Insula volumes are altered in patients with social anxiety disorder.

OBJECTIVE: In the present study, we aimed at examining the volumes of the insula in more pure patients with a social anxiety disorder. METHODS: We examined twenty-one patients with social anxiety disorder according to DSM-IV and twenty healthy controls. All patients and controls were applied to magnetic resonance imaging (MRI). Insula volumes were measured by using the manual tracing method in accordance with the standard anatomical atlases and related previous studies on insula volumes. RESULTS: We found that the mean posterior and anterior insula volumes for both sides of patients were statistically significantly reduced compared to those of healthy control subjects. CONCLUSION: Consequently, in the present study, we found that patients with a social anxiety disorder had reduced insula volumes compared to those of healthy control subjects. However, to get strong this finding, novel studies with a larger sample size are required.

Dissociations in cortical thickness and surface area in non-comorbid never-treated patients with social anxiety disorder.

BACKGROUND: Abnormalities of functional activation and cortical volume in brain regions involved in the neurobiology of fear and anxiety have been implicated in the pathophysiology of social anxiety disorder (SAD). However, few studies have performed separate measurements of cortical thickness (CT) and cortical surface area (CSA) which reflect different neurobiological processes. Thus, we aimed to explore the cortical morphological anomaly separately in SAD using FreeSurfer. METHODS: High-resolution structural magnetic resonance images were obtained from 32 non-comorbid never-treated adult SAD patients and 32 demography-matched healthy controls. Cortical morphometry indices including CT and CSA were separately determined by FreeSurfer and compared between the two groups via whole-brain vertex-wise analysis, while partial correlation analysis using age and gender as covariates were conducted. FINDINGS: The patients with SAD showed decreased CT but increased CSA near-symmetrically in the bilateral prefrontal cortex (PFC) of the dorsolateral, dorsomedial, and ventromedial subdivisions, as well as the right lateral orbitofrontal cortex; increased CSA in the left superior temporal gyrus (STG) was also observed in SAD. The CSA in the left PFC was negatively correlated with the disease duration. INTERPRETATION: As the balloon model hypothesis suggests that the tangentially stretched cortex may cause dissociations in cortical morphometry and affect the cortical capacity for information processing, our findings of dissociated morphological alterations in the PFC and cortical expansion in the STG may reflect the morphological alterations of the functional reorganization in those regions, and highlight the important role of those structures in the pathophysiology and neurobiology of SAD. FUNDING: This study was funded by the National Natural Science Foundation of China (Grant Nos. 31700964, 31800963, 81621003, and 81820108018).

Mapping gene expression in social anxiety reveals the main brain structures involved in this disorder.

Social Anxiety Disorder (SAD) is characterized by emotional and attentional biases as well as distorted negative self-beliefs. According this, we proposed to identify the brain structures and hub genes involved in SAD. An analysis in Pubmed and TRANSFAC was conducted and 72 genes were identified. Using Microarray data, from Allen Human Brain Atlas, it was possible to identify three modules of co-expressed genes from our gene set (R package WGCNA). Higher mean gene expression was found in cortico-medial group, basomedial nucleus, ATZ in amygdala and in head and tail of the caudate nucleus, nucleus accumbens and putamen in striatum. Our enrichment analysis identified the followed hub genes: DRD2, HTR1A, JUN, SP1 and HDAC4. We suggest that SAD is explained by delayed extinction of circuitry for conditioned fear. Caused by reduced activation of the dopaminergic and serotonergic systems,due diminished expectation of reward during social interactions.

Comparison of social anxiety between Japanese adults who stutter and non-stuttering controls.

PURPOSE: Adults who stutter (AWS) often develop social anxiety disorder. This study was to provide comparative data on the Liebowitz Social Anxiety Scale-Japanese version (LSAS-J) from AWS and non-stuttering adult controls. METHODS: LSAS-J, a 24-item self-reported survey of social phobia and avoidance across various daily situations, was administered to 130 AWS (Mean Age = 41.5 years, SD = 15.8, 111 males) and 114 non-stuttering adults (Mean Age = 39.5, SD = 14.9, 53 males). The test-retest reliability and internal consistency of the LSAS-J were assessed. A between-subject multivariate analysis of variance (MANOVA) was also conducted to determine whether attitude toward social anxiety differed between AWS and AWNS, or by age (<40 and ≥ 40 years old), or sex (female and male). RESULTS: AWS reported higher scores on both fear subscales of the LSAS-J. Age had no significant influence on the social anxiety levels reported by either participant group. Sex differences were found in the fear subscales, with females scoring higher on both fear subscales, although these were only marginally significant (p = .06). LSAS-J showed good test-retest reliability and high Cronbach's alpha coefficient, indicating that it is an internally consistent measure of attitudes about social anxiety. CONCLUSION: Given the similarly high incidence of social anxiety in adults in Japan who stutter compared with those in other countries, social anxiety should be identified and assessed during clinical decision making and before decisions are made about stuttering treatment. LSAS-J is an easy tool to administer, and showed reliable results of social phobia and avoidance for AWS.

Effect of d-cycloserine on fear extinction training in adults with social anxiety disorder.

Preclinical and clinical data have shown that D-cycloserine (DCS), a partial agonist at the N-methyl-d-aspartate receptor complex, augments the retention of fear extinction in animals and the therapeutic learning from exposure therapy in humans. However, studies with non-clinical human samples in de novo fear conditioning paradigms have demonstrated minimal to no benefit of DCS. The aim of this study was to evaluate the effects of DCS on the retention of extinction learning following de novo fear conditioning in a clinical sample. Eighty-one patients with social anxiety disorder were recruited and underwent a previously validated de novo fear conditioning and extinction paradigm over the course of three days. Of those, only 43 (53%) provided analyzable data. During conditioning on Day 1, participants viewed images of differently colored lamps, two of which were followed by with electric shock (CS+) and a third which was not (CS-). On Day 2, participants were randomly assigned to receive either 50 mg DCS or placebo, administered in a double-blind manner 1 hour prior to extinction training with a single CS+ in a distinct context. Day 3 consisted of tests of extinction recall and renewal. The primary outcome was skin conductance response to conditioned stimuli, and shock expectancy ratings were examined as a secondary outcome. Results showed greater skin conductance and expectancy ratings in response to the CS+ compared to CS- at the end of conditioning. As expected, this difference was no longer present at the end of extinction training, but returned at early recall and renewal phases on Day 3, showing evidence of return of fear. In contrast to hypotheses, DCS had no moderating influence on skin conductance response or expectancy of shock during recall or renewal phases. We did not find evidence of an effect of DCS on the retention of extinction learning in humans in this fear conditioning and extinction paradigm.

Sub-types of safety behaviours and their effects on social anxiety disorder.

Cognitive models suggest that social anxiety disorder (SAD) is maintained through the use of safety behaviours. Previous reports propose that these safety behaviours can be subdivided into two main categories: avoidance and impression management. Study 1 investigates whether certain safety behaviours are specific to SAD. The social behaviour questionnaire was administered to individuals with SAD (N = 106), post-traumatic stress disorder (N = 28) and non-patient controls (N = 59). A factor analysis (N = 164) replicated the previously reported avoidance and impression management subtypes. Scores for both subtypes were significantly higher in individuals with SAD than in individuals with post-traumatic stress disorder or non-patient controls. Study 2 investigated the causal role of such safety behaviours using an experimental design in a non-clinical population (N = 96). Pairs of participants each engaged in two conversations. In one of the conversations, a randomly selected participant performed either avoidance or impression management safety behaviours. In the other conversation, neither participant was instructed to use safety behaviours. Each participant rated their own anxiety and performance as well as rating the other person. Videos of the conversations were also rated. Both types of safety behaviour increased anxiety in the person performing the safety behaviour. The avoidance subtype also had broader effects on the other person that were largely absent from the impression management subtype. Taken together the studies provide support for the distinction between safety behaviour subtypes and have implications for the treatment of SAD.

Posttraumatic stress disorder, social anxiety disorder and childhood trauma: Differences in hippocampal subfield volume.

Volume-based hippocampal findings in Social Anxiety Disorder (SAD) and Posttraumatic Stress Disorder (PTSD) have been inconsistent, with very little investigation of hippocampal subfields. We assessed the effects of early childhood trauma on hippocampal subfields in participants with SAD with and without early childhood trauma and PTSD, compared to healthy controls. The sample comprised 26 participants SAD with early childhood trauma, 22 participants with SAD without early childhood trauma, 17 with PTSD secondary to early childhood trauma and 25 control participants. We used Freesurfer version 6 to determine hippocampal subfield volumes. Findings included significant reduction in right parasubiculum volume between the PTSD group secondary to early childhood trauma and the SAD group without early childhood trauma, as well as a significant reduction in left HATA (Hippocampal Amygdala Transition Area) volume between PTSD with early childhood trauma compared to controls, as well as compared to SAD with early childhood trauma. These findings did withstand correction for multiple resting using the false discovery rate. Our findings of an association of reduced volumes in the parasubiculum and HATA regions with PTSD secondary to childhood trauma are interesting. Further work should investigate whether parasubiculum and HATA regional volume reductions in PTSD are a specific effect of early childhood trauma or a specific manifestation of PTSD pathology. Further work should also be undertaken to determine if hippocampal subfield atrophy is associated with SAD in the setting of early childhood maltreatment.

Biobehavioral threat sensitivity and amygdala volume: A twin neuroimaging study.

Current literature on the relationship between dispositional fear (or threat sensitivity) and amygdala gray matter volume (GMV) is heterogeneous, with findings including positive, negative, and null correlations. A clearer understanding of this relationship would help to determine the potential utility of amygdala volume as a biomarker of anxious/depressive (internalizing) disorders and contribute to understanding of neural mechanisms for variations in fearfulness. The study reported here used voxel-based morphometry to quantify amygdala GMV scores from structural neuroimaging data in a sample of 44 monozygotic twins (i.e., 22 pairs). Dispositional threat sensitivity (THT) was quantified using a biobehavioral cross-domain score that combined neurophysiological indicators with a psychological scale measure. Analyses revealed expected high concordance for amygdala GMV between co-twins. With respect to the major question of the study, a negative correlation was found between biobehavioral THT scores and amygdala volume - with individuals higher in THT showing smaller amygdala GMV scores. More modest associations of amygdala GMV with symptoms of social phobia, and fear disorder symptomology more broadly, were mediated by THT. These results provide insight into prior mixed findings and support the combined use of biological and behavioral measures to quantify characteristics relevant to mental health problems.

Comparison of adults who stutter with and without social anxiety disorder.

PURPOSE: Social anxiety disorder is a debilitating anxiety disorder associated with significant life impairment. The purpose of the present study is to evaluate overall functioning for adults who stutter with and without a diagnosis of social anxiety disorder. METHOD: Participants were 275 adults who stuttered (18-80 years), including 219 males (79.6%) and 56 females (20.4%), who were enrolled to commence speech treatment for stuttering. Comparisons were made between participants diagnosed with social anxiety disorder (n = 82, 29.8%) and those without that diagnosis (n = 193, 70.2%). RESULTS: Although the socially anxious group was significantly younger than the non-socially anxious group, no other demographic differences were found. When compared to the non-socially anxious group, the socially anxious group did not demonstrate significantly higher self-reported stuttering severity or percentage of syllables stuttered. Yet the socially anxious group reported more speech dissatisfaction and avoidance of speaking situations, significantly more psychological problems, and a greater negative impact of stuttering. CONCLUSION: Significant differences in speech and psychological variables between groups suggest that, despite not demonstrating more severe stuttering, socially anxious adults who stutter demonstrate more psychological difficulties and have a more negative view of their speech. The present findings suggest that the demographic status of adults who stutter is not worse for those with social anxiety disorder. These findings pertain to a clinical sample, and cannot be generalized to the wider population of adults who stutter from the general community. Further research is needed to understand the longer-term impact of social anxiety disorder for those who stutter.

Extrastriatal dopamine D2-receptor availability in social anxiety disorder.

Alterations in the dopamine system are hypothesized to influence the expression of social anxiety disorder (SAD) symptoms. However, molecular imaging studies comparing dopamine function between patients and control subjects have yielded conflicting results. Importantly, while all previous investigations focused on the striatum, findings from activation and blood flow studies indicate that prefrontal and limbic brain regions have a central role in the pathophysiology. The objective of this study was to investigate extrastriatal dopamine D2-receptor (D2-R) availability in SAD. We examined 12 SAD patients and 16 healthy controls using positron emission tomography and the high-affinity D2-R radioligand [11C]FLB457. Parametric images of D2-R binding potential were derived using the Logan graphical method with cerebellum as reference region. Two-tailed one-way independent ANCOVAs, with age as covariate, were used to examine differences in D2-R availability between groups using both region-based and voxel-wise analyses. The region-based analysis showed a medium effect size of higher D2-R levels in the orbitofrontal cortex (OFC) in patients, although this result did not remain significant after correction for multiple comparisons. The voxel-wise comparison revealed elevated D2-R availability in patients within OFC and right dorsolateral prefrontal cortex after correction for multiple comparisons. These preliminary results suggest that an aberrant extrastriatal dopamine system may be part of the disease mechanism in SAD.

Altered Topological Properties of Brain Networks in Social Anxiety Disorder: A Resting-state Functional MRI Study.

Recent studies involving connectome analysis including graph theory have yielded potential biomarkers for mental disorders. In this study, we aimed to investigate the differences of resting-state network between patients with social anxiety disorder (SAD) and healthy controls (HCs), as well as to distinguish between individual subjects using topological properties. In total, 42 SAD patients and the same number of HCs underwent resting functional MRI, and the topological organization of the whole-brain functional network was calculated using graph theory. Compared with the controls, the patients showed a decrease in 49 positive connections. In the topological analysis, the patients showed an increase in the area under the curve (AUC) of the global shortest path length of the network (Lp) and a decrease in the AUC of the global clustering coefficient of the network (Cp). Furthermore, the AUCs of Lp and Cp were used to effectively discriminate the individual SAD patients from the HCs with high accuracy. This study revealed that the neural networks of the SAD patients showed changes in topological characteristics, and these changes were prominent not only in both groups but also at the individual level. This study provides a new perspective for the identification of patients with SAD.

Brain activation to task-irrelevant disorder-related threat in social anxiety disorder: The impact of symptom severity.

Unintentional and uncontrollable processing of threat has been suggested to contribute to the pathology of social anxiety disorder (SAD). The present study investigated the neural correlates of processing task-irrelevant, highly ecologically valid, disorder-related stimuli as a function of symptom severity in SAD. Twenty-four SAD patients and 24 healthy controls (HC) performed a feature-based comparison task during functional magnetic resonance imaging, while task-irrelevant, disorder-related or neutral scenes were presented simultaneously at a different spatial position. SAD patients showed greater activity than HC in response to disorder-related versus neutral scenes in brain regions associated with self-referential processing (e.g. insula, precuneus, dorsomedial prefrontal cortex) and emotion regulation (e.g. dorsolateral prefrontal cortex (dlPFC), inferior frontal gyrus). Symptom severity was positively associated with amygdala activity, and negatively with activation in dorsal anterior cingulate cortex and dlPFC in SAD patients. Additional correlation analysis revealed that amygdala-prefrontal coupling was positively associated with symptom severity. A network of brain regions is thus involved in SAD patients' processing of task-irrelevant, complex, ecologically valid, disorder-related scenes. Furthermore, increasing symptom severity in SAD patients seems to reflect a growing imbalance between neural mechanisms related to stimulus-driven bottom-up and regulatory top-down processes resulting in dysfunctional regulation strategies.

Prefrontal mediation of emotion regulation in social anxiety disorder during laughter perception.

Social anxiety disorder (SAD) is characterized by negatively biased perception of social cues and deficits in emotion regulation. While negatively biased perception is thought to maintain social anxiety, emotion regulation represents an ability necessary to overcome both biased perception and social anxiety. Here, we used laughter as a social threat in a functional magnetic resonance imaging (fMRI) study to identify cerebral mediators linking SAD with attention and interpretation biases and their modification through cognitive emotion regulation in the form of reappraisal. We found that reappraisal abolished the negative laughter interpretation bias in SAD and that this process was directly mediated through activation patterns of the left dorsolateral prefrontal cortex (DLPFC) serving as a cerebral pivot between biased social perception and its normalization through reappraisal. Connectivity analyses revealed reduced prefrontal control over threat-processing sensory cortices (here: the temporal voice area) during cognitive emotion regulation in SAD. Our results indicate a central role for the left DLPFC in SAD which might represent a valuable target for future research on interventions either aiming to directly modulate cognitive emotion regulation in SAD or to evaluate its potential as physiological marker for psychotherapeutic interventions relying on emotion regulation.

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.

Error-related brain activity in youth and young adults before and after treatment for generalized or social anxiety disorder.

Increased error monitoring, as measured by the error-related negativity (ERN), has been shown to persist after treatment for obsessive-compulsive disorder in youth and adults; however, no previous studies have examined the ERN following treatment for related anxiety disorders. We used a flanker task to elicit the ERN in 28 youth and young adults (8-26years old) with primary diagnoses of generalized anxiety disorder (GAD) or social anxiety disorder (SAD) and 35 healthy controls. Patients were assessed before and after treatment with cognitive-behavioral therapy (CBT) or selective serotonin reuptake inhibitors (SSRI), and healthy controls were assessed at a comparable interval. The ERN increased across assessments in the combined sample. Patients with SAD exhibited an enhanced ERN relative to healthy controls prior to and following treatment, even when analyses were limited to SAD patients who responded to treatment. Patients with GAD did not significantly differ from healthy controls at either assessment. Results provide preliminary evidence that enhanced error monitoring persists following treatment for SAD in youth and young adults, and support conceptualizations of increased error monitoring as a trait-like vulnerability that may contribute to risk for recurrence and impaired functioning later in life. Future work is needed to further evaluate the ERN in GAD across development, including whether an enhanced ERN develops in adulthood or is most apparent when worries focus on internal sources of threat.

Neuroanatomical correlates of individual differences in social anxiety in a non-clinical population.

Socially anxious individuals are characterized as those with distorted negative self-beliefs (NSBs), which are thought to enhance reactions of social distress (emotional reactivity) and social avoidance (social functioning). However, it remains unclear whether individual differences in social distress and social avoidance are represented by differences in brain morphometry. To probe into these neural correlates, we analyzed magnetic resonance images of a sample of 130 healthy subjects and used the Connectome Computation System (CCS) to evaluate these factors. The results showed that social distress was correlated with the cortical volume of the right orbitofrontal cortex (OFC) and the subcortical volume of the left amygdala, while social avoidance was correlated with the cortical volume of the right dorsolateral prefrontal cortex (DLPFC). Additionally, loneliness might mediate the relationship between the amygdala volume and the social distress score. Our results demonstrated that social distress and social avoidance were represented by segregated cortical regions in the healthy individuals. These findings might provide a valuable basis for understanding the stable brain structures underlying individual differences in social anxiety.