Childhood stress, grown-up brain networks: corticolimbic correlates of threat-related early life stress and adult stress response

Abstract

Background: Exposure to threat-related early life stress (ELS) has been related to vulnerability for stress-related disorders in adulthood, putatively via disrupted corticolimbic circuits involved in stress response and regulation. However, previous research on ELS has not examined both the intrinsic strength and flexibility of corticolimbic circuits, which may be particularly important for adaptive stress responding, or associations between these dimensions of corticolimbic dysfunction and acute stress response in adulthood.

Methods: Seventy unmedicated women varying in history of threat-related ELS completed a functional magnetic resonance imaging scan to evaluate voxelwise static (overall) and dynamic (variability over a series of sliding windows) resting-state functional connectivity (RSFC) of bilateral amygdala. In a separate session and subset of participants (n = 42), measures of salivary cortisol and affect were collected during a social-evaluative stress challenge.

Results: Higher severity of threat-related ELS was related to more strongly negative static RSFC between amygdala and left dorsolateral prefrontal cortex (DLPFC), and elevated dynamic RSFC between amygdala and rostral anterior cingulate cortex (rACC). Static amygdala-DLPFC antagonism mediated the relationship between higher severity of threat-related ELS and blunted cortisol response to stress, but increased dynamic amygdala-rACC connectivity weakened this mediated effect and was related to more positive post-stress mood.

Conclusions: Threat-related ELS was associated with RSFC within lateral corticolimbic circuits, which in turn was related to blunted physiological response to acute stress. Notably, increased flexibility between the amygdala and rACC compensated for this static disruption, suggesting that more dynamic medial corticolimbic circuits might be key to restoring healthy stress response.

Keywords: Childhood trauma; cortisol; early life stress; resting-state functional connectivity.

Conflict of interest statement

Conflict of interest

The authors report no conflicts of interest related to this paper. Over the past three years, Dr. Pizzagalli has received consulting fees from Akili Interactive Labs, BlackThorn Therapeutics, Boehringer Ingelheim, Pfizer, and Posit Science. All other authors report no biomedical financial interests.

Figures

Figure 1. Static and dynamic resting-state functional connectivity (RSFC) of bilateral amygdala is associated with severity of threat-related early life stress (ELS) in unmedicated women

(A) Displayed is the seed ROI in bilateral amygdala, anatomically defined using the AAL atlas. (B) Higher threat-related ELS severity was associated with stronger negative static RSFC (Fisher’s z-transformed Pearson’s correlations across the full duration of the resting scan) between a seed region of interest (ROI) in bilateral amygdala and regions of left dorsolateral prefrontal cortex (DLPFC). (C) Women with higher threat-related ELS severity exhibited increased dynamic RSFC (SD in Fisher’s z-transformed Pearson’s correlations across a series of sliding windows) between the amygdala ROI and areas of rostral anterior cingulate cortex (rACC), related to increased frequency of strong positive connectivity between these regions across sliding windows (see Figure S2). Note: Voxelwise static or dynamic RSFC analyses thresholded at peak p<0.005, two-sided t-test, FWE corrected p<0.05. Analyses controlled for age and motion outliers.

Figure 2. Associations between corticolimbic resting-state functional connectivity (RSFC) and physiological or affective responses to acute stress

Multiple regression revealed a main effect of static corticolimbic connectivity (RSFC between bilateral amygdala and dorsolateral prefrontal cortex, DLPFC) on cortisol response to acute stress (area under the curve with respect to ground, AUC), which was in turn moderated by dynamic corticolimbic RSFC (between amygdala and rostral anterior cingulate cortex, rACC). Displayed are scatterplots depicting the associations between static amygdala-DLPFC RSFC and AUC at (A) low (below median) amygdala-rACC dynamic RSFC, or (B) high (above median) amygdala-rACC dynamic RSFC. A separate repeated-measures analysis of variance revealed that dynamic amygdala-rACC RSFC moderated the effect of stress exposure on negative affect (rating of hostility/sadness/tension via a Visual Analog Mood Scale, VAMS), with moderation driven by decreased post-stress hostility among women with higher amygdala-rACC dynamic RSFC; there were no main or moderated effects of static corticolimbic RSFC. (C) Displayed is the scatterplot of the association between dynamic amygdala-rACC RSFC and VAMS hostility scores (+20 min) post-stress across the full sample. Note: in A, B, dynamic RSFC values are binned for visual display, only; all regressions were performed on continuous variables. Analyses controlled for age, motion outliers.

Figure 3. Summary

In the present sample, neural correlates of threat-related early life stress included more extreme resting-state antagonism in a lateral corticolimbic circuit including dorsolateral prefrontal cortex (DLPFC) and amygdala (highlighted by the concentric line looping through the two regions), but more variable resting-state functional connectivity in a medial corticolimbic circuit including rostral anterior cingulate (rACC) and amygdala (highlighted by the concentric line looping through the two regions). Threat-related early life stress severity had an indirect effect through stronger lateral corticolimbic antagonism (more negative resting-state functional connectivity) to predict blunted physiological (cortisol) response to stress, but higher levels of dynamic medial corticolimbic functional connectivity moderated this indirect effect and were independently predictive of lower negative mood after stress exposure. Together, these findings suggest that exposure to severe early life stress is related to both maladaptive and compensatory changes in corticolimbic circuits, e.g., more extreme antagonism in lateral circuits that disrupts healthy mobilization of physical resources in response to stressors, but also greater flexibility in medial circuits that compensates for lateral anomalies. Note: Indirect effect pathway highlighted in gray arrows; moderation effect pathway highlighted in double-black.