Emotion reactivity-related brain network analysis in generalized anxiety disorder: a task fMRI study.

BACKGROUND: Generalized anxiety disorder (GAD) is closely associated with emotional dysregulation. Patients with GAD tend to overreact to emotional stimuli and are impaired in emotional regulation. Using emotional regulation task, studies have found hypo-activation in prefrontal cortex (PFC) of GAD patients and concluded with inadequate top-down control. However, results remain inconsistent concerning PFC and limbic area's reactivity to emotional stimuli. What's more, only a few studies aim to identify how limbic area interacts with PFC in GAD patients. The current study aims to identify the difference in PFC-limbic circuitry response to emotional stimuli between GAD patients and healthy controls (HCs) from the perspective of brain network. Through brain network analysis, it revealed the connectivity between limbic area and PFC, and moreover, the orientation of connectivity, all of which gave a better test of inadequate top-down control hypothesis. METHODS: During fMRI scanning, participants were required to complete an emotional face identification task (fearful, neutral, happy facial expression). 30 participants (16 GAD patients, 14 HCs) were included in the formal analysis. A Bayesian-network based method was used to identify the brain network consisting of several pre-hypothesized regions of interest (ROIs) under each condition (negative, positive, neutral). In total, six graphs were obtained. Each of them represented the brain network that was common to the group under corresponding condition. RESULTS: Results revealed that GAD patients showed more bottom-up connection but less top-down connection regardless of condition, relative to HCs. Also, the insula was more connected but the amygdala was less connected regardless of condition, relative to HCs. the results also revealed a very different brain network response between GAD patients and HCs even under neutral condition. CONCLUSIONS: More bottom-up connection but less top-down connection may indicate that GAD patients are insufficient in top-down control, in keeping with inadequate top-down control hypothesis. The more connected insula may indicate GAD patients' abnormality in interoception processing. Relative to HCs, distinct brain network response pattern in GAD patients under neutral condition suggests GAD patients' abnormality in distinguishing safety from threat and intolerance of uncertainty.

Disrupted fronto-temporal function in panic disorder: a resting-state connectome study.

Recent neuroimaging studies have identified alterations in activity and connectivity among many brain regions as potential biomarkers for panic disorder. However, the functional connectome of panic disorder is not well understood. Therefore, a graph-theoretical approach was applied in this study to construct functional networks of patients and healthy controls in order to discover topological changes in panic disorder. 31 patients and 33 age and sex matched healthy controls underwent resting-state functional magnetic resonance imaging. Brain networks for each participant were structured using nodes from the Anatomical Automatic Labeling template and edges from connectivity matrices. Then, topological organizations of networks were calculated. Network-based statistical analysis was conducted, and global and nodal properties were compared between patients and controls. Unlike controls, patients with panic disorder displayed a small-world network. Patients also revealed decreased nodal efficiency in right superior frontal gyrus (SFG), middle frontal gyrus (MFG), right superior temporal gyrus (STG), and left middle temporal gyrus (MTG). Decreased functional connectivity was found in panic disorder between right MTG and extensive temporal regions. Among these disrupted regions, the decreased nodal efficiency of SFG showed a positive correlation with clinical symptoms while nodal betweenness centrality in angular gyrus showed a negative correlation. Our results indicated decreased function of global and regional information transmission in panic disorder and emphasized the role of temporal regions in its pathology.

Nitric Oxide Synthase Type 1 Methylation Is Associated With White Matter Microstructure in the Corpus Callosum and Greater Panic Disorder Severity Among Panic Disorder Patients.

Objectives: Methylation of the neuronal nitric oxide synthase (NOS1/nNOS) gene has recently been identified as a promising biomarker of psychiatric disorders. NOS1 plays an essential role in neurite outgrowth and may thus affect the microstructure development of white matter (WM) in the corpus callosum (CC), which is known to be altered in panic disorder (PD). We examined the relationship between NOS1 methylation, WM tracts in the CC, and symptoms based on this finding. Methods: Thirty-two patients with PD and 22 healthy controls (HCs) were recruited after age, gender, and the education level were matched. The cell type used was whole-blood DNA, and DNA methylation of NOS1 was measured at 20 CpG sites in the promoter region. Although 25 patients with PD were assessed with the Panic Disorder Severity Scale (PDSS), diffusion tensor imaging (DTI) scans were only collected from 16 participants with PD. Results: We observed that the PD group showed lower methylation than did the HCs group and positive correlations between the symptom severity of PD and methylation at CpG4 and CpG9. In addition, CpG9 methylation was significantly correlated with the fractional anisotropy (FA) and mean diffusivity (MD) values of the CC and its major components (the genu and the splenium) in the PD group. Furthermore, path analyses showed that CpG9 methylation offers a mediating effect for the association between the MD values of the genu of the CC and PD symptom severity (95% CI = -1.731 to -0.034). Conclusions: The results suggest that CpG9 methylation leads to atypical development of the genu of the CC, resulting in higher PD symptom severity, adding support for the methylation of NOS1 as a future prognostic indicator of PD.

Resting-state causal connectivity of the bed nucleus of the stria terminalis in panic disorder.

Panic disorder (PD) is associated with anticipatory anxiety, a sustained threat response that appears to be related to the bed nucleus of the stria terminalis (BNST). Individuals with panic disorder may demonstrate significant differences in causal connectivity of the BNST in comparison to healthy controls. To test this hypothesis, resting-state functional magnetic resonance imaging (fMRI) was used to identify aberrant causal connectivity of the BNST in PD patients. 19 PD patients and 18 healthy controls (HC) matched for gender, age and education were included. Granger causality analysis (GCA) utilizing the BNST as a seed region was used to investigate changes in directional connectivity. Relative to healthy controls, PD patients displayed abnormal directional connectivity of the BNST including enhanced causal connectivity between the left parahippocampal gyrus and left BNST, the right insula and the right BNST, the left BNST and the right dorsolateral prefrontal cortex (dlPFC) and right BNST to the left and right dlPFC. Furthermore, PD patients displayed weakened causal connectivity between the right dlPFC and the left BNST, the left dlPFC and the right BNST, the left BNST and the left dorsomedial prefrontal cortex (dmPFC), right insula, right fusiform, and right BNST to the right insula. The results suggest that PD strongly correlates with increased causal connectivity between emotional processing regions and the BNST and enhanced causal connectivity between the BNST and cognitive control regions.

Abnormal functional connectivity of habenula in untreated patients with first-episode major depressive disorder.

Major depressive disorder (MDD) is associated with abnormalities in emotional/cognitive processing and low reward sensitivity. The habenula has a pivotal role in these processes that may contribute to depression. However, there has been little research on the abnormal connectivity between the habenula and whole brain of first-onset MDD. We aimed to explore the differences of functional connectivity between patients and healthy controls using functional magnetic resonance imaging. We used seed-based resting-state fMRI to examine functional connectivity between the habenula and whole-brain in 49 first-episode depressive patients and 25 healthy controls. Compared to controls, patients with MDD demonstrated significant increases in functional connectivity between the habenula and the dorsolateral prefrontal cortex (dlPFC). Furthermore, the receiver operating characteristic (ROC) curve proved that connectivity between the habenula and dlPFC was highly predictive. Additionally, there was a positive correlation between Hamilton Rating Scale for Depression (HAMD) score and functional connectivity between the habenula and right dlPFC. We found that the aberrant functional connectivity to the habenula and dlPFC can distinguish MDD patients from the normal.

Identifying generalized anxiety disorder using resting state habenular circuitry.

Studies identify the habenula as a key subcortical component in anxiety, with a role in predicting error coding within the evaluative system. However, no clinical reports of generalized anxiety disorder (GAD) describe resting state functional connectivity of habenular circuits. We hypothesized that resting-state functional connectivities of habenula would show differences in neuroanatomical correlates of the evaluative system (prefrontal cortex, habenula) of patients with GAD. We obtained 22 patients with GAD and 21 HCs, matched for gender, age, and years of education. Resting-state functional connectivity of the habenula was assessed using a seed-based template imposed on whole brain MRI, which provided an objective and semi-automated segmentation algorithm in MNI space. Patients with GAD demonstrated enhanced connectivities in the bilateral premotor cortex, right ventrolateral prefrontal cortex, medial frontal cortex, as well as the left orbitofrontal cortex, and reduced connectivities in the left posterior cingulate cortex, and right pulvinar. Moreover, striking differences of abnormal connectivities between groups were observed via analysis of receiver operating characteristic curves (ROC) of statistically significant. These results including ROC curves suggest the potential importance of the habenula in evaluating and deciding to personally relevant reward-related information.

Frontoparietal network abnormalities of gray matter volume and functional connectivity in patients with generalized anxiety disorder.

We hypothesized that the frontoparietal region would exhibit differences in gray matter volume (GMV) and resting-state functional connectivity (rs-FC) in patients with generalized anxiety disorder (GAD) versus healthy controls (HCs). We also aimed to report on correlations between these neuroradiological findings and HAMA scores. We recruited 27 patients with GAD and 28 HCs, matched for gender, age and education. GMV was estimated using voxel-based morphometry (VBM). We found decreased GMV in the precentral gyrus (PrCG) and the superior frontal gyrus (SFG) in patients with GAD, which were used as regions of interest (ROI) for rs-FC analyses. We detected enhanced rs-FC in the inferior frontal gyrus (IFG) based on an increase in negative connections, and reduced rs-FC in the superior temporal gyrus (STG) based on a decrease in positive connections compared to HCs. The right PrCG may be a candidate biomarker in patients with GAD, as well as a potential stimulation target for improvement of anxiety symptoms. By combining GMV and rs-FC analyses, our findings help to understand the pathophysiology of GAD by combining GMV and rs-FC.