Background: Social anxiety disorder (SAD) is a serious psychiatric condition with a high prevalence, and a typical onset during childhood/adolescence. The condition runs in families, but it is... Show moreBackground: Social anxiety disorder (SAD) is a serious psychiatric condition with a high prevalence, and a typical onset during childhood/adolescence. The condition runs in families, but it is largely unknown which neurobiological characteristics transfer this genetic vulnerability ('endophenotypes'). Using data from the Leiden Family Lab study on SAD, including two generations of families genetically enriched for SAD, we investigated whether social anxiety (SA) co-segregated with changes in intrinsic functional connectivity (iFC), and examined heritability.Methods: Functional MRI data were acquired during resting-state in 109 individuals (56 males; mean age: 31.5, range 9.2-61.5 years). FSL's tool MELODIC was used to perform independent component analysis. Six networks of interest (default mode, dorsal attention, executive control, frontoparietal, limbic and salience) were identified at the group-level and used to generate subject-specific spatial maps. Voxel-wise regression models, with SA-level as predictor and voxel-wise iFC as candidate endophenotypes, were performed to investigate the association with SA, within masks of the networks of interest. Subsequently, heritability was estimated.Findings: SA co-segregated with iFC within the dorsal attention network (positive association in left middle frontal gyrus and right postcentral gyrus) and frontoparietal network (positive association within left middle temporal gyrus) (cluster-forming-threshold z>2.3, cluster-corrected extent-threshold p<0.05). Furthermore, iFC of multiple voxels within these clusters was at least moderately heritable.Interpretation: These findings provide initial evidence for increased iFC as candidate endophenotype of SAD, particularly within networks involved in attention. These changes might underlie attentional biases commonly present in SAD. (C) 2021 The Authors. Published by Elsevier B.V. Show less
Bas-Hoogendam, J.M.; Steenbergen, H. van; Tissier, R.L.M.; Wee, N.J.A. van der; Westenberg, P.M. 2020
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
In 2017 waren in Nederland tussen de 90.000 en 127.000 kinderen van 0 tot 18 jaar slachtoffer van een vorm van kindermishandeling. Zowel in Nederland als in andere landen lijkt het aantal... Show moreIn 2017 waren in Nederland tussen de 90.000 en 127.000 kinderen van 0 tot 18 jaar slachtoffer van een vorm van kindermishandeling. Zowel in Nederland als in andere landen lijkt het aantal slachtoffers van kindermishandeling niet te zijn afgenomen de afgelopen jaren. Dit heeft mogelijk te maken met de complexiteit van het probleem.Om tot een meer integratief beeld te komen van de antecedenten en consequenties van kindermishandeling bestudeerden we het functioneren van individuen op verschillende niveaus (fysiologie, cognitie, gedrag). Dit deden we binnen een multigenerationeel familieonderzoek.Samengenomen kunnen we op basis van de bevindingen verschillende conclusies trekken over mishandeling (bv. slaan, schelden) en verwaarlozing (bv. je kind onvoldoende van voedsel voorzien). Allereerst vonden we een sterkere evidentie voor de intergenerationele overdracht van mishandeling dan voor de intergenerationele overdracht van verwaarlozing. Daarnaast hing mishandeling samen met ouderlijk gedrag: ouders die mishandeling hadden ervaren in hun jeugd en mishandeling pleegden waren negatiever richting hun kinderen. Verwaarlozing, daarentegen, hing sterker samen met fysiologische reacties van ouders: ouders die meer waren verwaarloosd in hun jeugd lieten een verhoogde stressreactiviteit zien. Deze resultaten onderstrepen het belang om onderscheid te maken tussen mishandeling en verwaarlozing, zowel in onderzoek als in de praktijk. Show less
Patients with social anxiety disorder (SAD) are 'extremely shy': they are afraid of a negative evaluation by others and avoid social situations as much as possible, with negative influence on... Show morePatients with social anxiety disorder (SAD) are 'extremely shy': they are afraid of a negative evaluation by others and avoid social situations as much as possible, with negative influence on their lives. It is therefore important to gain insight in the factors that make children and adolescents vulnerable to develop SAD.SAD often runs in families: being ‘genetically close’ to a patient with SAD substantially increases the risk to develop the disorder. The studies summarized in this thesis aim to broaden our knowledge of this genetic vulnerability to SAD, by focusing on neurobiological endophenotypes as measured with structural and functional magnetic resonance imaging. We used data from the unique Leiden Family Lab study on Social Anxiety Disorder and demonstrated that several structural and functional brain alterations were genetically linked to the disorder. These results offer novel insights in the neurobiological pathways leading to SAD, and provide clues for prevention and intervention. Show less
The major challenge in analysing omic datasets is the strong dependencies which are present between samples and features. Taking into account and modelling the different dependency structures can... Show moreThe major challenge in analysing omic datasets is the strong dependencies which are present between samples and features. Taking into account and modelling the different dependency structures can lead to further improvements of our knowledge of the biological mechanisms. Therefore, improving our ability to predict diseases. This dissertation focuses on the development of new statistical methods designed to take into account the existing structures inside omic datasets by using mixed models, Gaussian graphical models, and machine learning approaches. Show less
Bas-Hoogendam, J.M.; Steenbergen, H. van; Tissier, R.L.M.; Houwing-Duistermaat, J.J.; Westenberg, P.M.; Wee, N.J.A. van der 2018
