Aberrant Amygdala-Frontal Cortex Connectivity During Perception of Fearful Faces and at Rest in Generalized Social Anxiety Disorder

Abstract

Background Generalized social anxiety disorder (gSAD) is characterized by exaggerated amygdala reactivity to social signals of threat, but if and how the amygdala interacts with functionally and anatomically connected prefrontal cortex (PFC) remains largely unknown. Recent evidence points to aberrant amygdala connectivity to medial PFC in gSAD at rest, but it is difficult to attribute functional relevance without the context of threat processing. Here, we address this by studying amygdala-frontal cortex connectivity during viewing of fearful faces and at rest in gSAD patients. Methods Twenty patients with gSAD and 17 matched healthy controls (HCs) participated in functional magnetic resonance imaging of an emotional face matching task, and a resting state task. Functional connectivity and psychophysiological interaction analysis were used to assess amygdala connectivity. Results Compared to HCs, gSAD patients exhibited less connectivity between amygdala and the rostral anterior cingulate cortex (ACC) and dorsolateral prefrontal cortex (DLPFC) while viewing fearful faces. gSAD patients also showed less connectivity between amygdala and rostral ACC at rest in the absence of fearful faces. DLPFC connectivity was negatively correlated with LSASFear. Conclusions Task and rest paradigms provide unique and important information about discrete and overlapping functional networks. In particular, amygdala coupling to DLPFC may be a phasic abnormality, emerging only in the presence of a social predictor of threat, whereas amygdala coupling to the rostral ACC may reflect both phasic and tonic abnormalities. These findings prompt further studies to better delineate intrinsic and externally-evoked brain connectivity in anxiety and depression in relation to amygdala dysfunction.

Resting-State Neuroimaging Studies: A New Way of Identifying Differences and Similarities among the Anxiety Disorders?

“…Consistent with the findings of Liao et al, 51 Pannekoek et al 48 demonstrated increased connectivity in the bilateral dorsal ACC seed and left precuneus and left lateral occipital cortex in patients with SAD, compared with healthy control subjects. Contrary to Prater et al, 50 they also found an increased functional coupling within the right amygdala seed and the left middle temporal gyrus, left supramarginal gyrus, and left lateral occipital gyrus. As several investigations have provided conflicting results regarding the functional coupling of SN subregions, future research is needed to distinguish which of these subregions show increased or decreased coupling with the broader SN in patients with SAD.…”

Reduced Anterior Temporal and Hippocampal Functional Connectivity During Face Processing Discriminates Individuals with Social Anxiety Disorder from Healthy Controls and Panic Disorder, and Increases Following Treatment

“…Although previous studies have demonstrated differences in activation and FC Liao et al, 2010;Prater et al, 2012;Hahn et al, 2011;Klumpp et al, 2012) between SAD and HCs, the current work is the first to use FC (and activation) to discriminate SAD vs HC diagnostic membership. The current approach of combining machine learning with large-scale, condition-dependent FC is more exploratory and data driven in identifying FC differences than previously used techniques such as PPI Analysis, which only assess FC with a single, a priori specified, 'seed' region at a time.…”

“…In addition to the exploratory, data-driven approach above, we examined FC previously identified to be anomalous in SAD, in particular reduced aINS-dACC and amygdala-dACC and amygdaladlPFC (Prater et al, 2012) in SAD during fear. Although FC differences were mostly consistent with these studies (particularly with the dACC, see Supplementary Results), including the above connections in addition to the two features identified above, individually or collectively, did not improve classification performance, whereas including only these connections resulted in poorer classification performance (AUC ¼ 0.53).…”

Hyper-Connectivity of Subcortical Resting-State Networks in Social Anxiety Disorder

“…Similar to the results from striatum seeds (specifically, the putamen), enhanced connectivity in supplementary motor regions in the SAD>HC contrast with the centromedial amygdala seed, re-iterate the "motor readiness" in SAD. Previous fcMRI studies (Liao et al, 2010a;Liao et al, 2010b;Hahn et al, 2011;Prater et al, 2013) have not provided adequate consideration to the functional heterogeneity of amygdala and have reported reduced functional connectivity in SAD. Low-resolution (3.75 x 3.75 x 5 mm) EPI employed in these studies could be partly attributed to the mixed findings because of the dominance of physiological noise to resting state time-series at bigger voxel volumes.…”

“…Of the existing fcMRI studies involving SAD populations, a few studies studies Liao et al, 2010a;Liao et al, 2010b;Liao et al, 2011;Qiu et al, 2011) used identical acquisition parameters including low-resolution (3.75 x 3.75 x 5 mm) voxels. Of the remaining studies, one had very limited coil sensitivity to detect Blood Oxygenation Level Dependent (BOLD) signal from subcortical regions (Pannekoek et al, 2012), and two had limited head coverage and/or low resolution (Hahn et al, 2011;Prater et al, 2013). Since physiological noise, a major confound in fcMRI, dominates at low-resolution (Triantafyllou et al, 2005), highresolution imaging is desirable in this context.…”