, 4.95%, and 8.54%, respectively. In conclusion, the developed method is suitable for use in future studies on the relationship among MEL, CA, and PX.
... Generally, 100-150 mg of caffeine (1 espresso contains approximately 90 mg) 3 hours before sleep causes significant sleep disruption in several different ways: increased sleep latency, decreased total amount of sleep, increased amount of superficial sleep stages and a reduction in the duration of the deep and REM sleep stages, as well as multiple sleep stage shifts (Burdan, 2015;Watson et al., 2016). Caffeine consumption also affects melatonin secretion and may delay the onset up to 40 minutes (Burke et al., 2015). There is evidence that regular consumers develop a tolerance to caffeine (Weibel et al., 2020). ...
Sleep hygiene is essential for the prevention of somatic and mental disorders, including the prevention of sleep disorders. However, it does not typically address individual differences. The aim of this review is threefold: first, to outline the empirical evidence for particular components of sleep hygiene rules; second, to indicate the importance of individualized sleep hygiene application with regard to the varying degree of validity of sleep hygiene rules in the population; third, to highlight a new field of sleep hygiene, namely light hygiene. PubMed and Google Scholar were used to identify studies that were published between 2007 and 2022. A search was conducted for studies related to sleeping rules topics: sleep regularity, regular exercise, alcohol, caffeine, napping, relaxation and meditation, food intake and light exposure. In applying these sleep hygiene principles, it is essential to pay attention to individual variables such as age, genetic predisposition, health status, and substance (caffeine, alcohol) possible dependence.
... Recent studies show that adenosine signalling is one of the molecular pathways by which Process S and Process C interact, allowing sleep/wake history to modulate circadian entrainment (Jagannath et al., 2021(Jagannath et al., , 2022. Caffeine, whose effects on wakefulness are mediated by adenosine receptors (Lazarus et al., 2011) is known to increase photic phase-shifts of the circadian system in both humans and mice and lengthen circadian period, whilst sleep deprivation reduces the effects of light on the clock (Challet et al., 2001;Oike et al., 2011;van Diepen et al., 2014;Burke et al., 2015;Ruby et al., 2018). Furthermore, adenosine receptor antagonists can both phase-shift the clock and mediate entrainment (Antle et al., 2001). ...
Sleep behaviour is broadly regulated by two drives, the circadian (Process C), which is orchestrated by the suprachiasmatic nuclei (SCN), and controls sleep timing, and the homeostatic (Process S), which controls sleep amount and the response to sleep deprivation (Borbely et al., 2016). However, the molecular pathways that mediate their independent effects, and their interactions remain unclear. Adenosine is an important integrator of both processes (Bjorness & Greene, 2009; Jagannath et al., 2021, 2022), such that adenosine levels track and modulate wakefulness, whilst adenosine signalling inhibits the circadian response to light. Therefore, we studied the sleep/circadian behaviour, and cortical and SCN transcriptomic profiles of a mouse model overexpressing Adenosine Kinase (Adk-Tg) (Fedele et al., 2005), (Palchykova et al., 2010). We found that overall, the Adk-Tg mouse slept less and showed lower amplitude circadian rhythms with an altered sleep/wake distribution across the 24h day, which correlated with changes in transcription of synaptic signalling genes that would shift the excitatory/inhibitory balance. In addition, the Adk-Tg mouse showed a reduced level of ERK phosphorylation, and attenuation of DNA repair related pathways. After sleep deprivation, however, the Adk-Tg mouse significantly increased relative to wildtype, immediate early gene expression levels including of Arc, but paradoxically reduced ERK phosphorylation. Thus, baseline sleep levels and timing are regulated by ERK signalling, whereas the response to sleep loss is mediated by the alteration of the transcriptomic landscape independently of ERK.
... To date, it is unknown if caffeine increases MFO in the same proportion during morning and evening exercise trials in women according to what has been previously established that women have a greater reliance on fat oxidation than men during submaximal exercise (Cano et al. 2022;Chenevière et al. 2011). In addition, the study of the effect of caffeine specifically in women at different times of the day is needed as the translation of data reported in male participants should be made with caution due to differences in body fat (Blaak 2001), circulating catecholamines (Friedlander et al. 1998) and oxidation rates of free fatty acids of women vs men (Roepstorff et al. 2002) in conjunction that caffeine intake has demonstrated and influenced human circadian timing (Burke et al. 2015). For this reason, the aim of the present study was to evaluate the influence of the time of the day on the effect of caffeine on MFO in women. ...
Purpose
Caffeine is a stimulant with well-recognized performance and metabolic benefits, however, there is a lack of studies investigating the time-of-day influence in the properties of caffeine to enhance fat oxidation in women. Thus, the aim of the present study was to evaluate the influence of the time of the day on the effect of caffeine on the maximal rate of fat oxidation during aerobic exercise in trained women.
Methods
Fourteen female athletes (25.5 ± 7.1 years) took part in a randomized, crossover, double-blind study. All participants undertook four different experimental trials combining the ingestion of 3 mg/kg caffeine and a placebo either in the morning (8.00–10.00 h) and in the evening (17.00–19.00 h) realizing an incremental test on a cycle ergometer with 3 min stages at workloads from 30 to 70% of maximal oxygen uptake (VO2max). Substrate oxidation rates were measured by indirect calorimetry. In each trial, the maximum rate of fat oxidation (MFO) and the intensity that elicited MFO (Fatmax) were measured.
Results
In comparison to placebo, MFO was significantly higher with caffeine both in the morning (0.24 ± 0.13 vs 0.30 ± 0.14 g/min; p < 0.001; ES = 0.79) and in the evening (0.21 ± 0.08 vs 0.28 ± 0.10 g/min; p = 0.002; ES = 0.72). No time-of-day effect on the capacity of caffeine to increase MFO was found (all p = 0.336)
Conclusion
The intake of 3 mg/kg of caffeine increased the use of fat as a fuel during exercise independently of the time-of-day in trained women.
Trial registration
The study was registered in ClinicalTrials.gov with the following ID: NCT05880186 by 15 May 2023.
... Lastly, we did not assess the participants' daily dietary intake or dietary content. Several nutrients/compounds, such as caffeine and amino acids, have regulatory effects on the circadian clock (Burke et al. 2015;Fukuda et al. 2018;Ikeda et al. 2018). Though we did not evaluate dietary intake on the day of the experiment, we asked each participant to maintain normal eating habits during the day before and on the day of sampling. ...
Ageing is associated with a decline in circadian clock systems, which correlates with the development of ageing-associated diseases. Chrononutrition is a field of chronobiology that examines the relationship between the timing of meal/nutrition and circadian clock systems. Although there is growing evidence regarding the role of chrononutrition in the prevention of lifestyle and ageing-related diseases, the optimal timing of meal intake to regulate the circadian clock in humans remains unknown. In this study, we investigated the relationship between clock gene expression and meal timing in young and older adults. In this cross-sectional study, we enrolled 51 healthy young men and 35 healthy older men (age, mean±standard deviation: 24 ± 4 and 70 ± 4 y, respectively). Under daily living conditions, beard follicle cells were collected at 4-h intervals over a 24-h period to evaluate clock gene expression. Participants were asked to record the timing of habitual sleep and wake-up, breakfast, lunch, and dinner. From these data, we calculated "From bedtime to breakfast time," "From wake up to first meal time," and "From dinner to bed time." NR1D1 and PER3 expressions in older adults at 06:00 h were significantly higher than those in young adults (P = 0.001). There were significant differences in the peak time for NR1D2 (P = 0.003) and PER3 (P = 0.049) expression between young and older adults. "From bedtime to breakfast time" was significantly longer in older adults than in young adults. In contrast, "From dinner to bed time" was significantly shorter in older adults than in young adults. Moreover, higher rhythmicity of NR1D1 correlated with longer "From bedtime to breakfast time" (r = -0.470, P = 0.002) and shorter "From wake up to first meal time" in young adults (r = 0.302, P = 0.032). Higher rhythmicity of PER3 correlated with longer "From bedtime to breakfast time" in older adults (r = -0.342, P = 0.045). These results suggest that the peak time of clock gene expression in older adults may be phase-advanced compared to that in young adults. In addition, a longer fasting duration from bedtime to breakfast in both young and older adults and earlier intake of meals after waking up in young adults may correlate with robust clock gene expression rhythms.
... By reducing slow wave sleep duration, caffeine may reduce the nighttime efficacy of the glymphatic system [61,62]. Caffeine has also been shown to delay circadian rhythms in vivo and in vitro [63]. If the glymphatic system participates in the clearance of purines during sleep, alterations in the system during sleep could contribute to excessive daytime sleepiness. ...
Purpose of Review
The glymphatic system is hypothesized to act as the brain’s filtration system to remove toxic solutes that accumulate throughout the day. Perivascular spaces (PVSs) play a fundamental role in the ability of the glymphatic system to function, and sleep influences the effectiveness of this system. This article reviews the complexity of the interplay between sleep, the glymphatic system, and PVS.
Recent Findings
New imaging techniques have illuminated the structure of PVS and their associations with differing disease states. Research has shown that sleep may play a key role in the function of PVS and the influence of adenosine, astrocyte, and aquaporin-4 channel in the function of the glymphatic system.
Summary
Emerging data suggest that differing pathological states such as neuroinflammatory conditions, neurodegenerative diseases, and cognitive dysfunction may be associated with underlying glymphatic system dysfunction, and sleep disorders could be a potential intervention target.
... Adenosine administration also lengthens circadian periods by increasing Per1 and Per2 gene expression (Jagannath et al., 2021), thereby modulating circadian regulation. Inhibition of adenosine signaling, like with caffeine, enhances the phase-shifting effects of light whereas adenosine agonists diminish the impact of light (Burke et al., 2015;Jagannath et al., 2021), showing that light signaling to the molecular clockwork can be directly altered by adenosine signaling. Recent evidence demonstrates that estrogen can block adenosine signaling in the median preoptic nucleus and attenuate the local effects of adenosine 2 A receptors in this brain region (Smith et al., 2022). ...
Sleep is a vital and evolutionarily conserved process, critical to daily functioning and homeostatic balance. Losing sleep is inherently stressful and leads to numerous detrimental physiological outcomes. Despite sleep disturbances affecting everyone, women and female rodents are often excluded or underrepresented in clinical and pre-clinical studies. Advancing our understanding of the role of biological sex in the responses to sleep loss stands to greatly improve our ability to understand and treat health consequences of insufficient sleep. As such, this review discusses sex differences in response to sleep deprivation, with a focus on the sympathetic nervous system stress response and activation of the hypothalamic-pituitary-adrenal (HPA) axis. We review sex differences in several stress-related consequences of sleep loss, including inflammation, learning and memory deficits, and mood related changes. Focusing on women's health, we discuss the effects of sleep deprivation during the peripartum period. In closing, we present neurobiological mechanisms, including the contribution of sex hormones, orexins, circadian timing systems, and astrocytic neuromodulation, that may underlie potential sex differences in sleep deprivation responses.
... Taking a dose of caffeine equal to two espressos three hours before normal sleep in healthy adults can delay the phase of the melatonin circadian rhythm by around 40 minutes. [39] ...
Shift work refers to work that takes place at different hours, including at night. It is estimated that 15% to 20% of the working population works in shift work, particularly in the healthcare, energy, communication systems, public safety, and hospitality industries. Research indicates that shift work, particularly night work, can lead to health problems such as fatigue, exposure to harmful work environments, increased risk of workplace accidents, and sleep disorders. Night work is also associated with increased risk of hypertension, nervous system dysfunction, cardiovascular dysfunction. Those working at night are also more prone to hormonal disorders, digestive disorders, lowered immunity, and cancer. Sleep-wake cycle disorders, such as excessive sleepiness during waking hours and insomnia at night, are symptoms of shift work intolerance syndrome, which can occur after several months or years of shift work. It is estimated that over 20% of shift workers suffer from sleep-wake cycle disorders, and various factors such as chronotype, age, gender, family and social obligations, medications, medical and psychiatric conditions, and shift work experience can impact tolerance of shift work. The treatment of sleep and wake disorders related to shift work includes planning for main sleep and supplementary naps, appropriate exposure to light, treatment with melatonin, taking sleeping and psychostimulant medications.
... 74,75 Caffeine has been shown to delay melatonin release in blind people. 76 In a study including the largest sample of blind individuals with circadian desynchronization, caffeine administration in the morning was reported to be beneficial in alleviating symptoms associated with desynchronized rhythms, such as decreased alertness and low mood, but not effective in regulating circadian rhythm. 77 Melatonin agonists other than tasimelteon may be useful in regulating circadian rhythm, but these agonists have different pharmacological and pharmacokinetic effects and have not been studied in non-24-hour sleep-wake disorder. ...
Various physiological systems and behaviors such as the sleep-wake cycle, vigilance, body temperature, and the secretion of certain hormones are governed by a 24-hour cycle called the circadian system. While there are many external stimuli involved the regulation of circadian rhythm, the most powerful environmental stimulus is the daily light-dark cycle. Blind individuals with no light perception develop circadian desynchrony. This leads to non-24-hour sleep-wake rhythm disorder, which is associated with sleep-wake disorders, as well as mood disorders and loss of appetite and gastrointestinal disturbances due to disrupted circadian hormone regulation. As the diagnosis is often delayed because of under-recognition in clinical practice, patients must cope with varying degrees of social and academic dysfunction. Most blind individuals report that non-24-hour sleep-wake rhythm disorder affects them more than blindness. In the treatment of totally blind patients suffering from non-24-hour sleep-wake rhythm disorder, the first-line management is behavioral approaches. Drug therapy includes melatonin and the melatonin agonist tasimelteon. Diagnosing blind individuals' sleep disorders is also relevant to treatment because they can be improved with the use of melatonin and its analogues or by phototherapy if they have residual vision. Therefore, assessing sleep problems and planning treatment accordingly for individuals presenting with blindness is an important issue for ophthalmologists to keep in mind.
... Second, with the proliferation of coffee shops on campus or near campus, as well as increased availability/accessibility of energy drinks (e.g., vending machines on campus), some students may consume caffeine in the late afternoon, evening, or even at night (e.g., Champlin et al. 2016;Robinson et al. 2013;Taylor et al. 2011). In experimental studies, caffeine consumption as early as 5pm disrupted sleep and delayed dim light melatonin onset (Burke et al. 2015;Drake et al. 2013;Gardiner et al. 2023), raising the possibility that some students who consider themselves to be eveningtypes have that perception in part because they regularly consume caffeine late in the day. Third, some students engage in daytime napping to compensate for short or poor quality sleep (Schulke and Zimmermann 2014). ...
Many students self-report that they are “night owls,” which can result from neurodevelopmental delays in the circadian timing system. However, whether an individual considers themselves to be an evening-type versus a morning-type (self-reported chronotype) may also be influenced by academic demands (e.g. class start times, course load) and behavioral habits (e.g. bedtime social media use, late caffeine consumption, daytime napping). If so, then chronotype should be malleable. We surveyed 858 undergraduate students enrolled in demanding science courses at up to three time points. The survey assessed morning/evening chronotype, global sleep quality, academics, and behavioral habits. Evening and morning-type students showed similar demographics, stress levels, and academic demands. At baseline measurements, relative to morning-types, evening-types showed significantly worse sleep quality and duration as well as 22% greater bedtime social media usage, 27% greater daytime napping duration, and 46% greater likelihood of consuming caffeine after 5pm. These behavioral habits partially mediated the effects of self-reported chronotype on sleep quality/duration, even after controlling for demographic factors. Interestingly, 54 students reported switching from being at least moderate evening-types at baseline to being at least moderate morning-types later in the semester and 56 students showed the reverse pattern (6.3% of students switched from “definitely” one chronotype to the other chronotype). Evening-to-morning “chrono-switchers” consumed less caffeine after 5pm and showed significantly better sleep quantity/quality at the later timepoint. Thus, some students may consider themselves to be night owls in part because they consume caffeine later, take more daytime naps, or use more social media at bedtime. Experimental work is needed to determine whether nudging night owls to behave like morning larks results in better sleep health or academic achievement.
... Within the submarine lighting environment, which does not provide strong light/dark cycle cues, it is possible that caffeine intake serves as a zeitgeber. In fact, some evidence suggests that caffeine impacts the circadian system by delaying (Burke et al., 2015) or advancing (Pierard et al., 2001) the human circadian clock (but see Weibel et al., 2020 for conflicting findings). Perhaps, then, Sailors' use of caffeine could serve as an external cue to help regulate their circadian and sleep/wake cycles because the circadian entrainment signals from the submarine lighting environment are weak. ...
Submariners face many environmental and operational challenges to maintaining good sleep, including suboptimal lighting, shift work, and frequent interruptions. Anecdotally, many Sailors consume caffeine to alleviate the effects of poor sleep on alertness, mood, and performance; however, caffeine itself may also degrade sleep quantity and/or quality. This study provides the first exploration of the potential relationship between caffeine use and sleep onboard submarines. Objective measures (wrist actigraphy, available from 45 participants), self-report sleep metrics, and self-reported caffeine consumption were collected from 58 US Navy Sailors before and during a routine submarine underway at sea lasting 30 days. Contrary to expectations, less caffeine was reportedly consumed at sea (232.8 ± 241.1 mg) than on land prior to the underway (M = 284.4 ± 251.7 mg; X2 (1) = 7.43, p = 0.006), positive rather than negative relationships were observed between caffeine consumption and sleep efficiency (F = 6.11, p = 0.02), and negative relationships were observed between caffeine consumption and wake after sleep onset (F = 9.36, p = 0.004) and sleep fragmentation (F = 24.73, p < 0.0001). However, in contrast, higher caffeine consumption was also negatively related to self-reported sleep duration while at sea (F = 4.73, p = 0.03). This observational study is the first to measure relationships between caffeine consumption and sleep quantity and/or quality in a submarine environment. We propose that the unique submarine environment and the unique caffeine consumption patterns of submariners should be considered in the development of potential countermeasures for sleepiness.
... Skipping breakfast and eating late at night can result in a shift of the circadian clock to nighttime, increasing the risk of obesity and diabetes (7). Various functional food components have been reported to contribute to the regulation of the circadian clock, for instance, caffeine (8), and flavonoids (9,10). Functional food components can contribute to the regulation of the circadian clock and are thought to have beneficial effects on health from a chrono-nutritional perspective. ...
Paramylon, a β-1,3-glucan storage polysaccharide derived from Euglena gracilis, has various health benefits, such as anti-obesity effects and modulation of immune function. However, whether paramylon intake affects the circadian clock remains unknown. In this study, we examined the effect of paramylon intake on the circadian clock. The results showed that the paramylon intake regulated peripheral clocks in mice. Furthermore, cecal pH and short-chain fatty acid concentrations after paramylon intake were measured. The correlation between changes in the expression of clock-related genes and alterations in the intestinal environment was confirmed. In addition, peripheral clock entrainment by paramylon intake was not observed in antibiotic-treated mice whose gut microbiota was weakened. These findings suggest that the regulation of the circadian clock by paramylon intake was mediated by changes in gut microbiota. In addition, the entraining effect of paramylon intake was also confirmed in mice bred under conditions mimicking social jetlag, which implies that paramylon intake may contribute to recovery from social jetlag. Thus, the appropriate consumption of paramylon may have a beneficial effect on health from a chrono-nutritional perspective.
... For shift work disorder, wake-enhancing agents, such as caffeine and modafinil, can be used to manage excessive sleepiness (Zee et al., 2013). While caffeine may influence the circadian response to light (Burke et al., 2015), it does not entrain the circadian clock in blind patients with non-24-h rhythms (St Hilaire & Lockley, 2015). ...
Obstructive sleep apnea is the most common sleep-related breathing disorder worldwide and remains underdiagnosed. Its multiple associated comorbidities contribute to a decreased quality of life and work performance as well as an increased risk of death. Standard treatment seems to have limited effects on cardiovascular and metabolic aspects of the disease, emphasising the need for early diagnosis and additional therapeutic approaches. Recent evidence suggests that the dysregulation of circadian rhythms, processes with endogenous rhythmicity that are adjusted to the environment through various cues, is involved in the pathogenesis of comorbidities. In patients with obstructive sleep apnea, altered circadian gene expression patterns have been demonstrated. Obstructive respiratory events may promote circadian dysregulation through the effects of sleep disturbance and intermittent hypoxia, with subsequent inflammation and disruption of neural and hormonal homeostasis. In this review, current knowledge on obstructive sleep apnea, circadian rhythm regulation, and circadian rhythm sleep disorders is summarised. Studies that connect obstructive sleep apnea to circadian rhythm abnormalities are critically evaluated. Furthermore, pathogenetic mechanisms that may underlie this association, most notably hypoxia signalling, are presented. A bidirectional relationship between obstructive sleep apnea and circadian rhythm dysregulation is proposed. Approaching obstructive sleep apnea as a circadian rhythm disorder may prove beneficial for the development of new, personalised diagnostic, therapeutic and prognostic tools. However, further studies are needed before the clinical approach to obstructive sleep apnea includes targeting the circadian system.
... Another crucial lifestyle factor would be the use of stimulants and hypnotics which, on top of altering sleep homeostasis, can cause circadian changes [3,125]. Individuals already experiencing circadian misalignment or sleep disturbances (e.g. ...
Delayed sleep–wake phase disorder (DSWPD) is a circadian rhythm sleep disorder characterised by a delay in the main sleep period, with patients experiencing difficulty getting to sleep and waking up at socially appropriate times. This often causes insomnia and compromised sleep, results in impairment to daytime function and is associated with a range of comorbidities. Besides interventions aimed at ameliorating symptoms, there is good evidence supporting successful phase advancement with bright light therapy or melatonin administration. However, no treatment to date addresses the tendency to phase delay, which is a common factor amongst the various contributing causes of DSWPD. Circadian phase markers such as core body temperature and circulating melatonin typically correlate well with sleep timing in healthy patients, but numerous variations exist in DSWPD patients that can make these unpredictable for use in diagnostics. There is also increasing evidence that, on top of problems with the circadian cycle, sleep homeostatic processes actually differ in DSWPD patients compared to controls. This naturally has ramifications for management but also for the current approach to the pathogenesis itself in which DSWPD is considered a purely circadian disorder. This review collates what is known on the causes and treatments of DSWPD, addresses the pitfalls in diagnosis and discusses the implications of current data on modified sleep homeostasis, making clinical recommendations and directing future research.
... It has also been found to have a disrupting effect on the body's circadian rhythm. [10] While caffeine consumption has short-term performance benefits, overuse can lead to insomnia or worsen preexisting symptoms. ...
Since the outbreak of the COVID-19 pandemic, the world has come to a standstill, with enforcement of the lockdown, several regulations, and restrictions that brought significant change to people's lifestyles, and induced waves of panic and delirium in individuals everywhere. This unfunded cross-sectional survey-based study aims to evaluate the pandemic's impact on sleep patterns in a sample of the general population worldwide. An online survey was constructed , composing of 31 questions. The Athens scale was used to estimate nocturnal sleep dysfunction and daytime dysfunction. The survey's target population was 13 years and above. 300 responses were received .A majority of the participants reported that they sleep late, have an increased screen time , and used electronics . 45% of the participants said they have insomnia and 55% of the participants claimed they did not have insomnia. Despite the majority claiming to not have insomnia, on employing the Athens scale to calculate individuals' insomnia scores, the results were quite contradictory .Nighttime routines and alarm usage were also monitored. .Therefore, this study has enabled to observe that there has been a definite impact in the sleep cycles of certain individuals since the beginning of the pandemic. Limitations of this study include sample size, random sampling and lack of additional profound data
Background
The influencing factors of primary dysmenorrhea in female college students were analyzed through meta-analysis to provide the corresponding basis for its prevention and treatment.
Methods
The databases, including China National Knowledge Infrastructure, Wanfang Data Knowledge Service Platform, VIP database, China Biology Medicine Disc, Pubmed, Embase, Cochrane library, and Web of science were searched for the literature on the influencing factors of primary dysmenorrhea in female college students was retrieved from the science database from the establishment of the database to July 17, 2023. The Newcastle-Ottawa Quality Scale was used to score the quality of cohort and case–control studies included in the study. The cross-sectional studies were scored by the Agency for Healthcare Research and Quality. Two researchers independently screened the literature, and if there was no consensus, the third party would make a judgment on whether to include the literature. The extracted content included the first author, publication year, country, study type, sample size, and influencing factors. Stata17.0 software was used for meta-analysis.
Results
A total of 23 studies were included, with a total sample size of 18,080 cases. Current evidence shows that the prevalence of primary dysmenorrhea in female college students is 70.3% (95%CI: 62.7–77.9%), and the combined odd ratio values (95%CI) of the main influencing factors are: family history of dysmenorrhea 2.116 (1.613–2.776), early age at menarche 2.200 (1.392–3.477), irregular menstrual cycle 1.662 (1.166–2.367), drinking cold drinks 1.717 (1.220–2.417), high caffeine intake 2.082 (1.379–3.144), stress 1.895 (1.515–2.282), medical specialty 1.827 (1.365–2.445), and adequate sleep 0.328 (0.232–0.463).
Conclusion
The prevalence of primary dysmenorrhea is high in female college students, and adequate sleep is a protective factor for primary dysmenorrhea. Family history of dysmenorrhea, early age at menarche, irregular menstrual cycle, drinking cold drinks, high caffeine intake, stress, and medical specialty were all risk factors.
Introduction and purpose: Circadian rhythms are internal processes that regulate the sleep-wake cycle and repeat roughly every 24 hours. These rhythms are driven by a biological clock, primarily located in the suprachiasmatic nucleus (SCN) of the brain. Synchronized with environmental cues such as light and darkness, they play a crucial role in regulating sleep-wake patterns, hormone secretion, metabolism, and other physiological functions. Disruptions in circadian rhythms can have wide-ranging effects on health. This review aims to synthesize the current state of knowledge on how lifestyle factors affect circadian rhythms and explore the subsequent implications for both mental and physical health. Description of the state of knowledge: Modern lifestyles factors characterized by artificial lighting, shift work, noise pollution, excessive caffeine use, worldwide traveling and irregular eating habits can significantly disrupt natural circadian rhythms. Such disruptions are associated with a spectrum of pathologies, such as sleep dysregulation, mood disorders (e.g., depression and bipolar disorder), metabolic impairments, and suboptimal immune responses. Summary: This review synthesizes current research findings on the impacts of lifestyle-induced circadian misalignment, highlighting the complex interactions between modern life and circadian biology. Maintaining circadian rhythm integrity is crucial not just for enhancing overall well-being but also as a preventive strategy against a wide range of diseases. Integrating this understanding into health practices is essential for addressing the pervasive impact of circadian disruptions in modern society.
Objective
The study aimed to determine the effects of caffeine consumption and sleep on post-spinal headache after spinal anesthesia.
Background
Post-spinal headache is among the most well-known and common complications of spinal anesthesia. Although caffeine consumption is recommended to prevent headache after spinal anesthesia, caffeine does not prevent headache and causes sleep-related problems. No study in the literature found a correlation between sleep and caffeine consumption after spinal anesthesia and post-spinal headache.
Methods
The research is a descriptive and cross-sectional study. The study sample comprised 425 patients who underwent elective surgery in a research hospital. The research data were collected by face-to-face interviews between April 2021 and December 2023. The “Sociodemographic and Clinical Characteristics Form,” “Richard-Campbell Sleep Scale,” “Insomnia Severity Index,” and “Visual Analog Scale” were used in data collection. Factors affecting post-spinal headache were determined using binary logistic regression analysis.
Results
According to the binary logistic regression, the insomnia severity score (OR = 1.234; p < .001), sleep quality score (OR = .992; p < .01), postoperative sleep duration (OR = .619; p < .05), and not consuming coffee (OR = .035; p < .001) are statistically significant predictors of post-spinal headache and explain 57.7% of the variance. A one-unit increase in patients’ insomnia severity increased the probability of experiencing a post-spinal headache by 23.4%. With a one-unit increase in sleep quality, there was an 8% decrease in the probability of experiencing spinal headache, and a 3.81% decrease in the probability of experiencing post-spinal headache with an increase in sleep duration after surgery. The probability of experiencing post-spinal headache was 0.35 times higher in individuals who did not consume caffeine after surgery than in those who consumed it.
Conclusion
The present study demonstrated that insomnia severity and sleep quality were more effective than caffeine consumption in preventing post-spinal headache. Insomnia and decreased sleep quality may cause a significant burden in developing post-spinal headache in patients and may cause post-spinal headache to be observed more frequently. Therefore, the use of caffeine in preventing or reducing post-spinal headache may adversely affect the duration and quality of sleep and increase the severity of insomnia.
G protein-coupled receptors (GPCRs) are central mediators of cell signaling and physiological function. Despite their biological significance, GPCRs have not been widely studied in the field of toxicology. Herein, we investigated these receptors as novel targets of plastic chemicals using a high-throughput drug screening assay with 126 human non-olfactory GPCRs. In a first-pass screen, we tested the activity of triphenol phosphate, bisphenol A, and diethyl phthalate, as well as three real-world mixtures of chemicals extracted from plastic food packaging covering all major polymer types. We found 11 GPCR-chemical interactions, of which the chemical mixtures exhibited the most robust activity at adenosine receptor 1 (ADORA1) and melatonin receptor 1 (MTNR1A). We further confirm that polyvinyl chloride and polyurethane products contain ADORA1 or MTNRA1 agonists using a confirmatory secondary screen and pharmacological knockdown experiments. Finally, an analysis of the associated gene ontology terms suggests that ADORA1 and MTNR1A activation may be linked to downstream effects on circadian and metabolic processes. This work highlights that signaling disruption caused by plastic chemicals is broader than that previously believed and demonstrates the relevance of nongenomic pathways, which have, thus far, remained unexplored.
Circadian rhythms have been shown to be ubiquitous and critically important in the experimental laboratory, accounting for the difference between life and death in response to identical stimulus. The partly endogenous nature of circadian rhythms has been well documented and methods for their characterisation have been developed enabling the cellular and molecular mechanisms to be understood. Chronobiology and Chronomedicine aims to provide a review of these mechanisms underlying circadian rhythms and illustrate the role of the brain’s suprachiasmatic nuclei in the ‘pace-making’ process and the effects caused by ‘clock genes’ present in almost all cells. Beyond the mechanisms involved, the book discusses the relationship between body systems, disease, and proper circadian function; in particular, how disruption of the circadian rhythm is associated with ill health and disease status from observations made at the organismic level. The book is organised to be an ideal introduction for the postgraduate in various fields, reviewing developments and outlining methods to show the depth and breadth of chronobiology and chronomedicine, as well as an invaluable companion to researchers and healthcare professionals working in the field with an interest in developing novel therapeutic approaches.
Flow is an intrinsically rewarding state characterised by positive affect and total task absorption. Because cognitive and physical performance are optimal in flow, chemical means to facilitate this state are appealing. Caffeine, a non-selective adenosine receptor antagonist, has been emphasized as a potential flow-inducer. Thus, we review the psychological and biological effects of caffeine that, conceptually, enhance flow. Caffeine may facilitate flow through various effects, including: i) upregulation of dopamine D1/D2 receptor affinity in reward-associated brain areas, leading to greater energetic arousal and ‘wanting’; ii) protection of dopaminergic neurons; iii) increases in norepinephrine release and alertness, which offset sleep-deprivation and hypoarousal; iv) heightening of parasympathetic high frequency heart rate variability, resulting in improved cortical stress appraisal, v) modification of striatal endocannabinoid-CB1 receptor-signalling, leading to enhanced stress tolerance; and vi) changes in brain network activity in favour of executive function and flow. We also discuss the application of caffeine to treat attention deficit hyperactivity disorder and caveats. We hope to inspire studies assessing the use of caffeine to induce flow.
Circadian rhythms play a pivotal role in governing various physiological processes, including physical performance. However, in individuals deprived of light perception, such as the blind, these circadian rhythms face disruption. This study aimed to explore the influence of disturbed circadian rhythms on short-term maximal physical performance in children and adolescents with visual impairment. Forty-five volunteers participated in this study, comprising 17 blind, 13 visually impaired, and 15 sighted participants. The participants underwent a series of tests assessing maximal isometric strength performance across two days. To mitigate the influence of morning session fatigue on the evening results, each participant group performed in two separate testing sessions (i.e. in the morning (7:00 h) and in the evening (17:00 h)) on non-consecutive days in a randomized and counterbalanced setting, with approximately 36 h of recovery time between sessions. To mitigate the impact of inter-individual differences on mean values and to account for the influence of age and sex on the studied variables, data were normalized. The outcomes revealed a significant diurnal variation in maximal isometric strength performance among sighted individuals, with peak performance observed in the evening. This pattern aligns with their well-entrained circadian rhythm. In contrast, blind and visually impaired individuals did not display significant diurnal variation, signaling disrupted circadian rhythms due to the absence of light perception. These findings emphasize the crucial consideration of circadian rhythms in assessments of physical performance, especially among participants with visual impairments.
The circadian rhythm affects multiple physiological processes, and disruption of the circadian system can be involved in a range of disease-related pathways. The genetic underpinnings of the circadian rhythm have been well-studied in model organisms. Significant progress has been made in understanding how clock genes affect the physiological functions of the nervous system. In addition, circadian timing is becoming a key factor in improving drug efficacy and reducing drug toxicity. The circadian biology of the target cell determines how the organ responds to the drug at a specific time of day, thus regulating pharmacodynamics. The current review brings together recent advances that have begun to unravel the molecular mechanisms of how the circadian clock affects neurophysiological and behavioral processes associated with human brain diseases. We start with a brief description of how the ubiquitous circadian rhythms are regulated at the genetic, cellular, and neural circuit levels, based on knowledge derived from extensive research on model organisms. We then summarize the latest findings from genetic studies of human brain disorders, focusing on the role of human clock gene variants in these diseases. Lastly, we discuss the impact of common dietary factors and medications on human circadian rhythms and advocate for a broader application of the concept of chronomedicine.
Pharmacological intervention of circadian rhythms is a potentially useful approach for ameliorating various health problems caused by disturbed circadian rhythms including sleep disorder and metabolic diseases. To find compounds that affect circadian rhythms, we screened mushroom extracts using mouse cells expressing the luciferase gene under the control of the mouse Bmal1 promoter. The culture filtrate extract from the basidiomycete Cyclocybe erebia enhanced the oscillation of bioluminescence caused by the expression of the luciferase gene and prolonged the period of bioluminescence. Bioassay-guided fractionation of the extract resulted in purification of compounds 1 and 2. Spectroscopic analyses along with single-crystal X-ray diffraction analysis, revealed that these compounds were diterpenoids with a unique skeleton and a fused ring system comprising 3-, 7-, and 5-membered rings. Compounds 1 and 2 were named cyclocircadins A and B, respectively. These findings suggested that natural diterpenoids could be a source of compounds with the activity affecting circadian rhythms.
Background:
Recent research suggests that caffeine intake is associated with a reduced risk of depression. However, the relationship between caffeine intake during different periods of the day and depression is still unclear.
Methods:
This cross-sectional study analyzed noninstitutionalized adults from the National Health and Nutrition Examination Survey, with a weighted representation of approximately 218 million US adults. Covariate-adjusted sample-weighted regressions were used to examine associations between caffeine intake and depression in different periods.
Results:
Caffeine intake during non-early morning periods (outside of 5:00-8:00 AM) is associated with a high prevalence of depression (unadjusted OR: 1.08, 95%CI: 1.05-1.11; adjusted OR: 1.03, 95 % CI: 1.00-1.06). Participants who consumed caffeine in the early morning (5:00-8:00 AM) had a lower prevalence of depression compared to participants who did not consume caffeine in the early morning (unadjusted OR: 0.75, 95%CI: 0.67-0.85; adjusted OR: 0.86, 95 % CI: 0.75-0.99).
Limitations:
Cross-sectional study could not determine the temporal association; patients with depression in this study were not clinically diagnosed with Major Depressive Disorder.
Conclusions:
Among US adults, early morning caffeine consumers had a lower prevalence of depression than non-consumers; caffeine intake during non-early morning periods is associated with a high prevalence of depression. Our results may suggest the importance of caffeine intake time for depression.
Caffeine is a naturally occurring alkaloid found in various plants. It acts as a stimulant, antioxidant, anti-inflammatory, and even an aid in pain management, and is found in several over-the-counter medications. This naturally derived bioactive compound is the best-known ingredient in coffee and other beverages, such as tea, soft drinks, and energy drinks, and is widely consumed worldwide. Therefore, it is extremely important to research the effects of this substance on the human body. With this in mind, caffeine and its derivatives have been extensively studied to evaluate its ability to prevent diseases and exert anti-aging and neuroprotective effects. This review is intended to provide an overview of caffeine’s effects on cancer and cardiovascular, immunological, inflammatory, and neurological diseases, among others. The heavily researched area of caffeine in sports will also be discussed. Finally, recent advances in the development of novel nanocarrier-based formulations, to enhance the bioavailability of caffeine and its beneficial effects will be discussed.
Researchers have been exploring the influence of light on health in office settings for over two decades; however, a greater understanding of physiological responses and technology advancements are shifting the way researchers study the influence of light in realistic environments. New technologies paired with Ecological Momentary Assessments (EMAs) administered via smartphones provide ways to collect information about individual light exposure and occupant response throughout the day. The study aims to document occupant response to tunable lighting in a real office environment, including potential beneficial or adverse health and well-being effects. Twenty-three office employees agreed to participate in a twelve-week study examining occupant response to two lighting conditions (static vs. dynamic). No significant differences were observed for any of the measures, highlighting the importance and complexity of in-situ studies conducted in realistic environments. While prior office studies have shown a significant influence on daytime sleepiness and sleep quality, research has not shown mood or stress to be significantly impacted by lighting conditions. Correlation analyses regarding lighting satisfaction, environmental satisfaction, and visual comfort demonstrate a significant relationship between certain items that may inform future studies. Further, the high correlation means it is reasonable to assume that many environmental factors in offices can influence occupant behavior and well-being.
Significance
We generated high-resolution multiorgan expression data showing that nearly half of all genes in the mouse genome oscillate with circadian rhythm somewhere in the body. Such widespread transcriptional oscillations have not been previously reported in mammals. Applying pathway analysis, we observed new clock-mediated spatiotemporal relationships. Moreover, we found a majority of best-selling drugs in the United States target circadian gene products. Many of these drugs have relatively short half-lives, and our data predict which may benefit from timed dosing.
Photic and non-photic stimuli have been shown to shift the phase of the human circadian clock. We examined how photic and non-photic time cues may be combined by the human circadian system by assessing the phase advancing effects of one evening dose of exogenous melatonin, alone and in combination with one session of morning bright light exposure.
Randomized placebo-controlled double-blind circadian protocol. The effects of four conditions, dim light (∼1.9 lux, ∼0.6 Watts/m(2))-placebo, dim light-melatonin (5 mg), bright light (∼3000 lux, ∼7 Watts/m(2))-placebo, and bright light-melatonin on circadian phase was assessed by the change in the salivary dim light melatonin onset (DLMO) prior to and following treatment under constant routine conditions. Melatonin or placebo was administered 5.75 h prior to habitual bedtime and 3 h of bright light exposure started 1 h prior to habitual wake time.
Sleep and chronobiology laboratory environment free of time cues.
Thirty-six healthy participants (18 females) aged 22 ± 4 y (mean ± SD).
Morning bright light combined with early evening exogenous melatonin induced a greater phase advance of the DLMO than either treatment alone. Bright light alone and melatonin alone induced similar phase advances.
Information from light and melatonin appear to be combined by the human circadian clock. The ability to combine circadian time cues has important implications for understanding fundamental physiological principles of the human circadian timing system. Knowledge of such principles is important for designing effective countermeasures for phase-shifting the human circadian clock to adapt to jet lag, shift work, and for designing effective treatments for circadian sleep-wakefulness disorders.
Burke TM; Markwald RR; Chinoy ED; Snider JA; Bessman SC; Jung CM; Wright Jr KP. Combination of light and melatonin time cues for phase advancing the human circadian clock. SLEEP 2013;36(11):1617-1624.
Adenosine signalling has long been a target for drug development, with adenosine itself or its derivatives being used clinically since the 1940s. In addition, methylxanthines such as caffeine have profound biological effects as antagonists at adenosine receptors. Moreover, drugs such as dipyridamole and methotrexate act by enhancing the activation of adenosine receptors. There is strong evidence that adenosine has a functional role in many diseases, and several pharmacological compounds specifically targeting individual adenosine receptors - either directly or indirectly - have now entered the clinic. However, only one adenosine receptor-specific agent - the adenosine A2A receptor agonist regadenoson (Lexiscan; Astellas Pharma) - has so far gained approval from the US Food and Drug Administration (FDA). Here, we focus on the biology of adenosine signalling to identify hurdles in the development of additional pharmacological compounds targeting adenosine receptors and discuss strategies to overcome these challenges.
Daily cyclical expression of thousands of genes in tissues such as the liver is orchestrated by the molecular circadian clock, the disruption of which is implicated in metabolic disorders and cancer. Although we understand much about the circadian transcription factors that can switch gene expression on and off, it is still unclear how global changes in rhythmic transcription are controlled at the genomic level. Here, we demonstrate circadian modification of an activating histone mark at a significant proportion of gene loci that undergo daily transcription, implicating widespread epigenetic modification as a key node regulated by the clockwork. Furthermore, we identify the histone-remodelling enzyme mixed lineage leukemia (MLL)3 as a clock-controlled factor that is able to directly and indirectly modulate over a hundred epigenetically targeted circadian "output" genes in the liver. Importantly, catalytic inactivation of the histone methyltransferase activity of MLL3 also severely compromises the oscillation of "core" clock gene promoters, including Bmal1, mCry1, mPer2, and Rev-erbα, suggesting that rhythmic histone methylation is vital for robust transcriptional oscillator function. This highlights a pathway by which the clockwork exerts genome-wide control over transcription, which is critical for sustaining temporal programming of tissue physiology.
Circadian clocks orchestrate 24-h oscillations of essential physiological and behavioral processes in response to daily environmental changes. These clocks are remarkably precise under constant conditions yet highly responsive to resetting signals. With the molecular composition of the core oscillator largely established, recent research has increasingly focused on clock-modifying mechanisms/molecules. In particular, small molecule modifiers, intrinsic or extrinsic, are emerging as powerful tools for understanding basic clock biology as well as developing putative therapeutic agents for clock-associated diseases. In this review, we will focus on synthetic compounds capable of modifying the period, phase, or amplitude of circadian clocks, with particular emphasis on the mammalian clock. We will discuss the potential of exploiting these small molecule modifiers in both basic and translational research.
AIthough intraclass correlation coefficients (lCCs) are commonIy used in behavioral measurement, pychometrics, and behavioral genetics, procodures available for forming inferences about ICC are not widely known. Following a review of the distinction between various forms of the ICC, this article presents procedures available for calculating confidence intervals and conducting tests on ICCs developed using data from one-way and two-way random and mixed-efFect analysis of variance models. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
To identify common genetic variants that predispose to caffeine-induced insomnia and to test whether genes whose expression changes in the presence of caffeine are enriched for association with caffeine-induced insomnia.
A hypothesis-free, genome-wide association study.
Community-based sample of Australian twins from the Australian Twin Registry.
After removal of individuals who said that they do not drink coffee, a total of 2,402 individuals from 1,470 families in the Australian Twin Registry provided both phenotype and genotype information.
A dichotomized scale based on whether participants reported ever or never experiencing caffeine-induced insomnia. A factor score based on responses to a number of questions regarding normal sleep habits was included as a covariate in the analysis. More than 2 million common single nucleotide polymorphisms (SNPs) were tested for association with caffeine-induced insomnia. No SNPs reached the genome-wide significance threshold. In the analysis that did not include the insomnia factor score as a covariate, the most significant SNP identified was an intronic SNP in the PRIMA1 gene (P = 1.4 × 10⁻⁶, odds ratio = 0.68 [0.53 - 0.89]). An intergenic SNP near the GBP4 gene on chromosome 1 was the most significant upon inclusion of the insomnia factor score into the model (P = 1.9 × 10⁻⁶, odds ratio = 0.70 [0.62 - 0.78]). A previously identified association with a polymorphism in the ADORA2A gene was replicated.
Several genes have been identified in the study as potentially influencing caffeine-induced insomnia. They will require replication in another sample. The results may have implications for understanding the biologic mechanisms underlying insomnia.
Caffeine is the most widely consumed centralnervous-system stimulant. Three main mechanisms of action of caffeine on the central nervous system have been described. Mobilization of intracellular calcium and inhibition of specific phosphodiesterases only occur at high non-physiological concentrations of caffeine. The only likely mechanism of action of the methylxanthine is the antagonism at the level of adenosine receptors. Caffeine increases energy metabolism throughout the brain but decreases at the same time cerebral blood flow, inducing a relative brain hypoperfusion. Caffeine activates noradrenaline neurons and seems to affect the local release of dopamine. Many of the alerting effects of caffeine may be related to the action of the methylxanthine on serotonine neurons. The methylxanthine induces dose-response increases in locomotor activity in animals. Its psychostimulant action on man is, however, often subtle and not very easy to detect. The effects of caffeine on learning, memory, performance and coordination are rather related to the methylxanthine action on arousal, vigilance and fatigue. Caffeine exerts obvious effects on anxiety and sleep which vary according to individual sensitivity to the methylxanthine. However, children in general do not appear more sensitive to methylxanthine effects than adults. The central nervous system does not seem to develop a great tolerance to the effects of caffeine although dependence and withdrawal symptoms are reported.
Synchronous oscillations of thousands of cellular clocks in the suprachiasmatic nucleus (SCN), the circadian centre, are coordinated by precisely timed cell-cell communication, the principle of which is largely unknown. Here we show that the amount of RGS16 (regulator of G protein signalling 16), a protein known to inactivate Gαi, increases at a selective circadian time to allow time-dependent activation of intracellular cyclic AMP signalling in the SCN. Gene ablation of Rgs16 leads to the loss of circadian production of cAMP and as a result lengthens circadian period of behavioural rhythm. The temporally precise regulation of the cAMP signal by clock-controlled RGS16 is needed for the dorsomedial SCN to maintain a normal phase-relationship to the ventrolateral SCN. Thus, RGS16-dependent temporal regulation of intracellular G protein signalling coordinates the intercellular synchrony of SCN pacemaker neurons and thereby defines the 24 h rhythm in behaviour.
The circadian rhythms of melatonin and body temperature are set to an earlier hour in women than in men, even when the women and men maintain nearly identical and consistent bedtimes and wake times. Moreover, women tend to wake up earlier than men and exhibit a greater preference for morning activities than men. Although the neurobiological mechanism underlying this sex difference in circadian alignment is unknown, multiple studies in nonhuman animals have demonstrated a sex difference in circadian period that could account for such a difference in circadian alignment between women and men. Whether a sex difference in intrinsic circadian period in humans underlies the difference in circadian alignment between men and women is unknown. We analyzed precise estimates of intrinsic circadian period collected from 157 individuals (52 women, 105 men; aged 18-74 y) studied in a month-long inpatient protocol designed to minimize confounding influences on circadian period estimation. Overall, the average intrinsic period of the melatonin and temperature rhythms in this population was very close to 24 h [24.15 ± 0.2 h (24 h 9 min ± 12 min)]. We further found that the intrinsic circadian period was significantly shorter in women [24.09 ± 0.2 h (24 h 5 min ± 12 min)] than in men [24.19 ± 0.2 h (24 h 11 min ± 12 min); P < 0.01] and that a significantly greater proportion of women have intrinsic circadian periods shorter than 24.0 h (35% vs. 14%; P < 0.01). The shorter average intrinsic circadian period observed in women may have implications for understanding sex differences in habitual sleep duration and insomnia prevalence.
Circadian rhythms are ubiquitous in eukaryotes, and coordinate numerous aspects of behaviour, physiology and metabolism, from sleep/wake cycles in mammals to growth and photosynthesis in plants. This daily timekeeping is thought to be driven by transcriptional-translational feedback loops, whereby rhythmic expression of 'clock' gene products regulates the expression of associated genes in approximately 24-hour cycles. The specific transcriptional components differ between phylogenetic kingdoms. The unicellular pico-eukaryotic alga Ostreococcus tauri possesses a naturally minimized clock, which includes many features that are shared with plants, such as a central negative feedback loop that involves the morning-expressed CCA1 and evening-expressed TOC1 genes. Given that recent observations in animals and plants have revealed prominent post-translational contributions to timekeeping, a reappraisal of the transcriptional contribution to oscillator function is overdue. Here we show that non-transcriptional mechanisms are sufficient to sustain circadian timekeeping in the eukaryotic lineage, although they normally function in conjunction with transcriptional components. We identify oxidation of peroxiredoxin proteins as a transcription-independent rhythmic biomarker, which is also rhythmic in mammals. Moreover we show that pharmacological modulators of the mammalian clock mechanism have the same effects on rhythms in Ostreococcus. Post-translational mechanisms, and at least one rhythmic marker, seem to be better conserved than transcriptional clock regulators. It is plausible that the oldest oscillator components are non-transcriptional in nature, as in cyanobacteria, and are conserved across kingdoms.
During fasting, mammals maintain normal glucose homeostasis by stimulating hepatic gluconeogenesis. Elevations in circulating glucagon and epinephrine, two hormones that activate hepatic gluconeogenesis, trigger the cAMP-mediated phosphorylation of cAMP response element-binding protein (Creb) and dephosphorylation of the Creb-regulated transcription coactivator-2 (Crtc2)--two key transcriptional regulators of this process. Although the underlying mechanism is unclear, hepatic gluconeogenesis is also regulated by the circadian clock, which coordinates glucose metabolism with changes in the external environment. Circadian control of gene expression is achieved by two transcriptional activators, Clock and Bmal1, which stimulate cryptochrome (Cry1 and Cry2) and Period (Per1, Per2 and Per3) repressors that feed back on Clock-Bmal1 activity. Here we show that Creb activity during fasting is modulated by Cry1 and Cry2, which are rhythmically expressed in the liver. Cry1 expression was elevated during the night-day transition, when it reduced fasting gluconeogenic gene expression by blocking glucagon-mediated increases in intracellular cAMP concentrations and in the protein kinase A-mediated phosphorylation of Creb. In biochemical reconstitution studies, we found that Cry1 inhibited accumulation of cAMP in response to G protein-coupled receptor (GPCR) activation but not to forskolin, a direct activator of adenyl cyclase. Cry proteins seemed to modulate GPCR activity directly through interaction with G(s)α. As hepatic overexpression of Cry1 lowered blood glucose concentrations and improved insulin sensitivity in insulin-resistant db/db mice, our results suggest that compounds that enhance cryptochrome activity may provide therapeutic benefit to individuals with type 2 diabetes.
A striking feature of the circadian clock is its flexible yet robust response to various environmental conditions. To analyze the biochemical processes underlying this flexible-yet-robust characteristic, we examined the effects of 1,260 pharmacologically active compounds in mouse and human clock cell lines. Compounds that markedly (>10 s.d.) lengthened the period in both cell lines, also lengthened it in central clock tissues and peripheral clock cells. Most compounds inhibited casein kinase Iepsilon (CKIepsilon) or CKIdelta phosphorylation of the PER2 protein. Manipulation of CKIepsilon/delta-dependent phosphorylation by these compounds lengthened the period of the mammalian clock from circadian (24 h) to circabidian (48 h), revealing its high sensitivity to chemical perturbation. The degradation rate of PER2, which is regulated by CKIepsilon/delta-dependent phosphorylation, was temperature-insensitive in living clock cells, yet sensitive to chemical perturbations. This temperature-insensitivity was preserved in the CKIepsilon/delta-dependent phosphorylation of a synthetic peptide in vitro. Thus, CKIepsilon/delta-dependent phosphorylation is likely a temperature-insensitive period-determining process in the mammalian circadian clock.
Caffeine is one of the most widely consumed stimulants in the world and has been proposed to promote wakefulness by antagonizing function of the adenosine A2A receptor. Here, we show that chronic administration of caffeine reduces and fragments sleep in Drosophila and also lengthens circadian period. To identify the mechanisms underlying these effects of caffeine, we first generated mutants of the only known adenosine receptor in flies (dAdoR), which by sequence is most similar to the mammalian A2A receptor. Mutants lacking dAdoR have normal amounts of baseline sleep, as well as normal homeostatic responses to sleep deprivation. Surprisingly, these mutants respond normally to caffeine. On the other hand, the effects of caffeine on sleep and circadian rhythms are mimicked by a potent phosphodiesterase inhibitor, IBMX (3-isobutyl-1-methylxanthine). Using in vivo fluorescence resonance energy transfer imaging, we find that caffeine induces widespread increase in cAMP levels throughout the brain. Finally, the effects of caffeine on sleep are blocked in flies that have reduced neuronal PKA activity. We suggest that chronic administration of caffeine promotes wakefulness in Drosophila, at least in part, by inhibiting cAMP phosphodiesterase activity.
The length of the endogenous period of the human circadian clock (tau) is slightly greater than 24 hours. There are individual differences in tau, which influence the phase angle of entrainment to the light/dark (LD) cycle, and in doing so contribute to morningness-eveningness. We have recently reported that tau measured in subjects living on an ultradian LD cycle averaged 24.2 hours, and is similar to tau measured using different experimental methods. Here we report racial differences in tau. Subjects lived on an ultradian LD cycle (1.5 hours sleep, 2.5 hours wake) for 3 days. Circadian phase assessments were conducted before and after the ultradian days to determine the change in circadian phase, which was attributed to tau. African American subjects had a significantly shorter tau than subjects of other races. We also tested for racial differences in our previous circadian phase advancing and phase delaying studies. In the phase advancing study, subjects underwent 4 days of a gradually advancing sleep schedule combined with a bright light pulse upon awakening each morning. In the phase delaying study, subjects underwent 4 days of a gradually delaying sleep schedule combined with evening light pulses before bedtime. African American subjects had larger phase advances and smaller phase delays, relative to Caucasian subjects. The racial differences in tau and circadian phase shifting have important implications for understanding normal phase differences between individuals, for developing solutions to the problems of jet lag and shift work, and for the diagnosis and treatment of circadian rhythm based sleep disorders such as advanced and delayed sleep phase disorder.
The circadian clock controls daily oscillations of gene expression at the cellular level. We report the development of a high-throughput circadian functional assay system that consists of luminescent reporter cells, screening automation, and a data analysis pipeline. We applied this system to further dissect the molecular mechanisms underlying the mammalian circadian clock using a chemical biology approach. We analyzed the effect of 1,280 pharmacologically active compounds with diverse structures on the circadian period length that is indicative of the core clock mechanism. Our screening paradigm identified many compounds previously known to change the circadian period or phase, demonstrating the validity of the assay system. Furthermore, we found that small molecule inhibitors of glycogen synthase kinase 3 (GSK-3) consistently caused a strong short period phenotype in contrast to the well-known period lengthening by lithium, another presumed GSK-3 inhibitor. siRNA-mediated knockdown of GSK-3β also caused a short period, confirming the phenotype obtained with the small molecule inhibitors. These results clarify the role of GSK-3β in the period regulation of the mammalian clockworks and highlight the effectiveness of chemical biology in exploring unidentified mechanisms of the circadian clock.
• screening
• small molecule library
• kinase
Circadian clocks are complex biochemical systems that cycle with a period of approximately 24 hours. They integrate temporal information regarding phasing of the solar cycle, and adjust their phase so as to synchronize an organism's internal state to the local environmental day and night. Nocturnal light is the dominant regulator of this entrainment. In mammals, information about nocturnal light is transmitted by glutamate released from retinal projections to the circadian clock in the suprachiasmatic nucleus of the hypothalamus. Clock resetting requires the activation of ionotropic glutamate receptors, which mediate Ca2+ influx. The response induced by such activation depends on the clock's temporal state: during early night it delays the clock phase, whereas in late night the clock phase is advanced. To investigate this differential response, we sought signalling elements that contribute solely to phase delay. We analysed intracellular calcium-channel ryanodine receptors, which mediate coupled Ca2+ signalling. Depletion of intracellular Ca2+ stores during early night blocked the effects of glutamate. Activators of ryanodine receptors induced phase resetting only in early night; inhibitors selectively blocked delays induced by light and glutamate. These findings implicate the release of intracellular Ca2+ through ryanodine receptors in the light-induced phase delay of the circadian clock restricted to the early night.
We examined the temporal modulation of intracellular calcium release channels in the suprachiasmatic nucleus (SCN). We found a circadian rhythm in [3H]ryanodine binding that was specific to the SCN. The peak in the rhythm occurred at CT 7 and was due to an increase in Bmax, which correlated well with immunoblots showing an increase in RyR-2 expression in the SCN. Double immunohistochemical studies showed that RyR-2 was expressed exclusively in neurons. Ryanodine and caffeine applied around CT 7-9 advanced the clock phase in a hamster brain slice preparation. No rhythm of IP3R was seen in any of the brain areas studied. Our results indicate that RyR-2 exhibits an endogenous rhythm, which influences the intracellular calcium dynamics and thus modulates SCN activity.
Caffeine and bright light effects on nighttime melatonin and temperature levels in women were tested during the luteal phase of the menstrual cycle (n=30) or the pseudo luteal phase for oral contraceptive users (n=32). Participants were randomly assigned to receive either bright (5000 lux) or dim room light (<88 lux) between 20:00 and 08:00 h under a modified constant routine protocol. Half the subjects in each lighting condition were administered either caffeine (100 mg) or placebo in a double-blind manner at 20:00, 23:00, 02:00 and 05:00 h. Results showed that the combination of bright light and caffeine enhanced nighttime temperature levels to a greater extent than did either caffeine or bright light alone. Both of the latter groups had higher temperature levels relative to the dim light placebo condition and the two groups did not differ. Temperature levels in the bright light caffeine condition were maintained at near peak circadian levels the entire night in the luteal and pseudo luteal phase. Melatonin levels were reduced throughout the duration of bright light exposure for all women. Caffeine reduced the onset of melatonin levels for women in the luteal phase, but it had little effect on melatonin levels for oral contraceptive users. The results for women in the luteal phase of the menstrual cycle are consistent with our previous findings in men. The results also suggest that oral contraceptives may alter the effects of caffeine on nighttime melatonin levels.
Endogenous circadian clocks are robust regulators of physiology and behavior. Synchronization or entrainment of biological clocks to environmental time is adaptive and important for physiological homeostasis and for the proper timing of species-specific behaviors. We studied subjects in the laboratory for up to 55 days each to determine the ability to entrain the human clock to a weak circadian synchronizing stimulus [scheduled activity-rest cycle in very dim (approximately 1.5 lux in the angle of gaze) light-dark cycle] at three approximately 24-h periods: 23.5, 24.0, and 24.6 h. These studies allowed us to test two competing hypotheses as to whether the period of the human circadian pacemaker is near to or much longer than 24 h. We report here that imposition of a sleep-wake schedule with exposure to the equivalent of candle light during wakefulness and darkness during sleep is usually sufficient to maintain circadian entrainment to the 24-h day but not to a 23.5- or 24.6-h day. Our results demonstrate functionally that, in normally entrained sighted adults, the average intrinsic circadian period of the human biological clock is very close to 24 h. Either exposure to very dim light and/or the scheduled sleep-wake cycle itself can entrain this near-24-h intrinsic period of the human circadian pacemaker to the 24-h day.
The 17beta-estradiol (E2) receptor isoforms [estrogen receptor (ER) alpha and ERbeta] bind E2 and selective ER modulators (SERMs) as homodimers (alpha/alpha or beta/beta) or heterodimers (alpha/beta) to regulate gene expression. Although recent studies have shown that ER homodimers regulate unique sets of E2-responsive genes, little information exists regarding the transcriptional actions of the ERalpha/beta heterodimer. This paper describes the development of a U2OS human osteosarcoma (osteoblast) cell line stably expressing both ERalpha and ERbeta isoforms at a ratio of 1:4, a ratio reported to exist in normal, mature osteoblast cells derived from cancellous bone. The regulation of endogenous genes by E2 and 4-hydroxy-tamoxifen were measured in these cells using gene microarrays and real-time RT-PCR. Both E2 and 4-hydroxy-tamoxifen were shown to regulate unique sets of endogenous genes in the U2OS-ERalpha/beta heterodimer cell line (20% and 27% of total, respectively), compared with all the genes regulated in U2OS-ER homodimer cell lines. Furthermore, two novel E2-regulated genes, retinoblastoma binding protein 1 and 7-dehydrocholesterol reductase, were found to contain estrogen response element-like sequences that directly bind the ERalpha/beta heterodimer. These results suggest that the expression of both ER isoforms, forming functional ERalpha/beta heterodimers, result in unique patterns of gene regulation, many of which are distinct from the genes regulated by the ER homodimers.
Caffeine, a component of tea, coffee and cola, induces wakefulness. It binds to adenosine A1 and A2A receptors as an antagonist, but the receptor subtype mediating caffeine-induced wakefulness remains unclear. Here we report that caffeine at 5, 10 and 15 mg kg(-1) increased wakefulness in both wild-type mice and A1 receptor knockout mice, but not in A2A receptor knockout mice. Thus, caffeine-induced wakefulness depends on adenosine A2A receptors.
Caffeine is the most widely used stimulant in Western countries. Some people voluntarily reduce caffeine consumption because it impairs the quality of their sleep. Studies in mice revealed that the disruption of sleep after caffeine is mediated by blockade of adenosine A2A receptors. Here we show in humans that (1) habitual caffeine consumption is associated with reduced sleep quality in self-rated caffeine-sensitive individuals, but not in caffeine-insensitive individuals; (2) the distribution of distinct c.1083T>C genotypes of the adenosine A2A receptor gene (ADORA2A) differs between caffeine-sensitive and -insensitive adults; and (3) the ADORA2A c.1083T>C genotype determines how closely the caffeine-induced changes in brain electrical activity during sleep resemble the alterations observed in patients with insomnia. These data demonstrate a role of adenosine A2A receptors for sleep in humans, and suggest that a common variation in ADORA2A contributes to subjective and objective responses to caffeine on sleep.
The mammalian circadian clockwork is modeled as transcriptional and posttranslational feedback loops, whereby circadian genes
are periodically suppressed by their protein products. We show that adenosine 3′,5′-monophosphate (cAMP) signaling constitutes
an additional, bona fide component of the oscillatory network. cAMP signaling is rhythmic and sustains the transcriptional
loop of the suprachiasmatic nucleus, determining canonical pacemaker properties of amplitude, phase, and period. This role
is general and is evident in peripheral mammalian tissues and cell lines, which reveals an unanticipated point of circadian
regulation in mammals qualitatively different from the existing transcriptional feedback model. We propose that daily activation
of cAMP signaling, driven by the transcriptional oscillator, in turn sustains progression of transcriptional rhythms. In this
way, clock output constitutes an input to subsequent cycles.
Caffeine is the most commonly used psychoactive stimulant worldwide. It reduces sleep and sleepiness by blocking access to the adenosine receptor. The level of adenosine increases during sleep deprivation, and is thought to induce sleepiness and initiate sleep. Light-induced phase shifts of the rest–activity circadian rhythms are mediated by light-responsive neurons of the suprachiasmatic nucleus (SCN) of the hypothalamus, where the circadian clock of mammals resides. Previous studies have shown that sleep deprivation reduces circadian clock phase-shifting capacity and decreases SCN neuronal activity. In addition, application of adenosine agonists and antagonists mimics and blocks, respectively, the effect of sleep deprivation on light-induced phase shifts in behaviour, suggesting a role for adenosine. In the present study, we examined the role of sleep deprivation in and the effect of caffeine on light responsiveness of the SCN. We performed in vivo electrical activity recordings of the SCN in freely moving mice, and showed that the sustained response to light of SCN neuronal activity was attenuated after 6 h of sleep deprivation prior to light exposure. Subsequent intraperitoneal application of caffeine was able to restore the response to light. Finally, we performed behavioural recordings in constant conditions, and found enhanced period lengthening during chronic treatment with caffeine in drinking water in constant light conditions. The data suggest that increased homeostatic sleep pressure changes circadian pacemaker functioning by reducing SCN neuronal responsiveness to light. The electrophysiological and behavioural data together provide evidence that caffeine enhances clock sensitivity to light.
Background and purpose:
Caffeine is one of the most commonly used psychoactive substances. Circadian rhythms consist of the main suprachiasmatic nucleus (SCN) clocks and peripheral clocks. Although caffeine lengthens circadian rhythms and modifies phase changes in SCN-operated rhythms, the effects on caffeine on the phase, period and amplitude of peripheral organ clocks are not known. In addition, the role of cAMP/Ca(2+) signalling in effects of caffeine on rhythm has not been fully elucidated.
Experimental approach:
We examined whether chronic or transient application of caffeine affects circadian period/amplitude and phase by evaluating bioluminescence rhythm in PER2::LUCIFERASE knock-in mice. Circadian rhythms were monitored in vitro using fibroblasts and ex vivo and in vivo for monitoring of peripheral clocks.
Key results:
Chronic application of caffeine (0.1-10 mM) increased period and amplitude in vitro. Transient application of caffeine (10 mM) near the bottom of the decreasing phase of bioluminescence rhythm caused phase advance in vitro. Caffeine (0.1%) intake caused a phase delay under light-dark or constant dark conditions, suggesting a period-lengthening effect in vivo. Caffeine (20 mg·kg(-1) ) at daytime or at late night-time caused phase advance or delay in bioluminescence rhythm in the liver and kidney respectively. The complicated roles of cAMP/Ca(2+) signalling may be involved in the caffeine-induced increase of period and amplitude in vitro.
Conclusions and implications:
Caffeine affects circadian rhythm in mice by lengthening the period and causing a phase shift of peripheral clocks. These results suggest that caffeine intake with food/drink may help with food-induced resetting of peripheral circadian clocks.
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.
1.1. Phase shifts of the ocular circadian rhythm in isolated eyes of the marine snail, Bulla gouldiana were produced by 3- and 6-hr pulses of agents that increase or mimic cyclic AMP (cAMP) activity.2.2. The magnitude and direction of phase shifts depended upon the circadian phase of the rhythm, and the phase response curve was similar to that produced by membrane hyperpolarizing treatments in this species.3.3. Phase shifts induced by cAMP were eliminated by a depolarizing agent, tetraethylammonium, applied simultaneously to experimental and control eyes.4.4. As in other species, cAMP may regulate circadian rhythms in Bulla, possibly through effects on membrane potential.
Reports 3 errors in the original article by K. O. McGraw and S. P. Wong (Psychological Methods, 1996, 1[1], 30–46). On page 39, the intraclass correlation coefficient (ICC) and r values given in Table 6 should be changed to r = .714 for each data set, ICC(C,1) = .714 for each data set, and ICC(A,1) = .720, .620, and .485 for the data in Columns 1, 2, and 3 of the table, respectively. In Table 7 (p. 41), which is used to determine confidence intervals on population values of the ICC, the procedures for obtaining the confidence intervals on ICC(A,k) need to be amended slightly. Corrected formulas are given. On pages 44–46, references to Equations A3, A,4, and so forth in the Appendix should be to Sections A3, A4, and so forth. (The following abstract of this article originally appeared in record 1996-03170-003.). Although intraclass correlation coefficients (ICCs) are commonly used in behavioral measurement, psychometrics, and behavioral genetics, procedures available for forming inferences about ICC are not widely known. Following a review of the distinction between various forms of the ICC, this article presents procedures available for calculating confidence intervals and conducting tests on ICCs developed using data from one-way and two-way random and mixed-effect analysis of variance models. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Caffeine and theophylline were found to increase the period length of the photo tactic rhythm of Chiarnydonionas reinhardii in a dose-related manner. Treatment with caffeine resulted in average period increase of 11.2% (3 mM), 16.4% (5 mM) , and 29% (10 mM ) . Theophylline caused smaller period increases than did caffeine : an average period lengthening of 4.2% (3 mM) and 6.1 % (5 mM).