ABSTRACT The subgenual anterior cingulate cortex (sgACC) has dominated the literature utilizing repetitive transcranial magnetic stimulation (rTMS) to treat depression for good reason: treatment focusing on the frontal-sgACC brain circuit is effective and changes in resting fMRI connectivity with the sgACC accompany symptom improvements. However, it has not yet been proven that TMS actually engages the sgACC which would support continued focus on this circuit at the exclusion of other potential targets from the fMRI literature. With the application of interleaved TMS/fMRI, it is possible to capture brain responses caused by TMS to any brain surface site. Using resting fMRI connectivity to guide TMS targeting, we seek to establish neuromodulation of the sgACC pathway (R61, Aim 1) and the best connectivity pipeline for robustly engaging the sgACC (R61, Aim 2). Upon establishing these successful benchmarks, the R33 phase will demonstrate that the sgACC evoked response at baseline predicts depression improvement when treatment delivered to this same circuit (R33, Aim1). To cement the relationship between modulation of the frontal-sgACC circuit with treatment and depression improvement, we hypothesize an association between brain changes and clinical changes (R33, Aim 2). We hypothesize that the R33 clinical associations with evoked brain responses will be established for active but not for sham rTMS. Together, this research will elucidate basic mechanisms of rTMS treatment that will accelerate brain circuit targeted neurotherapeutics.