PROJECT SUMMARY Serotonin and dopamine dysfunction have been long implicated in the pathophysiology of major depression. However, to date, delineating the role of these neuromodulators in depression has largely and necessarily relied on inference, with neuroimaging (including PET, fMRI, EEG) studies revealing responses in brain regions associated with dopamine and serotonin release and medications targeting the dopaminergic and serotoninergic systems improving symptoms for some individuals. In order to make significant advances in understanding the neural underpinnings of depression and developing novel therapeutics for the disorder, tracking neuromodulator responses quickly, accurately, and in vivo is required. Recent advances allow exactly the unprecedented ability to track neuromodulator responses with high temporal resolution and chemical specificity. Specifically, we are able to directly and simultaneously measure dopamine and serotonin responses in awake humans with the temporal resolution (~ 10 ms) required to examine the relationship of neuromodulator release with decision-making processes. The product of these advances is recordings of in vivo neuromodulator fluctuations at sub-second resolution. This application merges the clinical and affective neuroscience expertise of MPI Chiu with these advances of MPI Montague to directly examine the relationship of dopamine and serotonin responses to depression. To achieve this goal, we will record neuromodulator responses in participants with medication-resistant epilepsy who already have intracranial depth electrodes in place for phase-II monitoring. The depth electrodes are implanted by our neurosurgery colleagues at Virginia Tech’s medical affiliate Carilion Clinic (Project Co-I Witcher; Carilion Clinic clinical site PI). During recording, participants will be in a standard (i.e., non-surgical) hospital monitoring suite and perform i) an affective processing task (emotional Stroop) and ii) a value-based learning task (two-arm bandit) that have been shown by our group and others both to engage processes thought to be related to serotonin and dopamine function, and also to be related to negative mood and anhedonia symptoms, respectively, of depression.