Distributed neural signatures of discomfort induced by transcranial magnetic stimulation

Transcranial magnetic stimulation (TMS) is a cornerstone tool for causal inference in human brain function and an increasingly used neuromodulation therapy, yet it induces well-recognized discomfort that may systematically bias measured outcomes. Despite its ubiquity, the brain-wide neural signatures of this discomfort remain poorly characterized. Using concurrent TMS-fMRI across 11 cortical targets, we collected an unprecedented dataset (165 participants; 1,535 runs) including healthy participants and those with elevated affective symptoms. Cross-validated multivariate analyses identified neural signatures linking whole-brain responses to post-stimulation discomfort ratings, engaging distributed regions spanning sensorimotor, attentional, limbic, and default mode networks, with overlapping and group-specific engagement across groups. Discomfort-related activity accounted for 12% and 25% of TMS-evoked responses in healthy and elevated-symptom groups, respectively. These findings delineate brain-wide neural signatures of TMS-induced discomfort, revealing a critical component within TMS-evoked brain responses that should be explicitly measured and modeled to refine causal inference and inform therapeutic neuromodulation.