Early life stress, systemic inflammation, and neural correlates of implicit emotion regulation in adolescents

Abstract

Exposure to early life stress (ELS) increases the risk for developing psychopathology; however, the mechanisms underlying this association are not clear. In this study we examined systemic inflammation as a pathway that may link exposure to stress to altered neural correlates of implicit emotion regulation in adolescents with varying levels of exposure to ELS (n = 83; 52 females, 31 males; 15.63 ± 1.10 years). We measured ventrolateral prefrontal cortex (vlPFC) activation and functional connectivity (FC) between the bilateral amygdala and the vlPFC as adolescents completed an affect labeling task in the scanner and assessed concentrations of C-reactive protein (CRP) using a dried blood spot protocol. We found that CRP levels were negatively associated with vlPFC activation during implicit regulation of negatively-valenced stimuli, and that cumulative severity of ELS exposure moderated this neuroimmune association. Severity of ELS also significantly moderated the association between CRP levels and FC between the bilateral amygdala and l-vlPFC during implicit emotion regulation: in adolescents who had been exposed to more severe ELS, higher CRP was associated with more negative frontoamygdala FC during implicit regulation of negatively-valenced stimuli. Thus, ELS may disrupt the normative association between the immune system and the neural processes that underlie socioemotional functioning potentially increasing adolescents' risk for maladaptive outcomes.

Keywords: Adolescence; C-reactive protein; Early life stress; Emotion regulation; Inflammation; fMRI.

Fig. 1.

CRP is negatively associated with neural activation during implicit regulation of negative emotions. Data-driven analysis identified five clusters with significant CRP-related BOLD activation during the Negative Label > Negative Match contrast: l-vlPFC (red), R-vlPFC (orange), bilateral SFG (blue), R-SFG (not shown), and l-anterior insula (green); Z-threshold = 3.1 and α = 0.025. The two vlPFC clusters were used as seeds in the functional connectivity analysis. Cluster images displayed over a 1 mm MNI standard template.

Fig. 2.

Neuroimmune associations during implicit emotion regulation, labeling, and matching of negative emotions. PEs from the two vlPFC clusters displaying significant CRP-related activation were extracted during the negative implicit emotion regulation contrast (Label > Match) (blue), Negative Label condition (green), and Negative Match condition (red). Plots show that activation was negatively associated with CRP during the Label > Match and Label conditions, and activation was positively associated with CRP during the Match condition. PEs are reported in arbitrary units; CRP reported in log-MFI; *denotes significant association. PE = parameter estimate; vlPFC = ventrolateral prefrontal cortex; L = left; R = right.

Fig. 3.

ELS severity moderates the association of CRP with activation in the l-vlPFC during implicit emotion regulation. Top) Simple slopes of the ELS-CRP interaction. At greater ELS severity (solid red), adolescents with higher CRP show reduced activation in the l-vlPFC during the Negative Label > Negative Match contrast. Bottom) Johnson-Neyman plot displaying the levels where ELS has a significant moderating effect on the CRP-l-vlPFC activation relation (sig. range in red). The dotted red line marks the upper boundary of the interval (−0.99). The black horizontal bar represents the observed ELS severity levels (z-scored).

Fig. 4.

ELS severity moderates the association of CRP with frontoamygdala FC during implicit emotion regulation. Top) Simple slopes of the ELS-CRP interaction. At greater ELS severity (solid red), adolescents with higher CRP show more negative FC between the bilateral amygdala and l-vlPFC during the Negative Label > Negative Match contrast. Bottom) Johnson-Neyman plot displaying the levels where ELS has a significant moderating effect on the CRP-FC relation (sig. range in red). The dotted red line marks the upper boundary of the interval (0.12). The black horizontal bar represents the observed ELS severity levels (z-scored).