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Neural correlates of NOS1 ex1f-VNTR allelic variation in panic disorder and agoraphobia during fear conditioning and extinction in fMRI.

Authors
  • Ridderbusch, Isabelle C1
  • Yang, Yunbo2
  • Weber, Heike3
  • Reif, Andreas4
  • Herterich, Sabine5
  • Ströhle, Andreas6
  • Pfleiderer, Bettina7
  • Arolt, Volker8
  • Wittchen, Hans-Ulrich9
  • Lueken, Ulrike10
  • Kircher, Tilo2
  • Straube, Benjamin2
  • 1 Department of Psychiatry and Psychotherapy & Center for Mind, Brain and Behavior - CMBB, Philipps-Universität Marburg, Marburg, Germany. Electronic address: [email protected] , (Germany)
  • 2 Department of Psychiatry and Psychotherapy & Center for Mind, Brain and Behavior - CMBB, Philipps-Universität Marburg, Marburg, Germany. , (Germany)
  • 3 Department of Psychiatry, Psychosomatics, and Psychotherapy, University Hospital of Würzburg, Würzburg, Germany; Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt am Main, Germany. , (Germany)
  • 4 Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt am Main, Germany. , (Germany)
  • 5 Clinical Chemistry and Laboratory Medicine, University Hospital Würzburg, Würzburg, Germany. , (Germany)
  • 6 Department of Psychiatry and Psychotherapy, Campus Charité Mitte, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany. , (Germany)
  • 7 Medical Faculty, University of Münster and Department Clinical Radiology, University Hospital Münster, Münster, Germany. , (Germany)
  • 8 Department of Psychiatry and Psychotherapy, University Hospital Münster, Münster, Germany. , (Germany)
  • 9 Institute of Clinical Psychology and Psychotherapy, Technische Universität Dresden, Dresden, Germany; Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-Universität (LMU), München, Germany. , (Germany)
  • 10 Department of Psychology, Humboldt-Universität zu Berlin, Berlin, Germany. , (Germany)
Type
Published Article
Journal
NeuroImage Clinical
Publisher
Elsevier
Publication Date
Apr 23, 2020
Volume
27
Pages
102268–102268
Identifiers
DOI: 10.1016/j.nicl.2020.102268
PMID: 32361414
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Neuronal nitric oxide synthase (NOS-I) impacts on fear/anxiety-like behavior in animals. In humans, the short (S) allele of a functional promotor polymorphism of NOS1 (NOS1 ex1f-VNTR) has been shown to be associated with higher anxiety and altered fear conditioning in healthy subjects in the amygdala and hippocampus (AMY/HIPP). Here, we explore the role of NOS1 ex1f-VNTR as a pathophysiological correlate of panic disorder and agoraphobia (PD/AG). In a sub-sample of a multicenter cognitive behavioral therapy (CBT) randomized controlled trial in patients with PD/AG (n = 48: S/S-genotype n=15, S/L-genotype n=21, L/L-genotype n=12) and healthy control subjects, HS (n = 34: S/S-genotype n=7, S/L-genotype n=17, L/L-genotype=10), a differential fear conditioning and extinction fMRI-paradigm was used to investigate how NOS1 ex1f-VNTR genotypes are associated with differential neural activation in AMY/HIPP. Prior to CBT, L/L-allele carriers showed higher activation than S/S-allele carriers in AMY/HIPP. A genotype × diagnosis interaction revealed that the S-allele in HS was associated with a pronounced deactivation in AMY/HIPP, while patients showed contrary effects. The interaction of genotype × stimulus type (CS+, conditioned stimulus associated with an aversive stimulus vs. CS-, unassociated) showed effects on differential learning in AMY/HIPP. All effects were predominately found during extinction. Genotype associated effects in patients were not altered after CBT. Low statistical power due to small sample size in each subgroup is a major limitation. However, our findings provide first preliminary evidence for dysfunctional neural fear conditioning/extinction associated with NOS1 ex1f-VNTR genotype in the context of PD/AG, shedding new light on the complex interaction between genetic risk, current psychopathology and treatment-related effects. Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.

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