Early life stress modulates amygdala‐prefrontal functional connectivity: Implications for oxytocin effects

Abstract

Recent evidence suggests that early life stress (ELS) changes stress reactivity via reduced resting state functional connectivity (rs-FC) between amygdala and the prefrontal cortex. Oxytocin (OXT) modulates amygdala connectivity and attenuates responses to psychosocial stress, but its effect appears to be moderated by ELS. Here we first investigate the effect of ELS on amygdala-prefrontal rs-FC, and examine whether ELS-associated changes of rs-FC in this neural circuit predict its response to psychosocial stress. Secondly, we explore the joint effect of OXT and ELS on the amygdala-prefrontal circuit. Eighteen healthy young males participated in a resting-state fMRI study of OXT effects using a double-blind, randomized, placebo-controlled, within-subject crossover design. We measured the rs-FC to bilateral amygdalae and subsequently assessed changes of state anxiety and prefrontal responses to psychosocial stress. Multiple linear regressions showed that ELS, specifically emotional abuse, predicted reduced rs-FC between the right amygdala and pregenual anterior cingulate cortex (pgACC), which in turn predicted elevated state anxiety after psychosocial stress. In subjects with lower ELS scores, stronger pgACC-amygdala rs-FC predicted stronger pgACC deactivation during the psychosocial stress task, and this rest-task interaction was attenuated by OXT. In subjects with higher ELS scores however, the rest-task interaction was altered and OXT showed no significant effect. These findings highlight that ELS reduces pgACC-amygdala rs-FC and alters how rs-FC of this circuit predicts its stress responsiveness. Such changes in pgACC-amygdala functional dynamics may underlie the altered sensitivity to the effects of OXT after ELS.

Amygdala–Hippocampal Connectivity Changes During Acute Psychosocial Stress: Joint Effect of Early Life Stress and Oxytocin

“…At a first glance, this seems inconsistent with previous findings that ELS is associated with decreased amygdala-prefrontal FC during resting state (Burghy et al, 2012;Fan et al, 2014;Herringa et al, 2013). However, it is important to emphasize that task-evoked FC changes reflect transient changes in brain network coupling in response to specific task demands.…”

“…Task-evoked FC changes between amygdala and other limbic-prefrontal regions have been demonstrated during transient acute stress (Hermans et al, 2011;Vaisvaser et al, 2013;Veer et al, 2011). It has also been shown that ELS impacts structural connectivity and trait-like rs-FC within the limbic-prefrontal circuit (Burghy et al, 2012;Fan et al, 2014;Hart and Rubia, 2012;Herringa et al, 2013). Here we hypothesize that ELS influences stress-induced FC changes from amygdala to mPFC and hippocampus.…”

“…ELS-associated deficits in structural connectivity among these regions are also evident, supporting network abnormalities in the limbic-prefrontal circuit (Hart and Rubia, 2012). Recent studies have found ELS-associated decreases in resting-state FC (rs-FC) within the limbicprefrontal circuit (Burghy et al, 2012;Fan et al, 2014;Herringa et al, 2013). Although rs-FC is postulated to reflect trait-like individual differences in circuitry integrity, taskevoked FC changes (eg, measured by psychophysiological interactions (PPIs)) are supposed to reflect transient changes in brain network coupling in response to specific task demands.…”

“…resting state (Burghy et al, 2012;Fan et al, 2014;Herringa et al, 2013), suggesting ELS-associated aberration in the traitlike functional integrity of the limbic-prefrontal circuit. Adding to this evidence, our finding highlights the association between EA and transient task-evoked changes in amygdala-hippocampal FC in response to acute psychosocial stress.…”

Intranasal Oxytocin Affects Amygdala Functional Connectivity after Trauma Script-Driven Imagery in Distressed Recently Trauma-Exposed Individuals

“…Finally, for all significant results, we additionally adjusted for sex, lifetime PTSD, duration between intranasal administration and scanning, and (for fMRI analyses only) experienced childhood trauma in separate models (Fan et al, 2014;Paloyelis et al, 2014;Rilling et al, 2014).…”