Institute of Psychology, Leiden University, Wassenaarseweg 52, 2333 AK Leiden, The Netherlands; Department of Psychiatry, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands; Leiden Institute for Brain and Cognition, Leiden, The Netherlands.
Institute of Psychology, Leiden University, Wassenaarseweg 52, 2333 AK Leiden, The Netherlands; Leiden Institute for Brain and Cognition, Leiden, The Netherlands.
Neuroimage Clin. 2020;26:102247. doi: 10.1016/j.nicl.2020.102247. Epub 2020 Mar 16.
Social anxiety disorder (SAD) runs in families, but the neurobiological pathways underlying the genetic susceptibility towards SAD are largely unknown. Here, we employed an endophenotype approach, and tested the hypothesis that amygdala hyperreactivity to faces conditioned with a social-evaluative meaning is a candidate SAD endophenotype. We used data from the multiplex, multigenerational Leiden Family Lab study on Social Anxiety Disorder (eight families, n = 105) and investigated amygdala activation during a social-evaluative conditioning paradigm with high ecological validity in the context of SAD. Three neutral faces were repeatedly presented in combination with socially negative, positive or neutral sentences. We focused on two endophenotype criteria: co-segregation of the candidate endophenotype with the disorder within families, and heritability. Analyses of the fMRI data were restricted to the amygdala as a region of interest, and association analyses revealed that bilateral amygdala hyperreactivity in response to the conditioned faces co-segregated with social anxiety (SA; continuous measure) within the families; we found, however, no relationship between SA and brain activation in response to more specific fMRI contrasts. Furthermore, brain activation in a small subset of voxels within these amygdala clusters was at least moderately heritable. Taken together, these findings show that amygdala engagement in response to conditioned faces with a social-evaluative meaning qualifies as a neurobiological candidate endophenotype of social anxiety. Thereby, these data shed light on the genetic vulnerability to develop SAD.
社交焦虑障碍（SAD）在家族中存在，但导致 SAD 的遗传易感性的神经生物学途径在很大程度上尚不清楚。在这里，我们采用了一种内表型方法，并检验了以下假设，即杏仁核对面部的过度反应与具有社会评价意义的条件有关，这可能是 SAD 的候选内表型。我们使用了来自多基因、多代莱顿家族实验室社交焦虑障碍研究（8 个家庭，n=105）的数据，并在 SAD 背景下使用具有高度生态有效性的社会评价条件范式，调查了杏仁核的激活情况。三个中性面孔与社会上负面、正面或中性的句子反复呈现。我们关注两个内表型标准：候选内表型与家庭内疾病的共分离，以及遗传度。对 fMRI 数据的分析仅限于杏仁核作为感兴趣的区域，关联分析表明，双侧杏仁核对条件化面孔的过度反应与家庭内的社交焦虑（SA；连续测量）共分离；然而，我们没有发现 SA 与更具体的 fMRI 对比反应之间的关系。此外，这些杏仁核簇中一小部分体素内的大脑激活至少具有中度遗传性。总之，这些发现表明，杏仁核对具有社会评价意义的条件化面孔的反应可作为社交焦虑的神经生物学候选内表型。因此，这些数据揭示了遗传易感性导致 SAD 的机制。
