Specifically altered brain responses to threat in generalized anxiety disorder relative to social anxiety disorder and panic disorder

Background It is unknown whether there are neurobiological differences between various anxiety and depressive disorders, or whether they are characterized by shared neurobiological variation that cuts across diagnostic boundaries. For instance, multiple anxiety disorders and depression may be characterized by abnormalities in blood-oxygen-level dependent (BOLD) response during the processing of affective scenes and faces. To interrogate the shared or unique nature of these aberrations, research that examines the influence of transdiagnostic, dimensional predictors across multiple diagnoses is needed. Methods One-hundred and ninety-nine individuals, 142 with primary diagnoses of social anxiety disorder (SAD), generalized anxiety disorder (GAD) or major depressive disorder (MDD), and 57 who were free from psychiatric diagnoses (healthy controls, HCs) performed a face-matching task involving fearful, angry and happy faces (and geometric shapes) while undergoing functional magnetic resonance imaging. Results Across the three primary diagnoses, anxiety symptom scores were associated with increased Angry>Shapes activation in the bilateral insula, anterior/midcingulate and dorsolateral prefrontal cortex (dlPFC), while depressive symptoms were associated with reduced dlPFC activation for Angry>Shapes. Patient>HC differences were limited to non a priori regions, and no differences in BOLD activation were observed between diagnostic groups. Conclusions 1) Activation in paralimbic, cingulate and lateral prefrontal regions in response to angry faces is associated with transdiagnostic anxiety and depressive symptomatology. 2) Anxiety and depressive symptoms may exert opposing influences on lateral prefrontal activation. 3) Abnormal threat processing in GAD, SAD and MDD may reflect shared neural dysfunction that varies with symptom load.

Previous neuroimaging studies have mainly focused on alterations of static and dynamic functional connectivity in patients with generalized anxiety disorder (GAD). However, the characteristics of local brain activity over time in GAD are poorly understood. This study aimed to investigate the abnormal time‐varying local brain activity of GAD by using the amplitude of low‐frequency fluctuation (ALFF) method combined with sliding‐window approach. Group comparison results showed that compared with healthy controls (HCs), patients with GAD exhibited increased dynamic ALFF (dALFF) variability in widespread regions, including the bilateral dorsomedial prefrontal cortex, hippocampus, thalamus, striatum; and left orbital frontal gyrus, inferior parietal lobule, temporal pole, inferior temporal gyrus, and fusiform gyrus. The abnormal dALFF could be used to distinguish between patients with GAD and HCs. Increased dALFF variability values in the striatum were positively correlated with GAD symptom severity. These findings suggest that GAD patients are associated with abnormal temporal variability of local brain activity in regions implicated in executive, emotional, and social function. This study provides insight into the brain dysfunction of GAD from the perspective of dynamic local brain activity, highlighting the important role of dALFF variability in understanding neurophysiological mechanisms and potentially informing the diagnosis of GAD.

Sustained anticipatory anxiety is central to Generalized Anxiety Disorder (GAD). During anticipatory anxiety, phasic threat responding appears to be mediated by the amygdala, while sustained threat responding seems related to the bed nucleus of the stria terminalis (BNST). Although sustained anticipatory anxiety in GAD patients was proposed to be associated with BNST activity alterations, firm evidence is lacking. We aimed to explore temporal characteristics of BNST and amygdala activity during threat anticipation in GAD patients. Nineteen GAD patients and nineteen healthy controls (HC) underwent functional magnetic resonance imaging (fMRI) during a temporally unpredictable threat anticipation paradigm. We defined phasic and a systematic variation of sustained response models for blood oxygen level-dependent responses during threat anticipation, to disentangle temporally dissociable involvement of the BNST and the amygdala. GAD patients relative to HC responded with increased phasic amygdala activity to onset of threat anticipation and with elevated sustained BNST activity that was delayed relative to the onset of threat anticipation. Both the amygdala and the BNST displayed altered responses during threat anticipation in GAD patients, albeit with different time courses. The results for the BNST activation hint towards its role in sustained threat responding, and contribute to a deeper understanding of pathological sustained anticipatory anxiety in GAD.