BACKGROUND: Patients with social anxiety disorder (SAD) fear negative evaluation in social situations. Specifically, previous work indicated that social anxiety is associated with increased medial... Show moreBACKGROUND: Patients with social anxiety disorder (SAD) fear negative evaluation in social situations. Specifically, previous work indicated that social anxiety is associated with increased medial prefrontal cortex activation in response to unintentional social norm (SN) transgressions, accompanied by increased embarrassment ratings for such SN violations. Here, we used data from the multiplex, multigenerational LFLSAD (Leiden Family Lab study on Social Anxiety Disorder), which involved two generations of families genetically enriched for SAD, and investigated whether these neurobiological and behavioral correlates of unintentional SN processing are SAD endophenotypes. Of four endophenotype criteria, we examined two: first, the cosegregation of these characteristics with social anxiety (SA) within families of SAD probands (criterion 4), and second, the heritability of the candidate endophenotypes (criterion 3).METHODS: Participants (n = 110, age range 9.0-61.5 years, eight families) performed the revised Social Norm Processing Task; functional magnetic resonance imaging data and behavioral ratings related to this paradigm were used to examine whether brain activation in response to processing unintentional SN violations and ratings of embarrassment were associated with SA levels. Next, heritability of these measurements was estimated.RESULTS: As expected, voxelwise functional magnetic resonance imaging analyses revealed positive associations between SA levels and brain activation in the medial prefrontal cortex and medial temporal gyrus, superior temporal gyrus, and superior temporal sulcus, and these brain activation levels displayed moderate to moderately high heritability. Furthermore, although SA levels correlated positively with behavioral ratings of embarrassment for SN transgressions, these behavioral characteristics were not heritable.CONCLUSIONS: These results show, for the first time, that brain responses in the medial prefrontal cortex and medial temporal gyrus, superior temporal gyrus, and superior temporal sulcus, related to processing unintentional SN violations, provide a neurobiological candidate endophenotype of SAD. Show less
Bas-Hoogendam, J.M.; Steenbergen, H. van; Blackford, J.U.; Tissier, R.L.M.; Wee, N.J.A. van der; Westenberg, P.M. 2019
Background Social anxiety disorder (SAD) is an incapacitating disorder running in families. Previous work associated social fearfulness with a failure to habituate, but the habituation response to... Show moreBackground Social anxiety disorder (SAD) is an incapacitating disorder running in families. Previous work associated social fearfulness with a failure to habituate, but the habituation response to neutral faces has, as of yet, not been investigated in patients with SAD and their family members concurrently. Here, we examined whether impaired habituation to neutral faces is a putative neurobiological endophenotype of SAD by using data from the multiplex and multigenerational Leiden Family Lab study on SAD. Methods Participants (n = 110; age, 9.2 - 61.5 years) performed a habituation paradigm involving neutral faces, as these are strong social stimuli with an ambiguous meaning. We used functional magnetic resonance imaging data to investigate whether brain activation related to habituation was associated with the level of social anxiety within the families. Furthermore, the heritability of the neural habituation response was estimated. Results Our data revealed a relationship between impaired habituation to neutral faces and social anxiety in the right hippocampus and right amygdala. In addition, our data indicated that this habituation response displayed moderate - to-moderately high heritability in the right hippocampus. Conclusion The present results provide support for altered habituation as a candidate SAD endophenotype; impaired neural habitation cosegregrated with the disorder within families and was heritable. These findings shed light on the genetic susceptibility to SAD. Show less
Bas-Hoogendam, J.M.; Steenbergen, H. van; Blackford, J.U.; Tissier, R.L.M.; Wee, N.J.A. van der; Westenberg, P.M. 2019
BackgroundSocial anxiety disorder (SAD) is an incapacitating disorder running in families. Previous work associated social fearfulness with a failure to habituate, but the habituation response to... Show moreBackgroundSocial anxiety disorder (SAD) is an incapacitating disorder running in families. Previous work associated social fearfulness with a failure to habituate, but the habituation response to neutral faces has, as of yet, not been investigated in patients with SAD and their family members concurrently. Here, we examined whether impaired habituation to neutral faces is a putative neurobiological endophenotype of SAD by using data from the multiplex and multigenerational Leiden Family Lab study on SAD.MethodsParticipants (n = 110; age, 9.2 – 61.5 years) performed a habituation paradigm involving neutral faces, as these are strong social stimuli with an ambiguous meaning. We used functional magnetic resonance imaging data to investigate whether brain activation related to habituation was associated with the level of social anxiety within the families. Furthermore, the heritability of the neural habituation response was estimated.ResultsOur data revealed a relationship between impaired habituation to neutral faces and social anxiety in the right hippocampus and right amygdala. In addition, our data indicated that this habituation response displayed moderate ‐ to‐moderately high heritability in the right hippocampus.ConclusionThe present results provide support for altered habituation as a candidate SAD endophenotype; impaired neural habitation cosegregrated with the disorder within families and was heritable. These findings shed light on the genetic susceptibility to SAD. Show less
Bas-Hoogendam, J.M.; Steenbergen, H. van; Tissier, R.L.M.; Wee, N.J.A. van der; Westenberg, P.M. 2019
BACKGROUND: Patients with social anxiety disorder (SAD) fear negative evaluation in social situations. Specifically, previous work indicated that social anxiety is associated with increased medial... Show moreBACKGROUND: Patients with social anxiety disorder (SAD) fear negative evaluation in social situations. Specifically, previous work indicated that social anxiety is associated with increased medial prefrontal cortex activation in response to unintentional social norm (SN) transgressions, accompanied by increased embarrassment ratings for such SN violations. Here, we used data from the multiplex, multigenerational LFLSAD (Leiden Family Lab study on Social Anxiety Disorder), which involved two generations of families genetically enriched for SAD, and investigated whether these neurobiological and behavioral correlates of unintentional SN processing are SAD endophenotypes. Of four endophenotype criteria, we examined two: first, the cosegregation of these characteristics with social anxiety (SA) within families of SAD probands (criterion 4), and second, the heritability of the candidate endophenotypes (criterion 3).METHODS: Participants (n = 110, age range 9.0-61.5 years, eight families) performed the revised Social Norm Processing Task; functional magnetic resonance imaging data and behavioral ratings related to this paradigm were used to examine whether brain activation in response to processing unintentional SN violations and ratings of embarrassment were associated with SA levels. Next, heritability of these measurements was estimated.RESULTS: As expected, voxelwise functional magnetic resonance imaging analyses revealed positive associations between SA levels and brain activation in the medial prefrontal cortex and medial temporal gyrus, superior temporal gyrus, and superior temporal sulcus, and these brain activation levels displayed moderate to moderately high heritability. Furthermore, although SA levels correlated positively with behavioral ratings of embarrassment for SN transgressions, these behavioral characteristics were not heritable.CONCLUSIONS: These results show, for the first time, that brain responses in the medial prefrontal cortex and medial temporal gyrus, superior temporal gyrus, and superior temporal sulcus, related to processing unintentional SN violations, provide a neurobiological candidate endophenotype of SAD. Show less
Social anxiety disorder (SAD) is a serious and prevalent psychiatric condition, with a heritable component. However, little is known about the characteristics that are associated with the genetic... Show moreSocial anxiety disorder (SAD) is a serious and prevalent psychiatric condition, with a heritable component. However, little is known about the characteristics that are associated with the genetic component of SAD, the so-called "endophenotypes". These endophenotypes could advance our insight in the genetic susceptibility to SAD, as they are on the pathway from genotype to phenotype. The Leiden Family Lab study on Social Anxiety Disorder (LFLSAD) is the first multiplex, multigenerational study aimed to identify neurocognitive endophenotypes of social anxiety. The LFLSAD is characterized by a multidisciplinary approach and encompasses a variety of measurements, including a clinical interview, functional and structural magnetic resonance imaging and an electroencephalography experiment. Participants are family members from 2 generations, from families genetically enriched for SAD. The sample (n = 132 participants, from 9 families) was characterized by a high prevalence of SAD, in both generations (prevalence (sub)clinical SAD: 38.3%). Furthermore, (sub)clinical SAD was positively related to self-reported social anxiety, fear of negative evaluation, trait anxiety, behavioral inhibition, negative affect, and the level of depressive symptoms. By the multidimensional character of the measurements and thorough characterization of the sample, the LFLSAD offers unique opportunities to investigate candidate neurocognitive endophenotypes of SAD. OBJECTIVES METHODS RESULTS CONCLUSIONS Show less
Background:Social anxiety disorder (SAD) is a disabling psychiatric condition with a genetic background. Brainalterations in gray matter (GM) related to SAD have been previously reported, but it... Show moreBackground:Social anxiety disorder (SAD) is a disabling psychiatric condition with a genetic background. Brainalterations in gray matter (GM) related to SAD have been previously reported, but it remains to be elucidatedwhether GM measures are candidate endophenotypes of SAD. Endophenotypes are measurable characteristicson the causal pathway from genotype to phenotype, providing insight in genetically-based disease mechanisms.Based on a review of existing evidence, we examined whether GM characteristics meet two endophenotypecriteria, using data from a unique sample of SAD-patients and their family-members of two generations. First,we investigatedwhether GMcharacteristics co-segregate with socialanxiety within families genetically enrichedfor SAD. Secondly, heritability of the GM characteristics was estimated.Methods:Families with a genetic predisposition for SAD participated in the Leiden Family Lab study on SAD;T1-weighted MRI brain scans were acquired (n= 110, 8 families). Subcortical volumes, cortical thickness andcortical surface area were determined for a-priori determined regions of interest (ROIs). Next, associationswith social anxiety and heritabilities were estimated.Findings:Several subcortical and cortical GM characteristics, derived from frontal, parietal and temporal ROIs, co-segregated with social anxiety within families (uncorrected p-level) and showed moderate to high heritability.Interpretation:Thesefindings provide preliminary evidence that GM characteristics of multiple ROIs, which aredistributed over the brain, are candidate endophenotypes of SAD. Thereby, they shed light on the genetic vulner-ability for SAD. Future research is needed to confirm these results and to link them to functional brain alterationsand to genetic variations underlying these GM changes.Fund:Leiden University Research Profile‘Health, Prevention and the Human Life Cycle’. Show less
