Altered resting-state functional connectivity of basolateral and centromedial amygdala complexes in posttraumatic stress disorder

Abstract

The amygdala is a major structure that orchestrates defensive reactions to environmental threats and is implicated in hypervigilance and symptoms of heightened arousal in posttraumatic stress disorder (PTSD). The basolateral and centromedial amygdala (CMA) complexes are functionally heterogeneous, with distinct roles in learning and expressing fear behaviors. PTSD differences in amygdala-complex function and functional connectivity with cortical and subcortical structures remain unclear. Recent military veterans with PTSD (n=20) and matched trauma-exposed controls (n=22) underwent a resting-state fMRI scan to measure task-free synchronous blood-oxygen level dependent activity. Whole-brain voxel-wise functional connectivity of basolateral and CMA seeds was compared between groups. The PTSD group had stronger functional connectivity of the basolateral amygdala (BLA) complex with the pregenual anterior cingulate cortex (ACC), dorsomedial prefrontal cortex, and dorsal ACC than the trauma-exposed control group (p<0.05; corrected). The trauma-exposed control group had stronger functional connectivity of the BLA complex with the left inferior frontal gyrus than the PTSD group (p<0.05; corrected). The CMA complex lacked connectivity differences between groups. We found PTSD modulates BLA complex connectivity with prefrontal cortical targets implicated in cognitive control of emotional information, which are central to explanations of core PTSD symptoms. PTSD differences in resting-state connectivity of BLA complex could be biasing processes in target regions that support behaviors central to prevailing laboratory models of PTSD such as associative fear learning. Further research is needed to investigate how differences in functional connectivity of amygdala complexes affect target regions that govern behavior, cognition, and affect in PTSD.

Figure 1

Whole-brain voxel-wise resting-state function connectivity with left and right centromedial amygdala (CMA) seeds (orange overlay) and left and right basolateral amygdala (BLA) seeds (blue overlay) are seen in (a) a trauma-exposed control group and (b) a posttraumatic stress disorder (PTSD) group. Our results in the control group, consistent with results of Roy et al, 2009, showed CMA connectivity to extensive subcortical structures and a few cortical regions, whereas the BLA showed connectivity primarily to cortical structures.

Figure 2

basolateral amygdala (BLA) connectivity differences between posttraumatic stress disorder (PTSD) and the trauma-exposed control group. (a) The left BLA had stronger connectivity with the pregenual anterior cingulate cortex (ACC) (pgACC) and dorsomedial (dmPFC) in the PTSD group compared with the trauma-exposed control group (orange overlay). (b) The right BLA had stronger connectivity with the dorsal ACC in the PTSD group relative to the trauma-exposed control group (orange overlay). (c) The right BLA had stronger connectivity with the left inferior frontal gyrus (L-IFG) in the trauma-exposed control group than the PTSD group (teal green overlay). All statistical maps represent significance at Z>2.3 (p<0.05; corrected).

Figure 3

Earlier work in rodents and primates established distinct roles for the basolateral amygdala (BLA) and centromedial amygdala (CMA) complexes that we confirmed here in humans. We found a divergent relationship in connectivity strengths (using Fisher's r to z transformation) of BLA and CMA with select target regions. Three target regions were identified in the main analyses (see Figure 2) as exhibiting differences in BLA connectivity between posttraumatic stress disorder (PTSD) and trauma-exposed control groups. Scatter plots in the combined sample (PTSD+Control) highlight the significant connectivity relationships of BLA (x-axis) and CMA (y-axis) with two of the three target regions: (a) left inferior frontal gyrus (L-IFG) (r=–0.482, p=0.001) shaded in turquoise and (b) the dorsomedial (dm) PFC (r=–.361, p=0.02) shaded in gold. This divergent connectivity relationship between BLA and CMA was not significantly modulated by PTSD (p-values >0.05).