Concentration-effect relationships of plasma caffeine on EEG delta power and cardiac autonomic activity during human sleep

Acute caffeine intake affects brain and cardiovascular physiology, yet the concentration-effect relationships on the electroencephalogram and cardiac autonomic activity during sleep are poorly understood. To tackle this question, we simultaneously quantified the plasma caffeine concentration with ultra-high-performance liquid chromatography, as well as the electroencephalogram, heart rate and high-frequency (0.15-0.4 Hz) spectral power in heart rate variability, representing parasympathetic activity, with standard polysomnography during undisturbed human sleep. Twenty-one healthy young men in randomized, double-blind, crossover fashion, ingested 160 mg caffeine or placebo in a delayed, pulsatile-release caffeine formula at their habitual bedtime, and initiated a 4-hr sleep opportunity 4.5 hr later. The mean caffeine levels during sleep exhibited high individual variability between 0.2 and 18.4 μmol L$^{-1}$ . Across the first two non-rapid-eye-movement (NREM)-rapid-eye-movement sleep cycles, electroencephalogram delta (0.75-2.5 Hz) activity and heart rate were reliably modulated by waking and sleep states. Caffeine dose-dependently reduced delta activity and heart rate, and increased high-frequency heart rate variability in NREM sleep when compared with placebo. The average reduction in heart rate equalled 3.24 ± 0.77 beats per minute. Non-linear statistical models suggest that caffeine levels above ~7.4 μmol L$^{-1}$ decreased electroencephalogram delta activity, whereas concentrations above ~4.3 μmol L$^{-1}$ and ~ 4.9 μmol L$^{-1}$ , respectively, reduced heart rate and increased high-frequency heart rate variability. These findings provide quantitative concentration-effect relationships of caffeine, electroencephalogram delta power and cardiac autonomic activity, and suggest increased parasympathetic activity during sleep after intake of caffeine

Penetration of rifampicin into the brain tissue and cerebral extracellular space of rats

Rifampicin is used to treat neurosurgical shunt infections because of its excellent in-vitro activity against staphylococci and its adequate penetration into the CSF. However, nothing is known about rifampicin concentrations in the cerebral extracellular space (CES). We measured the penetration of rifampicin into the CES of anaesthetized rats by microdialysis using low-flow and equilibrium methods. Depending on the method, rifampicin concentrations in the CES were 0·3-1% of the serum concentration or 3-8% of brain tissue concentration, respectively. These experimental data in animals suggest that the recommended dose of rifampicin in man might be inadequate for treatment of some brain infection

Reduced subjective sleep quality in people rating themselves as electro-hypersensitive: An observational study

BACKGROUND: Disturbed sleep is among the most frequent health complaints of people exposed to radio frequency electromagnetic fields (RF-EMF) used in mobile telecommunication, particularly in individuals who consider themselves as EMF hypersensitive (EHS). We aimed at investigating whether the EHS status per se is associated with sleep complaints. Because allelic variants of the gene encoding the L-type, voltage-gated calcium channel Ca$_{v}$1.2 (CACNA1C) were previously associated with sleep complaints reminiscent of those reported by EHS individuals, we also explored whether self-rated EHS status and sleep quality associate with these gene variants. METHODS: A total of 2'040 participants (1'381 females) aged 18-30 years completed online, validated questionnaires on EMF sensitivity, subjective sleep quality, daytime sleepiness, mentation during sleep, and diurnal preference. They also provided a saliva sample for genotyping three functional variants of CACNA1C (rs7304986, rs16929277 and rs2302729). Eligible participants endorsing the question "Are you electro-hypersensitive?" were considered as "EHS" (n = 105), those denying this question yet believing to develop detrimental health symptoms due to prevailing electromagnetic pollution as "attributers" (n = 254), and the remaining participants as "non-EHS" (n = 1'406). We combined the EHS and attributers into one group for binary analyses. In exploratory analyses, we then tested possible associations between EMF sensitivity, subjective sleep variables and CACNA1C variants using linear and logistic regression. We used age, sex, level of education, presence of sleep disorders and habitual mobile phone use as covariates and corrected with Benjamini-Hochberg False Discovery Rate for multiple comparisons. RESULTS: The EHS/attributers consistently reported prolonged sleep latency, reduced sleep quality, higher sleepiness and more nocturnal mentation when compared to non-EHS. Habitual mobile phone use was not associated with self-rated sleep latency and sleep quality scores. While the T-allele of variant rs2302729 of CACNA1C was associated with both, self-reported EMF sensitivity and reduced subjective sleep quality, we found no evidence for the hypothesis that EHS mediates impaired sleep quality via this allelic variant. CONCLUSIONS: Irrespective of reported RF-EMF exposure, self-rated EHS/attributers rated subjective sleep quality worse than non-EHS individuals. TRIAL REGISTRATION: Swiss National Clinical Trials Portal (SNCTP000002285) and ClinicalTrials.gov (NCT03074617)

Electron-phonon-scattering dynamics in ferromagnetic metals and its influence on ultrafast demagnetization processes

We theoretically investigate spin-dependent carrier dynamics due to the electron-phonon interaction after ultrafast optical excitation in ferromagnetic metals. We calculate the electron-phonon matrix elements including the spin-orbit interaction in the electronic wave functions and the interaction potential. Using the matrix elements in Boltzmann scattering integrals, the momentum-resolved carrier distributions are obtained by solving their equation of motion numerically. We find that the optical excitation with realistic laser intensities alone leads to a negligible magnetization change, and that the demagnetization due to electron-phonon interaction is mostly due to hole scattering. Importantly, the calculated demagnetization quenching due to this Elliot-Yafet type depolarization mechanism is not large enough to explain the experimentally observed result. We argue that the ultrafast demagnetization of ferromagnets does not occur exclusively via an Elliott-Yafet type process, i.e., scattering in the presence of the spin-orbit interaction, but is influenced to a large degree by a dynamical change of the band structure, i.e., the exchange splitting

Metabolomics-based Sleepiness Markers for Risk Prevention and Traffic Safety (ME-SMART): a monocentric, controlled, randomized, crossover trial

Background: Too little sleep and the consequences thereof are a heavy burden in modern societies. In contrast to alcohol or illicit drug use, there are no quick roadside or workplace tests for objective biomarkers for sleepiness. We hypothesize that changes in physiological functions (such as sleep–wake regulation) are reflected in changes of endogenous metabolism and should therefore be detectable as a change in metabolic profiles. This study will allow for creating a reliable and objective panel of candidate biomarkers being indicative for sleepiness and its behavioral outcomes. Methods: This is a monocentric, controlled, randomized, crossover, clinical study to detect potential biomarkers. Each of the anticipated 24 participants will be allocated in randomized order to each of the three study arms (control, sleep restriction, and sleep deprivation). These only differ in the amount of hours slept per night. In the control condition, participants will adhere to a 16/8 h wake/sleep regime. In both sleep restriction and sleep deprivation conditions, participants will accumulate a total sleep deficit of 8 h, achieved by different wake/sleep regimes that simulate real-life scenarios. The primary outcome is changes in the metabolic profile (i.e., metabolome) in oral fluid. Secondary outcome measures will include driving performance, psychomotor vigilance test, d2 Test of Attention, visual attention test, subjective (situational) sleepiness, electroencephalographic changes, behavioral markers of sleepiness, changes in metabolite concentrations in exhaled breath and finger sweat, and correlation of metabolic changes among biological matrices. Discussion: This is the first trial of its kind that investigates complete metabolic profiles combined with performance monitoring in humans over a multi-day period involving different sleep–wake schedules. Hereby, we aim to establish a candidate biomarker panel being indicative for sleepiness and its behavioral outcomes. To date, there are no robust and easily accessible biomarkers for the detection of sleepiness, even though the vast damage on society is well known. Thus, our findings will be of high value for many related disciplines. Trial registration: ClinicalTrials.gov Identifier NCT05585515, released on 18.10.2022; Swiss National Clinical Trial Portal SNCTP000005089, registered on 12 August 2022

Functional ADA Polymorphism Increases Sleep Depth and Reduces Vigilant Attention in Humans

Homeostatically regulated slow-wave oscillations in non-rapid eye movement (REM) sleep may reflect synaptic changes across the sleep-wake continuum and the restorative function of sleep. The nonsynonymous c.22G>A polymorphism (rs73598374) of adenosine deaminase (ADA) reduces the conversion of adenosine to inosine and predicts baseline differences in sleep slow-wave oscillations. We hypothesized that this polymorphism affects cognitive functions, and investigated whether it modulates electroencephalogram (EEG), behavioral, subjective, and biochemical responses to sleep deprivation. Attention, learning, memory, and executive functioning were quantified in healthy adults. Right-handed carriers of the variant allele (G/A genotype, n = 29) performed worse on the d2 attention task than G/G homozygotes (n = 191). To test whether this difference reflects elevated homeostatic sleep pressure, sleep and sleep EEG before and after sleep deprivation were studied in 2 prospectively matched groups of G/A and G/G genotype subjects. Deep sleep and EEG 0.75- to 1.5-Hz oscillations in non-REM sleep were significantly higher in G/A than in G/G genotype. Moreover, attention and vigor were reduced, whereas waking EEG alpha activity (8.5-12 Hz), sleepiness, fatigue, and α-amylase in saliva were enhanced. These convergent data demonstrate that genetic reduction of ADA activity elevates sleep pressure and plays a key role in sleep and waking quality in human

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

Time-on-task decrement in vigilance is modulated by inter-individual vulnerability to homeostatic sleep pressure manipulation.

peer reviewedUnder sleep loss, vigilance is reduced and attentional failures emerge progressively. It becomes difficult to maintain stable performance over time, leading to growing performance variability (i.e., state instability) in an individual and among subjects. Task duration plays a major role in the maintenance of stable vigilance levels, such that the longer the task, the more likely state instability will be observed. Vulnerability to sleep-loss-dependent performance decrements is highly individual and is also modulated by a polymorphism in the human clock gene PERIOD3 (PER3). By combining two different protocols, we manipulated sleep-wake history by once extending wakefulness for 40 h (high sleep pressure condition) and once by imposing a short sleep-wake cycle by alternating 160 min of wakefulness and 80 min naps (low sleep pressure condition) in a within-subject design. We observed that homozygous carriers of the long repeat allele of PER3 (PER3 (5/5) ) experienced a greater time-on-task dependent performance decrement (i.e., a steeper increase in the number of lapses) in the Psychomotor Vigilance Task compared to the carriers of the short repeat allele (PER3 (4/4) ). These genotype-dependent effects disappeared under low sleep pressure conditions, and neither motivation, nor perceived effort accounted for these differences. Our data thus suggest that greater sleep-loss related attentional vulnerability based on the PER3 polymorphism is mirrored by a greater state instability under extended wakefulness in the short compared to the long allele carriers. Our results undermine the importance of time-on-task related aspects when investigating inter-individual differences in sleep loss-induced behavioral vulnerability