There is limited convergence in neuroimaging investigations into volumes of subcortical brain regions in social anxiety disorder (SAD). The inconsistent findings may arise from variations in... Show moreThere is limited convergence in neuroimaging investigations into volumes of subcortical brain regions in social anxiety disorder (SAD). The inconsistent findings may arise from variations in methodological approaches across studies, including sample selection based on age and clinical characteristics. The ENIGMA-Anxiety Working Group initiated a global mega-analysis to determine whether differences in subcortical volumes can be detected in adults and adolescents with SAD relative to healthy controls. Volumetric data from 37 international samples with 1115 SAD patients and 2775 controls were obtained from ENIGMA-standardized protocols for image segmentation and quality assurance. Linear mixed-effects analyses were adjusted for comparisons across seven subcortical regions in each hemisphere using family-wise error (FWE)-correction. Mixed-effects d effect sizes were calculated. In the full sample, SAD patients showed smaller bilateral putamen volume than controls (left: d = −0.077, pFWE = 0.037; right: d = −0.104, pFWE = 0.001), and a significant interaction between SAD and age was found for the left putamen (r = −0.034, pFWE = 0.045). Smaller bilateral putamen volumes (left: d = −0.141, pFWE < 0.001; right: d = −0.158, pFWE < 0.001) and larger bilateral pallidum volumes (left: d = 0.129, pFWE = 0.006; right: d = 0.099, pFWE = 0.046) were detected in adult SAD patients relative to controls, but no volumetric differences were apparent in adolescent SAD patients relative to controls. Comorbid anxiety disorders and age of SAD onset were additional determinants of SAD-related volumetric differences in subcortical regions. To conclude, subtle volumetric alterations in subcortical regions in SAD were detected. Heterogeneity in age and clinical characteristics may partly explain inconsistencies in previous findings. The association between alterations in subcortical volumes and SAD illness progression deserves further investigation, especially from adolescence into adulthood. Show less
Groenewold, N.A.; Bas-Hoogendam, J.M.; Amod, A.R.; Laansma, M.A.; Velzen, L.S. van; Aghajani, M.; ... ; Wee, N.J.A. van der 2023
There is limited convergence in neuroimaging investigations into volumes of subcortical brain regions in social anxiety disorder (SAD). The inconsistent findings may arise from variations in... Show moreThere is limited convergence in neuroimaging investigations into volumes of subcortical brain regions in social anxiety disorder (SAD). The inconsistent findings may arise from variations in methodological approaches across studies, including sample selection based on age and clinical characteristics. The ENIGMA-Anxiety Working Group initiated a global mega-analysis to determine whether differences in subcortical volumes can be detected in adults and adolescents with SAD relative to healthy controls. Volumetric data from 37 international samples with 1115 SAD patients and 2775 controls were obtained from ENIGMA-standardized protocols for image segmentation and quality assurance. Linear mixed-effects analyses were adjusted for comparisons across seven subcortical regions in each hemisphere using family-wise error (FWE)-correction. Mixed-effects d effect sizes were calculated. In the full sample, SAD patients showed smaller bilateral putamen volume than controls (left: d = −0.077, pFWE = 0.037; right: d = −0.104, pFWE = 0.001), and a significant interaction between SAD and age was found for the left putamen (r = −0.034, pFWE = 0.045). Smaller bilateral putamen volumes (left: d = −0.141, pFWE < 0.001; right: d = −0.158, pFWE < 0.001) and larger bilateral pallidum volumes (left: d = 0.129, pFWE = 0.006; right: d = 0.099, pFWE = 0.046) were detected in adult SAD patients relative to controls, but no volumetric differences were apparent in adolescent SAD patients relative to controls. Comorbid anxiety disorders and age of SAD onset were additional determinants of SAD-related volumetric differences in subcortical regions. To conclude, subtle volumetric alterations in subcortical regions in SAD were detected. Heterogeneity in age and clinical characteristics may partly explain inconsistencies in previous findings. The association between alterations in subcortical volumes and SAD illness progression deserves further investigation, especially from adolescence into adulthood. Show less
Chen, J.; Bos, E. van den; Karch, J.D.; Westenberg, P.M. 2022
Background: Social anxiety has long been related to reduced eye contact, and this feature is seen as a causal and a maintaining factor of social anxiety disorder. The present research adds to the... Show moreBackground: Social anxiety has long been related to reduced eye contact, and this feature is seen as a causal and a maintaining factor of social anxiety disorder. The present research adds to the literature by investigating the relationship between social anxiety and visual avoidance of faces in a reciprocal face-to-face conversation, while taking into account two aspects of conversations as potential moderating factors: conversational role and level of intimacy. Method: Eighty-five female students (17-25 years) completed the Leibowitz Social Anxiety Scale and had a face-to-face getting-acquainted conversation with a female confederate. We alternated conversational role (talking versus listening) and manipulated intimacy of the topics (low versus high). Participants' gaze behavior was registered with Tobii eye-tracking glasses. Three dependent measures were extracted regarding fixations on the face of the confederate: total duration, proportion of fixations, and mean duration. Results: The results revealed that higher levels of social anxiety were associated with reduced face gaze on all three measures. The relation with total fixation duration was stronger for low intimate topics. The relation with mean fixation duration was stronger during listening than during speaking. Conclusion: The results highlight the importance of studying gaze behavior in a naturalistic social interaction. Show less
Background A variety of information sources are used in the best-evidence diagnostic procedure in child and adolescent mental healthcare, including evaluation by referrers and structured assessment... Show moreBackground A variety of information sources are used in the best-evidence diagnostic procedure in child and adolescent mental healthcare, including evaluation by referrers and structured assessment questionnaires for parents. However, the incremental value of these information sources is still poorly examined. Aims To quantify the added and unique predictive value of referral letters, screening, multi-informant assessment and clinicians' remote evaluations in predicting mental health disorders. Method Routine medical record data on 1259 referred children and adolescents were retrospectively extracted. Their referral letters, responses to the Strengths and Difficulties Questionnaire (SDQ), results on closed-ended questions from the Development and Well-Being Assessment (DAWBA) and its clinician-rated version were linked to classifications made after face-to-face intake in psychiatry. Following multiple imputations of missing data, logistic regression analyses were performed with the above four nodes of assessment as predictors and the five childhood disorders common in mental healthcare (anxiety, depression, autism spectrum disorders, attention-deficit hyperactivity disorder, behavioural disorders) as outcomes. Likelihood ratio tests and diagnostic odds ratios were computed. Results Each assessment tool significantly predicted the classified outcome. Successive addition of the assessment instruments improved the prediction models, with the exception of behavioural disorder prediction by the clinician-rated DAWBA. With the exception of the SDQ for depressive and behavioural disorders, all instruments showed unique predictive value. Conclusions Structured acquisition and integrated use of diverse sources of information supports evidence-based diagnosis in clinical practice. The clinical value of structured assessment at the primary-secondary care interface should now be quantified in prospective studies. Show less
Several studies have investigated the relationship between adolescents' responses to stress and general anxiety and depression, but only few studies addressed the relationship between responses to... Show moreSeveral studies have investigated the relationship between adolescents' responses to stress and general anxiety and depression, but only few studies addressed the relationship between responses to stress and social anxiety. The current three-wave longitudinal study, that covered a period of 5 years with a time interval of on average two years between waves, examined concurrent as well as prospective relations between adolescents' self-reported stress responses, including coping responses, and self-perceived social anxiety. Both the predictive power of social anxiety for different stress responses and, reversely, of stress responses for social anxiety were evaluated. Participants were 331 youth (170 boys) aged 9 to 17 years old at Wave 1. Self-report questionnaires were used to measure social anxiety, responses to social stress, and depressive symptoms. Results showed significant concurrent relations between social anxiety and maladaptive stress responses. Moreover, the study yielded evidence for social anxiety predicting stress responses across time as well as stress responses predicting social anxiety, although evidence for the former link is stronger. The findings suggest that a relative lack of adaptive stress responses may heighten social anxiety and social anxiety in turn may trigger maladaptive as well as adaptive responses to social problems. The relevance of these findings for social anxiety prevention and intervention purposes are discussed. Show less
To identify adolescents who may be at risk for adverse outcomes, we examined the extent of COVID-19-related concerns reported by adolescents and investigated which prepandemic risk and protective... Show moreTo identify adolescents who may be at risk for adverse outcomes, we examined the extent of COVID-19-related concerns reported by adolescents and investigated which prepandemic risk and protective factors predicted these concerns during the COVID-19 pandemic. Dutch adolescents (N = 188; M-age = 13.49, SD = .81) were assessed before the pandemic and at eight and ten months into the pandemic. Results demonstrated that adolescents' most frequently reported COVID-19-related concerns were about social activities and getting delayed in school. Adolescents that have specific vulnerabilities before the pandemic (i.e., higher stress, maladaptive coping, or internalizing problems) experience more concerns during the pandemic, stressing the importance of guiding and supporting these adolescents in order to prevent adverse developmental outcomes. Show less
Although referral letters (RLs) form a nodal point in a patient's care journey, little is known about their informative value in child and adolescent mental healthcare. To determine the informative... Show moreAlthough referral letters (RLs) form a nodal point in a patient's care journey, little is known about their informative value in child and adolescent mental healthcare. To determine the informative value of RLs to child and adolescent psychiatry, we conducted a chart review in medical records of minors registered at specialized mental healthcare between January 2015 and December 2017 (The Netherlands). Symptoms indicated in RLs originating from general practice (N = 723) were coded and cross-tabulated with the best estimate clinical classifications made in psychiatry. Results revealed that over half of the minors in the sample were classified in concordance with at least one reason for referral. We found fair to excellent discriminative ability for indications made in RLs concerning the most common psychiatric classifications (95% CI AUC: 60.9-70.6 for anxiety disorders to 90.5-100.0 for eating disorders). Logistic regression analyses suggested no statistically significant effects of gender, age, severity or mental healthcare history, with the exception of age and attention deficit hyperactivity disorders (ADHD), as RLs better predicted ADHD with increasing age (OR = 1.14, 95% CI 1.03-1.27). Contextual problems, such as difficulties studying, problems with parents or being bullied were indicated frequently and associated with classifications in various disorder groups. To conclude, general practitioners' RLs showed informative value, contrary to common beliefs. Replication studies are needed to reliably incorporate RLs into the diagnostic work-up. Show less
Although referral letters (RLs) form a nodal point in a patient's care journey, little is known about their informative value in child and adolescent mental healthcare. To determine the informative... Show moreAlthough referral letters (RLs) form a nodal point in a patient's care journey, little is known about their informative value in child and adolescent mental healthcare. To determine the informative value of RLs to child and adolescent psychiatry, we conducted a chart review in medical records of minors registered at specialized mental healthcare between January 2015 and December 2017 (The Netherlands). Symptoms indicated in RLs originating from general practice (N = 723) were coded and cross-tabulated with the best estimate clinical classifications made in psychiatry. Results revealed that over half of the minors in the sample were classified in concordance with at least one reason for referral. We found fair to excellent discriminative ability for indications made in RLs concerning the most common psychiatric classifications (95% CI AUC: 60.9-70.6 for anxiety disorders to 90.5-100.0 for eating disorders). Logistic regression analyses suggested no statistically significant effects of gender, age, severity or mental healthcare history, with the exception of age and attention deficit hyperactivity disorders (ADHD), as RLs better predicted ADHD with increasing age (OR = 1.14, 95% CI 1.03-1.27). Contextual problems, such as difficulties studying, problems with parents or being bullied were indicated frequently and associated with classifications in various disorder groups. To conclude, general practitioners' RLs showed informative value, contrary to common beliefs. Replication studies are needed to reliably incorporate RLs into the diagnostic work-up. Show less
Chronic stress is associated with dysregulations in the physiological stress system, resulting in diverse negative developmental outcomes. Since adolescence is a period characterized by increased... Show moreChronic stress is associated with dysregulations in the physiological stress system, resulting in diverse negative developmental outcomes. Since adolescence is a period characterized by increased stress-sensitivity, and schools are an important environment for the developing adolescent, school-based interventions promoting psychosocial functioning are of particular interest to prevent adverse outcomes. The present study therefore aimed to investigate the effectiveness of such interventions on hypothalamic pituitary adrenal-axis (i.e., cortisol) and cardiovascular (i.e., blood pressure [BP] and heart rate [HR]/heart rate variability [HRV]) parameters of stress in adolescents, and examined moderators of effectiveness. The search resulted in the inclusion of k = 9 studies for cortisol, k = 16 studies for BP, and k = 20 studies for HR/HRV. The results indicated a significant small overall effect on reducing BP, but no significant effect for HR/HRV. For cortisol, large methodological variation in the few primary studies did not allow for quantitative analyses, but a qualitative review demonstrated inconsistent results. For BP and HR/HRV, larger effects were observed for intervention programs with a mindfulness and/or meditation component, for interventions without a cognitive-behavioural component and for interventions with a higher intensity. Providing adolescents with techniques to improve indicators of physiological stress may prevent emerging mental health problems. Show less
Bas-Hoogendam, J.M.; Steenbergen, H. van; Kadosh, K.C.; Westenberg, P.M.; Wee, N.J.A. van der 2021
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, J.M.; Steenbergen, H. van; Kadosh, K.C.; Westenberg, P.M.; Wee, N.J.A. van der 2021
The cognitive model of social anxiety disorder hypothesized that socially anxious individuals tend to negatively interpret ambiguous scenarios, which was termed an Interpretation bias (IB). The... Show moreThe cognitive model of social anxiety disorder hypothesized that socially anxious individuals tend to negatively interpret ambiguous scenarios, which was termed an Interpretation bias (IB). The Adolescents' Interpretation Bias Questionnaire (AIBQ) is a widely used self-report instrument to measure IB towards social situations for adolescents. The main objective of the current study was to culturally revise AIBQ in Chinese adolescents. In total, 960 adolescents participated, and four weeks later, 185 of them were re-measured with Chinese version of AIBQ (C-AIBQ). We tested construct validity, examined internal consistency and test-retest reliability, and assessed convergent and divergent validity of the C-AIBQ subscales. Overall, C-AIBQ variables showed satisfactory construct validity, internal consistency, test-retest reliability and convergent and discriminant validity, in particular the social negative interpretation subscale. Our results indicate that this instrument is adequate to measure interpretation bias in Chinese adolescents. Show less
Chen, J.; Bos, E. van den; Velthuizen, S.L.M.; Westenberg, P.M. 2021
Patients with social anxiety disorder appear to display aberrant gaze behavior across a variety of social situations. In contrast, the gaze behavior of high socially anxious (HSA) individuals from... Show morePatients with social anxiety disorder appear to display aberrant gaze behavior across a variety of social situations. In contrast, the gaze behavior of high socially anxious (HSA) individuals from the community seems to depend on the type of situation and the aberration might be limited to gaze avoidance. This study investigated the differential effect of social situation-a face-viewing task and a public speaking task-on gaze behavior in HSA participants from a community sample. Participants' eye movements were tracked using a wearable eye tracker. Two aspects of gaze behavior were measured: (1) gaze avoidance was assessed by total fixation time, fixation counts, and mean fixation time on faces; (2) hypervigilance was assessed by scan path length and mean distance between fixations. The results confirmed a moderating effect of task on total (though not mean) fixation time on faces and fixation counts. Compared to low socially anxious participants, HSA participants looked less frequently (hence shorter) at the audience during the speech only. This indicates that visual avoidance in HSA individuals does not occur by default, but only when risks of (negative) social consequences are perceived. High and low socially anxious participants showed no difference in hypervigilance in either situation. Show less
Roelofs, E.F.; Bas-Hoogendam, J.M.; Ewijk, H. van; Ganjgahi, H.; Werff, S.J.A. van der; Barendse, M.E.A.; ... ; Wee, N.J.A. van der 2020
Background: Social anxiety disorder (SAD) is a mental illness with a complex, partially genetic background.Differences in characteristics of white matter (WM) microstructure have been reported in... Show moreBackground: Social anxiety disorder (SAD) is a mental illness with a complex, partially genetic background.Differences in characteristics of white matter (WM) microstructure have been reported in patients with SADcompared to healthy controls. Also, WM characteristics are moderately to highly heritable. Endophenotypes are measurable characteristics on the road from genotype to phenotype, putatively reflective of genetically based disease mechanisms. In search of candidate endophenotypes of SAD we used a unique sample of SAD patients and their family members of two generations to explore microstructure of WM tracts as candidate endophenotypes. We focused on two endophenotype criteria: co-segregation with social anxiety within the families, and heritability.Methods: Participants (n = 94 from 8 families genetically vulnerable for SAD) took part in the Leiden Family Lab Study on Social Anxiety Disorder (LFLSAD). We employed tract-based spatial statistics to examine structural WM characteristics, being fractional anisotropy (FA), axial diffusivity (AD), mean diffusivity (MD) and radial diffusivity (RD), in three a-priori defined tracts of interest: uncinate fasciculus (UF), superior longitudinal fasciculus (SLF) and inferior longitudinal fasciculus (ILF). Associations with social anxiety symptoms and heritability were estimated.Results: Increased FA in the left and right SLF co-segregated with symptoms of social anxiety. These findings were coupled with decreased RD and MD. All characteristics of WM microstructure were estimated to be at least moderately heritable. Conclusion: These findings suggest that alterations in WM microstructure in the SLF could be candidate endophenotypes of SAD, as they co-segregated within families genetically vulnerable for SAD and are heritable. These findings further elucidate the genetic susceptibility to SAD and improve our understanding of the overall etiology. 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
Objective To quantify general practitioners' (GPs) sensitivity to anxiety disorders (ADs) when confronted with the range of symptoms common to children with ADs. Also, to explore GPs' conscious... Show moreObjective To quantify general practitioners' (GPs) sensitivity to anxiety disorders (ADs) when confronted with the range of symptoms common to children with ADs. Also, to explore GPs' conscious preferences and implicit tendencies for referral of children with ADs to mental healthcare.Design and setting In a cross-sectional vignette-based survey, all attendees of a Dutch continuing medical education conference for primary care physicians were presented with subtitled audio fragments of five vignettes that we constructed to mimic symptom presentation of children with ADs in general practice. We asked attendees to select per vignette the most plausible diagnoses and most adequate referral option, and for their general referral preferences when they suspect each of the most common mental health problems.Participants A sample of 229 GPs, resulting in a total of 1128 vignette evaluations.Main outcome measure GPs' selection rate of ADs in the five vignettes compared with a benchmark provided by mental health professionals (MHPs).Results Overall, recognition of ADs was less likely in GPs compared with MHPs (OR=0.26, 95% CI 0.15 to 0.46). GPs varied in their recognition of anxiety, with 44.1% not once selecting anxiety as the probable presenting problem. When asked explicitly, 63.9% of the GPs reported that they would refer a child to mental healthcare when they suspect probable ADs. By contrast, only 12.0% of the GPs who recognised anxiety in the vignettes actually selected that referral option.Conclusion A significant fraction of GPs did not notice the depicted symptoms as anxiety. Despite the widespread prevalence of ADs, GPs seem to overlook anxiety already in their early diagnostic opinion. Improving GPs' familiarity with initial symptom presentation, ADs' base-rate, relevance and impact yields potential for timely recognition. Show less
Social anxiety disorder (SAD) is serious psychiatric condition with a genetic background. Insight into the neurobiological alterations underlying the disorder is essential to develop effective... Show moreSocial anxiety disorder (SAD) is serious psychiatric condition with a genetic background. Insight into the neurobiological alterations underlying the disorder is essential to develop effective interventions that could relieve SAD-related suffering. In this expert review, we consider recent neuroimaging work on SAD. First, we focus on new results from magnetic resonance imaging studies dedicated to outlining biomarkers of SAD, including encouraging findings with respect to structural and functional brain alterations associated with the disorder. Furthermore, we highlight innovative studies in the field of neuroprediction and studies that established the effects of treatment on brain characteristics. Next, we describe novel work aimed to delineate endophenotypes of SAD, providing insight into the genetic susceptibility to develop the disorder. Finally, we outline outstanding questions and point out directions for future research. Show less
