The association between early life stress and prefrontal cortex activation during implicit emotion regulation is moderated by sex in early adolescence

Abstract

Early life stress (ELS) is a significant risk factor for the emergence of internalizing problems in adolescence. Beginning in adolescence, females are twice as likely as males to experience internalizing disorders. The present study was designed to examine sex differences in the association between ELS and internalizing problems in early pubertal adolescents, and whether and how corticolimbic function and connectivity may underlie these associations. Fifty-nine early pubertal males and 78 early pubertal females, ages 9-13 years (all Tanner Stage 3 or below) underwent functional magnetic resonance imaging as they performed an emotion label task that robustly interrogates corticolimbic function. Participants were also interviewed about their experience of ELS. Females exhibited a positive association between ELS and internalizing problems, whereas males exhibited no such association. Whole-brain and amygdala region of interest analyses indicated that whereas females exhibited a positive association between ELS and the ventrolateral prefrontal cortex during implicit emotion regulation, males showed no such association. Activation in these regions was positively associated with internalizing problems in females but not males; however, activation in these regions did not mediate the association between ELS and internalizing problems. Finally, both boys and girls exhibited an association between ELS and increased negative connectivity between the right ventrolateral prefrontal cortex and bilateral amygdala. Using a carefully characterized sample of early pubertal adolescents, the current study highlights important sex differences in the development of corticolimbic circuitry during a critical period of brain development. These sex differences may play a significant role in subsequent risk for internalizing problems.

Figure 1

A whole brain interaction model examining whether the linear association between ELS severity and brain regions involved in labeling emotion faces versus matching emotion faces differed by sex yielded three significant clusters in left vlPFC, right dlPFC/vlPFC and bilateral intracalcarine cortex. Activation maps are thresholded at Z>2.3 and corrected for multiple comparisons using a cluster-based p<.05. MNI coordinates are indicated for slice distance (in mm). Parameter estimates (showing the amount of signal change measured in arbitrary units) of BOLD signal response were extracted from each significant cluster and plotted in the bar graph. Parameter estimates were also related to internalizing problems in males and females separately. vlPFC = ventrolateral prefrontal cortex; dlPFC = dorsolateral prefrontal cortex.

Figure 2

Strength of connectivity between right dlPFC/vlPFC and bilateral amygdala was negatively associated with ELS severity across males and females. vlPFC = ventrolateral prefrontal cortex; dlPFC = dorsolateral prefrontal cortex.