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

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.

Keywords: Amygdala; Endophenotypes; Functional magnetic resonance imaging; Social anxiety disorder.

Fig. 1

Family within the LFLSAD. Families were included based on the combination of a parent with SAD (‘proband’; depicted in red) and a proband's child with SAD (red) or subclinical SAD (orange). In addition, family-members of two generations were invited, independent from the presence of SAD within these family-members (no SAD: light blue; did not participate: grey). Grandparents (generation 0; white) were not invited for participation. This family is slightly modified to guarantee anonymity; however, the number of family-members and the frequency of (sub)clinical SAD are depicted truthfully. Squares and circles represent men and women, respectively. Reprint of the figure published in (Bas-Hoogendam et al., 2018a). SAD: social anxiety disorder. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article) .

Fig. 2

Overview of the neutral faces paradigm (NFP). Stimuli were neutral faces selected from the FACES database (Ebner et al., 2010) (please note: the selected faces were different from the faces shown in this figure following the FACES Database Release Agreement); the paradigm consists of two fMRI phases, being a habituation phase (described in more detail in Supplemental Information as well as in (Bas-Hoogendam et al., 2019b)) and the social-evaluative conditioning phase (SCP) which is discussed in the present work. During the SCP, three neutral faces were consistently paired with either a positive endorsement, a negative comment or a socially-neutral statement, enabling participants to learn the social value of each face. At different time-points during the neutral faces paradigm (NFP), participants rated the faces on likeability and arousal.

Fig. 3

Behavioral ratings on the NFP. A) Ratings of likeability for the three conditions at the three timepoints. Faded colors at T1 and T2 indicate that the faces were not conditioned yet; at T3, participants had learned the social-evaluative value of the faces, as indicated by a significant interaction between time and condition, as well as an effect of condition at T3. Errorbars represent standard errors of the mean. B) Association between the level of social anxiety and learning the social-evaluative value of the faces (∆Likeability_T3_T2), depicted over all conditions (upper half) and separate for the three conditions (lower half). HP: habituation phase; NFP: neutral faces paradigm; SA: social anxiety; SCP: social-evaluative conditioning phase.

Fig. 4

Amygdala activation (group-level). Activation related to contrasts of interest within the amygdala regions of interest (depicted in green), over the whole sample (n = 105). The contrast ‘positive > neutral’ did not yield significant amygdala activation. Coordinates displayed slices (MNI space, x,y,z): −16, −8, −12 (contrasts ‘all faces > baseline’ and ‘negative conditioned face > neutral conditioned face’) and 20, −6, −12 (contrasts ‘all faces early > all faces late’ and ‘negative conditioned face > positive conditioned face’). Images are displayed according to radiological convention: right in the image is left in the brain.

Fig. 5

Association between social anxiety and brain activation in the amygdala. Amygdala activation related to viewing faces conditioned with a social-evaluative meaning (versus baseline) co-segregates with social anxiety within families. Significant positive associations between social anxiety and activation were present in both the left (36 voxels) and right (164 voxels) amygdala. Coordinates displayed slices (MNI space, x,y,z): 24, −8,−14. Images are displayed according to radiological convention: right in the image is left in the brain.