Anxiety and paranoia can lead to a significant and debilitating impact on quality of life. Both anxiety and paranoia are believed to involve abnormalities of a threat detection system that includes limbic structures such as the amygdala and interactions with neocortical areas. This proposal aims to directly examine the spatiotemporal dynamics underlying the threat detection neural circuit by performing physiological recordings in the relevant structures within the adult human brain. We will record invasive neurophysiological data in epilepsy patients implanted with electrodes for clinical reasons while they perform cognitive tasks aimed to discriminate threat signals. By virtue of the high spatiotemporal resolution, extensive and dynamic recordings, we will be able to investigate the following fundamental questions: 1) Do threat stimuli (words and audiovisual inputs) engage the amygdala and related medial temporal structures to a greater degree than non-threatening stimuli? 2) Is there a greater degree of limbic engagement to non-threatening stimuli in subjects with elevated levels of paranoia and anxiety? 3) Is the interaction between neocortical areas (including language and visual cortex) and medial temporal structures enhanced during the processing of threat stimuli? (4) Is threat detection invariant to the specific input modalities suh as semantic or audiovisual access? To address these questions, we have assembled a team with expertise in Neurology and Psychiatry (Dr. Weisholtz, Dr. Silbersweig, Dr. Butler), epilepsy (Dr. Weisholtz, Dr. Dworetzky, Dr. Madsen) and systems and computational neuroscience (Dr. Kreiman). We will address these questions by examining localized evoked potentials and induced high- frequency activity in the brain regions of interest and by contrasting the response between threat and neutral stimuli. Interactions between regions will be explored by calculating the degree of inter-regional oscillatory phase locking and correlated gamma power. We will assess the degree of paranoia and anxiety using the Paranoia Rating Scale and the State-Trait Anxiety Inventory.These research efforts will contribute to a better understanding of the inner circuits responsible for anxiety and paranoia, and ultimately to the development of predictive tools and targeted therapies.