The modulatory effects of non-invasive brain stimulation (NIBS) are highly variable between subjects. This variability may be due to uncontrolled caffeine consumption and circadian rhythms. Therefore, here we studied if caffeine consumption, systemically available caffeine measured in saliva, and daytime have effects on the excitability and plasticity of the motor cortex. Since both, time of the day and caffeine may mediate their effects via cortisol, we also quantified corticosteroids in saliva. Experiment 1 was performed in caffeine-naïve participants (n = 30) and compared the effects of PAS or tACS with different stimulation intensities on the motor cortex with or without caffeine 200 mg administered in a double-blind fashion. Experiment 2 was performed in regular caffeine consumers (n = 30) and compared the influence of time of day on the effects of tACS (true or sham) on the motor cortex also with or without caffeine administered in a double-blind fashion. Caffeine increased the saliva corticosteroid concentrations in both experimental groups, and corticosteroid concentrations were higher in the morning in caffeine consumers. Gender also affected corticosteroid concentrations. There was a positive correlation between caffeine concentrations and baseline cortical excitability in caffeine-adapted participants, and a negative correlation between poststimulation caffeine concentrations and motor evoked potential (MEP) amplitudes after sham stimulation in caffeine-naïve subjects. No correlations were found between poststimulation caffeine or corticosteroid concentrations, and plasticity aftereffects. PAS and tACS did not elicit changes in the corticosteroid concentrations. We conclude that moderate caffeine consumption alters cortical excitability but not plasticity aftereffects. This study was registered in the ClinicalTrials.gov with these registration IDs: 1) NCT03720665 https://clinicaltrials.gov/ct2/results?cond=NCT03720665&term=&cntry=&state=&city=&dist= 2) NCT04011670 https://clinicaltrials.gov/ct2/results?cond=&term=NCT04011670&cntry=&state=&city=&dist=.
The roles of caffeine and corticosteroids in modulating cortical excitability after paired associative stimulation (PAS) and transcranial alternating current stimulation (tACS) in caffeine-naïve and caffeine-adapted subjects