Genetics and Cognitive Vulnerability to Sleep Deprivation in Healthy Subjects: Interaction of ADORA2A, TNF-α and COMT Polymorphisms.

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-ß, 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).

Hypoxic alterations of cortisol circadian rhythm in man after simulation of a long duration flight.

Fatigue is often reported after long duration flights. Mild hypobaric hypoxia caused by pressurisation may be involved in this effect through disruption of circadian rhythms, independently of the number of time zones crossed. In this controlled crossover study, we assessed the effects of two levels of hypoxia equivalent to 8000 and 12,000 ft on the circadian rhythm of plasma cortisol, a marker of the circadian time structure. Sixteen healthy young male volunteers (23-39 years) were exposed in a hypobaric chamber for 8 h (08:00-16:00 h) to 8000 ft, followed 4 weeks later to 12,000 ft. Plasma cortisol was assayed during two 24-h cycles (control and hypoxic exposure) every 2h in all subjects. We found a significant change in the pattern of cortisol secretion during both hypoxic exposures, with an initial fall in cortisol followed by a transient rebound, whereas the phase and the 24-h mean level remained unchanged. The change in cortisol pattern followed the alterations in autonomic balance assessed by heart rate variability (HRV) spectral analysis. The normalised high frequencies and the low-to-high frequencies ratio showed a significant shift toward sympathetic dominance with some differences in time course for both altitudes studied. HRV analysis improved the interpretation of cortisol 24-h profiles. Our data, which strongly suggest that prolonged mild hypoxia alters the expression of cortisol circadian rhythm, should be taken into account to interpret secretory rhythm changes after transmeridian flights.

Prolonged mild hypoxia modifies human circadian core body temperature and may be associated with sleep disturbances.

Fatigue is often reported after long-haul airplane flights. Hypobaric hypoxia, observed in pressurized cabins, may play a role in this phenomenon by altering circadian rhythms. In a controlled cross-over study, we assessed the effects of two levels of hypoxia, corresponding to cabin altitudes of 8000 and 12,000 ft, on the rhythm of core body temperature (CBT), a marker of circadian rhythmicity, and on subjective sleep. Twenty healthy young male volunteers were exposed for 8 h (08:00-16:00 h) in a hypobaric chamber to a cabin altitude of 8000 ft and, 4 weeks later, 12,000 ft. Each subject served as his own control. For each exposure, CBT was recorded by telemetry for two 24h cycles (control and hypoxic exposure). After filtering out nonphysiological values, the individual CBT data were fitted with a five-order moving average before statistical group analysis. Sleep latency, sleep time, and sleep efficiency were studied by sleep logs completed every day in the morning. Our results show that the CBT rhythm expression was altered, mainly at 12,000 ft, with a significant increase of amplitude and a delay in the evening decline in CBT, associated with alterations of sleep latency. Mild hypoxia may therefore alter circadian structure and result in sleep disturbances. These results may explain in part the frequent complaints of prolonged post-flight fatigue after long flights, even when no time zones are crossed.