Brain activity during a working memory task after daily caffeine intake and caffeine withdrawal: a randomized double-blind placebo-controlled trial

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

The impact of sleep pressure, circadian phase and an ADA-polymorphism on working memory: a behavioral, electrophysiological, neuroimaging approach

The need for sleep, the so-called sleep pressure, increases continuously during wakefulness and decreases during sleep again, in particular during intense deep sleep (Borbely, 1982). This sleep homeostatic process is mediated by the increase and degradation of adenosine in frontal brain structures (Porkka-Heiskanen, 2013). At the behavioural level, it is commonly mirrored in declines of performance under high sleep pressure (Cajochen, Blatter, & Wallach, 2004). Adenosine is degraded by adenosine deaminase (ADA) (Landolt, 2008). Due to a polymorphism (rs73598374), ADA activity differs inter-individually. Lower ADA activity in G/A- compared to G/G-allele carriers (Battistuzzi, Iudicone, Santolamazza, & Petrucci, 1981)has been associated with a trait-like higher sleep pressure level, indicated by deeper sleep and worse vigilance performance (Bachmann et al., 2012). However, the impact of sleep pressure on several sleep and waking functions depends on circadian phase (Dijk & Franken, 2005): It is potentiated during the night while counteracted during daytime by circadian wake promoting mechanisms. Also, the influence of sleep pressure on neuro-behavioral performance depends on cognitive domain (Van Dongen, Baynard, Maislin, & Dinges, 2004). Performance relying on the frontal lobes, such as executive aspects of working memory (WM), has been suggested to be particularly vulnerable to high sleep pressure (Harrison & Horne, 2000). In a multi-methodological approach we compared thus circadian variations in sleep and in a set of waking functions according to the ADA-genotype. To capture both circadian variations and their interaction with sleep pressure, we compared two 40-h conditions, in which sleep pressure was either kept low by multiple napping (low sleep pressure) or accumulated during sleep deprivation (high sleep pressure). Nap sleep electroencephalographic (EEG) activity, vigilance, WM performance and underlying blood oxygen level-dependent (BOLD) activity was assessed in regular time intervals. Vigilance and WM performance was worse during high as compared to low sleep pressure, particularly during the night. Specifically in executive aspects of WM, sleep pressure-dependent performance modulations were evident in G/A- but not in G/G-allele carriers (Reichert, Maire, Gabel, Viola, et al., 2014). WM performance of G/A-allele carriers benefited during napping in particular from rapid eye movement (REM) sleep duration (Reichert, Maire, Gabel, Hofstetter, et al., 2014). At times of high circadian wake promotion G/A-allele carriers showed a reduced sleep ability, indicating changes of circadian arousal promotion in response to lower ADA activity. Accordingly, we observed at a cerebral level during high circadian sleep promotion, that G/A-allele carriers showed more corti-cal compensatory mechanisms during WM performance to cope with high sleep pressure at night. Overall, the data suggest that the impact of sleep pressure on performance, whether state- or trait-like, is modulated by circadian mechanisms. These mechanisms contribute to a differential resistance or vulnerability to sleep deprivation according to cognitive domain. References Bachmann, V., Klaus, F., Bodenmann, S., Schafer, N., Brugger, P., Huber, S., . . . Landolt, H. P. (2012). Cerebral Cortex, 22(4), 962-970. doi: bhr173 [pii]10.1093/cercor/bhr173 Borbely, A. A. (1982). A two process model of sleep regulation. Hum Neurobiol, 1(3), 195-204. Cajochen, C., Blatter, K., & Wallach, D. (2004). Psychologica Belgica, 44(1/2), 59-80. Dijk, D. J., & Franken, P. (2005). In R. T. Kryger MH, Dement WC (Ed.), Principles and Practice of Sleep Medicine (pp. 418-435). Philadelphia: Elsevier Saunders. Harrison, Y., & Horne, J. A. (2000). J Exp Psychol Appl, 6(3), 236-249. Landolt, H. P. (2008). Biochem Pharmacol, 75(11), 2070-2079. doi: 10.1016/j.bcp.2008.02.024S0006-2952(08)00104-4 [pii] Porkka-Heiskanen, T. (2013). Curr Opin Neurobiol, 23(5), 799-805. doi: 10.1016/j.conb.2013.02.010 Reichert, C. F., Maire, M., Gabel, V., Hofstetter, M., Viola, A. U., Kolodyazhniy, V., . . . Schmidt, C. (2014). PLoS One, 9(12), e113734. doi: 10.1371/journal.pone.0113734 Reichert, C. F., Maire, M., Gabel, V., Viola, A. U., Kolodyazhniy, V., Strobel, W., . . . Schmidt, C. (2014). J Biol Rhythms, 92(2), 119-130. Van Dongen, H. P., Baynard, M. D., Maislin, G., & Dinges, D. F. (2004). Sleep, 27(3), 423-433

Adenosine, caffeine, and sleep–wake regulation: state of the science and perspectives

For hundreds of years, mankind has been influencing its sleep and waking state through the adenosinergic system. For ~100 years now, systematic research has been performed, first started by testing the effects of different dosages of caffeine on sleep and waking behaviour. About 70 years ago, adenosine itself entered the picture as a possible ligand of the receptors where caffeine hooks on as an antagonist to reduce sleepiness. Since the scientific demonstration that this is indeed the case, progress has been fast. Today, adenosine is widely accepted as an endogenous sleep-regulatory substance. In this review, we discuss the current state of the science in model organisms and humans on the working mechanisms of adenosine and caffeine on sleep. We critically investigate the evidence for a direct involvement in sleep homeostatic mechanisms and whether the effects of caffeine on sleep differ between acute intake and chronic consumption. In addition, we review the more recent evidence that adenosine levels may also influence the functioning of the circadian clock and address the question of whether sleep homeostasis and the circadian clock may interact through adenosinergic signalling. In the final section, we discuss the perspectives of possible clinical applications of the accumulated knowledge over the last century that may improve sleep-related disorders. We conclude our review by highlighting some open questions that need to be answered, to better understand how adenosine and caffeine exactly regulate and influence sleep. Keywords: chronic caffeine; circadian; genetics; sleep deprivation; sleep homeostasis; sleep-wake disorder

Sleep-Wake Regulation and Its Impact on Working Memory Performance: The Role of Adenosine

The sleep-wake cycle is regulated by a fine-tuned interplay between sleep-homeostatic and circadian mechanisms. Compelling evidence suggests that adenosine plays an important role in mediating the increase of homeostatic sleep pressure during time spent awake and its decrease during sleep. Here, we summarize evidence that adenosinergic mechanisms regulate not only the dynamic of sleep pressure, but are also implicated in the interaction of homeostatic and circadian processes. We review how this interaction becomes evident at several levels, including electrophysiological data, neuroimaging studies and behavioral observations. Regarding complex human behavior, we particularly focus on sleep-wake regulatory influences on working memory performance and underlying brain activity, with a specific emphasis on the role of adenosine in this interplay. We conclude that a change in adenosinergic mechanisms, whether exogenous or endogenous, does not only impact on sleep-homeostatic processes, but also interferes with the circadian timing system

Human brain patterns underlying vigilant attention: impact of sleep debt, circadian phase and attentional engagement

AbstractSleepiness and cognitive function vary over the 24-h day due to circadian and sleep-wake-dependent mechanisms. However, the underlying cerebral hallmarks associated with these variations remain to be fully established. Using functional magnetic resonance imaging (fMRI), we investigated brain responses associated with circadian and homeostatic sleep-wake-driven dynamics of subjective sleepiness throughout day and night. Healthy volunteers regularly performed a psychomotor vigilance task (PVT) in the MR-scanner during a 40-h sleep deprivation (high sleep pressure) and a 40-h multiple nap protocol (low sleep pressure). When sleep deprived, arousal-promoting thalamic activation during optimal PVT performance paralleled the time course of subjective sleepiness with peaks at night and troughs on the subsequent day. Conversely, task-related cortical activation decreased when sleepiness increased as a consequence of higher sleep debt. Under low sleep pressure, we did not observe any significant temporal association between PVT-related brain activation and subjective sleepiness. Thus, a circadian modulation in brain correlates of vigilant attention was only detectable under high sleep pressure conditions. Our data indicate that circadian and sleep homeostatic processes impact on vigilant attention via specific mechanisms; mirrored in a decline of cortical resources under high sleep pressure, opposed by a subcortical “rescuing” at adverse circadian times.</jats:p

Fighting Sleep at Night: Brain Correlates and Vulnerability to Sleep Loss.

OBJECTIVE: Even though wakefulness at night leads to profound performance deterioration and is regularly experienced by shift workers, its cerebral correlates remain virtually unexplored. METHODS: We assessed brain activity in young healthy adults during a vigilant attention task under high and low sleep pressure during night-time, coinciding with strongest circadian sleep drive. We examined sleep-loss-related attentional vulnerability by considering a PERIOD3 polymorphism presumably impacting on sleep homeostasis. RESULTS: Our results link higher sleep-loss-related attentional vulnerability to cortical and subcortical deactivation patterns during slow reaction times (i.e., suboptimal vigilant attention). Concomitantly, thalamic regions were progressively less recruited with time-on-task and functionally less connected to task-related and arousal-promoting brain regions in those volunteers showing higher attentional instability in their behavior. The data further suggest that the latter is linked to shifts into a task-inactive default-mode network in between task-relevant stimulus occurrence. INTERPRETATION: We provide a multifaceted view on cerebral correlates of sleep loss at night and propose that genetic predisposition entails differential cerebral coping mechanisms, potentially compromising adequate performance during night work

Brain activity during a working memory task after daily caffeine intake and caffeine withdrawal: a randomized double-blind placebo-controlled trial

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/m2; 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