Janna Marie Bas-Hoogendam

Altered neural processing of emotional faces in remitted Cushing's disease

Patients with long-term remission of Cushings disease (CD) demonstrate residual psychological complaints. At present, it is not known how previous exposure to hypercortisolism affects psychological functioning in the long-term. Earlier magnetic resonance imaging (MRI) studies demonstrated abnormalities of brain structure and resting-state connectivity in patients with long-term remission of CD, but no data are available on functional alterations in the brain during the performance of emotional or cognitive tasks in these patients. We performed a cross-sectional functional MRI study, investigating brain activation during emotion processing in patients with long-term remission of CD. Processing of emotional faces versus a non-emotional control condition was examined in 21 patients and 21 matched healthy controls. Analyses focused on activation and connectivity of two a priori determined regions of interest: the amygdala and the medial prefrontal-orbitofrontal cortex (mPFC-OFC). We also assessed psychological functioning, cognitive failure, and clinical disease severity. Patients showed less mPFC activation during processing of emotional faces compared to controls, whereas no differences were found in amygdala activation. An exploratory psychophysiological interaction analysis demonstrated decreased functional coupling between the ventromedial PFC and posterior cingulate cortex (a region structurally connected to the PFC) in CD-patients. The present study is the first to show alterations in brain function and task-related functional coupling in patients with long-term remission of CD relative to matched healthy controls. These alterations may, together with abnormalities in brain structure, be related to the persisting psychological morbidity in patients with CD after long-term remission.

Neurobiological candidate endophenotypes of social anxiety disorder

Social anxiety disorder (SAD) is a disabling psychiatric disorder with a complex pathogenesis. Studies indicate a genetic component in the development of SAD, but the search for genetic mechanisms underlying this vulnerability is complicated. A focus on endophenotypes instead of the disorder itself may provide a fruitful path forward. Endophenotypes are measurable characteristics related to complex psychiatric disorders and reflective of genetically-based disease mechanisms, and could shed light on the ways by which genes contribute to the development of SAD. We review evidence for candidate MRI endophenotypes of SAD and discuss the extent to which they meet the criteria for an endophenotype, focussing on the amygdala, the medial prefrontal cortex, whole-brain functional connectivity and structural-anatomical changes. Strongest evidence is present for the primary endophenotype criterion of association between the candidate endophenotypes and SAD, while the other criteria, involving trait-stability, heritability and co-segregation of the endophenotype with the disorder within families, warrant further investigation. We highlight the potential of neuroimaging endophenotypes and stress the need for family studies into SAD endophenotypes.

Voxel-based morphometry multi-center mega-analysis of brain structure in social anxiety disorder

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.

How embarrassing! The behavioral and neural correlates of processing social norm violations.

Social norms are important for human social interactions, and violations of these norms are evaluated partly on the intention of the actor. Here, we describe the revised Social Norm Processing Task (SNPT-R), a paradigm enabling the study of behavioral and neural responses to intended and unintended social norm violations among both adults and adolescents. We investigated how participants (adolescents and adults, n = 87) rate intentional and unintentional social norm violations with respect to inappropriateness and embarrassment, and we examined the brain activation patterns underlying the processing of these transgressions in an independent sample of 21 adults using functional Magnetic Resonance Imaging (fMRI). We hypothesized to find activation within the medial prefrontal cortex, temporo-parietal cortex and orbitofrontal cortex in response to both intentional and unintentional social norm violations, with more pronounced activation for the intentional social norm violations in these regions and in the amygdala. Participants’ ratings confirmed the hypothesis that the three types of stories are evaluated differently with respect to intentionality: intentional social norm violations were rated as the most inappropriate and most embarrassing. Furthermore, fMRI results showed that reading stories on intentional and unintentional social norm violations evoked activation within the frontal pole, the paracingulate gyrus and the superior frontal gyrus. In addition, processing unintentional social norm violations was associated with activation in, among others, the orbitofrontal cortex, middle frontal gyrus and superior parietal lobule, while reading intentional social norm violations was related to activation in the left amygdala. These regions have been previously implicated in thinking about one’s self, thinking about others and moral reasoning. Together, these findings indicate that the SNPT-R could serve as a useful paradigm for examining social norm processing, both at the behavioral and the neural level.

The Leiden Family Lab study on Social Anxiety Disorder: A multiplex, multigenerational family study on neurocognitive endophenotypes

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 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.

Not intended, still embarrassed: Social anxiety is related to increased levels of embarrassment in response to unintentional social norm violations

BACKGROUNDnSocial 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 its 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.nnnMETHODSnAdults and adolescents (nu202f=u202f87) 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.nnnRESULTSnAs 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.nnnCONCLUSIONSnThese 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.

Subcortical brain volumes, cortical thickness and cortical surface area in families genetically enriched for social anxiety disorder – A multiplex multigenerational neuroimaging study

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 (nu202f=u202f110, 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’.

Sample size matters: A voxel-based morphometry multi-center mega-analysis of gray matter volume in social anxiety disorder

Sample Size Matters : A Voxel-Based Morphometry Multi-Center Mega-Analysis of Gray Matter Volume in Social Anxiety Disorder