Neural Signature of Fear Overgeneralization in Trauma Exposed Adults

New York State Psychiatric Institute Dba Research Foundation For Mental Hygiene, Inc, New York NY

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Abstract

? DESCRIPTION (provided by applicant): Populations exposed to severe trauma such as war veterans, disaster survivors, and assault victims are at high risk for a range of trauma related psychopathology. Over one third of the exposed individuals are likely to develop significant and disabling psychopathology including posttraumatic stress disorder (PTSD), generalized anxiety disorder (GAD), panic disorder (PD), and major depression. However, efforts to advance knowledge on neural mechanisms of trauma related abnormalities have been hampered by a diagnostic categorical approach that has been focused almost solely on PTSD, neglecting a critical need to identify neural mechanisms of shared domains/constructs across anxiety, mood, and trauma-related disorders, which can be reliably measured and serve as physiological targets for novel treatments. Conditioned fear overgeneralization, in which there is deficiency in distinguishing learned danger cues from resembling safe stimuli, has been recently proposed as a potential endophenotype that crosses diagnostic boundaries including patients with PTSD, GAD and PD. The neural circuitry of fear overgeneralization has been elucidated in both animals and healthy humans, suggesting deficient functioning of the hippocampus and fear network regions. To advance identification of a neural signature of trauma related psychopathology that can potentially serve as a novel, neuroscience informed treatment target, and consistent with the RDoC emphasis on neurally-based domains of function across disorders, the current 4-year R01 application will use an fMRI paradigm for assessing fear overgeneralization among subjects with and without exposure to trauma (N=120). Eighty adults with well-ascertained, severe exposure to trauma and 40 matched non-trauma exposed healthy adults will be assessed. Rings of gradually increasing size will be visually presented during fMRI, with extreme sizes serving as conditioned danger cues (CS+; paired with electric shock) and conditioned safety cues (CS-). The rings of intermediary size serve as `generalization stimuli' (GS) and create a continuum-of-size between CS+ and CS-. Graphically represented conditioned-fear responses across this continuum, known as generalization gradients, have been reliably shown to have a steepness (or slope) that reflects the degree of generalization. For skin conductance response (SCR), a less steep slope indicates greater generalization. Separate generalization gradients will be generated by the paradigm for: a) regional fMRI activations; b) SCR; and 3) self-reported risk of shock. Machine-learning methodology will be applied to identify an fMRI-based neural signature of overgeneralization and test its associations with functional impairment and symptom severity across trauma- associated diagnoses. If successful, findings from this study will significantly advance the characterization of an endophenotype that will serve as an objective measure of pathology and a novel target for interventions specifically designed to target the impaired mechanism of overgeneralization and its neural signature.