Time unpredictability increases BNST and amygdala activity during threat processing

 

Introduction Both animal studies and human studies suggest that the processing of aversive stimuli, from anticipation to confrontation, leads to an initial phasic response in the amygdala and an additional sustained response in the extended amygdala, in the bed nucleus of the stria terminalis (BNST). Furthermore, these effects seem to be modulated by the predictability of the aversive stimuli. However, there are few studies in humans that investigate these modulating effects of predictability in the confrontation with threatening stimuli on the activation of the amygdala and the BNST. In addition, no study has yet investigated a possible modulatory effect of the neuropeptide S receptor genotype (NPSR1) on susceptibility to temporal predictability.

Methods In this study, functional magnetic resonance imaging was used to investigate the anxiety network in 109 healthy subjects (37 males, age = 27.1 ± 6.3 years) during the anticipation and confrontation of a negative or neutral stimulus. An additional cue either signalled the exact time of the impending confrontation with the stimuli, or it signalled that the time is not predictable in time. ROI analyses with cluster-based permutations were used to identify significant clusters in the amygdala and BNST during threat prediction and confrontation. Genotype group differences in the significant clusters were analyzed.

Results The ROI analyses showed a higher activity during the announcement of an aversive stimulus compared to a neutral stimulus in the amygdala and the BNST. During the threat confrontation a main effect of predictability was shown in the right BNST and the right amygdala. Both regions showed a higher activation during the confrontation with unpredictable aversive stimuli. In addition, a significant major effect of valence during stimulus confrontation was observed in both the left BNST and the bilateral amygdala. Post-hoc analyses additionally showed that the valence effect of the left and right amygdala is modulated by the NPSR1 gene polymorphism. T-carriers showed a higher activity than homozygous A-carriers.

Conclusion A higher BNST activity during the valence information cue and during threat confrontation indicates that BNST activation is not limited to a persistent anticipatory response. A higher amygdala activity of AT/TT carriers of NPSR1 during threat confrontation is consistent with previous work and illustrates the risk potential of this allele. Future research will also use this study design in clinical samples to further investigate the modulation effects of temporal predictability and genotypes on anxiety-related brain activity.