AbstractPurpose Paired Associative Stimulation (PAS) is a non-invasive neuromodulation tool for inducing changes in motor cortex excitability. However, its applicability is limited by substantial inter-individual variability and inconsistent replicability. We tested whether an individualized PAS protocol (iPAS), in which the interstimulus interval (ISI) is calibrated to each participant's peripheral-cortical conduction time, enhances the efficacy and consistency of cortical plasticity induction compared to the conventional fixed-ISI protocol (PAS25, 25 ms. Methods In a randomized, single-blind, within-subject crossover study, 99 healthy participants each completed one PAS25 and one iPAS session in counterbalanced order. Motor evoked potentials (MEP) were recorded at baseline, and at 5-, 10-, and 20-minutes post-stimulation. The primary outcome was MEP amplitude modeled across all timepoints using a linear mixed-effects model with raw MEP amplitudes as the dependent variable. Results Both protocols increased MEP amplitudes relative to baseline. The primary analysis revealed a significant Condition × Timepoint interaction at 20minutes (p = 0.018). Post hoc contrasts showed that iPAS produced significantly greater MEP amplitudes than PAS25 at 5minutes (ratio = 1.15, p=0.023) and 20minutes (ratio = 1.23, p Conclusions By improving both the magnitude and reliability of motor cortex plasticity induction, and being readily implementable with standard neurophysiological equipment, iPAS may serve as the preferred alternative to conventional PAS, with potential applications in neurology, rehabilitation, and precision psychiatry.
Campana et al. (2026) studied this question.