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bioRxiv · 10.64898/2026.02.27.708526

Distributed neural signatures of discomfort induced by transcranial magnetic stimulation

Li, Z.·Jiao, Y.·Zhang, Y.·Zhang, N.·Etkin, A.·Boes, A. D.·Oathes, D. J.·Jiang, J.
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Abstract

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, a critical gap remains in understanding how TMS-induced discomfort is represented across the brain and to what extent it contributes to TMS-evoked neural responses. Using concurrent TMS-fMRI across 11 cortical targets, we collected an unprecedented dataset (165 participants; 1,535 runs) spanning healthy participants and those with elevated affective symptoms. Cross-validated multivariate modeling revealed that TMS-induced discomfort engages distributed cortical and subcortical regions across sensorimotor, attentional, default mode, and limbic networks, with both shared and group-specific patterns. Discomfort-related activity accounted for approximately 12% and 25% of TMS-evoked responses in healthy and elevated-symptom groups, respectively, and varied systematically across stimulating sites. These findings identify TMS-induced discomfort as a substantial and previously under-characterized component of TMS-evoked neural responses, underscoring the need to explicitly measure and model it. By providing a whole-brain map of regional contributions associated with TMS-induced discomfort and an analytic framework to dissociate direct neuromodulatory effects from discomfort-related responses, this work improves the interpretability of TMS-evoked signals and supports more rigorous causal inference and therapeutic applications.

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Li, Z., Jiao, Y., Zhang, Y., Zhang, N., Etkin, A., Boes, A. D., Oathes, D. J., Jiang, J.. 2026-03-02. Distributed neural signatures of discomfort induced by transcranial magnetic stimulation. https://doi.org/10.64898/2026.02.27.708526

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