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

Ridderbusch I.C., Yang, Y., Weber, H., Reif, A., Herterich, S., Ströhle, A., Pfleiderer, B., Arolt, V., Wittchen, H.-U., Lueken, U., Kircher, T., & Straube, B. (accepted). Neural correlates of NOS1 ex1f-VNTR allelic variation in panic disorder and agoraphobia during fear conditioning and extinction in fMRI. NeuroImage: Clinical IF: 3.943

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=15, S/L-genotype=21, L/L-genotype=12) and healthy control subjects, HS (n=34: S/S-genotype=7, S/L-genotype=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 x 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 x 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.

Keywords: panic disorder; NOS1; fear conditioning; extinction; imaging genetics