PROJECT SUMMARY/ABSTRACT Anxiety-related psychopathology is a serious detriment to mental health in the United States, with total lifetime prevalence a staggering 31.2%. The most commonly used clinical technique in the treatment of many forms of anxiety-related psychopathology is exposure therapy. However, some patients do not benefit from treatment and experience return of fear. One potential explanation is that exposure techniques are designed to primarily address only a circumscribed set of stimuli and experiences. Consequently, reductions in fear tend not to generalize to the broader, more nebulous network of fear associations typically seen in pathological anxiety. In line with the RDoC Initiative and NIMH Strategic Objective 1 to define the mechanism of complex behaviors, the Aims of this application investigate the neurobehavioral mechanisms of higher-order generalization processes through which networks of abstract or indirect associations develop and spread. To do this, we draw on and combine two experimental literatures, associative learning (e.g., Pavlovian conditioning) and episodic memory, to precisely model and test the complex interplay of emotion, learning, and memory that results in dense and difficult to treat higher-order fear associations. Aim 1 of this proposal will investigate the neural mechanisms of how neutral and conditioned fear memories are integrated and retrieved in post-traumatic stress disorder (PTSD) and control participants. Advanced fMRI neuroimaging techniques will be used to quantify the degree of integration and its relation to fear learning and generalization. Although Pavlovian conditioning models are useful for testing fear generalization, the burden of anxiety-related psychopathology is comprised of more than internal fear and anxiety experiences. Behavioral avoidance and its interference in everyday life is also a key component of these pathologies, and generalized forms of avoidance are particularly impairing and difficult to treat. Further, avoidance is quick to generalize across stimuli based on abstract concepts, such as categorical similarity (e.g., learning to avoid all people in a specific social group). Accordingly, Aim 2 will test how fear and avoidance generalize across stimuli of varying degrees of conceptual similarity and identify key anxiety-related individual differences in these processes. In this behavioral test, psychophysiological and self-report indices will be submitted to sophisticated multilevel and latent profile analyses to optimize prediction of maladaptive forms of avoidance generalization. The combined Aims laid out in this proposal will significantly bolster current knowledge of the neural, cognitive, and behavioral mechanisms of higher-order and conceptual generalization and link these mechanisms to clinical anxiety and related traits. Completion of these Aims will advance knowledge of the neuroscience of emotional learning and memory and contribute to future treatments of anxiety-related psychopathology.

PROJECT NARRATIVE Exposure therapy is the most effective available strategy for the treatment of anxiety-related psychopathology; however, this intervention frequently fails to alleviate or prevent the return of symptoms. Advancements in our understanding of the neurobehavioral mechanisms of higher-order fear and avoidance generalization might provide a framework for improving exposure therapy techniques. We will test two different forms of higher-order generalization – one related to the integration of prior memories into novel related fear memories, and the other related to conceptual generalization of avoidance – in people with PTSD and with a range of anxiety-related traits, with the goal of informing future treatments for anxiety- related psychopathology.