Distressing reactions to perceived threats in safe environments is a hallmark feature of anxiety-related disorders such as post-traumatic stress disorder (PTSD) and generalized anxiety disorder (GAD). The development of novel targeted neural circuit therapies requires an understanding of how neurophysiological activity relates to behavior and subjective emotional experience. To determine electrophysiological signatures related to emotionally negative and clinically relevant states, we characterize intracranial oscillatory changes within the amygdala and other fear circuitry nodes (including the hippocampus and ventromedial Prefrontal Cortex), during a range of aversive experiences in humans with and without treatment-resistant post-traumatic stress disorder (TR-PTSD) in support of clinical trial (NCT04152993). Additionally, we present pilot neural and behavioral data during a novel virtual reality fear conditioning task compatible with simultaneous intracranial electroencephalography and fear behavior recordings in naturalistically behaving humans. We found increases in amygdala theta activity during unpleasant portions of six separate paradigms (emotional image task, fear conditioning task, script driven imagery task, virtual reality fear conditioning task, and at home recordings during symptomatic TR-PTSD states). Subsequent use of elevations in low-frequency amygdala bandpower as a trigger for closed-loop neuromodulation led to significant reductions in TR-PTSD symptoms and changes in amygdala theta activity following one year of treatment. Altogether, our findings connect decades of rodent literature to clinical symptoms and intracranial neurophysiology in humans and demonstrate the viability of responsive neurostimulation in TR-PTSD.