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. 2015 Jun;40(7):1782-93.
doi: 10.1038/npp.2015.28. Epub 2015 Jan 29.

Influence of Early Life Stress on Intra- And Extra-Amygdaloid Causal Connectivity

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Free PMC article

Influence of Early Life Stress on Intra- And Extra-Amygdaloid Causal Connectivity

Merida M Grant et al. Neuropsychopharmacology. .
Free PMC article

Abstract

Animal models of early life stress (ELS) are characterized by augmented amygdala response to threat and altered amygdala-dependent behaviors. These models indicate the amygdala is a heterogeneous structure with well-differentiated subnuclei. The most well characterized of these being basolateral (BLA) and central nucleus (CeA). Parallel human imaging findings relative to ELS also reveal enhanced amygdala reactivity and disrupted connectivity but the influence of ELS on amygdala subregion connectivity and modulation of emotion is unclear. Here we employed cytoarchitectonic probability maps of amygdala subregions and Granger causality methods to evaluate task-based intra-amygdaloid and extra-amygdaloid connectivity with the network underlying implicit regulation of emotion in response to unconditioned auditory threat in healthy controls with ELS (N=20) and without a history of ELS (N=14). Groups were determined by response to the Childhood Trauma Questionnaire and threat response determined by unpleasantness ratings. Non-ELS demonstrated narrowly defined BLA-driven intra-amygdaloid paths and concise orbitofrontal cortex (OFC)-CeA-driven extra-amygdaloid connectivity. In contrast, ELS was associated with extensive and robust CeA-facilitated intra- and extra-amygdaloid paths. Non-ELS findings paralleled the known anatomical organization and functional relationships for both intra- and extra-amygdaloid connectivity, while ELS demonstrated atypical intra- and extra-amygdaloid CeA-dominant paths with compensatory modulation of emotion. Specifically, negative causal paths from OFC/BA32 to BLA predicted decreased threat response among non-ELS, while a unique within-amygdala path predicted modulation of threat among ELS. These findings are consistent with compensatory mechanisms of emotion regulation following ELS among resilient persons originating both within the amygdala complex as well as subsequent extra-amygdaloid communication.

Figures

Figure 1
Figure 1
Intra-Amygdala Granger Causality Paths. Robust causal paths were observed for (a) Non-ELS participants. Right BLA-dominant causal paths were primarily observed, which predicted robust activity in left BLA, and left SF, with less robust relationships with right SF. An additional path from right SF to left BLA was also observed. This model is consistent with known anatomical and functional organization of the amygdala observed in animal models of threat. In contrast (b) ELS participants demonstrated primarily right CeA dominant paths with robust relationships with left CeA, bilateral SF and bilateral BLA. Additional relationships between left SF and right BLA and right SF and left BLA were also observed. This pattern was not consistent with known anatomical and functional organization of the amygdala in response to threat. p-values are FDR-corrected. Abbreviations: BLA, basolateral; CeA, central nucleus; ELS, early life stress; FDR, false discovery rate; SF, superficial nuclei.
Figure 2
Figure 2
Extra-Amygdaloid Granger Causality Paths: CeA. (a) Non-ELS demonstrated a concise OFC-derived path that predicted bilateral CeA response. In contrast, the ELS group demonstrated a much more complex CeA-dominant pattern in which right CeA activity predicted activity in multiple cortical regions including bilateral DLPFC, BA 11, BA32, 25 and 24, and hippocampus. In addition right DLPFC predicted bilateral CeA, while left DLPFC predicted left CeA. Left hippocampus predicted bilateral CeA. p-values are FDR-corrected. Abbreviations: BA, Brodmann's Area; CeA, central nucleus; DLPFC, dorsal lateral prefrontal cortex; ELS, early life stress; FDR, false discovery rate; OFC, orbitofrontal cortex.
Figure 3
Figure 3
Extra-Amygdaloid Granger Causality Paths: BLA. (a) Non-ELS demonstrated BLA-dominant causal connectivity that predicted activity in bilateral BA 32, right BA11, right hippocampus, and left DLPFC. In addition BA11 predicted bilateral BLA. (b) Multiple cortical regions predicted bilateral BLA activity including right DLPFC, BA 32, left BA32 and BA24 which predicted right BLA. Right BA32, right DLPFC and left DLPFC predicted left BLA response. Left hippocampus also predicted right BLA response. p-values are FDR-corrected. Abbreviations: BA, Brodmann's Area; BLA, basolateral; DLPFC, dorsal lateral prefrontal cortex; ELS, early life stress; FDR, false discovery rate.
Figure 4
Figure 4
Extra-Amygdaloid Granger Causality Paths: SF. (a) Non-ELS demonstrated a concise OFC-dominant causal connectivity that predicted bilateral SF. In addition, left SF predicted right BA24 activity. (b) Again multiple cortical regions predicted right SF response including right DLPFC and BA32 and left DLPFC, BA32, BA24 and hippocampus. Left SF was predicted by left DLPFC, BA32, BA24 and hippocampus, as well as right DLPFC, BA32. p-values are FDR-corrected. Abbreviations: BA, Brodmann's Area; DLPFC, dorsal lateral prefrontal cortex; ELS, early life stress; FDR, false discovery rate; OFC, orbitofrontal cortex; SF, superficial nuclei.
Figure 5
Figure 5
Granger Causality Paths and Implicit Modulation of Emotion. As a measure of implicit regulation of emotion, we performed correlation analysis between connectivity coefficients for intra-amygdaloid and extra-amygdaloid lateral/medial paths with individual threat ratings for the UCS trials. (a) A negative causal path from right BA 11 (OFC) to left BLA was associated with less perceived threat in non-ELS, p<0.01 (b) Similarly, a negative causal path from left BA32 to left BLA was associated with less perceived threat in the non-ELS group, p<0.05 (c) A positive causal path from right hippocampus to right BLA was associated with less perceived threat in the non-ELS group, p<0.05 and (d) A positive causal path from right BLA to left CeA was associated with less perceived threat within the ELS group, p<0.05. Abbreviations: BA, Brodmann's Area; BLA, basolateral; CeA, central nucleus; ELS, early life stress; OFC, orbitofrontal cortex; UCS, unconditioned stimulus.

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