Intracranial Recording and Stimulation of the Human Hippocampal-Amygdala Circuit During Virtual Reality Fear Conditioning

PROJECT SUMMARY/ABSTRACT Anxiety disorders, including generalized anxiety disorder (GAD) and post-traumatic stress disorder (PTSD), are the most prevalent mental health conditions globally with a high rate of treatment resistance and substantial healthcare costs. These disorders are believed to stem from fear responses that are excessive and disproportionate to the situation. Therefore, understanding how the human brain processes fear and how this may go awry in anxiety disorders is crucial for developing effective therapies. Research using rodent models of anxiety suggests that the formation and regulation of fear responses to the environment require a complex interplay between two brain structures, the amygdala and hippocampus. However, it is unknown whether these findings can be translated to the human brain, and whether modulating neural activity associated with maladaptive fear responses can be used as a therapeutic tool to treat anxiety disorders. This project aims to 1) elucidate the neural mechanisms governing the acquisition, extinction, and renewal of fear and anxiety responses within the hippocampal-amygdala circuit in humans, 2) investigate whether targeted stimulation of the amygdala, aimed at dampening its role in maintaining fear responses to innocuous stimuli, can facilitate recovery from maladaptive fear responses, and 3) explore potential differences in outcomes based on individuals’ baseline anxiety levels. To address these questions, we will work with participants who have previously undergone surgical implantation of a responsive neurostimulation (RNS) device in the amygdala and hippocampus for the treatment of epilepsy or PTSD. The RNS is a chronically implanted intracranial recording and stimulation device that provides a unique opportunity to directly record from the hippocampal- amygdala circuit and deliver targeted stimulation. To simulate real-world fear responses and assess the impact of environmental context on fear learning, we designed a virtual reality (VR) experiment where participants acquire and subsequently extinguish fear responses to various stimuli within different virtual environments (e.g., library, grocery store), providing insights into how contextual cues influence fear responses. This award will allow me to complete a multifaceted career development plan under a world-class mentoring team. Building upon my prior experience with acutely implanted intracranial electrodes, I will broaden my skill set to encompass mobile (chronic) intracranial electrophysiology and targeted electrical stimulation. I will also develop expertise in the implementation of immersive, ambulatory VR experiments in human neuroscience research. Lastly, through seminars, coursework, and conferences, I will develop both as an experimental scientist and scientific communicator. Taken together, this will allow me to grow into an independent physician- scientist who effectively leverages innovative technologies to study the mechanisms of anxiety disorders.