Subcortical and psychopathological correlates of catecholamine-modulated long term fear acquisition and extinction

在“长期恐惧消退的儿茶酚胺能机制”项目中，我们进行了四项研究，包括脑电图、儿茶酚胺活性的药理操作和儿茶酚胺能基因变异（COMTVal158Met）的分子遗传评估。这些研究表明，长期恐惧习得与前中扣带皮层的振荡θ波活动有关，去甲肾上腺素激动剂育亨宾能增强长期恐惧习得，长期恐惧习得和恐惧消退的个体差异与COMTVal158Met有关。结果带来了新的问题，我们试图在随后的资助期内通过另外两项研究来回答这些问题。由于育亨宾对长期恐惧习得的影响是在外周而不是电皮层（即EEG）恐惧标记上观察到的，因此研究1的目的是将功能磁共振成像和育亨宾结合起来，阐明皮层下恐惧相关结构如杏仁核是否介导了去甲肾上腺素对长期恐惧习得的影响。N = 42名参与者执行为期两天的条件反射和消退范式的fmri适应变体，这是作为一部分开发的。在获得阶段后，参与者接受10毫克育亨宾或安慰剂（随机和双盲）。在随后的消退阶段和24小时后的回忆测试中，对育亨宾组和安慰剂组在条件和非条件刺激下的大脑活动进行了比较。研究2的目的是检验观察到的恐惧长期习得和消退指标是否为社交焦虑障碍（social anxiety disorder， SAD）提供潜在的风险标记。尽管对焦虑症的短期恐惧条件作用的研究较多，但对焦虑症是否具有长期稳定的恐惧习得和不稳定的恐惧消退的特征却鲜有研究。然而，特别是这种长期的学习和巩固过程，对焦虑症的发展和维持具有潜在的重要性。由于面部刺激的长期恐惧条件反射应该与SAD特别相关，我们的目的是比较N=20名SAD参与者和N=20名健康对照的长期恐惧条件反射和消退。为了进一步研究惊恐障碍的特异性，我们还将对N=20名惊恐障碍参与者进行测试。总之，预期的结果为结果提供了重要的扩展。他们告知育亨宾通过哪些脑区增强长期恐惧条件反射（研究1），以及增强的长期恐惧条件反射是否是焦虑症的潜在风险因素（研究2）。

In the project Catecholaminergic Mechanisms of Long-Term Fear Extinction four studies were conducted with N>200 multi-session measurements that included EEG, pharmacological manipulations of catecholamine activity and molecular genetic assessment of a catecholaminergic gene-variant (COMTVal158Met). These studies demonstrated that the long-term fear acquisition relates to oscillatory theta activity in the anterior midcingulate cortex, that the long-term fear acquisition is enhanced by the noradrenalin agonist yohimbine and that individual differences in long-term acquisition and extinction of fear are associated with COMTVal158Met. The results bring up new questions, which we attempt to answer with two additional studies during a subsequent funding period. Because the influence of yohimbine on the long-term fear acquisition was observed in peripheral but not electrocortical (i.e., EEG) fear markers, the goal of study 1 is to combine fMRI and yohimbine to clarify, whether subcortical fear-relevant structures like the amygdala mediate the effect of noradrenaline on long-term fear acquisition. N = 42 participants perform an fMRI-adapted variant of the two-day conditioning and extinction paradigm that was developed as part. Particpants receive 10 mg yohimbine or placebo (randomized and double-blind) after the acquisition phase. Brain activity to conditioned vs. non-conditioned stimuli during a subsequent extinction session and a recall test 24h later is compared between the yohimbin and placebo group. The goal of study 2 is to test, whether the observed indicators of long-term acquisition and extinction of fear provide potential risk markers for social anxiety disorder (SAD). In spite of many studies on short-term fear conditioning in anxiety disorders, it has been hardly investigated, whether anxiety disorders are characterized by more long-term stable fear acquisition and more labile fear extinction. Particularly such long-term learning- and consolidation processes, however, are of potential importance for the development and maintenance of anxiety disorders. Because the long-term fear conditioning of face stimuli should be of particular relevance for SAD, we aim to compare the long-term fear conditioning and extinction in N=20 participants with SAD and N=20 healthy controls. To further investigate the disorder specificity N=20 participants with panic disorder will also be tested. Together, the expected results provide important extensions to the results. They inform by which brain regions yohimbine potentiates long-term fear conditioning (study 1) and whether potentiated long-term fear conditioning is a potential risk factor for anxiety disorders (study 2).