PROJECT SUMMARY/ABSTRACT There are bidirectional neurobiological links between anxiety and epilepsy. However, the specific processes linking these conditions remain unclear. Stereo-electroencephalography (sEEG) is a critical tool for localizing the ictal onset zone in patients with treatment-resistant epilepsy (TRE) undergoing evaluation for resective surgery and provide an ideal approach to study the disruptions in the distributed networks that underlie this link. Further, investigation of these circuits and their causal impact on human behavior and cognition is possible through the delivery of electrical stimuli via the already implanted sEEG electrodes. The proposed work will assess anxiety-related disruptions in emotion regulation neurocircuitry using sEEG and test how stimulation to dorsomedial prefrontal cortex modulates the underlying networks in TRE. Completion of the proposed work will provide a causal understanding of the link between fronto-limbic network functions, anxiety, and epilepsy. The knowledge gained from this study will be applied to the field of mental health research to identify critical network nodes related to anxiety and demonstrate that this circuit can be modulated by electrical stimulation. The central hypothesis is that TRE is associated with disruption in the function of the fronto-limbic network (i.e., prefrontal cortex; amygdala), and in turn, this dysfunction disrupts healthy emotion regulation resulting in anxiety symptoms (Aim 1). Further, stimulation of dorsomedial prefrontal regions will directly influence anticipatory regulation of amygdala responses to threat (Aim 2). These aims will be accomplished in the context of a formal research plan, supported by a team of researchers with relevant expertise. Additionally, the data generated during the R21 effort will gather the preliminary data required for a competitive R01 randomized clinical trial application. The University of Alabama at Birmingham offers state-of-the-art research expertise and resources that will also serve to prepare this proposal for success. Specifically, the proposed work will utilize advanced sEEG recording and stimulation techniques, including functional connectivity and behavioral measures of emotion processes, one of the nation’s top epilepsy research and treatment centers, and a dynamic network of clinical research expertise, cores, and laboratories.