Association between white matter hyperintensity and anxiety/depression.

Although previous studies have explored the associations of white matter hyperintensity with psychiatric disorders, the sample size is small and the conclusions are inconsistent. The present study aimed to further systematically explore the association in a larger sample. All data were extracted from the UK Biobank. First, general linear regression models and logistic regression models were used to assess the association between white matter hyperintensity volume and anxiety/depression. White matter hyperintensity has been classified into periventricular white matter hyperintensity and deep white matter hyperintensity. Anxiety was determined by General Anxiety Disorder-7 score (n = 17,221) and self-reported anxiety (n = 15,333), depression was determined by Patient Health Questionnaire-9 score (n = 17,175), and self-reported depression (n = 14,519). Moreover, we employed Cox proportional hazard models to explore the association between white matter hyperintensity volume and anxiety/depression. The covariates included in fully adjusted model are age, gender, body mass index, Townsend deprivation index, healthy physical activity, cigarette consumption, alcohol consumption, educational attainment, diabetes, hypertension, and coronary heart disease. The results of the fully adjusted model showed that white matter hyperintensity volume was significantly associated with General Anxiety Disorder-7 score (periventricular white matter hyperintensity: ß = 0.152, deep white matter hyperintensity: ß = 0.094) and Patient Health Questionnaire-9 score (periventricular white matter hyperintensity: ß = 0.168). Logistic regression analysis results indicated that periventricular white matter hyperintensity volume (odds ratio = 1.153) was significantly associated with self-reported anxiety. After applying the Cox proportional hazard models, we found that larger white matter hyperintensity volume was associated with increased risk of depression (periventricular white matter hyperintensity: hazard ratio = 1.589, deep white matter hyperintensity: hazard ratio = 1.200), but not anxiety. In summary, our findings support a positive association between white matter hyperintensity volume and depression.

Brain volumes, behavioral inhibition, and anxiety disorders in children: results from the adolescent brain cognitive development study.

BACKGROUND: Magnetic resonance imaging (MRI) studies have identified brain changes associated with anxiety disorders (ADs), but the results remain mixed, particularly at a younger age. One key predictor of ADs is behavioral inhibition (BI), a childhood tendency for high avoidance of novel stimuli. This study aimed to evaluate the relationships between candidate brain regions, BI, and ADs among children using baseline data from the Adolescent Brain Cognitive Development (ABCD) study. METHODS: We analyzed global and regional brain volumes of 9,353 children (9-10 years old) in relation to BI and current ADs, using linear mixed models accounting for family clustering and important demographic and socioeconomic covariates. We further investigated whether and how past anxiety was related to brain volumes. RESULTS: Among included participants, 249 (2.66%) had a current AD. Larger total white matter (Beta = -0.152; 95% CI [-0.281, -0.023]), thalamus (Beta = -0.168; 95% CI [-0.291, -0.044]), and smaller hippocampus volumes (Beta = 0.094; 95% CI [-0.008, 0.196]) were associated with lower BI scores. Amygdala volume was not related to BI. Larger total cortical (OR = 0.751; 95% CI [0.580;0.970]), amygdala (OR = 0.798; 95%CI [0.666;0.956]), and precentral gyrus (OR = 0.802; 95% CI [0.661;0.973]) volumes were associated with lower odds of currently having ADs. Children with past ADs had smaller total white matter and amygdala volumes. CONCLUSIONS: The results show associations between brain volumes and both BI and ADs at an early age. Importantly, results suggest that ADs and BI have different neurobiological correlates and that earlier occurrences of ADs may influence brain structures related to BI and ADs, motivating research that can better delineate the similarities and divergence in the neurobiological underpinnings and building blocks of BI and ADs across their development in early life.

Sex-Specific Distributed White Matter Microarchitectural Alterations in Preadolescent Youths With Anxiety Disorders: A Mega-Analytic Study.

OBJECTIVE: Anxiety disorders are among the most common psychiatric disorders in youths and emerge during childhood. This is also a period of rapid white matter (WM) development, which is critical for efficient neuronal communication. Previous work in preadolescent children with anxiety disorders demonstrated anxiety disorder-related reductions in WM microstructural integrity (fractional anisotropy [FA]) in the uncinate fasciculus (UF), the major WM tract facilitating prefrontal cortical-limbic structural connectivity. Importantly, this association was found only in boys with anxiety disorders. To confirm this finding and more comprehensively understand WM changes in childhood anxiety, this mega-analytic study characterizes WM alterations related to anxiety disorders and sex in the largest sample of preadolescent children to date. METHODS: Diffusion tensor imaging data from published studies of preadolescent children with anxiety disorders and healthy volunteers (ages 8-12) (N=198) were combined with a new data set (N=97) for a total sample of 165 children with anxiety disorders and 132 healthy volunteers. Children with anxiety disorders met DSM-5 criteria for current generalized, separation, and/or social anxiety disorder. Analyses of tractography and voxel-wise data assessed between-group differences (anxiety disorder vs. healthy volunteer), effects of sex, and their interaction. RESULTS: Tract-based and voxel-wise analyses confirmed a significant reduction in UF FA in boys but not girls with anxiety disorders. Results also demonstrated other significant widespread anxiety disorder-related WM alterations specifically in boys, including in multiple commissural, association, projection, and brainstem regions. CONCLUSIONS: In addition to confirming male-specific anxiety disorder-related reductions in UF FA, the results demonstrate that anxiety disorders in boys and not girls are associated with broadly distributed WM alterations across the brain. These findings support further studies focused on understanding the extent to which WM alterations in boys with anxiety disorders are involved in pathophysiological processes that mediate anxiety disorders. The findings also suggest the possibility that WM microarchitecture could serve as a novel treatment target for childhood anxiety disorders.

Resting-state amygdala subregion and precuneus connectivity provide evidence for a dimensional approach to studying social anxiety disorder.

Social anxiety disorder (SAD) is a prevalent and disabling mental health condition, characterized by excessive fear and anxiety in social situations. Resting-state functional magnetic resonance imaging (fMRI) paradigms have been increasingly used to understand the neurobiological underpinnings of SAD in the absence of threat-related stimuli. Previous studies have primarily focused on the role of the amygdala in SAD. However, the amygdala consists of functionally and structurally distinct subregions, and recent studies have highlighted the importance of investigating the role of these subregions independently. Using multiband fMRI, we analyzed resting-state data from 135 participants (42 SAD, 93 healthy controls). By employing voxel-wise permutation testing, we examined group differences of fMRI connectivity and associations between fMRI connectivity and social anxiety symptoms to further investigate the classification of SAD as a categorical or dimensional construct. Seed-to-whole brain functional connectivity analysis using multiple 'seeds' including the amygdala and its subregions and the precuneus, revealed no statistically significant group differences. However, social anxiety severity was significantly negatively correlated with functional connectivity of the precuneus - perigenual anterior cingulate cortex and positively correlated with functional connectivity of the amygdala (specifically the superficial subregion) - parietal/cerebellar areas. Our findings demonstrate clear links between symptomatology and brain connectivity in the absence of diagnostic differences, with evidence of amygdala subregion-specific alterations. The observed brain-symptom associations did not include disturbances in the brain's fear circuitry (i.e., disturbances in connectivity between amygdala - prefrontal regions) likely due to the absence of threat-related stimuli.

Functional and Structural Abnormalities in the Pain Network of Generalized Anxiety Disorder Patients with Pain Symptoms.

Pain symptoms significantly impact the well-being and work capacity of individuals with generalized anxiety disorder (GAD), and hinder treatment and recovery. Despite existing literature focusing on the neural substrate of pain and anxiety separately, further exploration is needed to understand the possible neuroimaging mechanisms of the pain symptoms in GAD patients. We recruited 73 GAD patients and 75 matched healthy controls (HC) for clinical assessments, as well as resting-state functional and structural magnetic resonance imaging scans. We defined a pain-related network through a published meta-analysis, including the insula, thalamus, periaqueductal gray, prefrontal cortex, anterior cingulate cortex, amygdala, and hippocampus. Subsequently, we conducted the regional homogeneity (ReHo) and the gray matter volume (GMV) within the pain-related network. Correlation analysis was then employed to explore associations between abnormal regions and self-reported outcomes, assessed using the Patient Health Questionnaire-15 (PHQ-15) and pain scores. We observed significantly increased ReHo in the bilateral insula but decreased GMV in the bilateral thalamus of GAD compared to HC. Further correlation analysis revealed a positive correlation between ReHo of the left anterior insula and pain scores in GAD patients, while a respective negative correlation between GMV of the bilateral thalamus and PHQ-15 scores. In summary, GAD patients exhibit structural and functional abnormalities in pain-related networks. The enhanced ReHo in the left anterior insula is correlated with pain symptoms, which might be a crucial brain region of pain symptoms in GAD.

Responding to threat: Associations between neural reactivity to and behavioral avoidance of threat in pediatric anxiety.

BACKGROUND: Despite broad recognition of the central role of avoidance in anxiety, a lack of specificity in its operationalization has hindered progress in understanding this clinically significant construct. The current study uses a multimodal approach to investigate how specific measures of avoidance relate to neural reactivity to threat in youth with anxiety disorders. METHODS: Children with anxiety disorders (ages 6-12 years; n = 65 for primary analyses) completed laboratory task- and clinician-based measures of avoidance, as well as a functional magnetic resonance imaging task probing neural reactivity to threat. Primary analyses examined the ventral anterior insula (vAI), amygdala, and ventromedial prefrontal cortex (vmPFC). RESULTS: Significant but distinct patterns of association with task- versus clinician-based measures of avoidance emerged. Clinician-rated avoidance was negatively associated with right and left vAI reactivity to threat, whereas laboratory-based avoidance was positively associated with right vAI reactivity to threat. Moreover, left vAI-right amygdala and bilateral vmPFC-right amygdala functional connectivity were negatively associated with clinician-rated avoidance but not laboratory-based avoidance. LIMITATIONS: These results should be considered in the context of the restricted range of our treatment-seeking sample, which limits the ability to draw conclusions about these associations across children with a broader range of symptomatology. In addition, the limited racial and ethnic diversity of our sample may limit the generalizability of findings. CONCLUSION: These findings mark an important step towards bridging neural findings and behavioral patterns using a multimodal approach. Advancing understanding of behavioral avoidance in pediatric anxiety may guide future treatment optimization by identifying individual-specific targets for treatment.

The difference in volumetric alternations of the orbitofrontal-limbic-striatal system between major depressive disorder and anxiety disorders: A systematic review and voxel-based meta-analysis.

BACKGROUND: Major depressive disorder (MDD) and anxiety disorders (ANX) are psychiatric disorders with high mutual comorbidity rates that might indicate some shared neurobiological pathways between them, but they retain diverse phenotypes that characterize themselves specifically. However, no consistent evidence exists for common and disorder-specific gray matter volume (GMV) alternations between them. METHODS: A systematic review and meta-analysis on voxel-based morphometry studies of patients with MDD and ANX were performed. The effect of comorbidity was explicitly controlled during disorder-specific analysis and particularly investigated in patient with comorbidity. RESULTS: A total of 45 studies with 54 datasets comprising 2196 patients and 2055 healthy participants met the inclusion criteria. Deficits in the orbitofrontal cortex, striatum, and limbic regions were found in MDD and ANX. The disorder-specific analyses showed decreased GMV in the bilateral anterior cingulate cortex, right striatum, hippocampus, and cerebellum in MDD, while decreased GMV in the left striatum, amygdala, insula, and increased cerebellar volume in ANX. A totally different GMV alternation pattern was shown involving bilateral temporal and parietal gyri and left fusiform gyrus in patients with comorbidity. LIMITATIONS: Owing to the design of included studies, only partial patients in the comorbid group had a secondary comorbidity diagnosis. CONCLUSION: Patients with MDD and ANX shared a structural disruption in the orbitofrontal-limbic-striatal system. The disorder-specific effects manifested their greatest severity in distinct lateralization and directionality of these changes that differentiate MDD from ANX. The comorbid group showed a totally different GMV alternation pattern, possibly suggesting another illness subtype that requires further investigation.

Specific alterations of resting-state functional connectivity in the triple network related to comorbid anxiety in major depressive disorder.

The brain's default mode network (DMN) and the executive control network (ECN) switch engagement are influenced by the ventral attention network (VAN). Alterations in resting-state functional connectivity (RSFC) within this so-called triple network have been demonstrated in patients with major depressive disorder (MDD) or anxiety disorders (ADs). This study investigated alterations in the RSFC in patients with comorbid MDD and ADs to better understand the pathophysiology of this prevalent group of patients. Sixty-eight participants (52.9% male, mean age 35.3 years), consisting of 25 patients with comorbid MDD and ADs (MDD + AD), 20 patients with MDD only (MDD) and 23 healthy controls (HCs) were investigated clinically and with 3T resting-state fMRI. RSFC utilizing a seed-based approach within the three networks belonging to the triple network was compared between the groups. Compared with HC, MDD + AD showed significantly reduced RSFC between the ECN and the VAN, the DMN and the VAN and within the ECN. No differences could be found for the MDD group compared with both other groups. Furthermore, symptom severity and medication status did not affect RSFC values. The results of this study show a distinct set of alterations of RSFC for patients with comorbid MDD and AD compared with HCs. This set of dysfunctions might be related to less adequate switching between the DMN and the ECN as well as poorer functioning of the ECN. This might contribute to additional difficulties in engaging and utilizing consciously controlled emotional regulation strategies.

Brain network integration underpins differential susceptibility of adolescent anxiety.

BACKGROUND: Parenting is a common and potent environmental factor influencing adolescent anxiety. Yet, the underlying neurobiological susceptibility signatures remain elusive. Here, we used a longitudinal twin neuroimaging study to investigate the brain network integration and its heritable relation to underpin the neural differential susceptibility of adolescent anxiety to parenting environments. METHODS: 216 twins from the Beijing Twin Study completed the parenting and anxiety assessments and fMRI scanning. We first identified the brain network integration involved in the influences of parenting at age 12 on anxiety symptoms at age 15. We then estimated to what extent heritable sensitive factors are responsible for the susceptibility of brain network integration. RESULTS: Consistent with the differential susceptibility theory, the results showed that hypo-connectivity within the central executive network amplified the impact of maternal hostility on anxiety symptoms. A high anti-correlation between the anterior salience and default mode networks played a similar modulatory role in the susceptibility of adolescent anxiety to paternal hostility. Genetic influences (21.18%) were observed for the connectivity pattern in the central executive network. CONCLUSIONS: Brain network integration served as a promising neurobiological signature of the differential susceptibility to adolescent anxiety. Our findings deepen the understanding of the neural sensitivity in the developing brain and can inform early identification and personalized interventions for adolescents at risk of anxiety disorders.

Abnormal regional activity in the prefrontal-limbic circuit at rest: Potential imaging markers and treatment predictors in drug-naive anxiety disorders.

BACKGROUND: Previous research has identified functional impairments within the prefrontal-limbic circuit in individuals with anxiety disorders. However, the link between these deficiencies, clinical symptoms, and responses to antipsychotic treatment is still not fully understood. This study aimed to investigate abnormal regional activity within the prefrontal-limbic circuit among drug-naive individuals diagnosed with generalized anxiety disorder (GAD) and panic disorder (PD) and to analyze changes following treatment. METHODS: Resting-state magnetic resonance imaging was performed on a cohort of 118 anxiety disorder patients (64 GAD, 54 PD) and 61 healthy controls (HCs) at baseline. Among them, 52 patients with GAD and 44 patients with PD underwent a 4-week treatment regimen of paroxetine. Fractional amplitude of low-frequency fluctuation (fALFF) measurements and pattern classification techniques were employed to analyze the data in accordance with the human Brainnetome atlas. RESULTS: Both patients with GAD and PD demonstrated decreased fALFF in the right cHipp subregion of the hippocampus and increased fALFF in specified subregions of the cingulate and orbitofrontal lobe. Notably, patients with PD exhibited significantly higher fALFF in the left A24cd subregion compared to patients with GAD, while other ROI subregions showed no significant variations between the two patient groups. Whole-brain analysis revealed abnormal fALFF in both patient groups, primarily in specific areas of the cingulate and parasingulate gyrus, as well as the inferior and medial orbitofrontal gyrus (OFG). Following a 4-week treatment period, specific subregions in the GAD and PD groups showed a significant decrease in fALFF. Further analysis using support vector regression indicated that fALFF measurements in the right A13 and right A24cd subregions may be predictive of treatment response among anxiety disorder patients. CONCLUSIONS: Aberrant functional activity in certain subregions of the prefrontal-limbic circuit appears to be linked to the manifestation of anxiety disorders. These findings suggest potential imaging indicators for individual responses to antipsychotic treatment.

Anxiety may alter the role of fronto-striatal circuitry in adolescent risky decision-making.

BACKGROUND: Anxiety disorders often emerge in adolescence and are associated with risk aversion. Risk aversion conflicts with the typical adolescent approach-motivated phenotype and can interfere with learning and contribute to symptom maintenance. METHODS: We investigated the neural and behavioral correlates of risk avoidance in a diverse sample of adolescents (N = 137; MAge = 11.3; 34.3 % white, 22.1 % Latino, 20 % Asian, 14.3 % Black, 9.3 % Mixed Race) as they completed a task involving risky decision-making and response inhibition during fMRI. Voluntary cautious choice was compared to successful response inhibition to isolate the neural systems underlying the decision to avoid a risk and identify their relation to risk-taking and anxiety in adolescents. RESULTS: Anxious adolescents self-reported more avoidance but demonstrated normative risk-taking on the laboratory task. Interestingly, they responded quickly during response inhibition but took longer to decide in the face of risk. All youth showed widespread recruitment of decision-making and salience network regions when deciding to avoid risk. The neural mechanisms driving avoidance differed based on anxiety such that left inferior frontal gyrus (IFG) activation was linked to risk avoidance in adolescents with low anxiety and risk-taking in anxious adolescents, while striatal connectivity was linked to risk avoidance in anxious adolescents and risk-taking in those with low anxiety. LIMITATIONS: This work is cross-sectional and therefore cannot speak to causality or directionality of effects. CONCLUSIONS: These results suggest that the neural mechanisms contributing to adolescent risk-taking may function to promote avoidance in anxious youth, increasing vulnerability to maladaptive avoidance and further anxiety development.

Shared and distinctive dysconnectivity patterns underlying pure generalized anxiety disorder (GAD) and comorbid GAD and depressive symptoms.

The resting-state connectivity features underlying pure generalized anxiety disorder (GAD, G1) and comorbid GAD and depressive symptoms (G2) have not been directly compared. Furthermore, it is unclear whether these features might serve as potential prognostic biomarkers and change with treatment. Degree centrality (DC) in G1 (40 subjects), G2 (58 subjects), and healthy controls (HCs, 54 subjects) was compared before treatment, and the DC of G1 or G2 at baseline was compared with that after 4 weeks of paroxetine treatment. Using support vector regression (SVR), voxel-wise DC across the entire brain and abnormal DC at baseline were employed to predict treatment response. At baseline, G1 and G2 exhibited lower DC in the left mid-cingulate cortex and vermis IV/V compared to HCs. Additionally, compared to HCs, G1 had lower DC in the left middle temporal gyrus, while G2 showed higher DC in the right inferior temporal/fusiform gyrus. However, there was no significant difference in DC between G1 and G2. The SVR based on abnormal DC at baseline could successfully predict treatment response in responders in G2 or in G1 and G2. Notably, the predictive performance based on abnormal DC at baseline surpassed that based on DC across the entire brain. After treatment, G2 responders showed lower DC in the right medial orbital frontal gyrus, while no change in DC was identified in G1 responders. The G1 and G2 showed common and distinct dysconnectivity patterns and they could potentially serve as prognostic biomarkers. Furthermore, DC in patients with GAD could change with treatment.

Disrupted functional connectivity associated with cognitive impairment in generalized anxiety disorder (GAD) and comorbid GAD and depression: a follow-up fMRI study.

BACKGROUND: Impaired functional connectivity between the bilateral hemispheres may serve as the neural substrate for anxiety and depressive disorders, yet its role in comorbid generalized anxiety disorder (GAD) and depression, as well as the effect of treatment on this connectivity, remains unclear. We sought to examine functional connectivity between homotopic regions of the 2 hemispheres (voxel-mirrored homotopic connectivity [VMHC]) among people with GAD with and without comorbid depression at baseline and after a 4-week paroxetine treatment. METHODS: Drug-naïve patients with GAD, with or without comorbid depression and healthy controls underwent functional magnetic resonance imaging and clinical assessments at baseline and after treatment. We compared VMHC and seed-based functional connectivity across the 3 groups. We performed correlation analysis and support vector regression (SVR) to examine the intrinsic relationships between VMHC and symptoms. RESULTS: Both patient groups (n = 40 with GAD only, n = 58 with GAD and depression) showed decreased VMHC in the precuneus, posterior cingulate cortex and lingual gyrus compared with healthy controls (n = 54). Moreover, they showed decreased VMHC in different brain regions compared with healthy controls. However, we did not observe any significant differences between the 2 patient groups. Seeds from abnormal VMHC clusters in patient groups had decreased functional connectivity. Voxel-mirrored homotopic connectivity in the precuneus, posterior cingulate cortex and lingual gyrus was negatively correlated with cognitive impairment among patients with GAD only and among all patients. The SVR analysis based on abnormal VMHC showed significant positive correlations (p < 0.0001) between predicted and actual treatment responses. However, we did not observe significant differences in VMHC or functional connectivity after treatment. LIMITATIONS: A notable dropout rate and intergroup somatic symptom variations may have biased the results. CONCLUSION: Patients with GAD with or without comorbid depression exhibited shared and distinct abnormal VMHC patterns, which might be linked to their cognitive deficits. These patterns have the potential to serve as prognostic biomarkers for GAD.Clinical trial registration: ClinicalTrials.gov NCT03894085.

A systematic review and meta-analysis of resting-state fMRI in anxiety disorders: Need for data sharing to move the field forward.

Anxiety disorders are among the most prevalent psychiatric disorders. Neuroimaging findings remain uncertain, and resting state functional magnetic resonance (rs-fMRI) connectivity is of particular interest since it is a scalable functional imaging modality. Given heterogeneous past findings for rs-fMRI in anxious individuals, we characterize patterns across anxiety disorders by conducting a systematic review and meta-analysis. Studies were included if they contained at the time of scanning both a healthy group and a patient group. Due to insufficient study numbers, the quantitative meta-analysis only included seed-based studies. We performed an activation likelihood estimation (ALE) analysis that compared patients and healthy volunteers. All analyses were corrected for family-wise error with a cluster-level threshold of p < .05. Patients exhibited hypo-connectivity between the amygdala and the medial frontal gyrus, anterior cingulate cortex, and cingulate gyrus. This finding, however, was not robust to potential file-drawer effects. Though limited by strict inclusion criteria, our results highlight the heterogeneous nature of reported findings. This underscores the need for data sharing when attempting to detect reliable patterns of disruption in brain activity across anxiety disorders.

Dimensional distress and orbitofrontal thickness in anxiety patients.

Thickness of the medial orbitofrontal cortex (mOFC) was assessed as it varied with reported symptoms of anxiety and depression in a large sample of anxiety patients. A principal component analysis identified a primary factor of transdiagnostic dimensional distress that predicted 24% of the mOFC variance. Severity of distress symptomology was associated with thinning of the mOFC in both hemispheres for both men and women, regardless of the primary DSM diagnosis. Taken together, the data indicate that mOFC thickness might be useful as an objective measure of disorder severity as well as to assess pharmacological or psychological treatment outcome.

Topographical similarity of cortical thickness represents generalized anxiety symptoms in adolescence.

Generalized anxiety disorder (GAD) is a common condition characterized by excessive and uncontrollable worry, along with its high comorbidity rates. Despite increasing efforts to identify the neural underpinnings of GAD, neuroimaging research using cortical thickness have yielded largely inconsistent results. To address this, we adopted an inter-subject representational similarity analysis framework to explore a potential nonlinear relationship between vertex-wise cortical thickness and generalized anxiety symptom severity. We utilized a sample of 120 adolescents (13-18 years of age) from the Healthy Brain Network dataset. Here, we found greater topographical resemblance among participants with heightened generalized anxiety symptoms in the left caudal anterior cingulate and pericalcarine cortex. These results were not driven by the effects of age, sex, ADHD diagnosis, and GAD diagnosis. Such associations were not observed when including a group of younger participants (11-12 years of age) for analyses, highlighting the importance of age range selection when considering the link between cortical thickness and anxiety. Our findings reveal a novel cortical thickness topography that represents generalized anxiety in adolescents, which is embedded within the shared geometries between generalized anxiety symptoms and cortical thickness.

Evaluation of retinal thickness measured by optical coherence tomography in patients with generalized anxiety disorder.

PURPOSE: To compare the peripapillary retinal nerve fiber layer thickness, macular thickness, ganglion cell layer thickness, and inner plexiform layer thickness determined by Optic Coherence Tomography in the patient group diagnosed with a generalized anxiety disorder who did not receive any psychiatric medication with the healthy control group. METHODS: Forty newly diagnosed, drug-free Generalized Anxiety Disorder patients and 43 healthy age- and gender-matched control subjects were included in the study. Macular thickness, ganglion cell layer thickness, inner plexiform layer thickness, and peripapillary retinal nerve fiber layer thickness were measured using optical coherence tomography. Structured Clinical Interviews and a State-Trait Anxiety Scale were applied to both groups. RESULTS: Gender distributions (P = 0.965) and mean ages were similar between the groups (P = 0.340). Retinal nerve fiber layer thickness measurements were not significantly different between the groups. We observed statistically significant thinning in the inner superior, inner nasal, inner temporal, inner inferior, and outer inferior quadrants of the macula in the patient group compared to the control group (P = 0.046, P = 0.046, P = 0.020, P = 0.007, P = 0.014). We found thinning at the Ganglion cell layer in the inner inferior and outer temporal quadrants (Respectively P = 0.018, P = 0.049), inner plexiform layer in the inner nasal, inner temporal, and inner inferior quadrants (Respectively P = 0.046, P = 0.044, P = 0.011) compared to the control group. CONCLUSIONS: This is the first study to reveal thinning in the macula, ganglion cell layer, and inner plexiform layer in newly diagnosed, drug-free Generalized Anxiety Disorder patients compared to the control group.

Reduced vmPFC-insula functional connectivity in generalized anxiety disorder: a Bayesian confirmation study.

Differences in the correlated activity of networked brain regions have been reported in individuals with generalized anxiety disorder (GAD) but an overreliance on null-hypothesis significance testing (NHST) limits the identification of disorder-relevant relationships. In this preregistered study, we applied both a Bayesian statistical framework and NHST to the analysis of resting-state fMRI scans from females with GAD and matched healthy comparison females. Eleven a-priori hypotheses about functional connectivity (FC) were evaluated using Bayesian (multilevel model) and frequentist (t-test) inference. Reduced FC between the ventromedial prefrontal cortex (vmPFC) and the posterior-mid insula (PMI) was confirmed by both statistical approaches and was associated with anxiety sensitivity. FC between the vmPFC-anterior insula, the amygdala-PMI, and the amygdala-dorsolateral prefrontal cortex (dlPFC) region pairs did not survive multiple comparison correction using the frequentist approach. However, the Bayesian model provided evidence for these region pairs having decreased FC in the GAD group. Leveraging Bayesian modeling, we demonstrate decreased FC of the vmPFC, insula, amygdala, and dlPFC in females with GAD. Exploiting the Bayesian framework revealed FC abnormalities between region pairs excluded by the frequentist analysis and other previously undescribed regions in GAD, demonstrating the value of applying this approach to resting-state FC data in clinical investigations.

Gray matter associations with extinction-induced neural activation in patients with anxiety disorders.

The relationship between structural characteristics and extinction-induced brain activations in anxiety disorders (ANX) remains a space for greater exploration. In this study, we assessed gray matter volume (GMV) and its associated functional activations during fear extinction memory recall in an ANX cohort. We performed voxel-based morphometry analysis to examine GMVs from ANX (n = 92) and controls (n = 73). We further examined the correlation between GMVs and extinction-induced neural activations during recall across groups. In the patients' group, we observed decreased GMV in the anterior hippocampus and increased GMV in the dorsolateral prefrontal cortex (dlPFC). Hippocampal volume was positively correlated with ventromedial prefrontal cortex activation in healthy controls, while it was negatively correlated with dorsal anterior cingulate cortex (dACC) activation in ANX. The dlPFC volume was positively correlated with activations of dACC, pre- and post-central gyrus, and supramarginal gyrus only in healthy controls. Therefore, the link between structural and functional imbalance within the hippocampus and dlPFC might contribute to the pathophysiology of ANX. In the controls, the relationship between structural variance in the hippocampus and dlPFC and extinction-induced neural activations is consistent with a greater ability to regulate fear responding; associations that were absent in the ANX cohort. Furthermore, our findings of structure-function abnormalities within key nodes of emotional homeostasis in ANX point to dlPFC as a potential neural node to target using neuromodulation tools.

Cerebral hemodynamic response to generalized anxiety disorder.

BACKGROUND: Generalized anxiety disorder (GAD) is the least studied among anxiety disorders. Therefore, we aimed to compare the cervical blood flow velocities using doppler ultrasonography in untreated chronic GAD patients and healthy individuals. MATERIAL AND METHODS: In this study, thirty-eight GAD patients were enrolled. And thirty-eight healthy volunteers were recruited as control participants. The common carotid artery (CCA), internal carotid artery (ICA), and vertebral artery (VA) of both sides were explored. Also, we trained machine learning models based on cervical arteries characteristics to diagnose GAD patients. RESULTS: Patients with chronic untreated GAD showed a significant increase in peak systolic velocity (PSV) bilaterally in the CCA and the ICA (P value < 0.05). In GAD patients, the end-diastolic velocity (EDV) of bilateral CCA, VA, and left ICA was significantly decreased. The Resistive Index (RI) showed a significant increase in all patients with GAD. Moreover, the Support Vector Machine (SVM) model showed the best accuracy in identifying anxiety disorder. CONCLUSION: GAD is associated with hemodynamic alterations of extracranial cervical arteries. With a larger sample size and more generalized data, it is possible to make a robust machine learning-based model for GAD diagnosis.