Resting fMRI-guided TMS evokes subgenual anterior cingulate response in depression

Background: Depression alleviation following treatment with repetitive transcranial magnetic stimulation (rTMS) tends to be more effective when TMS is targeted to cortical areas with high (negative) resting state functional connectivity (rsFC) with the subgenual anterior cingulate cortex (sgACC). However, the relationship between sgACC-cortex rsFC and the TMS-evoked response in the sgACC is still being explored and has not yet been established in depressed patients. Objectives: In this study, we investigated the relationship between sgACC-cortical (site of stimulation) rsFC and induced evoked responses in the sgACC in healthy controls and depressed patients. Methods: For each participant (N = 115, 34 depressed patients), a peak rsFC cortical 'hotspot' for the sgACC and control targets were identified at baseline. Single pulses of TMS interleaved with fMRI readouts were administered to these targets to evoke downstream fMRI blood-oxygen-level-dependent (BOLD) responses in the sgACC. Generalized estimating equations were used to investigate the association between TMS-evoked BOLD responses in the sgACC and rsFC between the stimulation site and the sgACC. Results: Stimulations over cortical sites with high rsFC to the sgACC were effective in modulating activity in the sgACC in both healthy controls and depressed patients. Moreover, we found that in depressed patients, sgACC rsFC at the site of stimulation was associated with the induced evoked response amplitude in the sgACC: stronger positive rsFC values leading to stronger evoked responses in the sgACC. Conclusions: rsFC-based targeting is a viable strategy to causally modulate the sgACC. Assuming an anti- depressive mechanism working through modulation of the sgACC, the field's exclusive focus on sites anti- correlated with the sgACC for treating depression should be broadened to explore positively-connected sites.