Pathophysiology Of Social Anxiety Disorder Research Articles

The endocannabinoid system in social anxiety disorder: from pathophysiology to novel therapeutics.

Social anxiety disorder (SAD) is a highly prevalent psychiatric disorder that presents with an early age of onset, chronic disease course, and increased risk of psychiatric comorbidity. Current treatment options for SAD are associated with low response rates, suboptimal efficacy, and possible risk of adverse effects. Investigation of new neurobiological mechanisms may aid in the identification of more specific therapeutic targets for the treatment of this disorder. Emerging evidence suggests that the endogenous cannabinoid system, also referred to as the endocannabinoid system (ECS), could play a potential role in the pathophysiology of SAD. This review discusses the known pathophysiological mechanisms of SAD, the potential role of the ECS in this disorder, current drugs targeting the ECS, and the potential of these novel compounds to enhance the therapeutic armamentarium for SAD. Further investigational efforts, specifically in human populations, are warranted to improve our knowledge of the ECS in SAD.

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

BackgroundAbnormalities 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.MethodsHigh-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.FindingsThe 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.InterpretationAs 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.FundingThis study was funded by the 10.13039/501100001809National Natural Science Foundation of China (Grant Nos. 31700964, 31800963, 81621003, and 81820108018).

The Relationship between Plasma Oxytocin Levels and Social Anxiety Symptoms.

ObjectiveThe pathophysiology of social anxiety disorder (SAD) is not yet well understood, but previous research has suggested that oxytocin is associated with social behavior and may play a role in human anxiety states and anxiety-related traits. The aim of this study was to investigate the possible relationship between social anxiety symptoms and plasma oxytocin levels. MethodsTwenty-three male patients with SAD and 28 healthy male controls participated in this study. All participants were assessed using the Mini International Neuropsychiatric Interview (MINI) and the Liebowitz Social Anxiety Scale (LSAS). Multivariate regression analysis was performed to identify associations between plasma oxytocin levels and SAD. ResultsIn multiple regression models, after controlling for age and years of education, we found that higher oxytocin levels were significantly associated with higher total LSAS scores (R2=0.157, coefficient=0.145, 95% CI=-0.0005–0.291, p=0.051) and fear subscale scores (R2=0.134, coefficient=0.083, 95% CI=0.007–0.159, p=0.034) in the SAD group. ConclusionIn this study, increased plasma oxytocin levels were associated with higher social anxiety symptoms among SAD patients, but not among controls. This might be because among SAD patients, higher oxytocin (OT) secretion is an insufficient compensatory attempt to reduce social anxiety symptoms.

Altered Amygdala Resting-State Functional Connectivity and Hemispheric Asymmetry in Patients With Social Anxiety Disorder.

Background: The amygdala plays a key role in emotional hyperreactivity in response to social threat in patients with social anxiety disorder (SAD). We investigated resting-state functional connectivity (rs-FCN) of the left and right amygdala with various brain regions and functional lateralization in patients with SAD.Methods: A total of 36 patients with SAD and 42 matched healthy controls underwent functional magnetic resonance imaging (fMRI) at rest. Using the left and right amygdala as seed regions, we compared the strength of the rs-FCN in the patient and control groups. Furthermore, we investigated group differences in the hemispheric asymmetry of the functional connectivity maps of the left and right amygdala.Results: Compared with healthy controls, the rs-FCN between the left amygdala and the dorsolateral prefrontal cortex was reduced in patients with SAD, whereas left amygdala connectivity with the fusiform gyrus, anterior insula, supramarginal gyrus, and precuneus was increased or positively deflected in the patient group. Additionally, the strength rs-FCN between the left amygdala and anterior insula was positively associated with the severity of the fear of negative evaluation in patients with SAD (r = 0.338, p = 0.044). The rs-FCN between the right amygdala and medial frontal gyrus was decreased in patients with SAD compared with healthy controls, whereas connectivity with the parahippocampal gyrus was greater in the patient group than in the control group. The hemispheric asymmetry patterns in the anterior insula, intraparietal sulcus (IPS), and inferior frontal gyrus of the patient group were opposite those of the control group, and functional lateralization of the connectivity between the amygdala and the IPS was associated with the severity of social anxiety symptoms (r = 0.365, p = 0.037).Conclusion: Our findings suggest that in addition to impaired fronto-amygdala communication, the functional lateralization of amygdala function plays a central role in the pathophysiology of SAD.

Cerebellar Neural Circuits Involving Executive Control Network Predict Response to Group Cognitive Behavior Therapy in Social Anxiety Disorder.

Some intrinsic connectivity networks including the default mode network (DMN) and executive control network (ECN) may underlie social anxiety disorder (SAD). Although the cerebellum has been implicated in the pathophysiology of SAD and several networks relevant to higher-order cognition, it remains unknown whether cerebellar areas involved in DMN and ECN exhibit altered resting-state functional connectivity (rsFC) with cortical networks in SAD. Forty-six patients with SAD and 64 healthy controls (HC) were included and submitted to the baseline resting-state functional magnetic resonance imaging (fMRI). Seventeen SAD patients who completed post-treatment clinical assessments were included after group cognitive behavior therapy (CBT). RsFC of three cerebellar subregions in both groups was assessed respectively in a voxel-wise way, and these rsFC maps were compared by two-sample t tests between groups. Whole-brain voxel-wise regression was performed to examine whether cerebellar connectivity networks can predict response to CBT. Lower rsFC circuits of cerebellar subregions compared with HC at baseline (p<0.05, corrected by false discovery rate) were revealed. The left Crus I rsFC with dorsal medial prefrontal cortex was negatively correlated with symptom severity. The clinical assessments in SAD patients were significantly decreased after CBT. Higher pretreatment cerebellar rsFC with angular gyrus and dorsal lateral frontal cortex corresponded with greater symptom improvement following CBT. Cerebellar rsFC circuits involving DMN and ECN are possible neuropathologic mechanisms of SAD. Stronger pretreatment cerebellar rsFC circuits involving ECN suggest potential neural markers to predict CBT response.

Proton Magnetic Resonance Spectroscopy in Social Anxiety Disorder.

In the present study, 24 nonmedicated patients with social anxiety disorder (SAD) were compared with 24 healthy control subjects to assess metabolite levels in the anterior cingulate, insula, caudate, and putamen using proton magnetic resonance spectroscopy. The ratio of N-acetylaspartate (NAA)/creatine (Cr) was significantly higher in patients with SAD than in healthy control subjects in the anterior cingulate and insula. NAA/Cr ratios in the insula correlated positively with the Liebowitz Social Anxiety Scale total scores in patients with SAD. Our results support the significance and biochemical involvement of the anterior cingulate and insula in the pathophysiology of SAD.

Gray matter abnormalities in patients with social anxiety disorder: A voxel-based morphometry study

The main objective of this study was to investigate the gray matter volume (GMV) differences between the patients with social anxiety disorder (SAD) and healthy controls, using VBM analysis. A total of 27 consecutive patients (15 women and 12 men) with SAD and 27 age and sex-matched healthy control subjects were included in this study. With magnetic resonance imaging, we examined GMV differences between SAD and healthy control groups. We found that GMV in the right middle and inferior temporal, left superior parietal, left precuneus and right fusiform areas were significantly greater in patients with SAD than in healthy controls. In addition, GMV in the right inferior and middle temporal regions were positively correlated with the social avoidance and total social anxiety scores of the participants in the SAD group. Lastly, greater GMV in the left superior parietal and precuneal regions were correlated with the higher disability in the social life of the patients with SAD. Our results suggest that the regions that showed significant GMV differences between the two groups play an important role in the pathophysiology of SAD and increased GMV in these regions might reflect a pathological process of neural abnormalities in this disorder.

Animal models of social avoidance and social fear

Social fear and avoidance of social situations represent the main behavioral symptoms of social anxiety disorder (SAD), a highly prevalent anxiety disorder that is poorly elucidated and has rather unsatisfactory therapeutic options. Therefore, animal models are needed to study the underlying etiology and pathophysiology of SAD and to verify the efficacy of possible novel treatment approaches. In this review, we describe and discuss the most important paradigms that have been shown to induce social avoidance and fear in rodents, including foot shock exposure, restraint stress, social isolation, social instability, social defeat, conditioned defeat, social defeat/overcrowding, chronic subordinate colony housing, chronic mild stress, maternal separation and social fear conditioning. We also describe some of the behavioral paradigms used to assess social avoidance and fear in rodents, including the social interaction test, the social preference-avoidance test, the social approach-avoidance test, the three-chambered social approach test, the partition test and the modified Y-maze test. We focus on the behavioral alterations these paradigms induce, especially on social interaction, general anxiety and depressive-like behavior given that SAD is strongly comorbid with anxiety and affective disorders.

Changes in dopamine D2-receptor binding are associated to symptom reduction after psychotherapy in social anxiety disorder

The dopamine system has been suggested to play a role in social anxiety disorder (SAD), partly based on molecular imaging studies showing reduced levels of striatal dopaminergic markers in patients compared with control subjects. However, the dopamine system has not been examined in frontal and limbic brain regions proposed to be central in the pathophysiology of SAD. In the present study, we hypothesized that extrastriatal dopamine D2-receptor (D2-R) levels measured using positron emission tomography (PET) would predict symptom reduction after cognitive behavior therapy (CBT). Nine SAD patients were examined using high-resolution PET and the high-affinity D2-R antagonist radioligand [11C]FLB 457, before and after 15 weeks of CBT. Symptom levels were assessed using the anxiety subscale of Liebowitz Social Anxiety Scale (LSASanx). At posttreatment, there was a statistically significant reduction of social anxiety symptoms (P<0.005). Using a repeated measures analysis of covariance, significant effects for time and time × LSASanx change on D2-R-binding potential (BPND) were shown (P<0.05). In a subsequent region-by-region analysis, negative correlations between change in D2-R BPND and LSASanx change were found for medial prefrontal cortex and hippocampus (P<0.05). This is the first study to report a direct relationship between symptom change after psychological treatment and a marker of brain neurotransmission. Using an intra-individual comparison design, the study supports a role for the dopamine system in cortical and limbic brain regions in the pathophysiology of SAD.

Neural circuitry of submissive behavior in social anxiety disorder: A preliminary study of response to direct eye gaze

Fear of eye gaze is common in social anxiety disorder (SAD) and may represent an evolutionarily conserved submissive behavior. SAD subjects and healthy volunteers who underwent functional magnetic resonance imaging showed significant differences in neural activity in amygdala, fusiform, insula, anterior cingulate and prefrontal cortex in response to direct versus averted gaze. Neural response to direct gaze may identify brain regions important in the pathophysiology of SAD.

Increased Serotonin and Dopamine Transporter Binding in Psychotropic Medication–Naïve Patients with Generalized Social Anxiety Disorder Shown by123I-β-(4-Iodophenyl)-Tropane SPECT

There is circumstantial evidence for the involvement of serotonergic and dopaminergic systems in the pathophysiology of social anxiety disorder. In the present study, using SPECT imaging we examined the (123)I-beta-(4-iodophenyl)-tropane binding potential for the serotonin and dopamine transporters in patients with a generalized social anxiety disorder and in age- and sex-matched healthy controls. Twelve psychotropic medication-naïve patients with social anxiety disorder, generalized type (5 women and 7 men) and 12 sex- and age-matched healthy controls were studied. Volumes of interest were constructed on MRI-coregistered SPECT scans. Binding ratios were compared using the Mann-Whitney U test. Possible correlations between binding patterns and symptomatology were assessed using the Spearman rank correlation coefficient. Significantly higher binding potentials were found for the serotonin in the left and right thalamus of patients. Patients had also a significantly higher binding potential for the dopamine transporter in the striatum. The present study provided direct evidence for abnormalities in both the dopaminergic and the serotonergic systems in patients with generalized social anxiety disorder.

Low pregnenolone sulphate plasma concentrations in patients with generalized social phobia.

Animal studies have shown that neuroactive steroids modulate the activity of the gamma-aminobutyric acid type A/benzodiazepine receptor complex and that these steroids display anxiolytic or anxiogenic activity depending on their positive (e.g. allopregnanolone) or negative allosteric modulation (e.g. dehydroepiandrosterone sulphate) of this receptor. This study compared plasma levels of allopregnanolone, dehydroepiandrosterone sulphate and pregnenolone sulphate in healthy controls and in patients with generalized social phobia, as assessed with the Mini-International Neuropsychiatric Interview. Plasma concentrations of allopregnanolone, pregnenolone sulphate, and dehydroepiandrosterone sulphate were measured in 12 unmedicated male patients with generalized social phobia and 12 matched healthy male volunteers. Concentrations of pregnenolone sulphate were significantly lower in patients with generalized social phobia than in healthy controls. No statistically significant differences were found for the concentrations of allopregnanolone and dehydroepiandrosterone sulphate in plasma. These results are particularly interesting since we also observed lower pregnenolone sulphate concentrations in male patients suffering from generalized anxiety disorder. Their relevance to the pathophysiology of social anxiety disorder remains to be determined.