Amygdala hyperreactivity to faces conditioned with a social-evaluative meaning– a multiplex, multigenerational fMRI study on social anxiety endophenotypes

NeuroImage Clinical, vol. 26, pp. 102247

Abstract

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.

Authors 4

1. Janna Marie Bas‐Hoogendam corresponding Aachen Department of Psychiatry, Leiden University Medical Center Institute of Psychology, Leiden University Leiden Institute for Brain and Cognition

   Leiden University · Leiden University Medical Center

   Affiliation as printed

   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. Electronic address: j.m.hoogendam@fsw.leidenuniv.nl

   Department of Psychiatry, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands

   Institute of Psychology, Leiden University, Wassenaarseweg 52, 2333 AK Leiden, The Netherlands

   Leiden Institute for Brain and Cognition, Leiden, The Netherlands

2. Henk van Steenbergen Aachen Institute of Psychology, Leiden University Leiden Institute for Brain and Cognition

   Leiden University

   Affiliation as printed

   Institute of Psychology, Leiden University, Wassenaarseweg 52, 2333 AK Leiden, The Netherlands; Leiden Institute for Brain and Cognition, Leiden, The Netherlands. Electronic address: HvanSteenbergen@FSW.leidenuniv.nl

   Institute of Psychology, Leiden University, Wassenaarseweg 52, 2333 AK Leiden, The Netherlands

   Leiden Institute for Brain and Cognition, Leiden, The Netherlands

3. Nic J.A. van der Wee Aachen Department of Psychiatry, Leiden University Medical Center Leiden Institute for Brain and Cognition

   Leiden University · Leiden University Medical Center

   Affiliation as printed

   Department of Psychiatry, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands; Leiden Institute for Brain and Cognition, Leiden, The Netherlands. Electronic address: N.J.A.van_der_Wee@lumc.nl

   Department of Psychiatry, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands

   Leiden Institute for Brain and Cognition, Leiden, The Netherlands

4. P. Michiel Westenberg Aachen Institute of Psychology, Leiden University Leiden Institute for Brain and Cognition

   Leiden University

   Affiliation as printed

   Institute of Psychology, Leiden University, Wassenaarseweg 52, 2333 AK Leiden, The Netherlands; Leiden Institute for Brain and Cognition, Leiden, The Netherlands. Electronic address: westenberg@fsw.leidenuniv.nl

   Institute of Psychology, Leiden University, Wassenaarseweg 52, 2333 AK Leiden, The Netherlands

   Leiden Institute for Brain and Cognition, Leiden, The Netherlands