Fronto-insular circuit mechanisms of accelerated intermittent theta burst stimulation

Using SHIELD tissue clearing, c-Fos immunolabeling, and light sheet imaging to map whole-brain responses to aiTBS, we delineate a network of downstream structures activated by PL-aiTBS, including pronounced effects in insular cortex, which were confirmed by fiber photometry. Chemogenetic and projection-specific optogenetic studies established the necessity and sufficiency of a fronto-insular circuit in mediating aiTBS effects on motivated approach and avoidance behavior.

Finally, we validate a key role for TMS-evoked responses in the human insula, showing in intracortical stereo-EEG recordings that prefrontal TMS modulates neuronal activity in insular cortex acutely and that resting state fMRI measures of fronto-insular connectivity predict individual differences in antidepressant responses to aiTBS. Together, these results identify a critical role for aiTBS-induced activation of a fronto-insular circuit in supporting specific antidepressant-like behavioral effects and establish a model for studying aiTBS mechanisms and optimizing stimulation parameters.