@article{nokey,

title = {Repeated caffeine intake suppresses cerebral grey matter responses to chronic sleep restriction in an A1 adenosine receptor-dependent manner: a double-blind randomized controlled study with PET-MRI},

author = {Y.-S. Lin and D. Lange and D. Baur and A. Foerge and E.-M. Elmenhorst and B. Neumaier and A. Bauer and D. Aeschbach and H.-P. Landolt and D. Elmenhorst},

doi = {10.1038/s41598-024-61421-8},

year  = {2024},

date = {2024-06-03},

journal = {Scientific Reports},

volume = {14},

issue = {1},

pages = {12724},

abstract = {Evidence has shown that both sleep loss and daily caffeine intake can induce changes in grey matter (GM). Caffeine is frequently used to combat sleepiness and impaired performance caused by insufficient sleep. It is unclear (1) whether daily use of caffeine could prevent or exacerbate the GM alterations induced by 5-day sleep restriction (i.e. chronic sleep restriction, CSR), and (2) whether the potential impact on GM plasticity depends on individual differences in the availability of adenosine receptors, which are involved in mediating effects of caffeine on sleep and waking function. Thirty-six healthy adults participated in this double-blind, randomized, controlled study (age = 28.9 ± 5.2 y/; F:M = 15:21; habitual level of caffeine intake < 450 mg; 29 homozygous C/C allele carriers of rs5751876 of ADORA2A, an A2A adenosine receptor gene variant). Each participant underwent a 9-day laboratory visit consisting of one adaptation day, 2 baseline days (BL), 5-day sleep restriction (5 h time-in-bed), and a recovery day (REC) after an 8-h sleep opportunity. Nineteen participants received 300 mg caffeine in coffee through the 5 days of CSR (CAFF group), while 17 matched participants received decaffeinated coffee (DECAF group). We examined GM changes on the 2nd BL Day, 5th CSR Day, and REC Day using magnetic resonance imaging and voxel-based morphometry. Moreover, we used positron emission tomography with [18F]-CPFPX to quantify the baseline availability of A1 adenosine receptors (A1R) and its relation to the GM plasticity. The results from the voxel-wise multimodal whole-brain analysis on the Jacobian-modulated T1-weighted images controlled for variances of cerebral blood flow indicated a significant interaction effect between caffeine and CSR in four brain regions: (a) right temporal-occipital region, (b) right dorsomedial prefrontal cortex (DmPFC), (c) left dorsolateral prefrontal cortex (DLPFC), and (d) right thalamus. The post-hoc analyses on the signal intensity of these GM clusters indicated that, compared to BL, GM on the CSR day was increased in the DECAF group in all clusters but decreased in the thalamus, DmPFC, and DLPFC in the CAFF group. Furthermore, lower baseline subcortical A1R availability predicted a larger GM reduction in the CAFF group after CSR of all brain regions except for the thalamus. In conclusion, our data suggest an adaptive GM upregulation after 5-day CSR, while concomitant use of caffeine instead leads to a GM reduction. The lack of consistent association with individual A1R availability may suggest that CSR and caffeine affect thalamic GM plasticity predominantly by a different mechanism. Future studies on the role of adenosine A2A receptors in CSR-induced GM plasticity are warranted.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{nokey,

title = {Brain activity during a working memory task after daily caffeine intake and caffeine withdrawal: a  randomized double-blind placebo-controlled trial.},

author = {Y.-S. Lin and J. Weibel and H.-P. Landolt and F. Santini and H. Slawik and S. Borgwardt and C. Cajochen and C. F. Reichert},

doi = {10.1038/s41598-022- 26808-5},

year  = {2023},

date = {2023-01-18},

urldate = {2023-01-18},

journal = {Scientific Reports},

volume = {13},

number = {1002},

issue = {1},

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.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Lin2022,

title = {Time to recover from daily caffeine intake},

author = {Y.-S. Lin and J. Weibel and H.-P. Landolt and F Santini and C Garbazza and J Kistler and S Rehm and K Rentsch and S Borgwardt and C Cajochen and C. F. Reichert},

url = {https://www.frontiersin.org/articles/10.3389/fnut.2021.787225/full},

doi = {10.3389/fnut.2021.787225. },

year  = {2022},

date = {2022-02-02},

journal = {Front Nutr.},

volume = {8},

number = {787225},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Weibel2021b,

title = {Regular caffeine intake delays REM sleep promotion and attenuates sleep quality in healthy men},

author = {J. Weibel and Y.-S. Lin and H.-P. Landolt and C. Berthomier and M. Brandenwinder and J. Kistler and S. Rehm and K. Rentsch and M. Meyer and S. Borgwardt and C. Cajochen and C. F. Reichert },

url = {https://journals.sagepub.com/doi/pdf/10.1177/07487304211013995},

doi = {10.1177/07487304211013995},

year  = {2021},

date = {2021-05-23},

journal = {Journal of Biological Rhythms},

abstract = {Acute  caffeine  intake  can  attenuate  homeostatic  sleep  pressure  and  worsen  sleep  quality.  Caffeine  intake—particularly  in  high  doses  and  close  to  bedtime—may  also  affect  circadian-regulated  rapid  eye  movement  (REM)  sleep  promotion,  an  important  determinant  of  subjective  sleep  quality.  However,  it  is  not  known  whether  such  changes  persist  under  chronic  caffeine  consumption  during  daytime.  Twenty  male  caffeine  consumers  (26.4  ±  4  years  old,  habitual  caffeine  intake  478.1  ±  102.8  mg/day)  participated  in  a  double-blind  crossover  study. Each volunteer completed a caffeine (3 × 150 mg caffeine daily for 10 days), a withdrawal (3 × 150 mg caffeine for 8 days then placebo), and a placebo condition. After 10 days of controlled intake and a fixed sleep-wake cycle, we recorded electroencephalography  for  8  h  starting  5  h  after  habitual  bedtime  (i.e.,  start  on  average at 04:22 h which is around the peak of circadian REM sleep promotion). A 60-min evening nap preceded each sleep episode and reduced high sleep pres-sure levels. While total sleep time and sleep architecture did not significantly differ between the three conditions, REM sleep latency was longer after daily caffeine intake compared with both placebo and withdrawal. Moreover, the accumulation of REM sleep proportion was delayed, and volunteers reported more difficulties with awakening after sleep and feeling more tired upon wake-up in the caffeine condition  compared  with  placebo.  Our  data  indicate  that  besides  acute  intake,  also  regular  daytime  caffeine  intake  affects  REM  sleep  regulation  in  men,  such  that  it  delays  circadian  REM  sleep  promotion  when  compared  with  placebo.  Moreover, the observed caffeine-induced deterioration in the quality of awakening may suggest a potential motive to reinstate caffeine intake after sleep.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Lin2021,

title = {Daily Caffeine Intake Induces Concentration-Dependent Medial Temporal Plasticity in Humans: A Multimodal Double-Blind Randomized Controlled Trial },

author = { Y.-S. Lin and J. Weibel and H. Landolt and F. Santini and M. Meyer and J. Brunmair and S. Meyer-Menches and C. gerner and S. Borgwardt and C. Cajochen and C. F. Reichert},

url = {http://www.chronobiology.ch/wp-content/uploads/2021/02/Lin_2021_CC_acc_uncorrect.pdf},

doi = {doi.org/10.1093/cercor/bhab005},

year  = {2021},

date = {2021-02-15},

journal = {Cerebral Cortex},

abstract = {Caffeine is commonly used to combat high sleep pressure on a daily basis. However, interference with sleep–wake regulation could disturb neural homeostasis and insufficient sleep could lead to alterations in human gray matter. Hence, in this double-blind, randomized, cross-over study, we examined the impact of 10-day caffeine (3 × 150 mg/day) on human gray matter volumes (GMVs) and cerebral blood flow (CBF) by fMRI MP-RAGE and arterial spin-labeling sequences in 20 habitual caffeine consumers, compared with 10-day placebo (3 × 150 mg/day). Sleep pressure was quantified by electroencephalographic slow-wave activity (SWA) in the previous nighttime sleep. Nonparametric voxel-based analyses revealed a significant reduction in GMV in the medial temporal lobe (mTL) after 10 days of caffeine intake compared with 10 days of placebo, voxel-wisely adjusted for CBF considering the decreased perfusion after caffeine intake compared with placebo. Larger GMV reductions were associated with higher individual concentrations of caffeine and paraxanthine. Sleep SWA was, however, neither different between conditions nor associated with caffeine-induced GMV reductions. Therefore, the data do not suggest a link between sleep depth during daily caffeine intake and changes in brain morphology. In conclusion, daily caffeine intake might induce neural plasticity in the mTL depending on individual metabolic processes.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Reichert2020,

title = {Wide awake at bedtime? The effects of caffeine on sleep and circadian timing in teenagers - a randomized crossover trial.},

author = {C. F. Reichert and S. Veitz and M. Bühler and G. Gruber and G. Deuring and S. S. Rehm, K. Rentsch and C. Garbazza and M. Meyer and H. Slawik and Y.-S. Lin and J. Weibel},

url = {http://www.chronobiology.ch/wp-content/uploads/2021/09/1-s2.0-S0006295220305190-main.pdf},

doi = {https://doi.org/10.1016/j.bcp.2020.114283},

year  = {2020},

date = {2020-10-15},

journal = {Biochemical Pharmacology},

abstract = {Adolescents often suffer from short and mistimed sleep. To counteract the resulting daytime sleepiness they frequently consume caffeine. However, caffeine intake may exaggerate sleep problems by disturbing sleep and circadian timing. In a 28-hour double-blind randomized crossover study, we investigated to what extent caffeine disturbs slow-wave sleep (SWS) and delays circadian timing in teenagers. Following a 6-day ambulatory phase of caffeine abstinence and fixed sleep-wake cycles, 18 male teenagers (14–17 years old) ingested 80 mg caffeine vs. placebo in the laboratory four hours prior to an electro-encephalographically (EEG) recorded nighttime sleep episode. Data were analyzed using both frequentist and Bayesian statistics. The analyses suggest that subjective sleepiness is reduced after caffeine compared to placebo. However, we did not observe a strong caffeine-induced reduction in subjective sleep quality or SWS, but rather a high inter-individual variability in caffeine-induced SWS changes. Exploratory analyses suggest that particularly those individuals with a higher level of SWS during placebo reduced SWS in response to caffeine. Regarding salivary melatonin onsets, caffeine-induced delays were not evident at group level, and only observed in participants exposed to a higher caffeine dose relative to individual bodyweight (i.e., a dose > 1.3 mg/kg). Together, the results suggest that 80 mg caffeine are sufficient to induce alertness at a subjective level. However, particularly teenagers with a strong need for deep sleep might pay for these subjective benefits by a loss of SWS during the night. Thus, caffeine-induced sleep-disruptions might change along with the maturation of sleep need.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Weibel2020,

title = {Caffeine-dependent changes of sleep-wake regulation: Evidence foradaptation after repeated intake},

author = {J. Weibel and Y.-S. Lin and H.-P. Landolt and C. Garbazza and V. Kolodyazhniy and J. Kistler and S. Rehm and K. Rentsch and S. Borgwardt and C. Cajochen and C. F. Reichert },

url = {http://www.chronobiology.ch/1-s2-0-s0278584619304798-main-2/},

doi = {10.1016/j.pnpbp.2019.109851 },

year  = {2020},

date = {2020-04-20},

journal = {Progress in Neuro-Psychopharmacology and Biological Psychiatry},

abstract = {Background: Circadian and sleep-homeostatic mechanisms regulate timing and quality of wakefulness. To enhance wakefulness, daily consumption of caffeine in the morning and afternoon is highly common. However, the effects of such a regular intake pattern on circadian sleep-wake regulation are unknown. Thus, we investigated if daily daytime caffeine intake and caffeine withdrawal affect circadian rhythms and wake-promotion in habitual consumers.

Methods: Twenty male young volunteers participated in a randomised, double-blind, within-subject study with three conditions: i) caffeine (150 mg 3 x daily for 10 days), ii) placebo (3 x daily for 10 days) and iii) withdrawal (150 mg caffeine 3 x daily for eight days, followed by a switch to placebo for two days). Starting on day nine of treatment, salivary melatonin and cortisol, evening nap sleep as well as sleepiness and vigilance performance throughout day and night were quantified during 43 h in an in-laboratory, light and posture-controlled protocol.

Results: Neither the time course of melatonin (i.e. onset, amplitude or area under the curve) nor the time course of cortisol was significantly affected by caffeine or withdrawal. During withdrawal, however, volunteers reported increased sleepiness, showed more attentional lapses as well as polysomnography-derived markers of elevated sleep propensity in the late evening compared to both the placebo and caffeine condition.

Conclusions: The typical pattern of caffeine intake with consumption in both the morning and afternoon hours may not necessarily result in a circadian phase shift in the evening nor lead to clear-cut benefits in alertness. The time-of-day independent effects of caffeine withdrawal on evening nap sleep, sleepiness and performance suggest an adaptation to the substance, presumably in the homeostatic aspect of sleep-wake regulation.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}