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Major Depressive Disorder (MDD) often is a recurrent and chronic disorder. We investigated the neurocognitive underpinnings of the incremental risk for poor disease course by exploring relations between enduring depression and brain functioning during regulation of negative and positive emotions using cognitive reappraisal.We used fMRI-data from the longitudinal Netherlands Study of Depression and Anxiety acquired during an emotion regulation task in 77 individuals with MDD. Task-related brain activity was related to disease load, calculated from presence and severity of depression in the preceding nine years. Additionally, we explored task related brain-connectivity. Brain functioning in individuals with MDD was further compared to 35 controls to explore overlap between load-effects and general effects related to MDD history/presence.Disease load was not associated with changes in affect or with brain activity, but with connectivity between areas essential for processing, integrating and regulating emotional information during downregulation of negative emotions. Results did not overlap with general MDD-effects. Instead, MDD was generally associated with lower parietal activity during downregulation of negative emotions. During upregulation of positive emotions, disease load was related to connectivity between limbic regions (although driven by symptomatic state), and connectivity between frontal, insular and thalamic regions was lower in MDD (vs controls).Results suggest that previous depressive load relates to brain connectivity in relevant networks during downregulation of negative emotions. These abnormalities do not overlap with disease-general abnormalities and could foster an incremental vulnerability to recurrence or chronicity of MDD. Therefore, optimizing emotion regulation is a promising therapeutic target for improving long-term MDD course.

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 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

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 patients with SAD compared 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.

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.

Background: Social anxiety disorder (SAD) is a disabling psychiatric condition with a genetic background. Brain alterations in gray matter (GM) related to SAD have been previously reported, but it remains to be elucidated whether GM measures are candidate endophenotypes of SAD. Endophenotypes are measurable characteristics on 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 endophenotype criteria, using data from a unique sample of SAD-patients and their family-members of two generations. First, we investigated whether GM characteristics co-segregate with social anxiety within families genetically enriched for 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 and cortical surface area were determined for a-priori determined regions of interest (ROIs). Next, associations with 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: These findings provide preliminary evidence that GM characteristics of multiple ROIs, which are distributed over the brain, are candidate endophenotypes of SAD. Thereby, they shed light on the genetic vulnerability for SAD. Future research is needed to confirm these results and to link them to functional brain alterations and to genetic variations underlying these GM changes. Fund: Leiden University Research Profile ‘Health, Prevention and the Human Life Cycle’. Keywords: Social anxiety disorder, Family study, Endophenotypes, Structural MRI

Social anxiety disorder (SAD) is a prevalent and disabling mental disorder, associated with significant psychiatric co-morbidity. Previous research on structural brain alterations associated with SAD has yielded inconsistent results concerning the direction of the changes in gray matter (GM) in various brain regions, as well as on the relationship between brain structure and SAD-symptomatology. These heterogeneous findings are possibly due to limited sample sizes. Multi-site imaging offers new opportunities to investigate SAD-related alterations in brain structure in larger samples.An international multi-center mega-analysis on the largest database of SAD structural T1-weighted 3T MRI scans to date was performed to compare GM volume of SAD-patients (n=174) and healthy control (HC)-participants (n=213) using voxel-based morphometry. A hypothesis-driven region of interest (ROI) approach was used, focusing on the basal ganglia, the amygdala-hippocampal complex, the prefrontal cortex, and the parietal cortex. SAD-patients had larger GM volume in the dorsal striatum when compared to HC-participants. This increase correlated positively with the severity of self-reported social anxiety symptoms. No SAD-related differences in GM volume were present in the other ROIs. Thereby, the results of this mega-analysis suggest a role for the dorsal striatum in SAD, but previously reported SAD-related changes in GM in the amygdala, hippocampus, precuneus, prefrontal cortex and parietal regions were not replicated. Our findings emphasize the importance of large sample imaging studies and the need for meta-analyses like those performed by the Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium. Keywords: Social anxiety disorder, Structural MRI, Voxel-based morphometry, Gray matter, Mega-analysis, Striatum