Distinct phasic and sustained brain responses and connectivity of amygdala and bed nucleus of the stria terminalis during threat anticipation in panic disorder

The bed nucleus of the stria terminalis (BNST) and the laterobasal nucleus (LB), centromedial nucleus (CM), and superficial nucleus (SF) of the amygdala form an interconnected dynamical system, whose combined activity mediates a variety of behavioral and autonomic responses in reaction to homeostatic challenges. Although previous research provided deeper insight into the structural and functional connections between these nuclei, studies investigating their resting‐state functional magnetic resonance imaging (fMRI) connectivity were solely based on undirected connectivity measures. Here, we used high‐quality data of 391 subjects from the Human Connectome Project to estimate the effective connectivity (EC) between the BNST, the LB, CM, and SF through spectral dynamic causal modeling, the relation of the EC estimates with age and sex as well as their stability over time. Our results reveal a time‐stable asymmetric EC structure with positive EC between all amygdala nuclei, which strongly inhibited the BNST while the BNST exerted positive influence onto all amygdala nuclei. Simulation of the impulse response of the estimated system showed that this EC structure shapes partially antagonistic (out of phase) activity flow between the BNST and amygdala nuclei. Moreover, the BNST‐LB and BNST‐CM EC parameters were less negative in males. In conclusion, our data points toward partially separated information processing between BNST and amygdala nuclei in the resting‐state.

The central extended amygdala (EAc)—including the bed nucleus of the stria terminalis (BST) and central nucleus of the amygdala (Ce)—plays a critical role in triggering fear and anxiety and is implicated in the development of a range of debilitating neuropsychiatric disorders. While it is widely believed that these disorders reflect the coordinated activity of widely distributed neural circuits, the functional architecture of the EAc network, and the degree to which the BST and the Ce show distinct patterns of functional connectivity, is unclear. Here, we used a novel combination of approaches to trace the connectivity of the BST and the Ce in 130 healthy, racially diverse, community-dwelling adults. Multiband imaging, high-precision registration techniques, and spatially unsmoothed data maximized anatomical specificity. Using newly developed seed regions, whole-brain regression analyses revealed robust functional connectivity between the BST and Ce via the sublenticular extended amygdala, the ribbon of subcortical gray matter encompassing the ventral amygdalofugal pathway. Both regions displayed coupling with the ventromedial prefrontal cortex (vmPFC), midcingulate cortex (MCC), insula, and anterior hippocampus. The BST showed stronger connectivity with the thalamus, striatum, periaqueductal gray, and several prefrontal territories. The only regions showing stronger functional connectivity with the Ce were neighboring regions of the dorsal amygdala, amygdalohippocampal area, and anterior hippocampus. These observations provide a baseline against which to compare a range of special populations, inform our understanding of the role of the EAc in normal and pathological fear and anxiety, and showcase image registration techniques which may be useful for researchers working with ‘de-identified’ neuroimaging data.

In a previous study, we investigated the resting‐state fMRI effective connectivity (EC) between the bed nucleus of the stria terminalis (BNST) and the laterobasal (LB), centromedial (CM), and superficial (SF) amygdala. We found strong negative EC from all amygdala nuclei to the BNST, while the BNST showed positive EC to the amygdala. However, the validity of these findings remains unclear, since a reproduction in different samples has not been done. Moreover, the association of EC with measures of anxiety offers deeper insight, due to the known role of the BNST and amygdala in fear and anxiety. Here, we aimed to reproduce our previous results in three additional samples. We used spectral Dynamic Causal Modeling to estimate the EC between the BNST, the LB, CM, and SF, and its association with two measures of self‐reported anxiety. Our results revealed consistency over samples with regard to the negative EC from the amygdala nuclei to the BNST, while the positive EC from BNST to the amygdala was also found, but weaker and more heterogenic. Moreover, we found the BNST‐BNST EC showing a positive and the CM‐BNST EC, showing a negative association with anxiety. Our study suggests a reproducible pattern of negative EC from the amygdala to the BNST along with weaker positive EC from the BNST to the amygdala. Moreover, less BNST self‐inhibition and more inhibitory influence from the CM to the BNST seems to be a pattern of EC that is related to higher anxiety.