Microstructural white matter alterations associated with social anxiety disorders: A systematic review.

BACKGROUND: Social anxiety disorder (SAD) is a psychiatric condition characterized by impaired social functioning that negatively impacts individuals' quality of life. Previous neuroimaging studies have revealed morphological and functional changes in various brain regions associated with SAD. Recent advances in diffusion tensor imaging (DTI) and diffusion-weighted imaging (DWI) have enabled the investigation of microstructural white matter (WM) alterations in SAD. This study aims to provide an overview of DTI/DWI studies exploring WM microstructure changes in SAD. METHODS: A systematic search on PubMed, Scopus, Web of Science, and PsycINFO was conducted for relevant records on July 8, 2023. An exploratory meta-analysis was also performed. RESULTS: Eight studies were reviewed. Consistent findings indicated reduced fractional anisotropy and increased diffusivity measures in different WM tracts in SAD patients compared to healthy controls. These alterations were mostly observed within regions of the fronto-limbic network, like uncinate fasciculus (UF) and superior and inferior longitudinal fasciculi (SLF and ILF). Finally, our exploratory meta-analysis on four studies utilizing a voxel-wise analytic approach yielded no significant differences between SAD patients and controls. LIMITATIONS: Limited number of studies, small sample sizes, and heterogeneity in analysis methods. CONCLUSIONS: Patients with SAD exhibited altered WM integrity, particularly in the UF, SLF, and ILF, compared to healthy controls. However, due to the limited number of included studies, our meta-analysis yielded no significant differences between SAD patients and controls. Therefore, future research is crucial to unravel the link between altered WM structure and the involvement of other limbic and cortical structures in SAD pathogenesis.

Neural correlates of context-dependent extinction recall in social anxiety disorder: relevance of intrusions in response to aversive social experiences.

BACKGROUND: There are phenomenological similarities between social anxiety disorder (SAD) and posttraumatic stress disorder, such as a provoking aversive event, posttraumatic stress symptoms (e.g. intrusions) in response to these events and deficient (context-dependent) fear conditioning processes. This study investigated the neural correlates of context-dependent extinction recall and fear renewal in SAD, specifically in patients with intrusions in response to an etiologically relevant aversive social event. METHODS: During functional magnetic resonance imaging a two-day context-dependent fear conditioning paradigm was conducted in 54 patients with SAD and 54 healthy controls (HC). This included fear acquisition (context A) and extinction learning (context B) on one day, and extinction recall (context B) as well as fear renewal (contexts C and A) one day later. The main outcome measures were blood oxygen level-dependent responses in regions of interest and skin conductance responses. RESULTS: Patients with SAD showed reduced differential conditioned amygdala activation during extinction recall in the safe extinction context and during fear renewal in the acquisition context compared to HC. Patients with clinically relevant intrusions moreover exhibited hypoactivation of the ventromedial prefrontal cortex (vmPFC) during extinction learning, extinction recall, and fear renewal in a novel context, while amygdala activation more strongly decreased during extinction learning and increased during fear renewal in the acquisition context compared with patients without intrusions. CONCLUSIONS: Our study provides first evidence that intrusions in SAD are associated with similar deficits in context-dependent regulation of conditioned fear via the vmPFC as previously demonstrated in posttraumatic stress disorder.

A brain model of altered self-appraisal in social anxiety disorder.

The brain's default mode network has a central role in the processing of information concerning oneself. Dysfunction in this self-referential processing represents a key component of multiple mental health conditions, particularly social anxiety disorder (SAD). This case-control study aimed to clarify alterations to network dynamics present during self-appraisal in SAD participants. A total of 38 adolescents and young adults with SAD and 72 healthy control participants underwent a self-referential processing fMRI task. The task involved two primary conditions of interest: direct self-appraisal (thinking about oneself) and reflected self-appraisal (thinking about how others might think about oneself). Dynamic causal modeling and parametric empirical Bayes were then used to explore differences in the effective connectivity of the default mode network between groups. We observed connectivity differences between SAD and healthy control participants in the reflected self-appraisal but not the direct self-appraisal condition. Specifically, SAD participants exhibited greater excitatory connectivity from the posterior cingulate cortex (PCC) to medial prefrontal cortex (MPFC) and greater inhibitory connectivity from the inferior parietal lobule (IPL) to MPFC. In contrast, SAD participants exhibited reduced intrinsic connectivity in the absence of task modulation. This was illustrated by reduced excitatory connectivity from the PCC to MPFC and reduced inhibitory connectivity from the IPL to MPFC. As such, participants with SAD showed changes to afferent connections to the MPFC which occurred during both reflected self-appraisal as well as intrinsically. The presence of connectivity differences in reflected and not direct self-appraisal is consistent with the characteristic fear of negative social evaluation that is experienced by people with SAD.

Altered Putamen Activation for Social Comparison-Related Feedback in Social Anxiety Disorder: A Pilot Study.

INTRODUCTION: Social anxiety disorder (SAD) is characterized by abnormal processing of performance-related social stimuli. Previous studies have shown altered emotional experiences and activations of different sub-regions of the striatum during processing of social stimuli in patients with SAD. However, whether and to what extent social comparisons affect behavioural and neural responses to feedback stimuli in patients with SAD is unknown. MATERIALS AND METHODS: To address this issue, emotional ratings and functional magnetic resonance imaging (fMRI) responses were assessed while patients suffering from SAD and healthy controls (HC) were required to perform a choice task and received performance feedback (correct, incorrect, non-informative) that varied in relation to the performance of fictitious other participants (a few, half, or most of others had the same outcome). RESULTS: Across all performance feedback conditions, fMRI analyses revealed reduced activations in bilateral putamen when feedback was assumed to be received by only a few compared to half of the other participants in patients with SAD. Nevertheless, analysis of rating data showed a similar modulation of valence and arousal ratings in patients with SAD and HC depending on social comparison-related feedback. CONCLUSIONS: This suggests altered neural processing of performance feedback depending on social comparisons in patients with SAD.

Gray matter abnormalities in patients with major depressive disorder and social anxiety disorder: a voxel-based meta-analysis.

BACKGROUND: Major depressive and social anxiety disorders have a high comorbidity rate and similar cognitive patterns. However, their unique and shared neuroanatomical characteristics have not been fully identified. METHODS: Voxel-based morphometric studies comparing gray matter volume between patients with major depressive disorder/social anxiety disorder and healthy controls were searched using 4 electronic databases from the inception to March 2022. Stereotactic data were extracted and subsequently tested for convergence and differences using activation likelihood estimation. In addition, based on the result of the meta-analysis, behavioral analysis was performed to assess the functional roles of the regions affected by major depressive disorder and/or social anxiety disorder. RESULTS: In total, 34 studies on major depressive disorder with 2873 participants, and 10 studies on social anxiety disorder with 1004 subjects were included. Gray matter volume conjunction analysis showed that the right parahippocampal gyrus region, especially the amygdala, was smaller in patients compared to healthy controls. The contrast analysis of major depressive disorder and social anxiety disorder revealed lower gray matter volume in the right lentiform nucleus and medial frontal gyrus in social anxiety disorder and lower gray matter volume in the left parahippocampal gyrus in major depressive disorder. Behavioral analysis showed that regions with lower gray matter volume in social anxiety disorder are strongly associated with negative emotional processes. CONCLUSIONS: The shared and unique patterns of gray matter volume abnormalities in patients with major depressive and social anxiety disorder may be linked to the underlying neuropathogenesis of these mental illnesses and provide potential biomarkers. PROSPERO registration number: CRD42021277546.

Brain mediators of biased social learning of self-perception in social anxiety disorder.

Social anxiety disorder (SAD) is characterized by an excessive fear of social evaluation and a persistently negative view of the self. Here we test the hypothesis that negative biases in brain responses and in social learning of self-related information contribute to the negative self-image and low self-esteem characteristic of SAD. Adult participants diagnosed with social anxiety (N = 21) and matched controls (N = 23) rated their performance and received social feedback following a stressful public speaking task. We investigated how positive versus negative social feedback altered self-evaluation and state self-esteem and used functional Magnetic Resonance Imaging (fMRI) to characterize brain responses to positive versus negative feedback. Compared to controls, participants with SAD updated their self-evaluation and state self-esteem significantly more based on negative compared to positive social feedback. Responses in the frontoparietal network correlated with and mirrored these behavioral effects, with greater responses to positive than negative feedback in non-anxious controls but not in participants with SAD. Responses to social feedback in the anterior insula and other areas mediated the effects of negative versus positive feedback on changes in self-evaluation. In non-anxious participants, frontoparietal brain areas may contribute to a positive social learning bias. In SAD, frontoparietal areas are less recruited overall and less attuned to positive feedback, possibly reflecting differences in attention allocation and cognitive regulation. More negatively biased brain responses and social learning could contribute to maintaining a negative self-image in SAD and other internalizing disorders, thereby offering important new targets for interventions.

Disrupted brain gray matter connectome in social anxiety disorder: a novel individualized structural covariance network analysis.

Phenotyping approaches grounded in structural network science can offer insights into the neurobiological substrates of psychiatric diseases, but this remains to be clarified at the individual level in social anxiety disorder (SAD). Using a recently developed approach combining probability density estimation and Kullback-Leibler divergence, we constructed single-subject structural covariance networks (SCNs) based on multivariate morphometry (cortical thickness, surface area, curvature, and volume) and quantified their global/nodal network properties using graph-theoretical analysis. We compared network metrics between SAD patients and healthy controls (HC) and analyzed the relationship to clinical characteristics. We also used support vector machine analysis to explore the ability of graph-theoretical metrics to discriminate SAD patients from HC. Globally, SAD patients showed higher global efficiency, shorter characteristic path length, and stronger small-worldness. Locally, SAD patients showed abnormal nodal centrality mainly involving left superior frontal gyrus, right superior parietal lobe, left amygdala, right paracentral gyrus, right lingual, and right pericalcarine cortex. Altered topological metrics were associated with the symptom severity and duration. Graph-based metrics allowed single-subject classification of SAD versus HC with total accuracy of 78.7%. This finding, that the topological organization of SCNs in SAD patients is altered toward more randomized configurations, adds to our understanding of network-level neuropathology in SAD.

Dysfunction of default mode network characterizes generalized anxiety disorder relative to social anxiety disorder and post-traumatic stress disorder.

BACKGROUND: The perseverative cognition of generalized anxiety disorder (GAD) is distinctive compared to other anxiety disorders. However, the disease-specific and shared neuropathophysiological mechanisms of GAD remain unclear. METHODS: We recruited medication-free patients of GAD (N = 33), social anxiety disorder (SAD; N = 36), post-traumatic stress disorder (PTSD; N = 59), and healthy controls (HC; N = 50). All subjects underwent clinical assessments and resting-state functional magnetic resonance imaging. We compared both the amplitude low-frequency fluctuation (ALFF) and seed-based functional connectivity across the whole brain, using the significantly different regions from the ALFF analyses as seed regions, followed by post-hoc tests. RESULTS: We found that ALFF of the left angular gyrus (AG), left inferior parietal lobule (IPL), left precentral gyrus, left middle temporal gyrus, and left cerebellum were higher in GAD compared with SAD, PTSD and HC. This trend was further corroborated by the higher functional connectivity between left AG and bilateral IPL, left inferior temporal gyrus, and left medial prefrontal cortex (mPFC) in GAD. In addition, GAD and SAD both showed abnormally higher left AG-right insula connectivity. Significant correlations were found between anxiety symptom severity and the left AG regional activity and left AG-left mPFC connectivity. LIMITATIONS: We did not compare the differences in neuroimaging between GAD and other anxiety disorders, such as panic disorder. CONCLUSIONS: The default mode network dysfunction may underlie the distinctive perseverative thoughts of GAD relative to other anxiety disorders, and left AG-right insula connectivity may reflect somatic anxiety of anxiety disorder spectrum.

Associations between resting-state neural connectivity and positive affect in social anxiety disorder.

INTRODUCTION: Social anxiety disorder (SAD) has been characterized by deficits in social motivation and lack of reactivity to pleasurable stimuli (i.e., positive affect; [PA]). Recent neuroimaging work has shifted toward examining positively valenced motivational systems in SAD focused on reward responses. However, little is known about the associations of reward connectivity and PA in individuals with SAD. As such, the purpose of the current study was to determine whether connectivity among key units of reward neurocircuitry meaningfully relate to PA and whether these key units are more heterogeneous in SAD as compared to controls. METHODS: Thirty-one participants who met diagnostic criteria for SAD and 33 control participants were included (Mage = 24.8, SD = 6.9; 55% cisgender man). Seed-based timeseries correlations were conducted in NiTime to extract region of interest (ROI) coupling correlation strength values. ANOVAs were carried out to assess whether individuals with SAD differed in ROI-to-ROI connectivity strength as compared to controls. Correlations and variance analyses were also conducted to examine the relationship between ROI-to-ROI connectivity strength and PA, as well as heterogeneity in connectivity strength and PA expression. RESULTS: Weaker connectivity between the left and right orbital frontal cortex was observed when comparing the SAD to the control group. Within the SAD group, PA was associated with several reward-related ROI couplings; however, these links were not observed among controls. Results further demonstrated that individuals with SAD had significantly more variability in reward connectivity strength as compared to controls. CONCLUSION: Overall, these results provide emergent evidence for the association between reward regions and PA in individuals with SAD. Additionally, these findings show that individuals with SAD demonstrate greater heterogeneity in reward connectivity.

Dorsal anterior cingulate cortex activity during cognitive challenge in social anxiety disorder.

BACKGROUND: Social anxiety disorder (SAD) is associated with aberrant emotional information processing while little is known about non-emotional cognitive processing biases. The dorsal anterior cingulate cortex (dACC) has been implicated in SAD neuropathology and is activated both by emotional and non-affective cognitive challenges like the Multisource Interference Task (MSIT). METHODS: Here, we used fMRI to compare dACC activity and test performance during MSIT in 69 SAD patients and 38 healthy controls. In addition to patient-control comparisons, we examined whether neural activity in the dACC correlated with social anxiety, trait anxiety or depression levels. RESULTS: The MSIT activated the dACC as expected but with no differences in task performance or neural reactivity between SAD patients and controls. There were no significant correlations between dACC activity and social or trait anxiety symptom severity. In patients, there was a significant negative correlation between dACC activity and depressive symptoms. CONCLUSIONS: In absence of affective challenge, we found no disorder-related cognitive profile in SAD patients since neither MSIT task performance nor dACC neural activity deviated in patients relative to controls.

Randomized controlled trial of computerized approach/avoidance training in social anxiety disorder: Neural and symptom outcomes.

Social anxiety is associated with diminished automatic approach toward positive social cues that may limit the ability to connect with others. This diminished approach bias may be a modifiable treatment target. We evaluated the effects of an approach avoidance training procedure on positive emotions, social relationship outcomes, clinical symptoms, and neural indices of social approach and reward processing. Forty-five individuals with social anxiety disorder were randomized (parallel 1:1 randomization) to complete computerized Approach Positive training (n = 21) or Balanced training(n = 24). Sessions included a standardized social interaction task. Participants were blind to training group. Participants completed clinical outcome measures and functional magnetic resonance imaging at baseline and post intervention with an MRI-compatible AAT and the social incentive delay task (SID). Both groups displayed significant improvements of similar magnitude on the primary outcome of social connectedness (between group post-treatment d = -0.21) but not positive affect (d = -0.09), from before to after treatment, persisting through follow-up. Groups demonstrated significant improvements on additional outcomes including anxiety, depression, and anhedonia symptoms. Participants in Approach Positive AAT demonstrated increased activation in the thalamus and medial prefrontal cortex during social versus neutral- approach relative to Balanced AAT during the fMRI AAT. Participants in Balanced AAT showed increased activation in regions within an a priori-defined striatum region of interest mask during anticipation of social reward (vs. baseline) in the SID relative to Approach Positive AAT. At a neural processing level AAT may influence the valuation and motivations associated with positive social cues regulated by the mPFC and thalamus. NCT02136212, NIMH R00MH090243.

Large-scale brain functional network abnormalities in social anxiety disorder.

BACKGROUND: Although aberrant brain regional responses are reported in social anxiety disorder (SAD), little is known about resting-state functional connectivity at the macroscale network level. This study aims to identify functional network abnormalities using a multivariate data-driven method in a relatively large and homogenous sample of SAD patients, and assess their potential diagnostic value. METHODS: Forty-six SAD patients and 52 demographically-matched healthy controls (HC) were recruited to undergo clinical evaluation and resting-state functional MRI scanning. We used group independent component analysis to characterize the functional architecture of brain resting-state networks (RSNs) and investigate between-group differences in intra-/inter-network functional network connectivity (FNC). Furtherly, we explored the associations of FNC abnormalities with clinical characteristics, and assessed their ability to discriminate SAD from HC using support vector machine analyses. RESULTS: SAD patients showed widespread intra-network FNC abnormalities in the default mode network, the subcortical network and the perceptual system (i.e. sensorimotor, auditory and visual networks), and large-scale inter-network FNC abnormalities among those high-order and primary RSNs. Some aberrant FNC signatures were correlated to disease severity and duration, suggesting pathophysiological relevance. Furthermore, intrinsic FNC anomalies allowed individual classification of SAD v. HC with significant accuracy, indicating potential diagnostic efficacy. CONCLUSIONS: SAD patients show distinct patterns of functional synchronization abnormalities both within and across large-scale RSNs, reflecting or causing a network imbalance of bottom-up response and top-down regulation in cognitive, emotional and sensory domains. Therefore, this could offer insights into the neurofunctional substrates of SAD.

Altered single-subject gray matter structural networks in social anxiety disorder.

Previous fMRI studies have reported more random brain functional graph configurations in social anxiety disorder (SAD). However, it is still unclear whether the same configurations would occur in gray matter (GM) graphs. Structural MRI was performed on 49 patients with SAD and on 51 age- and gender-matched healthy controls (HC). Single-subject GM networks were obtained based on the areal similarities of GM, and network topological properties were analyzed using graph theory. Group differences in each topological metric were compared, and the structure-function coupling was examined. These network measures were further correlated with the clinical characteristics in the SAD group. Compared with controls, the SAD patients demonstrated globally decreased clustering coefficient and characteristic path length. Altered topological properties were found in the fronto-limbic and sensory processing systems. Altered metrics were associated with the illness duration of SAD. Compared with the HC group, the SAD group exhibited significantly decreased structural-functional decoupling. Furthermore, structural-functional decoupling was negatively correlated with the symptom severity in SAD. These findings highlight less-optimized topological configuration of the brain structural networks in SAD, which may provide insights into the neural mechanisms underlying the excessive fear and avoidance of social interactions in SAD.

Resting state connectivity predictors of symptom change during gaze-contingent music reward therapy of social anxiety disorder.

BACKGROUND: Social anxiety disorder (SAD) is common, first-line treatments are often only partially effective, and reliable predictors of treatment response are lacking. Here, we assessed resting state functional connectivity (rsFC) at pre-treatment and during early treatment as a potential predictor of response to a novel attention bias modification procedure, gaze-contingent music reward therapy (GC-MRT). METHODS: Thirty-two adults with SAD were treated with GC-MRT. rsFC was assessed with multi-voxel pattern analysis of fMRI at pre-treatment and after 2-3 weeks. For comparison, 20 healthy control (HC) participants without treatment were assessed twice for rsFC over the same time period. All SAD participants underwent clinical evaluation at pre-treatment, early-treatment (week 2-3), and post-treatment. RESULTS: SAD and depressive symptoms improved significantly from pre-treatment to post-treatment. After 2-3 weeks of treatment, decreased connectivity between the executive control network (ECN) and salience network (SN), and increased connectivity within the ECN predicted improvement in SAD and depressive symptoms at week 8. Increased connectivity between the ECN and default mode network (DMN) predicted greater improvement in SAD but not depressive symptoms at week 8. Connectivity within the DMN decreased significantly after 2-3 weeks of treatment in the SAD group, while no changes were found in HC over the same time interval. CONCLUSION: We identified early changes in rsFC during a course of GC-MRT for SAD that predicted symptom change. Connectivity changes within the ECN, ECN-DMN, and ECN-SN may be related to mechanisms underlying the clinical effects of GC-MRT and warrant further study in controlled trials.

Topography of the Anxious Self: Abnormal Rest-Task Modulation in Social Anxiety Disorder.

Social anxiety disorder (SAD) is characterized by social anxiety/fear, self-attention, and interoception. Functional magnetic resonance imaging studies demonstrate increased activity during symptom-sensitive tasks in regions of the default-mode network (DMN), amygdala (AMG), and salience network (SN). What is the source of this task-unspecific symptom-sensitive hyperactivity in DMN? We address this question by probing SAD resting state (rs) changes in DMN including their relation to other regions as possible source of task-unspecific hyperactivity in the same regions. Our findings show the following: (1) rs-hypoconnectivity within-DMN regions; (2) rs-hyperconnectivity between DMN and AMG/SN; (3) task-evoked hyperactivity in the abnormal rs-regions of DMN and AMG/SN during different symptom-sensitive tasks; (4) negative relationship of rest and task changes in especially anterior DMN regions as their rs-hypoconnectivity is accompanied by task-unspecific hyperactivity; (5) abnormal top-down/bottom-up modulation between anterior DMN regions and AMG during rest and task. Findings demonstrate that rs-hypoconnectivity among DMN regions is negatively related to task-unspecific hyperactivity in DMN and AMG/SN. We propose a model of "Topography of the Anxious Self" in SAD (TAS-SAD). Abnormal DMN-AMG/SN topography during rest, as trait feature of an "unstable social self", is abnormally aggravated during SAD-sensitive situations resulting in task-related hyperactivity in the same regions with an "anxious self" as state feature.

Evaluation of Resting-State Functional Magnetic Resonance Imaging Findings of Patients with Social Anxiety Disorder. / Sosyal Anksiyete Bozuklugu Olan Hastalarda Dinlenim Durumu Islevsel Manyetik Rezonans Görüntüleme Bulgularinin Incelenmesi.

OBJECTIVE: The most prominent functional magnetic resonance imaging findings about social anxiety disorder are increased activity in emotional regulation areas (amygdala, insula, hippocampus, dorsal anterior cingulate cortex) and fear circuit, and altered activity in prefrontal cortex. This study aims to investigate network abnormalities during resting state. METHOD: Resting state functional magnetic resonance images of 21 drug-free patients with social anxiety disorder and 21 healthy controls (matched on age, gender, and years of education) were recorded. Resting state functional connectivity networks were obtained with independent component analysis, and were compared by using the voxel based t-test between the two groups. RESULTS: Patients with social anxiety disorder displayed decreased intrinsic functional connectivity in the anterior component of the salience network (left orbitofrontal cortex) and increased intrinsic functional connectivity in the posterior component of the salience network (left supramarginal gyrus). CONCLUSION: Most of the studies about social anxiety disorder mainly focused on fear circuit and emotional regulation areas by using anxiety provoking tasks or by using seed based analysis of functional connectivity. By applying a whole-brain independent component analysis, we found altered functional connectivity in the salience network, but no significant difference was found in the fear circuit areas. Our results suggest that abnormal connectivity in the salience network might play a crucial role in the neurobiology of social anxiety disorder.

Comparing the Effectiveness of Brain Structural Imaging, Resting-state fMRI, and Naturalistic fMRI in Recognizing Social Anxiety Disorder in Children and Adolescents.

Social anxiety disorder (SAD) is a common anxiety disorder in childhood and adolescence. Studies on SAD in adults have reported both structural and functional aberrancies of the brain at the group level. However, evidence has shown differences in anxiety-related brain abnormalities between adolescents and adults. Since children and adolescents can afford limited scan time, optimizing the scan tasks is essential for SAD research in children and adolescents. Thus, we need to address whether brain structure, resting-state fMRI, and naturalistic imaging enable individualized identification of SAD in children and adolescents, which measurement is more effective, and whether pooling multi-modal features can improve the identification of SAD. We comprehensively addressed these questions by building machine learning models based on parcel-wise brain features. We found that naturalistic fMRI yielded higher classification accuracy (69.17%) than the other modalities and the classification performance showed dependence on the contents of the movie. The classification models also identified contributing brain regions, some of which exhibited correlations with the symptoms scores of SAD. However, pooling brain features from the three modalities did not help enhance the classification accuracy. These results support the application of carefully designed naturalistic imaging in recognizing children and adolescents at risk of SAD.

Structural and functional deficits and couplings in the cortico-striato-thalamo-cerebellar circuitry in social anxiety disorder.

Although functional and structural abnormalities in brain regions involved in the neurobiology of fear and anxiety have been observed in patients with social anxiety disorder (SAD), the findings have been heterogeneous due to small sample sizes, demographic confounders, and methodological differences. Besides, multimodal neuroimaging studies on structural-functional deficits and couplings are rather scarce. Herein, we aimed to explore functional network anomalies in brain regions with structural deficits and the effects of structure-function couplings on the SAD diagnosis. High-resolution structural magnetic resonance imaging (MRI) and resting-state functional MRI images were obtained from 49 non-comorbid patients with SAD and 53 demography-matched healthy controls. Whole-brain voxel-based morphometry analysis was conducted to investigate structural alterations, which were subsequently used as seeds for the resting-state functional connectivity analysis. In addition, correlation and mediation analyses were performed to probe the potential roles of structural-functional deficits in SAD diagnosis. SAD patients had significant gray matter volume reductions in the bilateral putamen, right thalamus, and left parahippocampus. Besides, patients with SAD demonstrated widespread resting-state dysconnectivity in cortico-striato-thalamo-cerebellar circuitry. Moreover, dysconnectivity of the putamen with the cerebellum and the right thalamus with the middle temporal gyrus/supplementary motor area partially mediated the effects of putamen/thalamus atrophy on the SAD diagnosis. Our findings provide preliminary evidence for the involvement of structural and functional deficits in cortico-striato-thalamo-cerebellar circuitry in SAD, and may contribute to clarifying the underlying mechanisms of structure-function couplings for SAD. Therefore, they could offer insights into the neurobiological substrates of SAD.

Frontoparietal and Default Mode Network Contributions to Self-Referential Processing in Social Anxiety Disorder.

Social anxiety disorder (SAD) is characterized by negative self-referential processing, which triggers excessive emotional reactivity. In healthy individuals, positive self-views typically predominate and are supported by regions of the default mode network (DMN) that represent self-related information and regions of the frontoparietal control network (FPCN) that contribute to metacognitive awareness and emotion regulation. The current study used functional magnetic resonance imaging (fMRI) to examine patterns of DMN and FPCN activation during positive and negative self-referential judgments in SAD patients (N = 97) and controls (N = 34). As expected, SAD patients demonstrated a striking difference in self-beliefs compared with non-anxious healthy controls, endorsing fewer positive traits and more negative traits. However, SAD patients and controls demonstrated largely similar patterns of DMN and FPCN recruitment during self-referential judgements. No significant group differences were observed. However, equivalence testing identified numerous regions demonstrating effect sizes that were not small enough to conclude that they were practically equivalent to zero, despite the nonsignificant null hypothesis test. These regions may be key targets to investigate in future studies using larger samples.

Resting-state neuroimaging in social anxiety disorder: a systematic review.

There has been a growing interest in resting-state brain alterations in people with social anxiety disorder. However, the evidence has been mixed and contested and further understanding of the neurobiology of this disorder may aid in informing methods to increase diagnostic accuracy and treatment targets. With this systematic review, we aimed to synthesize the findings of the neuroimaging literature on resting-state functional activity and connectivity in social anxiety disorder, and to summarize associations between brain and social anxiety symptoms to further characterize the neurobiology of the disorder. We systematically searched seven databases for empirical research studies. Thirty-five studies met the inclusion criteria, with a total of 1611 participants (795 people with social anxiety disorder and 816 controls). Studies involving resting-state seed-based functional connectivity analyses were the most common. Individuals with social anxiety disorder (vs. controls) displayed both higher and lower connectivity between frontal-amygdala and frontal-parietal regions. Frontal regions were the most consistently implicated across other analysis methods, and most associated with social anxiety symptoms. Small sample sizes and variation in the types of analyses used across studies may have contributed to the inconsistencies in the findings of this review. This review provides novel insights into established neurobiological models of social anxiety disorder and provides an update on what is known about the neurobiology of this disorder in the absence of any overt tasks (i.e., resting state). The knowledge gained from this body of research enabled us to also provide recommendations for a more standardized imaging pre-processing approach to examine resting-state brain activity and connectivity that could help advance knowledge in this field. We believe this is warranted to take the next step toward clinical translation in social anxiety disorder that may lead to better treatment outcomes by informing the identification of neurobiological targets for treatment.