Transcranial magnetic stimulation (TMS) is a widely used neuromodulation treatment for depression, but its mechanisms are poorly understood. Indirect clinical evidence suggests that TMS enhances plasticity within the prefrontal cortical target site and engages downstream networks. However, establishing causal mechanisms to help optimize the large stimulation parameter space has been challenging. Using an optogenetic model of accelerated intermittent theta burst stimulation (prelimbic [PL]-aiTBS) that drives rapid antidepressant-like effects, we examined cell type-specific effects on synapse-related gene expression, increased spine density, and increased excitatory currents in prefrontal intratelencephalic projection neurons. Whole-brain c-Fos immunolabeling, fiber photometry, chemogenetic, and projection-specific optogenetic manipulations revealed that PL-aiTBS activates a fronto-insular network that is necessary and sufficient for its antidepressant-like behavioral effects. Finally, we validate a key role for fronto-insular connectivity and TMS-evoked responses in the human insula using intracortical stereo-electroencephalogram (EEG) and resting-state fMRI. These results establish a fronto-insular circuit as a critical mediator of the antidepressant effects of aiTBS.
