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


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.

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Figure 1: Correlation between late-afternoon cortisol at age 4.5 years and rs-FC to the left amygdala at 18 years.
Figure 2: SEM examining the moderating effect of gender on the mediation through childhood late-afternoon basal cortisol level of the association between ELS and amygdala-vmPFC rs-FC.
Figure 3: SEM examining the moderating effect of gender on the mediation through amygdala-vmPFC rs-FC of the relation between childhood late afternoon basal cortisol level and adolescent anxiety.
Figure 4
Figure 5: SEM examining the moderating effect of gender on the mediation through amygdala-vmPFC rs-FC of the relation between childhood afternoon basal cortisol and adolescent depression.


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This work was supported by US National Institutes of Health grants P50 MH084051, R01-MH044340 and P50-MH052354; the John D. and Catherine T. MacArthur Foundation Research Network on Psychopathology and Development; and the HealthEmotions Research Institute, Department of Psychiatry, University of Wisconsin School of Medicine and Public Health. Support for P.L.R. was provided by the Canadian Institutes for Health Research post-doctoral fellowship. We thank M. Anderle, R. Fisher, L. Angelos, C. Hermes, A. Koppenhaver and C. Boldt for assistance with data collection and recruitment, and D. Jackson, J. Ollinger, G. Kirk, N. Vack, J. Koger and I. Dolski for general, technical and administrative assistance.

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C.A.B., D.E.S., P.L.R., J.M.A., M.J.E., R.J.D. and R.M.B. wrote and revised the manuscript. C.A.B., D.E.S., P.L.R., E.K.M., N.H.K., M.J.E. and R.M.B. performed data processing, statistical and/or image analyses. M.E.F. and A.S.H. collected data, created figures and assisted with editing the manuscript. C.A.B., D.E.S., P.L.R., J.A.O., M.J.E., R.J.D. and R.M.B. contributed to the interpretation of the data. M.J.E., R.J.D. and R.M.B. supervised the project.

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Correspondence to Cory A Burghy.

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Burghy, C., Stodola, D., Ruttle, P. et al. Developmental pathways to amygdala-prefrontal function and internalizing symptoms in adolescence. Nat Neurosci 15, 1736–1741 (2012).

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