Intrinsic functional connectivity of the central extended amygdala

Abstract

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.

Resting‐state fMRI effective connectivity between the bed nucleus of the stria terminalis and amygdala nuclei

“…Our results show an asymmetric connectivity structure, such that the BNST is strongly negatively connected to all amygdala nuclei, but itself shows positive EC to these nuclei. This has not been uncovered in previous studies due to the use of symmetric measures of FC (Avery et al, 2014;Oler et al, 2012;Oler et al, 2017;Tillman et al, 2018;Torrisi et al, 2015). These studies revealed positively correlated BOLD signal fluctuations in the rsfMRI between amygdala nuclei and BNST, which we could reproduce as well (see Figure S1 and Tables S1 and S2, Supporting Information).…”

“…Although further investigations with a larger number of brain regions are required to elucidate the specific EC-based network structure of BNST and amygdala, previous rsfMRI FC studies suggest different connectivity profiles for the BNST, the LB, CM, and SF. For example, the BNST has been found to be coupled to regions of the default mode network (Avery et al, 2014;Tillman et al, 2018;Torrisi et al, 2015), while the direct comparison between the BNST and the CM shows that the BNST is stronger connected to regions involved in the default mode network and the CM shows preferential coupling to regions that coordinate responses to sensory stimuli (Gorka, Torrisi, Shackman, Grillon, & Ernst, 2018;Tillman et al, 2018).…”

“…Their results again showed significant positive rsFC between BNST and CM in accordance with their previous findings. Another study by Tillman et al (2018) similarly investigated the whole-brain rsFC of the BNST and the CM and found positive FC of the BNST with the central and medial nuclei of the amygdala. These results point toward a positive interconnectedness between BNST and all amygdala nuclei.…”

Functional Connectivity within the Primate Extended Amygdala Is Heritable and Associated with Early-Life Anxious Temperament

“…4, pink outline) and thresholded at p Ͻ 0.01 (uncorrected). Finally, mediation analyses were performed using the statsmodels mediation analysis tool (statsmodels.stats.mediation, version 0.8.0) to test the extent to which FDG-PET significantly accounted for the relationship between Ce functional connectivity and AT (Imai et al, 2010;Tingley et al, 2014).…”

“…These EAc regions are considered to be a macrostructural anatomical unit based on similarities in cell types, robust structural and functional connectivity, and similar projections to downstream effector regions (Heimer and Van Hoesen, 2006;Oler et al, 2012Oler et al, , 2017A. S. Fox et al, 2015a;Shackman et al, 2017;Tillman et al, 2018). Preclinical and clinical studies have implicated the EAc in adaptive and maladaptive fear and anxiety behavior (Avery et al, 2016;Gungor and Paré, 2016;Shackman and Fox, 2016), and the EAc is well positioned to orchestrate the extreme threat responses that are characteristic of anxiety and depressive disorders (Shackman et al, 2016b;Fox and Shackman, 2017).…”