Neuroanatomical findings on youth anxiety disorders are notoriously difficult to replicate, small in effect size and have limited clinical relevance. These concerns have prompted a paradigm shift... Show moreNeuroanatomical findings on youth anxiety disorders are notoriously difficult to replicate, small in effect size and have limited clinical relevance. These concerns have prompted a paradigm shift toward highly powered (that is, big data) individual-level inferences, which are data driven, transdiagnostic and neurobiologically informed. Here we built and validated supervised neuroanatomical machine learning models for individual-level inferences, using a case–control design and the largest known neuroimaging database on youth anxiety disorders: the ENIGMA-Anxiety Consortium (N = 3,343; age = 10–25 years; global sites = 32). Modest, yet robust, brain-based classifications were achieved for specific anxiety disorders (panic disorder), but also transdiagnostically for all anxiety disorders when patients were subgrouped according to their sex, medication status and symptom severity (area under the receiver operating characteristic curve, 0.59–0.63). Classifications were driven by neuroanatomical features (cortical thickness, cortical surface area and subcortical volumes) in fronto-striato-limbic and temporoparietal regions. This benchmark study within a large, heterogeneous and multisite sample of youth with anxiety disorders reveals that only modest classification performances can be realistically achieved with machine learning using neuroanatomical data. Show less
Bas, J.M.; Groenewold, N.A.; 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
Bas, J.M.; Bernstein, Rachel; Benson, Brenda E.; Buss, Kristin A.; Gunther, Kelley E.; Pérez-Edgar, Koraly; ... ; Pine, Daniel S. 2022
Cross-sectional Diffusion Tensor Imaging (DTI) studies have reported alterations in white matter (WM) microstructure in adolescents with internalizing psychopathology. Yet, longitudinal studies... Show moreCross-sectional Diffusion Tensor Imaging (DTI) studies have reported alterations in white matter (WM) microstructure in adolescents with internalizing psychopathology. Yet, longitudinal studies investigating the course of WM microstructure are lacking. This study explored WM alterations and its relation to clinical symptoms over time in adolescents with internalizing disorders. DTI scans were acquired at baseline and after three months in 22 adolescents with clinical depression and comorbid anxiety (INT), and 21 healthy peers (HC) (age: 12-18). Tract-based spatial statistics was used for three voxelwise analyses: i) changes in WM microstructure between and within the INT and HC group; ii) associations between changes in symptom severity and changes in WM microstructure within youths with INT; and iii) associations between baseline WM parameters with changes in symptom severity within youths with INT. Data did not reveal changes in WM microstructure between or within groups over three months' time nor associations between changes in WM microstructure and changes in self-reported symptoms (analyses corrected for age, gender and puberty stage). Lower baseline levels of fractional anisotropy (FA) in the right posterior corona radiata (PCR) and right cingulum were associated with a higher decrease of depressive symptoms within the INT group. Post hoc analysis of additional WM parameters in the significant FA clusters showed that higher levels of baseline mean diffusivity and radial diffusivity in the PCR were associated with a lower decrease in depressive symptoms. Baseline WM microstructure characteristics were associated with a higher decrease in depressive symptoms over time. These findings increase our understanding of neurobiological mechanisms underlying the course of internalizing disorders in adolescents. Show less
Bas, J.M.; Steenbergen, H. van; Kadosh, K.C.; Westenberg, P.M.; Wee, N.J.A. van der 2021
This review summarizes the last decade of work by the ENIGMA (Enhancing NeuroImaging Genetics through Meta Analysis) Consortium, a global alliance of over 1400 scientists across 43 countries,... Show moreThis review summarizes the last decade of work by the ENIGMA (Enhancing NeuroImaging Genetics through Meta Analysis) Consortium, a global alliance of over 1400 scientists across 43 countries, studying the human brain in health and disease. Building on large-scale genetic studies that discovered the first robustly replicated genetic loci associated with brain metrics, ENIGMA has diversified into over 50 working groups (WGs), pooling worldwide data and expertise to answer fundamental questions in neuroscience, psychiatry, neurology, and genetics. Most ENIGMA WGs focus on specific psychiatric and neurological conditions, other WGs study normal variation due to sex and gender differences, or development and aging; still other WGs develop methodological pipelines and tools to facilitate harmonized analyses of "big data" (i.e., genetic and epigenetic data, multimodal MRI, and electroencephalography data). These international efforts have yielded the largest neuroimaging studies to date in schizophrenia, bipolar disorder, major depressive disorder, post-traumatic stress disorder, substance use disorders, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, autism spectrum disorders, epilepsy, and 22q11.2 deletion syndrome. More recent ENIGMA WGs have formed to study anxiety disorders, suicidal thoughts and behavior, sleep and insomnia, eating disorders, irritability, brain injury, antisocial personality and conduct disorder, and dissociative identity disorder. Here, we summarize the first decade of ENIGMA's activities and ongoing projects, and describe the successes and challenges encountered along the way. We highlight the advantages of collaborative large-scale coordinated data analyses for testing reproducibility and robustness of findings, offering the opportunity to identify brain systems involved in clinical syndromes across diverse samples and associated genetic, environmental, demographic, cognitive, and psychosocial factors. 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
Social anxiety disorder (SAD), an impairing and often chronic psychiatric disorder (1), has a lifetime prevalence between 6 and 13% (2–5) and is prevailing worldwide (6). At present, treatment for... Show moreSocial anxiety disorder (SAD), an impairing and often chronic psychiatric disorder (1), has a lifetime prevalence between 6 and 13% (2–5) and is prevailing worldwide (6). At present, treatment for SAD is often suboptimal (7–10). Insight in the neurobiological changes underlying the socially-anxious brain is of utmost importance to improve preventive and therapeutic interventions.Until now, several studies have examined alterations in brain structure associated with SAD, by using magnetic resonance imaging (MRI). This method enables investigating changes in gray matter (GM) (11). Results of MRI studies on GM characteristics related to SAD show, however, little consistency and have small effect sizes (12–14).Recently, Wang et al. (15) described a voxel-based meta-analysis on GM volume (GMV) differences between SAD-patients and healthy participants. Such a meta-analytic review is very welcome in order to quantitatively summarize the results of previously published studies and to further increase our understanding of SAD-related GMV alterations. Unfortunately, the paper did not live up to its promise. Wang et al. state that SAD is associated with increased cortical and decreased subcortical GMVs, but these conclusions cannot be deduced from their data. Here, we want to point out several shortcomings that seriously affect this work. Show less
Bas, J.M.; Steenbergen, H. van; Wee, N.J.A. van der; Westenberg, P.M. 2018
Social anxiety disorder (SAD) is associated with altered social norm (SN) processing: SAD-patients rate stories on SN violations as more inappropriate and more embarrassing than healthy... Show moreSocial anxiety disorder (SAD) is associated with altered social norm (SN) processing: SAD-patients rate stories on SN violations as more inappropriate and more embarrassing than healthy participants, with the most prominent effect for stories on unintentional SN violations (i.e. committing a blunder). Until now it's unknown how levels of social anxiety (SA) are related to ratings of SN violations in the general population, in which SA-symptoms are present at a continuum. More insight in this relationship could improve our understanding of the symptom profile of SAD. Therefore, we investigated the relation between ratings of SN violations and SA-levels in the general population. Adults and adolescents (n = 87) performed the revised Social Norm Processing Task (SNPT-R) and completed self-report questionnaires on social anxiety. Repeated-measures ANCOVAs were used to investigate the effect of SA on the ratings of inappropriateness and embarrassment. As hypothesized, participants with higher SA-levels rated SN violations as more inappropriate and more embarrassing. Whereas participants with low-to-intermediate SA-levels rated unintentional SN violations as less embarrassing than intentional SN violations, participants with high SA-levels (z-score SA ≥ 1.6) rated unintentional SN violations as equally embarrassing as intentional SN violations. These findings indicate that increased embarrassment for unintentional SN violations is an important characteristic of social anxiety. These high levels of embarrassment are likely related to the debilitating concern of socially-anxious people that their skills and behavior do not meet expectations of others, and to their fear of blundering. This concern might be an important target for future therapeutic interventions. 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
Bas, J.M.; Steenbergen, H. van; Tissier, R.L.M.; Houwing-Duistermaat, J.J.; Westenberg, P.M.; Van der Wee, N.J.A. 2018
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
Bas, J.M.; Steenbergen, H. van; Pannekoek, J.N.; Fouche, J.P.; Lochner, C.; Hattingh, C.J.; ... ; Wee, N.J.A. van der 2017
