Background The optimal target in the dorsolateral prefrontal cortex for treating depression with repetitive transcranial magnetic stimulation (rTMS) remains unknown. Better efficacy has been associated with stimulation sites that are 1) more anterior and lateral and 2) more functionally connected to the subgenual cingulate. Here we prospectively test whether these factors predict response in individual patients. Methods A primary cohort (Boston, n = 25) with medication-refractory depression underwent conventional open-label rTMS to the left dorsolateral prefrontal cortex. A secondary cohort (Michigan, n = 16) underwent 4 weeks of sham followed by open-label rTMS for nonresponders (n = 12). In each patient, the location of the stimulation site was recorded with frameless stereotaxy. Connectivity between each patient’s stimulation site and the subgenual cingulate was assessed using resting-state functional connectivity magnetic resonance imaging from a cohort of healthy subjects (n = 1000) and confirmed using connectivity from patients with depression (n = 38). Results In our primary cohort, antidepressant efficacy was predicted by stimulation sites that were both more anterolateral (r = .51, p < .01) and more negatively correlated with the subgenual cingulate (r = −.55, p < .005). However, subgenual connectivity was the only independent predictor of response and the only factor to predict response to active (r = −.52, p < .05) but not sham rTMS in our secondary cohort. Conclusions This study provides prospective validation that functional connectivity between an individual’s rTMS cortical target and the subgenual cingulate predicts antidepressant response. Implications for improving the cortical rTMS target for depression are discussed.

Prospective Validation That Subgenual Connectivity Predicts Antidepressant Efficacy of Transcranial Magnetic Stimulation Sites