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Previous research has highlighted the role of the excitation/inhibition (E/I) ratio for typical and atypical development, mental health, cognition, and learning. Other research has highlighted the benefits of high-frequency transcranial random noise stimulation (tRNS)—an excitatory form of neurostimulation—on learning. We examined the E/I as a potential mechanism and studied whether tRNS effect on learning depends on E/I as measured by the aperiodic exponent as its putative marker. In addition to manipulating E/I using tRNS, we also manipulated the level of learning (learning/overlearning) that has been shown to influence E/I. Participants (n = 102) received either sham stimulation or 20-minute tRNS over the dorsolateral prefrontal cortex (DLPFC) during a mathematical learning task. We showed that tRNS increased E/I, as reflected by the aperiodic exponent, and that lower E/I predicted greater benefit from tRNS specifically for the learning task. In contrast to previous magnetic resonance spectroscopy (MRS)-based E/I studies, we found no effect of the level of learning on E/I. A further analysis using a different data set suggest that both measures of E/I (EEG versus MRS) may reflect, at least partly, different biological mechanisms. Our results highlight the role of E/I as a marker for neurostimulation efficacy and learning. This mechanistic understanding provides better opportunities for augmented learning and personalized interventions. Previous work has suggested that the excitation/inhibition ratio (E/I) contributes to typical and atypical development, mental health, cognition and learning. This study reveals that the E/I ratio in the brain plays an important role in neurostimulation efficacy and is a possible marker for learning.

Accumulating evidence from human-based research has highlighted that the prevalent one-size-fits-all approach for neural and behavioral interventions is inefficient. This approach can benefit one individual, but be ineffective or even detrimental for another. Studying the efficacy of the large range of different parameters for different individuals is costly, time-consuming and requires a large sample size that makes such research impractical and hinders effective interventions. Here an active machine learning technique is presented across participants-personalized Bayesian optimization (pBO)-that searches available parameter combinations to optimize an intervention as a function of an individual's ability. This novel technique was utilized to identify transcranial alternating current stimulation (tACS) frequency and current strength combinations most likely to improve arithmetic performance, based on a subject's baseline arithmetic abilities. The pBO was performed across all subjects tested, building a model of subject performance, capable of recommending parameters for future subjects based on their baseline arithmetic ability. pBO successfully searches, learns, and recommends parameters for an effective neurointervention as supported by behavioral, simulation, and neural data. The application of pBO in human-based research opens up new avenues for personalized and more effective interventions, as well as discoveries of protocols for treatment and translation to other clinical and non-clinical domains.