Arousal levels explain inter-subject variability of neuromodulation effects

Over the past two decades, the postulated modulatory effects of transcranial direct current stimulation (tDCS) on the human brain have been extensively investigated, with attractive real-world applications. However, recent concerns on reliability of tDCS effects have been raised, principally due to reduced replicability and to the great interindividual variability in response to tDCS. These inconsistencies are likely due to the interplay between the level of induced cortical excitability and unaccounted individual state-dependent factors. On these grounds, we aimed to verify whether the behavioural effects induced by a common prefrontal tDCS montage were dependent on the participants’ arousal levels. Pupillary dynamics were recorded during an auditory oddball task while applying either a sham or real tDCS. The tDCS effects on reaction times and pupil dilation were evaluated as a function of subjective and physiological arousal predictors. Both predictors significantly explained performance during real tDCS, namely reaction times improved only with moderate arousal levels; likewise, pupil dilation was affected according to the ongoing levels of arousal. These findings highlight the critical role of arousal in shaping the neuromodulatory outcome, and thus encourage a more careful interpretation of null or negative results.