IntroductionSleep deprivation is known to induce cardiovascular responses. Several studies have shown the beneficial effect of caffeine on neurobehavioral performance during sleep deprivation, but less is known about its influence on the cardiovascular and inflammatory responses associated with sleep deprivation. The aim of this study is to evaluate the impact of acute caffeine intake on (1) peripheral blood pressures, and (2) heart rate, and cutaneous vascular conductance (CVC) and related biomarkers of endothelial activation, during total sleep deprivation (TSD), considering habitual caffeine consumption.Methods41 subjects followed a randomized, placebo-controlled, cross-over study and underwent 2 conditions of TSD (38 h), one with caffeine intake at 09:00 and 14:00 (2.5 mg/kg), and the other with placebo intake.ResultsWe confirm that TSD increases systolic and diastolic arterial pressures (p = 0.001 and p = 0.002 for main effects respectively) and heart rate (p = 0.001), and decreases endothelium-dependent and -independent CVC (p = 0.001). Acute caffeine intake inflates the increase in arterial pressures and IL-6 levels, while it does not affect CVC and levels of E-selectin and monocyte chemotaxis protein-1 (MCP-1). Moreover, chronic caffeine consumption had significant main effects on systolic arterial pressure (p = 0.03), heart rate (p = 0.02), IL-6 levels (p = 0.02), and acetylcholine (ACh)-induced CVC (p = 0.02), and interacted with TSD on E-selectin levels and ACh-induced CVC (p = 0.02 respectively).ConclusionAcute caffeine intake provokes immuno-inflammatory and cardiovascular responses, and chronic caffeine consumption should be limited to the lowest efficient doses.Clinical Trial Registrationhttps://clinicaltrials.gov/study/NCT03859882, identifier NCT03859882.

The effect of sleep restriction (SR) on the physiological responses to normobaric hypoxia (NH) remains unknown. This study examined whether acute SR the night prior to a 5-h exposure to 3,500 m NH impacts (i) the resting ventilatory response, (ii) circulating pro- and anti-inflammatory cytokines, and (iii) their potential association. Seventeen healthy men (31 ± 7 yr; 77.1 ± 8.5 kg) were exposed to 5 h of NH (FIO2 = 13.6

Rationale:In specific operational contexts (i.e., military aviation), the off-label use of modafinil is officially regulated. However, safety concerns are still raised. Objectives:To study the stability and robustness of interindividual differences in modafinil sensitivity, both in terms of risks and benefits in military student pilots. Methods:Eleven healthy military student pilots (21 ± 2 yr; 1 woman) were tested in a within-subject randomized counterbalanced crossover design to compare modafinil (2 × 200 mg; EXP) vs. placebo (CON) effects during extended wakefulness (24 h). Throughout both trials, participant's vital signs, mood, vigilance [i.e., Psychomotor Vigilance Task (PVT)] and self-monitoring ability were measured. Additionally, four participants were genotyped [i.e., COMT (rs4680) and PER3 (rs228697)]. We used Pearson correlation coefficients to evaluate the relationship between PVT performance and the performance self-monitoring scores. To evaluate the stability of interindividual differences in the effectiveness of modafinil to improve PVT performance and sleepiness, an intraclass correlation coefficient (ICC) was calculated for the delta score (CON-EXP) of both outcome measures. Results:Modafinil significantly improved PVT performance (p ≤ 0.034) and sleepiness (p ≤ 0.029) at 2a.m. and 4a.m. during the sleep deprivation night. The stability of the non-adjusted reaction time-delta score was very high (ICC = 0.90). Non-adjusted reaction time only correlated with the performance self-monitoring scores in CON (r ≥ -0.35; p < 0.001). Conclusion:Stable interindividual differences in the effectiveness of modafinil to counteract the sleep deprivation-associated decrease in vigilance exist. Further research should focus on quantifying the extent to which modafinil-induced overconfidence and subjective rebound sleepiness actually constitute potential problems in operational environments (e.g., perhaps using war game simulations).

Total sleep deprivation (TSD) alters local cold tolerance and could thus increase the risk of cold injury. We evaluated the impact of acute caffeine intake, the main countermeasure to TSD-related deleterious effects, on local cold tolerance before and after TSD. Thirty-six healthy subjects underwent two TSD protocols (i.e., continuous wakefulness), with randomized crossover intake of acute caffeine or placebo (2.5 mg/kg) administered twice during wakefulness. Before and after 33 h of TSD, finger (index and annular) temperature and skin blood flow were assessed during cold-water immersion (CWI, 5°C, 20 min) followed by 20 min of rewarming in ambient air. We showed no significant effects of TSD on mean finger temperature during CWI in the placebo condition, but a significant reduction of the minimal temperature (8.86°C ± 0.35°C vs. 8.64°C ± 0.27°C, p = 0.02). During rewarming, we showed a reduction in temperature in the placebo condition (p = 0.02 for the mean temperature and p = 0.03 for the maximal) and an increase in the skin blood flow disparity between fingers at the four points of laser speckle rewarming measurements (p = 0.03). After TSD, acute caffeine intake (vs. placebo) increased mean (+2.11°C ± 0.21°C, p = 0.01) and minimal (+0.61°C ± 0.10°C, p = 0.02) finger temperatures during CWI, and improved rewarming after CWI (mean and maximal temperatures) (+2.28°C ± 0.08°C, p = 0.01, and +2.06°C ± 0.12°C, p = 0.02, respectively). Before TSD, acute caffeine intake significantly increased (vs. placebo) mean temperatures during CWI (p = 0.03) and reduced pain from the onset (p = 0.03) to the end of CWI (p = 0.02) and the first 2 min of rewarming (p = 0.04). There was also a significant main effect of habitual daily caffeine consumption on minimal finger temperatures during CWI, which decreased significantly between 0 and 600 mg consumption (R2 = -0.43, p = 0.01), independently of the effects of day (before and after TSD) and treatment (caffeine and placebo conditions). These findings suggest that acute caffeine intake could be a protective countermeasure to local cold tolerance, particularly during TSD. However, habitual daily caffeine consumption is a factor of individual variability that should be recorded during CWI protocols. Clinical trial NCT03859882.

Sleep and muscle injury-related pain are in negative relationship, and sleep extension may be a favorable countermeasure. In response to muscle injury, an adaptive sleep response has been described in rats, characterized by an increase in total sleep time (TST) and nonrapid eye movement (NREM) sleep. This study examined the effects of photoperiod lengthening (a model of sleep prolongation in rats) on the sleep characteristics of muscle-injured rats and whether this lengthening could benefit injury-induced mechanical hyperalgesia using the Von Frey test. Switching from the conventional 12:12 light/dark (LD) photoperiod (light on: 08:00–20:00) to LD 16:8 (light extended to 24:00) gives rats an extra window of sleep. Our results show higher TST and NREM sleep times in LD 16:8 versus LD 12:12 injured rats during 4 h of light lengthening for 7 d postinjury, showing the efficiency of photoperiod lengthening to increase sleep time in injured rats. In addition, a cumulative effect with the adaptive sleep response to muscle injury occurred with higher TST and NREM sleep times in LD 16:8 injured versus noninjured rats during the dark period, reflecting the high need for sleep after the injury. Greater stability and higher relative delta power of NREM sleep during the extended light period were also observed in injured rats. Finally, the extended photoperiod limits the muscle injury-induced mechanical hyperalgesia for 13 d and allows faster recovery of the baseline mechanical threshold. This is associated with reduced pro-inflammatory cytokines levels in the hippocampus, a brain structure involved in pain processing.

Background: Caffeine is a well-known psychostimulant reputed to alleviate the deleterious effects of sleep deprivation. Nevertheless, caffeine can alter sleep duration and quality, particularly during recovery sleep. We evaluated the effects of acute caffeine intake on the duration and quality of recovery sleep following total sleep deprivation (TSD), taking into account daily caffeine consumption. Methods: Forty-one participants performed a double-blind, crossover TSD protocol (38 h of continuous wakefulness) with acute caffeine or placebo. Caffeine (2.5 mg/kg) or placebo was administered twice during continuous wakefulness (last treatment 6.5 h before bedtime for the recovery night). Polysomnographic measurements were recorded using a connected headband. Results: TSD was associated with a rebound in total sleep time (TST) on the recovery night (+110.2 ± 23.2 min, p < 0.001). Caffeine intake decreased this recovery TST (−30.2 ± 8.2 min p = 0.02) and the N3 sleep stage duration (−35.6 ± 23.2 min, p < 0.01). Caffeine intake altered recovery sleep continuity (increased number of long awakenings), stability (higher stage transition frequency), and organization (less time spent in complete sleep cycle) and decreased the delta power spectral density during NREM sleep. On the recovery night, habitual daily caffeine consumption was negatively correlated with TST in caffeine and placebo conditions and positively correlated with wake after sleep onset (WASO) duration and with the frequency of long (>2 min) awakenings in the caffeine condition only. Conclusions: Acute caffeine intake during TSD affects nighttime recovery sleep, with an interaction with daily consumption. These results may influence advice on caffeine intake for night-shift workers. (NCT03859882).

Introduction: Exposure to moderate levels of simulated hypoxia has subtle cognitive effects relative to ground level, in healthy individuals. However, there are few data on the cognitive consequences of the combination of hypoxia and partial sleep deprivation, which is a classic military or civilian operational context. In this study, we tested the hypothesis that exposure to moderate hypoxia while sleep-restricted impairs several domains of cognition, and we also assessed physiological parameters and salivary concentrations of cortisol and alpha-amylase. Method: Seventeen healthy males completed two sessions of cognitive tests (sustained attention using the PVT psychomotor vigilance task and executive functions using the Go-NoGo inhibition task and N-Back working memory task) after 30 min (T + 30 ') and 4 h (T + 240 ') of exposure in a normobaric hypoxic tent (FIO2 = 13.6 %, similar or equal to 3,500 m) (HY). This was completed after one night of sleep restriction (3 a.m. to 6 a.m. bedtime, SRHY) and one night of habitual sleep (10 p.m. to 6 a.m. bedtime, HSHY) (with cross-over randomization). The two nights sleep architecture and physiological parameters (oxygen saturation (SpO(2)) and heart rate (HR) during T + 30 ' and T + 240 ' sessions were analyzed. Salivary cortisol and alpha-amylase (sAA) concentrations were analyzed before hypoxia, after the T + 30 ' and T + 240 ' cognitive sessions, and after leaving the hypoxic tent. Results: Sustained attention (RT and number of lapses in the PVT) and executive functions (Go-NoGo and 1-Back and 2-Back parameters, as inhibition and working memory signatures) were impaired in the SRHY condition compared to HSHY. SpO(2) and HR were higher after 4 h compared with 30 min of hypoxia in the HSHY condition, while only HR was statistically higher in the SRHY condition. In SRHY, salivary AA concentration was lower and cortisol was higher than in HSHY. A significant increase in sAA concentration is observed after the cognitive session at 4 h of hypoxia exposure compared to that at 30 min, only in the SRHY condition. There are significant positive correlations between reaction time and the corresponding heart rate (a non-invasive marker of physiological stress) for the executive tasks in the two sleep conditions. This was not observed for salivary levels of sAA and cortisol, respective reliable indicators of the sympathoadrenomedullary system and the hypothalamic-pituitary adrenocortical system. Conclusion: Exposure to moderate normobaric hypoxia (similar or equal to 3500 m / similar or equal to 11,500 ft simulated) after a single night of 3-hour sleep impairs cognitive performance after 30 min and 4 h of exposure. The key determinants and/or mechanism(s) responsible for cognitive impairment when exposed to moderate hypoxia with sleep restriction, particularly on the executive function, have yet to be elucidated.

STUDY OBJECTIVES:This study describes macro- and micro-sleep responses to a myotoxic skeletal muscle injury and investigates possible mechanisms.METHODS:We recorded the electroencephalogram (EEG)/electromyogram (EMG) of 24 Wistar rats before and after induction of tibialis anterior muscle injury (n = 8 per group: control, control + buprenorphine and injured). A top-down analysis of sleep characteristics was processed from total sleep time (TST), sleep stages, sleep stability, spectral analysis, and spindles. To further investigate the mechanisms involved, we analyzed the protein level of sleep regulatory molecules including tumor necrosis factor- α (TNF-α), interleukin-1β (IL-1β), insulin-like growth factor-1 (IGF-1), and brain and muscle ARNT-like 1 (BMAL1) in plasma, frontal cortex, hippocampus, and tibialis anterior, collected at day +2 after injury from non-EEG/EMG implanted rats.RESULTS:Muscle injury induces a significant increase in TST at 48 and 72 h post-injury, specific to non-rapid eye movement (NREM) sleep. These increases occur during the dark period and are associated with the higher stability of sleep over 24 h, without change in the different power/frequency spectral bands of NREM/REM sleep. There was no corresponding sleep increase in slow-wave activity or spindle density, nor were there changes in brain levels of the sleep-regulating proinflammatory cytokine IL-1β, which is otherwise involved in the local response to injury. Conversely, decreased protein levels of brain IGF-1 and muscle BMAL1, a core circadian clock gene, after injury may play a role in increased sleep time.CONCLUSION:Muscle injury induces an increase in total sleep time at 48- and 72-h post-injury, specific to NREM sleep during the dark period in rats and is associated with higher sleep stability over 24 h.

Pro-inflammatory cytokines are involved in sleep-wake regulation and are associated with caffeine consumption. This is a cross-sectional study in 1023 active French workers investigating associations between self-reported sleep complaints (>3months) and total sleep time (TST) with nine single-nucleotide-polymorphisms (SNPs) including pro-inflammatory cytokines, according to caffeine con-sumption. Participants were characterized as low, moderate and high (0-50, 51-300, and >300 mg/day) caffeine consumers. After adjusting the odd ratios (OR) for age, gender, and smoking, the risk of sleep complaints was higher in subjects with genetic mutations in tumor necrosis factor alpha (TNF-a, rs 1800629) (ORa [95%CI] = 1.43 [1.07-1.92] for both G/A and A/A aggregate genotypes) or interleukin-1 beta (IL-1(3, rs1143627) (ORa = 1.61 [1.08-2.4 4] for homozygous A/A genotype), and the risk was higher when subjects carry the mutations in TNF-a plus IL-1(3 regardless of caffeine consumption. When stratified with caffeine consumption, the risk of sleep complaints was higher in TNF-a A allele carriers in high caffeine consumers, and in homozygous A/A genotype of IL-1(3 in moderate and high consumers. None of the nine SNPs influence TST, with the exception of the mutation on CYP1A2 and only when stratified with caffeine consumption. Our results also indicated more caffeine side-effects when carrying mutation on IL1(3. This study showed that polymorphisms in TNF-a and/or IL-1(3 influenced sleep complaints but did not influence total sleep time. This suggests that management of sleep complaints, which can be addressed by clinical interventions, should consider the influence of the genetic profile of pro-inflammatory cytokines.(c) 2022 Published by Elsevier B.V.

L’objectif principal de CIRCADIEM était de caractériser les effets de la disruption des rythmes circadiens et de sommeil sur des biomarqueurs immunitaires chez des infirmières travaillant de nuit ou de jour. Agendas de sommeil et de travail chez 95 infirmières permanentes de nuit (21:00 à 07:00) et 96 infirmières de jour alternant matin (07:00 à 14:00) et après-midi (14:00 à 21:00). Mesures des niveaux sanguins circulants des cellules immunitaires, de l’interleukine-6 et de la CRP en début et fin de poste (7:00, 14 :00 et 21:00) et du temps total/24 h de sommeil, de la dette de sommeil et du jet-lag social. Les infirmières de nuit versus celles de jour rapportaient : (i) des temps de sommeil par 24 h (5,4 ± 1,4 h) plus courts, une dette de sommeil (3,2 ± 1,4 h) et un jet-lag social (6,7 ± 2,4 h) plus importants ; (ii) des niveaux de lymphocytes totaux, B-mémoire, T-auxiliaire et C-cytotoxiques et d’interleukine-6 les plus bas à 21:00, augmentant durant la nuit pour atteindre leurs pics le matin- à l’inverse des variations immunitaires attendues et mesurées chez celles de jours. De plus, nos analyses multivariées rapportent des effets combinés ou distincts de la dette de sommeil et du jet-lag social selon les biomarqueurs immunitaires uniquement chez les travailleuses de nuit mais pas chez celles de jour. Les rythmes des cellules immunitaires sont modifiés par le travail de nuit, avec une sensibilité distincte selon les types de cellules immunitaires à la désynchronisation circadienne et la dette de sommeil, et de possibles répercussions pour la vulnérabilité aux infections.

Introduction: Genes encoding catechol-O-methyl-transferase (COMT) and adenosine A2A receptor (ADORA2A) have been shown to influence cognitive performances and responses to caffeine intake during prolonged wakefulness. The rs4680 single-nucleotide polymorphism (SNP) of COMT differentiates on memory score and circulating levels of the neurotrophic factor IGF-1. This study aimed to determine the kinetics of IGF-1, testosterone, and cortisol concentrations during prolonged wakefulness under caffeine or placebo intake in 37 healthy participants, and to analyze whether the responses are dependent on COMT rs4680 or ADORA2A rs5751876 SNPs. Methods: In caffeine (2.5 mg/kg, twice over 24 h) or placebo-controlled condition, blood sampling was performed at 1 h (08:00, baseline), 11 h, 13 h, 25 h (08:00 next day), 35 h, and 37 h of prolonged wakefulness, and at 08:00 after one night of recovery sleep, to assess hormonal concentrations. Genotyping was performed on blood cells. Results: Results indicated a significant increase in IGF-1 levels after 25, 35, and 37 h of prolonged wakefulness in the placebo condition, in subjects carrying the homozygous COMT A/A genotype only (expressed in absolute values [±SEM]: 118 ± 8, 121 ± 10, and 121 ± 10 vs. 105 ± 7 ng/mL for A/A, 127 ± 11, 128 ± 12, and 129 ± 13 vs. 120 ± 11 ng/mL for G/G, and 106 ± 9, 110 ± 10, and 106 ± 10 vs. 101 ± 8 ng/mL for G/A, after 25, 35, and 37 h of wakefulness versus 1 h; p < 0.05, condition X time X SNP). Acute caffeine intake exerted a COMT genotype-dependent reducing effect on IGF-1 kinetic response (104 ± 26, 107 ± 27, and 106 ± 26 vs. 100 ± 25 ng/mL for A/A genotype, at 25, 35, and 37 h of wakefulness vs. 1 h; p < 0.05 condition X time X SNP), plus on resting levels after overnight recovery (102 ± 5 vs. 113 ± 6 ng/mL) (p < 0.05, condition X SNP). Testosterone and cortisol concentrations decreased during wakefulness, and caffeine alleviated the testosterone reduction, unrelated to the COMT polymorphism. No significant main effect of the ADORA2A SNP was shown regardless of hormonal responses. Conclusion: Our results indicated that the COMT polymorphism interaction is important in determining the IGF-1 neurotrophic response to sleep deprivation with caffeine intake (NCT03859882).

(1) Background: Caffeine is a psychostimulant that is well known to mitigate the deleterious effects of sleep debt. Our aim was to assess the effects of acute caffeine intake on cognitive vulnerability and brain activity during total sleep deprivation (TSD), taking into account habitual caffeine consumption. (2) Methods: Thirty-seven subjects were evaluated in a double-blind, crossover, total sleep deprivation protocol with caffeine or placebo treatment. Vigilant attention was evaluated every six hours during TSD using the psychomotor vigilance test (PVT) with EEG recordings. The influence of habitual caffeine consumption was analyzed by categorizing subjects into low, moderate, and high consumers. (3) Results: The PVT reaction time (RT) increased during TSD and was lower in the caffeine condition vs. the placebo condition. The RT was shorter in the low-caffeine consumers compared to moderate and high consumers, regardless of conditions and treatments. The TSD-related increase in EEG power was attenuated by acute caffeine intake independently of habitual caffeine consumption, and the individual alpha frequency (IAF) was lower in the high-consumption group. The IAF was negatively correlated with daytime sleepiness. Moreover, a correlation analysis showed that the higher the daily caffeine consumption, the higher the RT and the lower the IAF. (4) Conclusions: A high level of habitual caffeine consumption decreases attentional performance and alpha frequencies, decreasing tolerance to sleep deprivation.

Adding relaxation techniques during nap or auditory stimulation of EEG slow oscillation (SO) during nighttime sleep may limit cognitive impairments in sleep-deprived subjects, potentially through alleviating stress-releasing effects. We compared daytime sleepiness, cognitive performances, and salivary stress biomarker responses in 11 volunteers (aged 18–36) who underwent 5 days of sleep restriction (SR, 3 h per night, with 30 min of daily nap) under three successive conditions: control (SR-CT), relaxation techniques added to daily nap (SR-RT), and auditory stimulation of sleep slow oscillations (SO) during nighttime sleep (SR-NS). Test evaluation was performed at baseline (BASE), the fifth day of chronic SR (SR5), and the third and fifth days after sleep recovery (REC3, REC5, respectively). At SR5, less degradation was observed for percentage of commission errors in the executive Go–noGo inhibition task in SR-RT condition compared to SR-CT, and for sleepiness score in SR-NS condition compared both to SR-CT and SR-RT. Beneficial effects of SR-RT and SR-NS were additionally observed on these two parameters and on salivary α-amylase (sAA) at REC3 and REC5. Adding relaxation techniques to naps may help performance in inhibition response, and adding nocturnal auditory stimulation of SO sleep may benefit daytime sleepiness during sleep restriction with persistent effects during recovery. The two strategies activated the autonomic nervous system, as shown by the sAA response.

Introduction:It is widely admitted that both total sleep deprivation (TSD) and extended task engagement (Time-On-Task, TOT) induce a cognitive fatigue state in healthy subjects.Even if EEG theta activity and adenosine both increase with cognitive fatigue, it remains unclear if these modifications are common mechanisms for both sustained attention and executive processes.Methods: We performed a double-blind counter-balanced (placebo (PCBO) and caffeine (CAF) -2×2.5 mg/kg/24 h)) study on 24 healthy subjects (33.7 ± 5.9 y).Subjects participated in an experimental protocol including an habituation/training day followed by a baseline day (D0 and D1) and a total sleep deprivation (TSD) day beginning on D1 at 23:00 until D2 at 21:00.Subjects performed the psychomotor vigilance test (PVT) assessing sustained attention, followed by the executive Go-NoGo inhibition task and the 2-NBack working memory task at 09:15 on D1 and D2.Results: We showed differential contributions of TSD and TOT on deficits in sustained attention and both executive processes.An alleviating effect of caffeine intake is only observed on sustained attention deficits related to TSD and not at all on TOT effect.The caffeine dose slows down the triggering of sustained attention deficits related to TOT effect.Discussion: These results suggest that sustained attention deficits induced by TSD rely on the adenosinergic mechanism whereas TOT effect observed for both sustained attention and executive would not.

Objectives We aimed to examine the effects of circadian and sleep rhythm disruptions on immune biomarkers among hospital healthcare professionals working night shifts and rotating day shifts. Methods Hospital nurses working either as permanent night shifters (n=95) or as day shifters rotating between morning and afternoon shifts (n=96) kept a daily diary on their sleep and work schedules over a full working week. Blood samples were collected at the beginning and end of the last shift during the week, and participants were categorized into three groups based on work shift: morning shift (39 day shifters sampled at 7:00 and 14:00), afternoon shift (57 day shifters sampled at 14:00 and 21:00), and night shift (95 night shifters sampled at 21:00 and 7:00). Circulating blood counts in immune cells, interleukin-6 and C-reactive protein concentrations as well as total sleep time per 24 hours during work days (TST24w) and free days (TST24f), sleep debt (TST24f — TST24w) and social jet-lag (a behavioral proxy of circadian misalignment) were assessed. Results Compared with day shifters, night shifters had shorter sleep duration (TST24w=5.4 ± 1.4h), greater sleep debt (3.2 ± 1.4 h) and social jet-lag (6.7 ± 2.4 h). Variations of immune biomarkers concentrations were consistent with the expected diurnal variations among day shifters (i.e., low level in the morning, increase during the day, peak value in the evening). By contrast, in night shifters, blood concentrations of total lymphocytes, T-helper cells, cytotoxic T-cells, memory B-cells and interleukin-6 were lower at 21:00, increased during the night, and reached higher values at 7:00. Multivariate analyses ruled out significant impact of TST24w, sleep debt, and social jet-lag on immune biomarkers concentrations among day shifters. In contrast, among night shifters, multivariate analyses indicated a combined effect of total sleep time (TST24w), sleep debt and social jet-lag for total lymphocytes and T-helper cells but only a social jet-lag effect for interleukin-6 and a single total sleep time effect for neutrophil and B-Cells. Conclusions Altogether, our results point to intricate response patterns of immune rhythms to circadian misalignment and sleep debt in night shifters. Specifically, these altered pattern expressions of immune cells may increase vulnerability to infections and reduce vaccination efficiency in night workers.

This study investigates whether a functional single nucleotide polymorphism of HMOX2 (heme oxygenase-2) (rs4786504 T>C) is involved in individual chemosensitivity to acute hypoxia, as assessed by ventilatory responses, in European individuals. These responses were obtained at rest and during submaximal exercise, using a standardized and validated protocol for exposure to acute normobaric hypoxia. Carriers of the ancestral T allele (n = 44) have significantly lower resting and exercise hypoxic ventilatory responses than C/C homozygous carriers (n = 40). In the literature, a hypoxic ventilatory response threshold to exercise has been identified as an independent predictor of severe high altitude-illness (SHAI). Our study shows that carriers of the T allele have a higher risk of SHAI than carriers of the mutated C/C genotype. Secondarily, we were also interested in COMT (rs4680 G > A) polymorphism, which may be indirectly involved in the chemoreflex response through modulation of autonomic nervous system activity. Significant differences are present between COMT genotypes for oxygen saturation and ventilatory responses to hypoxia at rest. In conclusion, this study adds information on genetic factors involved in individual vulnerability to acute hypoxia and supports the critical role of the ≪ O2 sensor ≫ - heme oxygenase-2 - in the chemosensitivity of carotid bodies in Humans.

This study investigated whether four single nucleotide polymorphisms (SNPs) moderated caffeine effects on vigilance and performance in a double-blind and crossover total sleep deprivation (TSD) protocol in 37 subjects. In caffeine (2 × 2.5 mg/kg/24 h) or placebo-controlled condition, subjects performed a psychomotor vigilance test (PVT) and reported sleepiness every six hours (Karolinska sleepiness scale (KSS)) during TSD. EEG was also analyzed during the 09:15 PVT. Carriers of the TNF-α SNP A allele appear to be more sensitive than homozygote G/G genotype to an attenuating effect of caffeine on PVT lapses during sleep deprivation only because they seem more degraded, but they do not perform better as a result. The A allele carriers of COMT were also more degraded and sensitive to caffeine than G/G genotype after 20 h of sleep deprivation, but not after 26 and 32 h. Regarding PVT reaction time, ADORA2A influences the TSD effect but not caffeine, and PER3 modulates only the caffeine effect. Higher EEG theta activity related to sleep deprivation was observed in mutated TNF-α, PER3, and COMT carriers, in the placebo condition particularly. In conclusion, there are genetic influences on neurobehavioral impairments related to TSD that appear to be attenuated by caffeine administration. (NCT03859882).

Several genetic polymorphisms differentiate between healthy individuals who are more cognitively vulnerable or resistant during total sleep deprivation (TSD). Common metrics of cognitive functioning for classifying vulnerable and resilient individuals include the Psychomotor Vigilance Test (PVT), Go/noGo executive inhibition task, and subjective daytime sleepiness. We evaluated the influence of 14 single-nucleotide polymorphisms (SNPs) on cognitive responses during total sleep deprivation (continuous wakefulness for 38 h) in 47 healthy subjects (age 37.0 ± 1.1 years). SNPs selected after a literature review included SNPs of the adenosine-A2A receptor gene (including the most studied rs5751876), pro-inflammatory cytokines (TNF-α, IL1-β, IL-6), catechol-O-methyl-transferase (COMT), and PER3. Subjects performed a psychomotor vigilance test (PVT) and a Go/noGo-inhibition task, and completed the Karolinska Sleepiness Scale (KSS) every 6 h during TSD. For PVT lapses (reaction time >500 ms), an interaction between SNP and SDT (p < 0.05) was observed for ADORA2A (rs5751862 and rs2236624) and TNF-α (rs1800629). During TSD, carriers of the A allele for ADORA2A (rs5751862) and TNF-α were significantly more impaired for cognitive responses than their respective ancestral G/G genotypes. Carriers of the ancestral G/G genotype of ADORA2A rs5751862 were found to be very similar to the most resilient subjects for PVT lapses and Go/noGo commission errors. Carriers of the ancestral G/G genotype of COMT were close to the most vulnerable subjects. ADORA2A (rs5751862) was significantly associated with COMT (rs4680) (p = 0.001). In conclusion, we show that genetic polymorphisms in ADORA2A (rs5751862), TNF-α (rs1800629), and COMT (rs4680) are involved in creating profiles of high vulnerability or high resilience to sleep deprivation. (NCT03859882).

OBJECTIVE:Powered two-wheelers (PTW) make up a large proportion of fatal accidents. The aim of this study was to investigate the effects of time-of-day and total sleep deprivation (SD) on simulated motorcycling performance during extended riding sessions (60 min), while evaluating stress mechanisms. APPROACH:A total of 16 healthy males participated in four simulated motorcycling sessions at 07:00, 11:00, 15:00 and 19:00, including city (8 min), country (2 min) and highway pathways (40 min), after a normal night of sleep and after total SD (30 h), in a randomized counterbalanced order. The recorded motorcycle parameters included: variation of lateral position, number of inappropriate line crossings (ILC), falls, riding errors, speed and speed limit violations. Subject parameters included the number of microsleeps in each pathway, the number of lapses during the 3-min psychomotor vigilance task (PVT-Brief version), and the Karolinska sleepiness scale (KSS) score. Saliva samples were used to assess cortisol (sC), α-amylase (sAA), and chromogranin-A (sCgA). ANOVAs and Pearson's correlation analysis were performed between these variables. MAIN RESULTS:Most parameters were influenced by an interaction effect between 'Motorcycling pathways' × 'SD' (speed (p < 0.05), legal speed violations (p < 0.01), variation of lateral position (p < 0.001), falls (p < 0.001), EEG-microsleeps (p < 005)). An interaction effect between 'SD' × 'Time-of-day' influenced the number of ILCs (p < 0.01), sC (p < 0.05) and sCgA (p < 0.05) levels. SD affected KSS scores (p < 0.001) and PVT lapses (p < 0.05). The highest disturbances were associated with highway motorcycling simulation. SIGNIFICANCE:Sleepiness due to circadian or SD and fatigue effects significantly affect riding and increase the risks involved with PTWs. The activation of both stress systems seems not sufficient to alleviate these deleterious effects.