Project Summary Neuromodulation is becoming the new frontier in psychiatry. Our recent advances in the understanding of neural circuits involved in fear and its regulation provide us with a well-defined targets and circuits to manipulate to restore normal functioning. Transcranial magnetic stimulation (TMS) provides a great tool to non-invasively manipulate such circuits. Despite some great clinical success in TMS and its application to psychiatric conditions, the mechanisms of how TMS impacts fear circuits are not understood and its parameters currently employed are not fully optimized. Our objectives are to 1) understand how varying TMS parameters affect targeted brain regions in order to 2) optimize its impact on enhancing fear extinction memory consolidation in a population with known fear extinction deficiencies: posttraumatic stress disorder (PTSD). As with all manipulations, not all participants will respond to TMS and fear reduction induced by TMS will vary across subjects. An exploratory objective is to develop mathematical models for predicting who will respond to TMS based on the magnitude of conditioned and unconditioned fear along with clinical and anxiety measures. Subjects will undergo our well-established fear conditioning and extinction paradigm across 3 days. On day 1, they will be aversively conditioned to two cues. On day 2, subjects will undergo extinction training where conditioned cues will be paired with TMS in a temporally and anatomically specific manner. On day 3, conditioned cues will be presented in the fMRI scanner. The network to be investigated is the fear extinction circuit: the ventromedial prefrontal cortex (vmPFC), dorsal anterior cingulate cortex (dACC), hippocampus, and amygdala. Skin conductance response (SCR) will also be measured. We will explore the impact of narrow TMS timing variance (relative to onset of conditioned fear stimuli) and anatomical location on fear extinction memory on the activation of fear extinction network. Our target will be the dorsolateral prefrontal cortex (dlPFC) that is functionally coupled with the vmPFC. Using the principles of response surface methodology (RSM), we will characterize and establish the effect of temporal and anatomical variations of TMS relative to the conditioned cue on conditioned fear reduction (aim 1). We will then use the optimized TMS parameters to test if TMS can restore extinction memory deficit in subjects with PTSD (aim 2). An exploratory aim will be to develop mathematical models to predict TMS success in obtaining the best outcome on extinction memory based on SCR and clinical data. Our findings would provide key translational data applying knowledge gathered from rodents into the human brain and could help us understand the mechanisms of neuromodulation regarding change in the neural correlates of fear extinction network in PTSD patients.