Complexity of Resting Cortical Activity Predicts Neurophysiological Responses to Theta- Burst Stimulation but Fails to Generalize: A Rigorous Machine-Learning Approach

Background: Substantial variability in individual responses to intermittent theta-burst stimulation (iTBS) limits its clinical efficacy, yet neurophysiological predictors underlying this variability remain unclear. While most machine-learning (ML) studies have focused on modeling behavioral or clinical effects of repetitive transcranial magnetic stimulation (rTMS), the few studies examining neurophysiological outcomes have typically utilized limited feature sets in single-visit settings, which captured only inter-subject variability and most importantly lacked independent validation sets. Methods: To address these gaps, we first employed statistical and reliability analysis to understand the statistical relationship between resting state EEG and responses to iTBS. Next, we employed supervised machine learning models that integrated baseline resting-state EEG (rsEEG) features and transcranial magnetic stimulation (TMS)-evoked measures, including motor-evoked potentials (MEPs) and TMS-evoked potentials (TEPs), to predict neurophysiological responses to a single iTBS session applied over the primary motor cortex in two independent test-retest studies of healthy adults. Results: Internal cross-validation within the training cohort yielded promising performance (accuracy: 81%), identifying coarse-grained multiscale distribution entropy of rsEEG as the most robust predictor of local cortical excitability changes indexed by the 100-131ms window of TEPs. However, predictive performance markedly declined upon external validation (accuracy: 69%), reflecting unstable relationships between predictors and outcomes likely driven by substantial intra- and inter-individual variability of iTBS-induced changes in neurophysiological outcomes. Conclusions: These findings emphasize that while EEG complexity measures can capture baseline brain states relevant for neuromodulation to a certain degree, the inherent instability of single-session iTBS effects significantly constrains model generalizability and underscores the necessity of test-retest paradigm to avoid overly optimistic performance estimates. Future studies with multi-session and individualized stimulation protocols are urgently needed to better characterize neurophysiological mechanisms underlying rTMS effects and ultimately enhance its therapeutic potential.