Feng Zhou1, Yayuan Geng1, Fei Xin1, Jialin Li1, Pan Feng2, Congcong Liu1, Weihua Zhao1, Tingyong Feng2, Adam J Guastella3, Richard P Ebstein4, Keith M Kendrick1, Benjamin Becker5. 1. Clinical Hospital of Chengdu Brain Science Institute and Ministry of Education (MOE) Key Laboratory for Neuroinformation, University of Electronic Science and Technology of China, Chengdu, China. 2. Faculty of Psychology, Southwest University, Chongqing, China; Key Laboratory of Cognition and Personality, Ministry of Education, Southwest University, Chongqing, China. 3. Autism Clinic for Translational Research, Brain and Mind Centre, Central Clinical School, Faculty of Medicine, University of Sydney, Camperdown, Australia; Youth Mental Health Unit, Brain and Mind Centre, Central Clinical School, Faculty of Medicine, University of Sydney, Camperdown, Australia. 4. China Center for Behavior Economics and Finance, Southwestern University of Finance and Economics, Chengdu, China. 5. Clinical Hospital of Chengdu Brain Science Institute and Ministry of Education (MOE) Key Laboratory for Neuroinformation, University of Electronic Science and Technology of China, Chengdu, China. Electronic address: ben_becker@gmx.de.
Abstract
BACKGROUND: Deficient extinction learning and threat adaptation in the ventromedial prefrontal cortex (vmPFC)-amygdala circuitry strongly impede the efficacy of exposure-based interventions in anxiety disorders. Recent animal models suggest a regulatory role of the renin-angiotensin system in both these processes. Against this background, the present randomized placebo-controlled pharmacologic functional magnetic resonance imaging experiment aimed at determining the extinction enhancing potential of the angiotensin II type 1 receptor antagonist losartan (LT) in humans. METHODS:Seventy healthy male subjects underwentPavlovian threat conditioning and received single-dose LT (50 mg) or placebo administration before extinction. Psychophysiological threat reactivity (skin conductance response) and neural activity during extinction served as primary outcomes. Psychophysiological interaction, voxelwise mediation, and novel multivariate pattern classification analyses were used to determine the underlying neural mechanisms. RESULTS: LT significantly accelerated the decline of the psychophysiological threat response during within-session extinction learning. On the neural level, the acceleration was accompanied and critically mediated by threat-specific enhancement of vmPFC activation. Furthermore, LT enhanced vmPFC-basolateral amygdala coupling and attenuated the neural threat expression, particularly in the vmPFC, during early extinction. CONCLUSIONS: Overall the results indicate that LT facilitates within-session threat memory extinction by augmenting threat-specific encoding in the vmPFC and its regulatory control over the amygdala. The findings document a pivotal role of angiotensin regulation of extinction learning in humans and suggest that adjunct LT administration has the potential to facilitate the efficacy of exposure-based interventions in anxiety disorders.
RCT Entities:
BACKGROUND:Deficient extinction learning and threat adaptation in the ventromedial prefrontal cortex (vmPFC)-amygdala circuitry strongly impede the efficacy of exposure-based interventions in anxiety disorders. Recent animal models suggest a regulatory role of the renin-angiotensin system in both these processes. Against this background, the present randomized placebo-controlled pharmacologic functional magnetic resonance imaging experiment aimed at determining the extinction enhancing potential of the angiotensin II type 1 receptor antagonist losartan (LT) in humans. METHODS: Seventy healthy male subjects underwent Pavlovian threat conditioning and received single-dose LT (50 mg) or placebo administration before extinction. Psychophysiological threat reactivity (skin conductance response) and neural activity during extinction served as primary outcomes. Psychophysiological interaction, voxelwise mediation, and novel multivariate pattern classification analyses were used to determine the underlying neural mechanisms. RESULTS: LT significantly accelerated the decline of the psychophysiological threat response during within-session extinction learning. On the neural level, the acceleration was accompanied and critically mediated by threat-specific enhancement of vmPFC activation. Furthermore, LT enhanced vmPFC-basolateral amygdala coupling and attenuated the neural threat expression, particularly in the vmPFC, during early extinction. CONCLUSIONS: Overall the results indicate that LT facilitates within-session threat memory extinction by augmenting threat-specific encoding in the vmPFC and its regulatory control over the amygdala. The findings document a pivotal role of angiotensin regulation of extinction learning in humans and suggest that adjunct LT administration has the potential to facilitate the efficacy of exposure-based interventions in anxiety disorders.
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