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 (EEG) 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 EEG, heart rate and high-frequency (0.15-0.4 Hz) spectral power in heart rate variability (HR-HRV), representing parasympathetic activity, with standard polysomnography during undisturbed human sleep. Twenty-one healthy young men ingested in randomized, double-blind, cross-over fashion, 160 mg caffeine or placebo in a delayed, pulsatile-release caffeine formula at their habitual bedtime, and initiated a four-hour sleep opportunity 4.5 hours later. The mean caffeine levels during sleep exhibited high individual variability between 0.2 and 18.4 µmol/l. Across the first two NREM-REM sleep cycles, EEG 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 HR-HRV in NREM sleep when compared to placebo. The average reduction in heart rate equaled 3.24 ± 0.77 beats per minute. Non-linear statistical models suggest that caffeine levels above ∼ 7.4 µmol/l decreased EEG delta activity, whereas concentrations above ∼ 4.3 µmol/l and ∼ 4.9 µmol/l, respectively, reduced heart rate and increased HR-HRV. The findings provide quantitative concentration-effect relationships of caffeine, EEG delta power and cardiac autonomic activity and suggest increased parasympathetic activity during sleep after intake of caffeine. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial NCT04975360 ### Funding Statement This study did not receive any funding. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study protocol was approved by the Cantonal Ethics Committee of the Canton of Zurich (BASEC: 2018-00533). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The data produced in the present study are available upon reasonable request to the authors.