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. Although it is widely believed that these disorders reflect the coordinated activity of 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 imaging 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 that are likely to be useful for researchers working with "deidentified" neuroimaging data.

Keywords: affective neuroscience; amygdala; anxiety; bed nucleus of the stria terminalis (BST/BNST); central extended amygdala.

Figure 1

The EAc. (a) Simplified schematic of key EAc inputs and outputs in humans and other primates. The EAc (magenta) encompasses the BST, which encircles the anterior commissure, and the Ce. As shown by the translucent white arrow at the center of the figure, much of the sensory (yellow), contextual (blue), and regulatory (green) inputs to the EAc are indirect (i.e., polysynaptic), and first pass through adjacent amygdala nuclei before arriving at the Ce or the BST. Both regions are poised to orchestrate momentary states of fear and anxiety via dense projections to downstream effector regions (orange). Portions of this figure were adapted from the atlas of (Mai, Paxinos, & Voss, 2007; see also Yilmazer‐Hanke, 2012). (b) BST and Ce seeds. Figure depicts the location of the BST and Ce seeds used in the present study. See Supporting Information, Figure S5 for bilateral views and a more detailed description of seed derivation. (c) Structural connections of the EAc. In humans and other primates, the BST (dorsorostral magenta region) and the Ce (ventrocaudal magenta region) are structurally connected via two major fiber bundles (gold), the ventral amygdalofugal pathway and the stria terminalis (Johnston, 1923; Nauta, 1961; Yilmazer‐Hanke, 2012). From the Ce, the ventral amygdalofugal pathway courses forward and medially, passing through the SLEA, a bridge of neurons harbored within the substantia innominata. The stria terminalis, which arches dorsally over the thalamus, provides a second, less direct connection between the two major divisions of the central extended amygdala. Figure depicts deterministic tractography (gold) of these two fiber bundles. Image kindly provided by Do Tromp. Abbreviations: BL = basolateral nucleus of the amygdala; BM = basomedial nucleus of the amygdala; BST = bed nucleus of the stria terminalis; Ce = central nucleus of the amygdala; EAc = central division of the extended amygdala; La = lateral nucleus of the amygdala; Me = medial nucleus of the amygdala; SLEA = sublenticular extended amygdala [Color figure can be viewed at http://wileyonlinelibrary.com]

Figure 2

Intrinsic functional connectivity of the EAc. Left and center columns depict the results of whole‐brain regression analyses for the BST and the Ce seed regions, respectively, conservatively thresholded at p < .05 whole‐brain Šidák corrected. The right column depicts the intersection or conjunction (Boolean “AND”) of the two thresholded maps (Nichols et al., 2005). The BST seed showed significant functional connectivity with neighboring voxels in the basal forebrain (cyan arrowheads) and voxels in the region of the Ce (green arrowheads), while the Ce seed showed significant coupling with neighboring voxels in the dorsal amygdala and distal voxels in the region of the BST. Analyses also demonstrated that the BST and Ce exhibit robust functional connectivity with intermediate voxels located along the path of the ventral amygdalofugal pathway in the sublenticular extended amygdala (magenta arrowheads). Finally, both regions showed significant coupling with the amygdalohippocampal area and anterior hippocampus (white arrowheads), posterior insula (brown arrowheads), and superior temporal sulcus (black arrowheads). Note: Results are depicted here and reported in the accompanying tables for clusters of at least 80 mm³. See Figures 3 and 5 for additional views of these contrasts. Abbreviations: BST = bed nucleus of the stria terminalis; Ce = central nucleus of the amygdala; EAc = central division of the extended amygdala; L = left hemisphere; R = right hemisphere [Color figure can be viewed at http://wileyonlinelibrary.com]

Figure 3

The BST and the Ce are functionally linked via the SLEA. Clusters in the region of the SLEA (cyan arrowheads). Conventions are similar to Figure 2. Abbreviations: BST = bed nucleus of the stria terminalis; Ce = central nucleus of the amygdala; L = left hemisphere; R = right hemisphere; SLEA = sublenticular extended amygdala. See Figures 2 and 5 for additional views of these contrasts [Color figure can be viewed at http://wileyonlinelibrary.com]

Figure 4

Differential functional connectivity of the BST versus Ce. Results of a paired t test comparing the intrinsic functional connectivity of the BST and Ce. The left and right columns depict regions showing significantly stronger coupling with the BST and Ce, respectively. For ease of interpretation, differences were only examined in the subset of 12,004 voxels, where functional connectivity was significant for the BST, the Ce, or both seeds (Figures 2 and 3). Consistent with other analyses, results were thresholded at p < .05 Šidák corrected for the extent of the 12,004‐voxel mask. Results revealed significantly stronger coupling between the BST and the basal ganglia, including the caudate, putamen, and nucleus accumbens (cyan arrowheads). The BST also showed significantly stronger connectivity with the thalamus (magenta arrowheads) and a region of the brainstem consistent with the dorsal periaqueductal gray (green arrowheads; see also Supporting Information, Figure S9). The only regions showing stronger connectivity with the Ce were neighboring regions of the amygdala (white arrowheads), including voxels in the region of the amygdalohippocampal area, anterior hippocampus (not depicted) and the basolateral, basomedial, cortical, and medial nuclei. Note: Results are depicted here and reported in the accompanying tables for clusters of at least 80 mm³. See Figure 5 for additional views of the BST > Ce contrast. Abbreviations: BST = bed nucleus of the stria terminalis; Ce = central nucleus of the amygdala; L = left hemisphere; R = right hemisphere [Color figure can be viewed at http://wileyonlinelibrary.com]

Figure 5

Intrinsic functional connectivity of the EAc and midline cortical regions. The first two columns depict the results of whole‐brain regression analyses for the BST and Ce seed regions, respectively (p < .05, whole‐brain Šidák corrected). The third column depicts the intersection (Boolean “AND”) of the two thresholded maps. The fourth column depicts the results of a paired t test comparing the intrinsic functional connectivity of the BST and Ce (p < .05, small‐volume Šidák corrected). Both seeds show significant functional connectivity with the posterior cingulate/precuneus (green arrowhead), posterior MCC (cyan arrowheads), and vmPFC (magenta arrowhead). Relative to the Ce, the BST shows significantly stronger coupling with the anterior MCC and pgACC (brown arrowheads) and the vmPFC (orange arrowheads). Orange inset depicts a coronal slice through the vmPFC cluster, which extends along the rostral–caudal axis from area 10r/m and the inferior frontopolar gyrus to the rostral gyrus and pgACC. Conventions are similar to Figure 2 (first three columns) and Figure 4 (fourth column). See Figures 2, 3, 4 for additional views of these contrasts. Abbreviations: BST = bed nucleus of the stria terminalis; Ce = central nucleus of the amygdala; EAc = central divisions of the extended amygdala; L = left hemisphere; MCC = midcingulate cortex; pgACC = pregenual anterior cingulate cortex; R = right hemisphere; vmPFC = ventromedial prefrontal cortex [Color figure can be viewed at http://wileyonlinelibrary.com]