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Neural correlates of NOS1 ex1f-VNTR allelic variation in panic disorder and agoraphobia during fear conditioning and extinction in fMRI.
NeuroImage: Clinical ( IF 4.2 ) Pub Date : 2020-04-23 , DOI: 10.1016/j.nicl.2020.102268
Isabelle C Ridderbusch 1 , Yunbo Yang 1 , Heike Weber 2 , Andreas Reif 3 , Sabine Herterich 4 , Andreas Ströhle 5 , Bettina Pfleiderer 6 , Volker Arolt 7 , Hans-Ulrich Wittchen 8 , Ulrike Lueken 9 , Tilo Kircher 1 , Benjamin Straube 1
Affiliation  

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.

中文翻译:

fMRI中恐惧调节和消退期间惊恐障碍和广场恐惧症中NOS1 ex1f-VNTR等位基因变异的神经相关性。

神经元一氧化氮合酶(NOS-1)影响动物的恐惧/焦虑样行为。在人类中,NOS1(NOS1 ex1f-VNTR)的功能性启动子多态性的短(S)等位基因已显示出与杏仁核和海马体(AMY / HIPP)健康受试者中更高的焦虑度和恐惧条件有关。在这里,我们探讨了NOS1 ex1f-VNTR作为惊恐障碍和广场恐惧症(PD / AG)的病理生理相关性的作用。在多中心认知行为疗法(CBT)的PD / AG患者随机对照试验的子样本中(n = 48:S / S基因型n = 15,S / L基因型n = 21,L / L-基因型n = 12)和健康对照组,HS(n = 34:S / S基因型n = 7,S / L基因型n = 17,L / L基因型= 10),采用差异恐惧调节和消光fMRI范例研究了NOS1 ex1f-VNTR基因型与AMY / HIPP中差异神经激活的关系。在进行CBT之前,在AMY / HIPP中,L / L等位基因携带者比S / S等位基因携带者具有更高的激活性。基因型×诊断相互作用表明,HS中的S等位基因与AMY / HIPP的明显失活有关,而患者表现出相反的作用。基因型×刺激类型(CS +,与刺激性刺激相关的条件刺激与CS-,无关联)之间的相互作用显示了对AMY / HIPP差异学习的影响。在灭绝过程中主要发现所有影响。CBT后,患者的基因型相关效应未改变。由于每个亚组的样本量小,统计功效低是一个主要限制。然而,
更新日期:2020-04-23
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