Major Depressive Disorder (MOD) is a leading cause of disability in the US. About 20% of people with MOD (~4 million Americans) fail repeated antidepressant (AD) trials, resulting in "treatment resistant depression" (TRD). Few effective treatments exist for TRD. Even electroconvulsive therapy (ECT) is less efficacious in TRD, with -68% of ECT-treated TRD patients relapsing into MDD within one year. In 2005, the US FDA granted TRD-specific indication for Vagus Nerve Stimulation (VMS). A randomized clinical trial of VMS with an open-label extension indicated a 27% response rate and a 15.8% remission rate in TRD patients with MDD. Most patients who responded maintained AD response for a 12 month period. Although these results are promising, the majority of TRD-VNS subjects did not show AD response. VMS is also invasive and expensive, requiring surgery for VNS device implantation. The ability to determine beforehand which patients are likely to benefit from VNS is therefore an important issue. Further, little is known about how the brain responds to VNS to produce AD response. Functional imaging, including Positron Emission Tomography or PET scanning, plays a key role in identifying anatomical and physiological correlates of MDD and AD response in the human brain. Our pilot PET studies of TRD patients revealed VNS-induced changes in brain activity that suggest possible mechanisms of action for VNS. We propose a prospective PET-VNS study that examines acute, subacute (3 month), and chronic (12-18 month) changes in regional brain activity in response to VNS in TRD patients. Further, regional brain activity changes will be correlated with AD outcomes. Improved understanding of VNS mechanisms of action at the neurophysiological level will enhance theoretical knowledge of MDD and AD response, may assist development of MDD treatments, and may allow for advance identification of patients most likely to benefit from VNS. Depression is a leading cause of disability in the US. Millions of people suffer from depression that does not respond to standard treatments. Vagus nerve stimulation (VNS) is a promising new treatment for these patients. The proposed study will look at how the brain changes in response to VNS treatment. Further, the study will examine how these brain changes relate to changes in depression.