Intracranial Neural Mechanisms of Fear Response in Humans with and without Anxiety-Related Disorders

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PROJECT SUMMARY/ABSTRACT Accumulating evidence from rodent studies suggests that the expression of fear emerges from electrophysiological changes within a neural network that includes the ventromedial prefrontal cortex (vmPFC), basolateral amygdala (BLA), and anterior hippocampus (aHPC)5. It is unclear whether this network exhibits similar dynamics during fear-related states in humans and how this activity is altered during inappropriate expression of fear that is often observed in individuals with anxiety-related disorders such as post-traumatic stress disorder (PTSD) or generalized anxiety disorder (GAD). The proposed study will investigate the relationship between deep brain activity (intracranial electroencephalographic and single unit) and physiological response (skin conductance response, pupil size, and heart rate/variability) in humans who are implanted with microwire electrodes for clinical evaluation and treatment of epilepsy who will complete a virtual reality fear conditioning task. Over the project period, the study will have access to 25 rare participants with and without anxiety disorders (i.e. post-traumatic stress disorder [PTSD] and/or generalized anxiety disorder [GAD]) implanted with depth electrodes in the vmPFC, BLA, and/or aHPC through an ongoing collaboration between clinical and basic science leaders at UCLA and the Veteran’s Administration Greater Los Angeles Healthcare System. Since our studies address basic questions surrounding the role of vmPFC-BLA-aHPC dynamics in regulating fear response, a process often compromised in psychiatric disease, it is anticipated that findings will bridge decades of human and animal fear-related research and lay the scientific foundation for improved understanding and treatment of anxiety-related disorders. In addition to completing the described research, I will undergo extensive professional and academic training to prepare me for my ultimate-goal of becoming a neurosurgeon-scientist. This will include mentorship from basic scientist experts in invasive human recording compatible experiments (Dr. Nanthia Suthana) and high level statistical analysis (Dr. Jonathan Kao) in addition to clinical and investigative guidance from a neurosurgeon- scientist (Dr. Jean Phillipe Langevin). Through working with these individuals along with my senior collaborators (Drs. Michelle Craske and Michael Fanselow), I will learn to design clinically relevant behavioral experiments, record invasive human neurophysiology, obtain expert knowledge in neuroscience and neuroanatomy, achieve a highly developed skillset for signals processing and statistical analysis and hone my clinical, writing, and presentation skills.