Influence of early life stress on intra- and extra-amygdaloid causal connectivity

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.