Developmental pathways to amygdala-prefrontal function and internalizing symptoms in adolescence

Abstract

Early life stress (ELS) and function of the hypothalamic-pituitary-adrenal axis predict later psychopathology. Animal studies and cross-sectional human studies suggest that this process might operate through amygdala-ventromedial prefrontal cortex (vmPFC) circuitry implicated in the regulation of emotion. Here we prospectively investigated the roles of ELS and childhood basal cortisol amounts in the development of adolescent resting-state functional connectivity (rs-FC), assessed by functional connectivity magnetic resonance imaging (fcMRI), in the amygdala-PFC circuit. In females only, greater ELS predicted increased childhood cortisol levels, which predicted decreased amygdala-vmPFC rs-FC 14 years later. For females, adolescent amygdala-vmPFC functional connectivity was inversely correlated with concurrent anxiety symptoms but positively associated with depressive symptoms, suggesting differing pathways from childhood cortisol levels function through adolescent amygdala-vmPFC functional connectivity to anxiety and depression. These data highlight that, for females, the effects of ELS and early HPA-axis function may be detected much later in the intrinsic processing of emotion-related brain circuits.

Figure 1

Correlation between late afternoon cortisol at child age 4.5 yrs and resting-state fcMRI to the left amygdala at 18 yrs. Connectivity between the left amygdala and vmPFC is significantly negatively associated with childhood cortisol (R² = 0.36, FDR-corrected p = 0.01). This effect is driven entirely by females, represented by the magenta data points (R² = 0.61, FDR-corrected p = 0.01).

Figure 2

Structural equation model examining the moderating effect of gender on the mediation through childhood late afternoon basal cortisol of the association between early life stress and amygdala-vmPFC fcMRI. The SEM model demonstrated good fit: Chi² = 1.89, p > 0.05; RMSEA = 0.00; SRMR = 0.03; CFI = 1.00. Paths are marked with unstandardized coefficients. Gender significantly moderated associations between ELS and childhood cortisol and childhood cortisol and amygdala-vmPFC fcMRI estimates and the mediating effect of childhood cortisol was marginally significant (Indirect Est. = −0.06, p = 0.09). In females only, higher levels of ELS predicted increased levels of childhood afternoon basal cortisol, which, in turn, predicted decreased amygdala-vmPFC functional connectivity. * p < 0.05, ** p < 0.01

Figure 3

Structural equation model examining the moderating effect of gender on the mediation through amygdala-vmPFC fcMRI of the relation between childhood late afternoon basal cortisol and adolescent anxiety. The SEM model demonstrated good fit: Chi2 = 9.95, p > 0.05; RMSEA = 0.11; SRMR = 0.04; CFI = 0.94. Paths are marked with unstandardized coefficients. Gender only significantly moderated the association between childhood cortisol and amygdala-vmPFC fcMRI and the mediating effect of adolescent amygdala-vmPFC fcMRI was marginally significant (Indirect Est. = 0.13, p = 0.08). For females only, the developmental pathway between childhood cortisol and adolescent anxiety symptoms operates through inverse associations with adolescent amygdala-vmPFC fcMRI. * p < 0.05, ** p < 0.01

Figure 4

Partial correlation between resting-state left amygdala-vmPFC fcMRI and concurrent self-reported anxious symptoms in adolescent females, controlling for concurrent symptoms of depression and externalizing behaviors (R² = 0.31, p = 0.004).

Figure 5

Structural equation model examining the moderating effect of gender on the mediation through amygdala-vmPFC fcMRI of the relation between childhood afternoon cortisol and adolescent depression. The SEM model demonstrated good fit: Chi² = 7.56, p > 0.05; RMSEA = 0.07; SRMR = 0.03; CFI = 0.97. Paths are marked with unstandardized coefficients. There was a marginally-significant direct effect of childhood cortisol on adolescent depressive symptoms, and the mediating effect of adolescent amygdala-vmPFC fcMRI was significant (Indirect Est. = −0.18, p = 0.02). In both male sand females, increased amygdala-vmPFC functional connectivity predicted increased depressive symptoms. For females, a developmental pathway between childhood cortisol and adolescent depressive symptoms operates partially through an inverse association with adolescent amygdala-vmPFC fcMRI. ^t p = 0.07, * p < 0.05, ** p < 0.01