Finding safe and effective treatments for late-life depression is imperative given the aging of the general population and the significant risk of suicide in this demographic. This K-23 application will prepare the candidate to achieve his long-term goal of developing safe and effective interventions for severe depression among the aging, guided by neurobiological mechanisms of outcomes. Elderly patients with severe medication resistant depression need viable treatment options. When medications fail, or illness severity demands emergent treatment, Electroconvulsive Therapy (ECT) remains the gold standard, but its use is limited due to risks of cognitive impairment and other side effects. This is a special concern for elderly patients with co-morbid dementia and medical illnesses. Our ability to meet this pressing need is hampered by insufficient knowledge of the neural mechanisms underlying the cognitive side effects of ECT, and a means to differentiate them from mechanisms of antidepressant action. Magnetic seizure therapy (MST) is in development as a means of reducing the cognitive side effects of ECT through a more focal seizure induction. Studies have found MST-induced seizures to be more focal, with less amnesia, but no studies in the elderly have been conducted to date. The ability to optimize MST as a less invasive but effective treatment for severe depression would be facilitated through knowledge of its mechanisms of action in comparison with ECT, though little is known about the functional neurobiological effects of MST and how they compare with ECT. Specifically, there have been no imaging studies of MST. Furthermore, focal seizure induction with MST represents a tool to study the effects of seizures related to side effects and differentiate those from mechanisms responsible for antidepressant response. Indeed, contrasting the effects of these two modalities that both induce seizures but differ so markedly in cognitive side effects presents an unparalleled opportunity to define the brain mechanisms responsible for ECT-induced amnesia. We propose to study these mechanisms with topographical EEG and FDG-PET, in a randomized controlled trial of ECT vs. MST in depressed elders. This study will provide pilot data for more extensive future work in depression in the elderly. Furthermore, this work will shed light on the mechanisms of action of the most effective treatment for depression, providing the first test of whether regional differences in the neural response to seizures result in differential clinical effects of depression and cognitive function. The career development plan is designed to enable the candidate to become a proficient, independent investigator working at the convergence of functional neuroimaging, late-life mood disorders, and neurostimulation interventions. Training in geriatric depression, brain stimulation, neurophysiology, neuroimaging, research trial design, and biostatistics will support the candidate's development into an independent investigator in the field of rational intervention development for depression in late life. PUBLIC HEALTH RELEVANCE: The project will establish a scientific paradigm of rational treatment development in brain stimulation, whose aim is to maximize efficacy and minimize side effects through evidence-based targeting of areas responsible for depression on one hand and, to minimize side effects by avoiding stimulation of the brain centers responsible for deleterious effects, on the other.