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

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.

SUBMITTER: Ridderbusch IC

PROVIDER: S-EPMC7200443 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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

Ridderbusch Isabelle C IC Yang Yunbo Y Weber Heike H Reif Andreas A Herterich Sabine S Ströhle Andreas A Pfleiderer Bettina B Arolt Volker V Wittchen Hans-Ulrich HU Lueken Ulrike U Kircher Tilo T Straube Benjamin B

NeuroImage. Clinical 20200423

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 behavi ...[more]

PMID: 32361414

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Project description:The extinction of contextual fear is commonly an essential requirement for successful exposure therapy for fear disorders. However, experimental work on extinction of contextual fear is limited, and there little or no directly relevant theoretical work. Here, we extend BACON, a neurocomputational model of context fear conditioning that provides plausible explanations for a number of aspects of context fear conditioning, to deal with extinction (calling the model BaconX). In this model, contextual representations are formed in the hippocampus and association of fear to them occurs in the amygdala. Representation creation, conditionability, and development of between-session extinction are controlled by degree of confidence (assessed by the Bayesian weight of evidence) that an active contextual representation is in fact that of the current context (i.e., is "valid"). The model predicts that: (1) extinction which persists between sessions will occur only if at a sessions end there is high confidence that the active representation is valid. It follows that the shorter the context placement-to-US (shock) interval ("PSI") and the less is therefore learned about context, the longer extinction sessions must be for enduring extinction to occur, while too short PSIs will preclude successful extinction. (2) Short-PSI deficits can be rescued by contextual exposure even after conditioning has occurred. (3) Learning to discriminate well between a conditioned and similar safe context requires representations of each to form, which may not occur if PSI was too short. (4) Extinction-causing inhibition must be applied downstream of the conditioning locus for reasonable generalization properties to be generated. (5) Context change tends to cause return of extinguished contextual fear. (6). Extinction carried out in the conditioning context generalizes better than extinction executed in contexts to which fear has generalized (as done in exposure therapy). (7) BaconX suggests novel approaches to exposure therapy.

Dataset Information

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

Publications

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

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