2010 — 2012 |
Lissek, Shmuel Mordechai |
R00Activity Code Description: To support the second phase of a Career/Research Transition award program that provides 1 -3 years of independent research support (R00) contingent on securing an independent research position. Award recipients will be expected to compete successfully for independent R01 support from the NIH during the R00 research transition award period. |
Generalization of Conditioned Fear as a Pathogenic Marker of Ptsd @ University of Minnesota
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.
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0.958 |
2016 — 2020 |
Lissek, Shmuel Mordechai |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Generalized Fear-Conditioning & Avoidance: Neurobiology & Transdiagnostic Import @ University of Minnesota
Project Summary: The objective of this project is to neurally, behaviorally, psychologically, and clinically characterize fundamental Pavlovian and instrumental dimensions of potential threat through which emotional and behavioral responses to threat cues generalize to resembling, safe stimuli. Such generalization is aligned with the potential threat construct due to the threat ambiguity, or uncertain threat value, inherent in these safe `generalization' stimuli. The Pavlovian dimension of interest is generalization of conditioned fear: a fundamental Pavlovian process through which fear transfers, or generalizes, to safe stimuli resembling a conditioned threat-cue (CS+). The targeted instrumental dimension is generalized avoidance: active decisions to withdraw from safe stimuli resembling the CS+ that are motivationally prompted by Pavlovian generalization. Given lab-based findings have linked heightened Pavlovian generalization to a variety of traditional anxiety disorders (PTSD, GAD, panic), overgeneralization represents a promising dimension of potential threat with transdiagnostic relevance to anxiety pathology. One central aspect of this project is testing personality and psychiatric factors (e.g., trait fear, internalizing, externalizing) that may account for the relevance of generalization and its neurobiology across traditional anxiety disorders. A second key aspect, is studying neural processes by which Pavlovian generalization evokes instrumental generalized avoidance of benign stimuli (resembling danger cues), which, when excessive, is likely to impair day-to-day functioning in anxiety patients. Unfortunately, human fear- conditioning experiments in clinical samples, have focused almost exclusively on passive-emotional, Pavlovian conditioning, to the virtual exclusion of studying active-behavioral, instrumental avoidance. The current fMRI project fills this gap by applying a novel Pavlovian-instrumental generalization paradigm to neurally and behaviorally elucidate Pavlovian processes leading to generalized instrumental avoidance. Personality moderators (e.g., dispositional resilience) of relations between Pavlovian and instrumental generalization will also be examined. The studied adult samples will display a wide range of symptom severity across traditional anxiety disorders and will include trauma survivors (N=114), and anxiety-clinic patients and healthy comparisons (N=159). Central goals of this proposal include: 1) elucidating the neurobiology of Pavlovian and instrumental generalization and their interaction, 2) testing relations between neural substrates of Pavlovian and instrumental generalization and broad psychiatric dysfunction (Aims2-3); and 3) assessing the degree to which relations between these dimensions of generalization and broad dysfunction are driven by transdiagnostic, psychometrically validated personality traits. This third and final goal is critical to the project, because individual difference measures capturing empirically-validated psychological constructs will likely track relations between fundamental conditioning processes (e.g., generalization) and general dysfunction, better than traditional, polythetic, diagnostic entities, that, by and large, do not reflect any single coherent psychological process.
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0.958 |