Optogenetic insights into short- and long-duration random noise electrical stimulation.

Previous research by Paulus's group in humans showed that 10 min of transcranial random noise stimulation (tRNS) enhances motor-evoked potentials for over 1 h. In contrast, 4 min of tRNS attenuates task-evoked blood oxygen level-dependent (BOLD) responses, suggesting that shorter durations reduce task-related cortical activity. Importantly, this effect occurs during task execution and reflects attenuation of evoked activity rather than direct suppression of baseline cortical excitability. In this context, prior human neuroimaging findings highlight a conceptual bridge between facilitatory and attenuating effects of random noise stimulation, emphasizing the need to identify the cellular mechanisms underlying these duration-dependent outcomes. Here, we tested whether long-term (10 min) and short-term (2 min) cortical random noise stimulation (RNS) engages distinct physiological mechanisms using optogenetic transgenic mice. We used Thy1-ChR2-YFP and VGAT-ChR2-YFP mice, in which blue light evokes glutamate or GABA release, respectively. Optogenetic stimulation did not alter the facilitation of somatosensory-evoked potentials induced by 10 min of cortical RNS in either transgenic line compared with wild-type mice. In contrast, it reversed the attenuation induced by 2 min of cortical RNS. Sham stimulation had no effect. These findings indicate that long-duration cortical RNS facilitates cortical responses through a ceiling or saturation effect on cortical excitability, whereby a 10-min drive engages the full range of available facilitation regardless of the neurotransmitter pathway activated, whereas short-duration cortical RNS attenuates responses via neurotransmission-dependent mechanisms involving the glutamate-GABA balance. This distinction has important implications for optimizing tRNS protocols in human studies.NEW & NOTEWORTHY Using optogenetic mouse models, we show that the duration of cortical random noise stimulation (RNS) determines whether cortical responses are facilitated or attenuated. Long-duration stimulation produces a ceiling or saturation effect on cortical excitability that is equivalent across RNS alone, Brownian optogenetic noise-photostimulation (BONP) alone, and their combination, independent of the specific neurotransmitter pathway activated, whereas short-duration stimulation induces attenuation through glutamate-GABA-dependent mechanisms. These findings provide mechanistic insight into duration-dependent tRNS effects.