Genetic Determinants of Neurobehavioral Responses to Caffeine Administration during Sleep Deprivation: A Randomized, Cross Over Study (NCT03859882)

Abstract

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).

Keywords: PVT; adenosine; caffeine; catecholamine; gene clock; genetics; pro-inflammatory cytokine; total sleep deprivation.

Figure 1

Experimental design. D0 is the habituation day, D1 is the baseline day, D2 is the day of prolonged wakefulness (i.e., sleep deprivation, between 00:00–20:30) and D3 is the recovery sleep and end of the study. Night sleep are the black bars, awaking periods black line, cognitive tests are the striped bars, and caffeine or placebo intake are the black arrows. Visual Analogic Scales (VAS), Karolinska Sleepiness Scale (KSS), and Psychomotor Vigilance Task (PVT) have been assessed at D1: 09:15, 15:15, 21:15 and D2: 03:15, 09:15, 15:15). VAS, KSS, PVT; Placebo or caffeine (2.5 mg/kg) treatment (at D1 and D2: 08:30, 14:30).

Figure 2

Mean PVT performance over 38-h of prolonged wakefulness for a number of lapses (A), speed (B), KSS score (C), and the EEG theta-to-alpha ratio (D) during PVT in the centrotemporal brain region at 09:15 on D1 (baseline) and D2 (sleep deprivation) days as a function of placebo (PBO) or caffeine (CAF) condition. Values are mean ± SEM. * difference between baseline and continuous wakefulness, # between PBO and CAF conditions.

Figure 3

PVT number of lapses across consecutive 6-h intervals of awakening according to polymorphisms of TNF-α (A), ADORA2A (B), PER3 (C), and COMT (D) in placebo (PBO) and caffeine (CAF) conditions. Caffeine was consumed 45-min before PVT after 2-h, 8-h, 26-h, and 32-h of prolonged wakefulness. * is a SNP difference (p < 0.05), # is a treatment difference (p < 0.05) for one genotype.

Figure 4

EEG theta and alpha normalized power on D2 day (sleep deprivation) relative to D1 day (baseline) (z-score) on brain scalps during PVT at 09:15 according to polymorphisms of TNF-α (A), ADORA2A (B) and PER3 (C), and COMT (D) in placebo (PBO) and caffeine (CAF) conditions. Caffeine was consumed 45-min before PVT at D1 and D2.

Figure 5

Correlation analysis at 26-h of prolonged wakefulness (D2 day at 09:15) between EEG theta power in the centrotemporal brain region and the number of lapses during the PVT for all genetic polymorphisms in placebo (blue circle, grey line) and caffeine (red circle, black line) conditions.