Adapting threat-related memories towards changing environments is a fundamental ability of organisms. One central process of fear reduction is suggested to be extinction learning, experimentally modeled by extinction training that is repeated exposure to a previously conditioned stimulus (CS) without providing the expected negative consequence (unconditioned stimulus, US). Although extinction training is well investigated, evidence regarding process-related changes in neural activation over time is still missing. Using optimized delayed extinction training in a multicentric trial we tested whether: 1) extinction training elicited decreasing CS-specific neural activation and subjective ratings, 2) extinguished conditioned fear would return after presentation of the US (reinstatement), and 3) results are comparable across different assessment sites and repeated measures. We included 100 healthy subjects (measured twice, 13-week-interval) from six sites. 24h after fear acquisition training, extinction training, including a reinstatement test, was applied during fMRI. Alongside, participants had to rate subjective US-expectancy, arousal and valence. In the course of the extinction training, we found decreasing neural activation in the insula and cingulate cortex as well as decreasing US-expectancy, arousal and negative valence towards CS+. Re-exposure to the US after extinction training was associated with a temporary increase in neural activation in the anterior cingulate cortex (exploratory analysis) and changes in US-expectancy and arousal ratings. While ICCs-values were low, findings from small groups suggest highly consistent effects across time-points and sites. Therefore, this delayed extinction fMRI-paradigm provides a solid basis for the investigation of differences in neural fear-related mechanisms as a function of anxiety-pathology and exposure-based treatment.

中文翻译：

---

延迟恐惧消退过程中扣带回和小岛活动的神经适应：评估部位和重复测量的可复制模式

使与威胁有关的记忆适应不断变化的环境是有机体的一项基本能力。建议减少恐惧的一个主要过程是灭绝学习，该实验是通过灭绝训练以实验方式建模的，该训练是反复暴露于先前有条件的刺激（CS）而没有提供预期的负面后果（美国无条件的刺激）。尽管对灭绝训练进行了充分的研究，但仍缺乏有关神经激活随时间变化的过程相关变化的证据。通过在多中心试验中使用优化的延迟灭绝训练，我们测试了以下各项：1）灭绝训练是否引起CS特异性神经激活和主观评分的降低，2）在美国出现后恢复的已消除的条件性恐惧（恢复原状），3）结果在不同评估地点和重复测量中具有可比性。我们纳入了六个地点的100名健康受试者（两次测量，间隔13周）。在恐惧获取训练后24小时，在功能磁共振成像期间进行了包括恢复测试在内的灭绝训练。同时，参与者必须对主观的美国期望，唤醒和效价进行评估。在灭绝训练的过程中，我们发现岛突和扣带回皮层的神经激活减少，以及对CS +的US期望，唤醒和负价降低。灭绝训练后再次暴露于美国与前扣带回皮层中神经激活的暂时增加（探索性分析）以及美国预期和唤醒等级的变化有关。尽管ICC值较低，小组的研究结果表明，各个时间点和地点的效果高度一致。因此，这种延迟消光功能磁共振成像范式为研究神经恐惧相关机制的差异提供了坚实的基础，这些差异与焦虑病理和基于暴露的治疗有关。