Abstract Neuroprotective effects of caffeine have been frequently reported in the context of disease and cognitive dysfunction as well as in epidemiological studies in humans. However, evidence on caffeine effects on neural and memory functions during daily intake in a healthy cognitive state remains scarce. This randomized double-blind placebo-controlled crossover study investigated working memory functions by N-back tasks and functional magnetic resonance imaging (fMRI) after daily caffeine intake compared to a placebo baseline and to acute caffeine withdrawal in 20 young healthy volunteers. Each volunteer was given 3 times 150 mg caffeine for 10 days in the daily caffeine condition, 3 times 150 mg mannitol for 10 days in the placebo condition, and 9-day caffeine plus 1-day mannitol in the acute withdrawal condition. During the 10 th day, participants performed 4 N-back sessions (two loads each: 0- and 3-back) under controlled laboratory conditions. During the 4 th session of N-Back (i.e. at 5.5 h, 36.5 h and > 10 days after the last caffeine intake in the caffeine, withdrawal, and placebo condition, respectively) we assessed blood-oxygen-level-dependent (BOLD) activity. During the entire 10 th day, in 0-back tasks, we observed longer reaction times (RTs) in the withdrawal compared to the placebo (Cohen’s d = 0.7) and caffeine condition (Cohen’s d = 0.6), but no significant effects of conditions on error rates. In contrast, in 3-back tasks (controlled for 0-back), the RTs in the caffeine condition were longer compared to placebo (Cohen’s d = 0.6) and withdrawal (Cohen’s d = 0.5). Error rates were higher during both caffeine and withdrawal conditions compared to placebo (Cohen’s d of both contrasts = 0.4). Whole-brain analyses on fMRI data did not reveal significant condition-dependent differences in activities between task loads. Across task loads, however, we observed a reduced hippocampal activation (Cohen’s d = −1.3) during the caffeine condition compared to placebo, while no significant difference in brain activities between withdrawal and placebo conditions. Taken together, the worse working memory function and the hippocampal hypoactivation implicate a potential detrimental effect of daily caffeine intake on neurocognitive functions of healthy adults. Moreover, they echo the hippocampal volumetric reduction reported previously in the same volunteers. Lastly, acute withdrawal from daily caffeine intake impairs both low-order cognitive processes and working memory performance. Taking earlier studies on acute caffeine effects into account, our findings indicate that daily caffeine intake elicits a dynamic change in cerebral activities during the course of repeated consumption, with unknown consequences in the long run.
Caffeine is the most widely consumed natural stimulant in history. While caffeine is commonly used to mitigate sleepiness and to boost performance, it is intentionally avoided to prevent adverse consequences on nocturnal sleep. The latter has been particularly investigated under conditions of acute evening intake. Sleep disrupting effects are mainly attributed to caffeine’s impact on the homeostatic component of sleep-wake regulation as caffeine antagonizes the sleep factor adenosine. This results in delayed sleep onset and superficial sleep. Furthermore, evidence accumulates that acute caffeine intake in the evening impacts also on the circadian axis of sleep-wake regulation by reducing and delaying melatonin secretion, which is the primary endogenous marker of the internal timekeeping system. The overarching aim of the present thesis was to investigate whether these caffeine-induced alterations in the homeostatic and circadian sleep-wake features can also be detected under chronic exposure to caffeine timed to morning and afternoon hours, which presents a common intake pattern in coffee drinkers.
Twenty male young habitual caffeine consumers participated in a double-blind, crossover study comprising a placebo (3 x placebo daily), a caffeine (3 x 150 mg caffeine daily), and a withdrawal (3 x 150 mg caffeine for eight days then change to placebo) condition, each lasting 11 days. After nine days of continuous treatment, volunteers were studied during a 43-h laboratory part under strictly controlled conditions. During scheduled wakefulness, we regularly assessed sleepiness, vigilance performance, and circadian hormonal markers (i.e., melatonin and cortisol) while polysomnography was recorded during scheduled sleep episodes at different times of the day to quantify sleep structure and intensity.
First, we were interested whether daily caffeine intake in the morning and afternoon hours disrupts nighttime sleep structure and intensity, indexed as reduced slow-wave sleep (SWS) duration and decreased slow-wave activity (SWA; 0.75-4.5 Hz). Surprisingly, neither daytime caffeine consumption nor its acute cessation strongly impaired nighttime sleep architecture or subjective sleep quality in comparison to placebo. Nevertheless, during both caffeine and withdrawal conditions spectral power density in the sigma frequencies (12-16 Hz) was reduced, starting 8 and 15 hours after the last caffeine intake in the caffeine and withdrawal condition, respectively. Opposite to the reported higher sigma power after acute caffeine intake in other studies, the observed reduction in the sigma frequencies might point to early signs of caffeine withdrawal which occur as soon as regular caffeine intake is stopped.
Second, we investigated whether daily daytime caffeine intake impacts on circadian hormonal rhythms and wake-promotion as well as waking performance. Interestingly, our results indicate that habitual caffeine consumption in the morning and afternoon hours does not strongly affect the diurnal secretion of melatonin and cortisol nor enhances circadian wake-promotion in the evening. Moreover, in contrast to the common perception of the stimulating properties of caffeine, such a common intake pattern did not go along with clear-cut benefits in sleepiness or vigilance performance when comparing it to the placebo condition. However, the abrupt cessation from caffeine was associated with increased subjective sleepiness, worse vigilance performance, and increased sleep pressure in the evening as indexed by shortened sleep latency, increased total sleep time, and longer SWS. Together, these findings suggest an adaptation after repeated intake, presumably in the homeostatic aspect of sleep-wake regulation, which manifests itself as soon as chronic caffeine intake is ceased. In contrast to previous studies, we did not find evidence for circadian phase shifts.
In a last step, we explored the impact of daily caffeine intake and its acute cessation on circadian-regulated rapid eye movement (REM) sleep promotion in a sleep episode timed to the morning hours. Similar to nighttime sleep, total sleep time, and sleep architecture at this time of day were not strongly affected by caffeine or its withdrawal. Nonetheless, after daily daytime caffeine intake it took volunteers longer to enter REM sleep, its accumulation was slower, and subjective quality of awakening was worse compared to continuous placebo intake. As the latter might be counteracted in turn by caffeine intake, it might encourage caffeine consumption particularly in people who shift their sleep to morning or daytime hours which often occurs in shift-workers.
Taken together, we have first evidence that repeated daytime caffeine intake in the morning and afternoon hours does not strongly disrupt nocturnal sleep nor hormonal markers of the circadian timing system such as the diurnal secretion of melatonin and cortisol. However, daily daytime caffeine intake might still weaken the circadian sleep signal under conditions of strong circadian REM sleep promotion. Moreover, the daily exposure to caffeine bears the risk of developing withdrawal symptoms as early as 8 hours after its last intake, such as increased sleepiness, worse performance, and subtle changes in nighttime sleep. Together these withdrawal-induced alterations point to changes primarily in the homeostatic component of sleep-wake regulation and might be attributed to differences in adenosine signaling. The circadian timekeeping system, however, stays rather stable under conditions of daily daytime caffeine intake. In summary, this thesis provides novel insights into the consequences of daily presence and nightly abstinence of the world’s most popular psychoactive substance on homeostatic and circadian measures of sleep-wake regulation.
Abstract Caffeine elicits widespread effects in the central nervous system and is the most frequently consumed psychostimulant worldwide. First evidence indicates that, during daily intake, the elimination of caffeine may slow down and the primary metabolite, paraxanthine, may accumulate. The neural impact of such adaptions is virtually unexplored. In this report, we leveraged the data of a laboratory study with N= 20 participants and three within-subject conditions: caffeine (150 mg caffeine x 3/day x 10 days), placebo (150 mg mannitol x 3/day x 10 days), and withdrawal (caffeine x 9 days, afterwards placebo x 1 day). Using liquid chromatography–mass spectrometry coupled with tandem mass spectrometry, we determined the course of salivary caffeine and paraxanthine, measured regularly at day 10. We assessed grey matter (GM) intensity and cerebral blood flow (CBF) in the withdrawal condition as compared to their changes in caffeine in our previous report. The results indicate high remaining levels of paraxanthine and of caffeine carried overnight during daily intake, and the levels of paraxanthine remained higher than in placebo during withdrawal. After 36 h of withdrawal, the previously reported caffeine-induced GM reduction was partially mitigated, while CBF was elevated compared to placebo. Our findings unveil that conventional daily caffeine intake does not provide sufficient time to clear up psychoactive compounds and restore cerebral responses, even after 36 hours of abstinence. They also suggest investigating consequences of a paraxanthine accumulation during daily caffeine intake.
Abstract Acute caffeine intake has been found to increase working memory (WM)-related brain activity in healthy adults without improving behavioral performances. The impact of daily caffeine intake—a ritual shared by 80% of the population worldwide—and of its discontinuation on working memory and its neural correlates remained unknown. In this double-blind, randomized, crossover study, we examined working memory functions in 20 young healthy non-smokers (age: 26.4 ± 4.0 years; body mass index: 22.7 ± 1.4 kg/m 2 ; and habitual caffeine intake: 474.1 ± 107.5 mg/day) in a 10-day caffeine (150 mg × 3 times/day), a 10-day placebo (3 times/day), and a withdrawal condition (9-day caffeine followed by 1-day placebo). Throughout the 10th day of each condition, participants performed four times a working memory task (N-Back, comprising 3- and 0-back), and task-related blood-oxygen-level-dependent (BOLD) activity was measured in the last session with functional magnetic resonance imaging. Compared to placebo, participants showed a higher error rate and a longer reaction time in 3- against 0-back trials in the caffeine condition; also, in the withdrawal condition we observed a higher error rate compared to placebo. However, task-related BOLD activity, i.e., an increased attention network and decreased default mode network activity in 3- versus 0-back, did not show significant differences among three conditions. Interestingly, irrespective of 3- or 0-back, BOLD activity was reduced in the right hippocampus in the caffeine condition compared to placebo. Adding to the earlier evidence showing increasing cerebral metabolic demands for WM function after acute caffeine intake, our data suggest that such demands might be impeded over daily intake and therefore result in a worse performance. Finally, the reduced hippocampal activity may reflect caffeine-associated hippocampal grey matter plasticity reported in the previous analysis. The findings of this study reveal an adapted neurocognitive response to daily caffeine exposure and highlight the importance of classifying impacts of caffeine on clinical and healthy populations.
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