Generalization of Conditioned Fear as a Pathogenic Marker of PTSD

PTSD is a debilitating psychiatric condition precipitated by exposure to extreme, or life threatening, trauma with an estimated lifetime prevalence between 8% and 9% in U.S. adults. One core symptom of PTSD is intense psychological distress in the presence of stimuli that resemble one or more aspects of the trauma experience (DSM-IV). This phenomenon referred to as stimulus generalization has received surprisingly little empirical testing in the context of clinical anxiety in general, and PTSD more specifically. The current proposal represents the first effort to study the neurobiology and pharmacology of this PTSD-relevant learning phenomenon across those with and without PTSD, The objective of this particular proposal is to apply fMRI, psychophysiologic, and pharmacologic methods to: 1) identify brain mechanisms associated with generalization of conditioned fear, 2) test the degree to which such mechanisms operate aberrantly among those with PTSD, and, 3) examine the pharmacologic reversibility of these abnormalities using a partial agonist at the NMDA receptor complex (D-cycloserine) shown to increase discrimination of CS+ (danger cue) and CS- (safety cue) in animal studies. To fullfill the objectives of this application, a generalization paradigm has been designed and psychophysiologically validated in which 6 rings presented on a computer screen gradually increase in size. For half of participants the smallest ring is the conditioned stimulus paired with electric shock (CS+) and the largest is the unpaired stimulus (CS-), and for the other half of participants this is reversed. Anxious arousal measured psychophysiologically, and activity in fear-related brain structures measured via fMRI are predicted to gradually decrease as the presented stimulus gradually becomes less similar to the CS-i-, forming a generalization slope or gradient. One central hypothesis of the current application is that those with PTSD will display less steep gradients of generalization (i.e., more fear generalization) compared to healthy controls.