Repetitive transcranial magnetic stimulation (rTMS) targeting the left dorsolateral prefrontal cortex (DLPFC) is effective in adults with depression. rTMS is twice as likely to result in response (relative risk or RR: 2.35 [95% confidence interval or CI: 1.70-3.25]) and remission (RR: 2.24 [95% CI: 1.53-3.27] than a sham procedure Evidence in youth is also encouraging, with a 66% response rate in our pilot data (see Summary of Progress). The DLPFC plays a critical role in emotional regulation, directly connecting it to depressive symptomology. Our lab and others have clearly implicated structural and functional deficits in the DLPFC in youth with MDD. What is not known is what biomarkers best predict response, remission, and recovery with rTMS in youth with treatment resistant MDD. As response is not universal, this is a significant gap in our knowledge. Our basic model is that rTMS increases expression of BDNF, up-regulates activity of endocannabinoids, increases glutamate concentrations, and increases DLPFC activity - correcting the deficit seen in MDD. These biologic changes enhance executive control of mood state (see our pilot data in the Summary of Progress). These positive effects may be moderated by comorbidity (i.e., social phobia) and genotype (i.e., BDNF). How this model fits with response, remission, and recovery has yet to be fully tested and this information has the potential to be directly clinically meaningful. The central aim of the project is to evaluate predictors of rTMS response, remission, and recovery based on integrated neuroimaging, physiological, and clinical measures. While not a clinical trial per se (efficacy is not the primary outcome measure), we will use a non-randomized sham lead in to a single active (rTMS) arm study design as a framework for biomarker discovery.