Localizing and modulating competing memories of fear and safety in the human brain

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PROJECT SUMMARY. Pathologies characterized by excessive fear and anxiety are the most common mental illness with a 12-month prevalence estimate of about 40 million American adults. The primary treatment for anxiety and stress-related disorders is exposure therapy, which is informed by theoretical and technical aspects of Pavlovian extinction. However, extinguished behaviors are prone to relapse under a variety of circumstances. Further, clinical research reveals serious deficits across a host of psychiatric conditions in the ability to form and retrieve extinction memories, which likely contributes to relapse following extinction-based therapies. Accordingly, there is strong motivation to better understand how extinction memories are encoded, stored, and expressed so as to bolster the strength and generalization of clinical treatment. Pioneering research in rodents reveals that fear conditioning and extinction generate separate and measurable memory traces within and across discrete brain regions. Whether such an organization exists in the human brain is unknown. More precise knowledge on how threat and safety memories are represented and interact in the human brain will advance innovative treatments for pathological anxiety that are built on the neuroscience of learning and memory. The goal of this research is to better understand how competing memories of fear and safety are formed, stored, and retrieved in the human brain. To build directly on mechanistic insights from animal models, we utilize Pavlovian fear conditioning and extinction in adult humans during functional magnetic resonance imaging (fMRI). The research leverages advances in multivariate pattern analysis techniques, and integrates theoretical and technical advancements of fear extinction research from animal models with computational approaches developed to study human memory. Each study includes healthy adults and individuals with posttraumatic stress disorder (PTSD), as linking advances in fear extinction research to the pathophysiology of PTSD can have direct benefit to exposure therapy—the gold-standard treatment based on the principles of extinction. We also evaluate extinction memory at 24-hours and again at 1 month. Assessing long-term extinction retrieval in humans is extremely rare, but consistent with diagnostic criteria for assessing PTSD, and thus furthers the bridge to translational relevance. Aim 1 attempts to identify separate and stable memory traces of fear and extinction in by identifying the correspondence (overlap) between neural activity related to the formation and retrieval of fear and extinction over time. Aim 2 decodes a multivariate neural signature selective to the contextual encoding of extinction memories. Aim 3 uses a non-pharmacological behavioral strategy to modulate the strength of extinction to determine how enhanced fear extinction affects multivariate neural signature of extinction memory retrieval over time. These findings have the potential to establish new risk and resilience factors for anxiety and stress-related pathologies, and may ultimately contribute to innovative neuroscience-based treatments for psychiatric conditions marked by excessive fear and the inability to regulate unwanted emotional responses.