Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

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

Nature Neuroscience volume 15, pages 1736–1741 (2012)Cite this article

Subjects

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

References

  1. McEwen, B.S. Stress, adaptation, and disease: allostasis and allostatic load. Ann. NY Acad. Sci. 840, 33–44 (1998).

    Article  CAS  Google Scholar 

  2. Gunnar, M. & Quevedo, K. The neurobiology of stress and development. Annu. Rev. Psychol. 58, 145–173 (2007).

    Article  Google Scholar 

  3. Essex, M.J. et al. Influence of early life stress on later hypothalamic-pituitary-adrenal axis functioning and its covariation with mental health symptoms: a study of the allostatic process from childhood into adolescence. Dev. Psychopathol. 23, 1039–1058 (2011).

    Article  Google Scholar 

  4. Essex, M.J., Klein, M.H., Cho, E. & Kalin, N.H. Maternal stress beginning in infancy may sensitize children to later stress exposure: effects on cortisol and behavior. Biol. Psychiatry 52, 776–784 (2002).

    Article  CAS  Google Scholar 

  5. Lupien, S.J. et al. Larger amygdala but no change in hippocampal volume in 10-year-old children exposed to maternal depressive symptomatology since birth. Proc. Natl. Acad. Sci. USA 108, 14324–14329 (2011).

    Article  CAS  Google Scholar 

  6. Ochsner, K.N. & Gross, J.J. The cognitive control of emotion. Trends Cogn. Sci. 9, 242–249 (2005).

    Article  Google Scholar 

  7. Price, J.L. & Drevets, W.C. Neurocircuitry of mood disorders. Neuropsychopharmacology 35, 192–216 (2010).

    Article  Google Scholar 

  8. Sánchez, M.M., Young, L.J., Plotsky, P.M. & Insel, T.R. Distribution of corticosteroid receptors in the rhesus brain: relative absence of glucocorticoid receptors in the hippocampal formation. J. Neurosci. 20, 4657–4668 (2000).

    Article  Google Scholar 

  9. Lupien, S.J. et al. Effects of stress throughout the lifespan on the brain, behavior, and cognition. Nature Rev. Neuro 10, 434–445 (2009).

  10. Anisman, H., Zaharia, M.D., Meaney, M.J. & Merali, Z. Do early-life events permanently alter behavioral and hormonal responses to stressors? Int. J. Dev. Neurosci. 16, 149–164 (1998).

    Article  CAS  Google Scholar 

  11. Weinstock, M. Gender differences in the effects of prenatal stress on brain development and behaviour. Neurochem. Res. 32, 1730–1740 (2007).

    Article  CAS  Google Scholar 

  12. Bourke, C.H., Harrell, C.S. & Neigh, G. N. Stress-induced sex differences: adaptations mediated by the glucocorticoid receptor. Horm. Behav. 62, 210–218 (2012).

    Article  CAS  Google Scholar 

  13. Kim, M.J. et al. The structural and functional connectivity of the amygdala: from normal emotion to pathological anxiety. Behav. Brain Res. 223, 403–410 (2011).

    Article  Google Scholar 

  14. Kim, M.J., Gee, D.G., Loucks, R.A., Davis, F.C. & Whalen, P.J. Anxiety dissociates dorsal and ventral medial prefrontal cortex functional connectivity with the amygdala at rest. Cereb. Cortex 21, 1667–1673 (2011).

    Article  Google Scholar 

  15. Veer, I.M. et al. Endogenous cortisol is associated with functional connectivity between the amygdala and medial prefrontal cortex. Psychoneuroendocrinology 37, 1039–1047 (2012).

    Article  CAS  Google Scholar 

  16. Davidson, R.J. & McEwen, B.S. Social influences on neuroplasticity: stress and interventions to promote well-being. Nat. Neurosci. 15, 689–695 (2012).

    Article  CAS  Google Scholar 

  17. Kim, M.J. & Whalen, P.J. The structural integrity of an amygdala–prefrontal pathway predicts trait anxiety. J. Neurosci. 29, 11614–11618 (2009).

    Article  CAS  Google Scholar 

  18. Urry, H.L. et al. Amygdala and ventromedial prefrontal cortex are inversely coupled during regulation of negative affect and predict the diurnal pattern of cortisol secretion among older adults. J. Neurosci. 26, 4415–4425 (2006).

    Article  CAS  Google Scholar 

  19. Pruessner, J.C. et al. Stress regulation in the central nervous system: evidence from structural and functional neuroimaging studies in human populations-2008 Curt Richter Award Winner. Psychoneuroendocrinology 35, 179–191 (2010).

    Article  Google Scholar 

  20. Thomason, M.E., Hamilton, J.P. & Gotlib, I.H. Stress-induced activation of the HPA axis predicts connectivity between subgenual cingulate and salience network during rest in adolescents. J. Child Psychol. Psychiatry 52, 1026–1034 (2011).

    Article  Google Scholar 

  21. Damosiseaux, J.S. & Greicus, M.D. Greater than the sum of its parts: a review of studies combining structural connectivity and resting-state functional connectivity. Brain Struct. Funct. 213, 525–533 (2009).

    Article  Google Scholar 

  22. van den Heuvel, M.P., Mandl, R.C., Kahn, R.S. & Hulshoff Pol, H.E. Functionally linked resting-state networks reflect the underlying structural connectivity architecture of the human brain. Hum. Brain Mapp. 30, 3127–3141 (2009).

    Article  Google Scholar 

  23. Christianson, J.P., Thompson, B.M., Watkins, L.R. & Maier, S.F. Medial prefrontal cortical activation modulates the impact of controllable and uncontrollable stressor exposure on a social exploration test of anxiety in the rat. Stress 12, 445–450 (2009).

    Article  Google Scholar 

  24. Hakamata, Y. et al. Gender difference in relationship between anxiety-related personality traits and cerebral brain glucose metabolism. Psychiat. Res. 173, 206–211 (2009).

    Article  CAS  Google Scholar 

  25. Northoff, G., Wiebking, C., Feinberg, T. & Panksepp, J. The 'resting-state hypothesis' of major depressive disorder—a translational subcortical-cortical framework for a system disorder. Neurosci. Biobehav. Rev. 35, 1929–1945 (2011).

    Article  Google Scholar 

  26. Sheline, Y.I. et al. The default mode network and self-referential processes in depression. Proc. Natl. Acad. Sci. USA 106, 1942–1947 (2009).

    Article  CAS  Google Scholar 

  27. Lui, S. et al. Resting-state functional connectivity in treatment-resistant depression. Am. J. Psychiatry 168, 642–648 (2011).

    Article  Google Scholar 

  28. Myers-Schulz, B. & Koenigs, M. Functional anatomy of ventromedial prefrontal cortex: implications for mood and anxiety disorders. Mol. Psychiatry 17, 132–141 (2012).

    Article  CAS  Google Scholar 

  29. Beesdo, K. et al. Common and distinct amygdala-function perturbations in depressed vs anxious adolescents. Arch. Gen. Psychiatry 66, 275–285 (2009).

    Article  Google Scholar 

  30. Amunts, K. et al. Cytoarchitectonic mapping of the human amygdala, hippocampal region and entorhinal cortex: intersubject variability and probability maps. Anat. Embryol. (Berl.) 210, 343–352 (2005).

    Article  CAS  Google Scholar 

  31. Talairach, J. & Tournoux, P. Co-planar Stereotaxic Atlas of the Human Brain: 3-Dimensional Proportional System: An Approach to Cerebral Imaging. (Thieme, 1988).

  32. Schreiber, J.E. et al. Environmental influences on family similarity in afternoon cortisol levels: twin and parent-offspring designs. Psychoneuroendocrinology 31, 1131–1137 (2006).

    Article  CAS  Google Scholar 

  33. Essex, M.J. et al. The confluence of mental, physical, social, and academic difficulties in middle childhood. II: Developing the MacArthur Health and Behavior questionnaire. Am. Acad. Child Adolesc. Psychiatry 41, 588–603 (2002).

    Article  Google Scholar 

  34. Compas, B.E. Coping with stress during childhood and adolescence. Psychol. Bull. 101, 393–403 (1987).

    Article  CAS  Google Scholar 

  35. Sarason, I. et al. Assessing the impact of life changes: development of the Life Experiences Survey. J. Consult. Clin. Psychol. 46, 932–946 (1978).

    Article  CAS  Google Scholar 

  36. Muthén, L.K. & Muthén, B.O. Mplus User's Guide 5th edn. (2008).

  37. Murgatroyd, C. & Spengler, D. Epigenetic programming of the HPA axis: early life decides. Stress 14, 581–589 (2011).

    Article  CAS  Google Scholar 

  38. Michels, N. et al. Negative life events, emotions and psychological difficulties as determinants of salivary cortisol in Belgian primary school children. Psychoneuroendocrinology 37, 1506–1515 (2012).

    Article  CAS  Google Scholar 

  39. Cox, R.W. AFNI: software for analysis and visualization of functional magnetic resonance neuroimages. Comput. Biomed. Res. 29, 162–173 (1996).

    Article  CAS  Google Scholar 

  40. Smith, S.M. et al. Advances in functional and structural MR image analysis and implementation as FSL. Neuroimage 23, S208–S219 (2004).

    Article  Google Scholar 

  41. Saad, Z.S. et al. A new method for improving functional-to-structural MRI alignment using local Pearson correlation. Neuroimage 44, 839–848 (2009).

    Article  Google Scholar 

  42. Zhang, Y., Brady, M. & Smith, S. Segmentation of brain MR images through a hidden Markov random field model and the expectation-maximization algorithm. IEEE Trans. Med. Imaging 20, 45–57 (2001).

    Article  CAS  Google Scholar 

  43. Biswal, B., Zerrin Yetkin, F., Haughton, V.M. & Hyde, J.S. Functional connectivity in the motor cortex of resting human brain using echo-planar MRI. Magn. Reson. Med. 34, 537–541 (1995).

    Article  CAS  Google Scholar 

  44. Barrett, P. Structural equation modelling: adjudging model fit. Pers. Individ. Dif. 42, 815–824 (2007).

    Article  Google Scholar 

  45. Hu, L. & Bentler, P.M. Cutoff criteria for fit indexes in covariance structure analysis: conventional criteria versus new alternatives. Struct. Equ. Modeling 6, 1–55 (1999).

    Article  Google Scholar 

  46. Bentler, P.M. & Chou, C.P. Practical issues in structural modeling. Sociol. Methods Res. 16, 78–117 (1987).

    Article  Google Scholar 

  47. Preacher, K.J. & Hayes, A.F. Asymptotic and resampling strategies for assessing and comparing indirect effects in multiple mediator models. Behav. Res. Methods 40, 879–891 (2008).

    Article  Google Scholar 

Download references

Acknowledgements

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.

Author information

Authors and Affiliations

  1. Waisman Laboratory for Brain Imaging and Behavior, University of Wisconsin-Madison, Madison, Wisconsin, USA

    Cory A Burghy, Diane E Stodola, Michelle E Fox, Andrea S Hayes & Richard J Davidson

  2. Department of Psychiatry, University of Wisconsin-Madison, Madison, Wisconsin, USA

    Paula L Ruttle, Erin K Molloy, Jeffrey M Armstrong, Jonathan A Oler, Ned H Kalin, Marilyn J Essex, Richard J Davidson & Rasmus M Birn

  3. Department of Psychology, University of Wisconsin-Madison, Madison, Wisconsin, USA

    Ned H Kalin & Richard J Davidson

  4. Department of Medical Physics, University of Wisconsin-Madison, Madison, Wisconsin, USA

    Rasmus M Birn

Authors
  1. Cory A Burghy
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Diane E Stodola
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Paula L Ruttle
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Erin K Molloy
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jeffrey M Armstrong
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jonathan A Oler
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Michelle E Fox
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Andrea S Hayes
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ned H Kalin
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Marilyn J Essex
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Richard J Davidson
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Rasmus M Birn
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

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.

Corresponding author

Correspondence to Cory A Burghy.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Table 1 (PDF 45 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

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). https://doi.org/10.1038/nn.3257

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn.3257

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing