Pre-stimulus Brain States Predict and Control Variability in Stimulation Responses

Does the ongoing brain state determine how it responds to localized electrical stimulation? This fundamental question has major implications for neuroscience and medicine, as stimulation outcomes remain highly variable even when identical parameters ("how") and target sites ("where") are used. Such unpredictability undermines reproducibility, limits clinical reliability, and forces current protocols to rely on empirical trial-and-error rather than principled, evidence-based strategies. Mounting evidence suggests that the brain's state prior to stimulation—a crucial "when" factor—shapes responses, yet the most reliable predictive markers remain unknown. Here, we systematically characterize the links between pre-stimulus (spontaneous) activity and post-stimulus (evoked) responses using simultaneous high-density EEG and stereotactic EEG from 36 epilepsy patients across ~320 sessions (>10,000 individual stimulations). We show that large-scale neural dynamics robustly predict stimulation outcomes, with a subset of measures—particularly network synchronization, functional connectivity, and spatiotemporal signal diversity—consistently forecasting responses across sessions. Whole-brain activity enhanced prediction compared to local assessments, and predictability varied across networks, being strongest in sensorimotor and visual regions. These findings establish a quantitative framework for state-dependent brain stimulation: by timing interventions to optimal pre-stimulus states, variability can be reduced and reproducibility enhanced. Our results directly address the fundamental question of where and when to stimulate, providing a pathway toward evidence-based protocols with improved therapeutic precision.