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Early life stress, cortisol, frontolimbic connectivity, and depressive symptoms during puberty

  • Katharina Kircanski (a1), Lucinda M. Sisk (a2), Tiffany C. Ho (a2), Kathryn L. Humphreys (a3), Lucy S. King (a2), Natalie L. Colich (a4), Sarah J. Ordaz (a2) and Ian H. Gotlib (a2)...


Early life stress (ELS) is a risk factor for the development of depression in adolescence; the mediating neurobiological mechanisms, however, are unknown. In this study, we examined in early pubertal youth the associations among ELS, cortisol stress responsivity, and white matter microstructure of the uncinate fasciculus and the fornix, two key frontolimbic tracts; we also tested whether and how these variables predicted depressive symptoms in later puberty. A total of 208 participants (117 females; M age = 11.37 years; M Tanner stage = 2.03) provided data across two or more assessment modalities: ELS; salivary cortisol levels during a psychosocial stress task; diffusion magnetic resonance imaging; and depressive symptoms. In early puberty there were significant associations between higher ELS and decreased cortisol production, and between decreased cortisol production and increased fractional anisotropy in the uncinate fasciculus. Further, increased fractional anisotropy in the uncinate fasciculus predicted higher depressive symptoms in later puberty, above and beyond earlier symptoms. In post hoc analyses, we found that sex moderated several additional associations. We discuss these findings within a broader conceptual model linking ELS, emotion dysregulation, and depression across the transition through puberty, and contend that brain circuits implicated in the control of hypothalamic–pituitary–adrenal axis function should be a focus of continued research.


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Author for correspondence: Katharina Kircanski, Emotion and Development Branch, National Institute of Mental Health, 9000 Rockville Pike, Building 15K, MSC-2670, Bethesda, MD 20892-2670; E-mail:


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Authors Katharina Kircanski and Lucinda M. Sisk contributed equally to the article.



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Adrian, M., Zeman, J., & Veits, G. (2011). Methodological implications of the affect revolution: A 35-year review of emotion regulation assessment in children. Journal of Experimental Child Psychology, 110, 171197. doi:10.1016/j.jecp.2011.03.009
Aghajani, M., Veer, I. M., Van Lang, N. D. J., Meens, P. H. F., Van Den Bulk, B. G., Rombouts, S. A. R. B., … Van Der Wee, N. J. (2014). Altered white-matter architecture in treatment-naive adolescents with clinical depression. Psychological Medicine, 44, 22872298. doi:10.1017/S0033291713003000
Alink, L. R. A., Cicchetti, D., Kim, J., & Rogosch, F. A. (2012). Longitudinal associations among child maltreatment, social functioning, and cortisol regulation. Developmental Psychology, 48, 224236. doi:10.1037/a0024892
Basser, P. J., Pajevic, S., Pierpaoli, C., Duda, J., & Aldroubi, A. (2000). In vivo fiber tractography using DT-MRI data. Magnetic Resonance in Medicine, 141, C4014005. doi:10.1061/(ASCE)EI.1943-5541.0000225
Beauchaine, T. P. (2015). Future directions in emotion dysregulation and youth psychopathology. Journal of Clinical Child and Adolescent Psychology, 44, 875896. doi:10.1080/15374416.2015.1038827
Beauchaine, T. P., & Gatzke-Kopp, L. M. (2012). Instantiating the multiple levels of analysis perspective in a program of study on externalizing behavior. Development and Psychopathology, 24, 10031018. doi:10.1017/S0954579412000508
Bracht, T., Linden, D., & Keedwell, P. (2015). A review of white matter microstructure alterations of pathways of the reward circuit in depression. Journal of Affective Disorders, 187, 4553. doi:10.1016/j.jad.2015.06.041
Bunea, I. M., Szentágotai-Tǎtar, A., & Miu, A. C. (2017). Early-life adversity and cortisol response to social stress: A meta-analysis. Translational Psychiatry, 7, 1274. doi:10.1038/s41398-017-0032-3
Burke, H. M., Davis, M. C., Otte, C., & Mohr, D. C. (2005). Depression and cortisol responses to psychological stress: A meta-analysis. Psychoneuroendocrinology, 30, 846856. doi:10.1016/j.psyneuen.2005.02.010
Callaghan, B. L., & Tottenham, N. (2016). The stress acceleration hypothesis: Effects of early-life adversity on emotion circuits and behavior. Current Opinion in Behavioral Sciences, 7, 7681. doi:10.1016/j.cobeha.2015.11.018
Choi, J., Jeong, B., Rohan, M. L., Polcari, A. M., & Teicher, M. H. (2009). Preliminary evidence for white matter tract abnormalities in young adults exposed to parental verbal abuse. Biological Psychiatry, 65, 227234. doi:10.1016/j.biopsych.2008.06.022
Cicchetti, D., Rogosch, F. A., Gunnar, M. R., & Toth, S. L. (2010). The differential impacts of early physical and sexual abuse and internalizing problems on daytime cortisol rhythm in school-aged children. Child Development, 81, 252269. doi:10.1111/j.1467-8624.2009.01393.x
Coleman, L., & Coleman, J. (2002). The measurement of puberty: A review. Journal of Adolescence, 25, 535550. doi:10.1207/S15327949PAC0804_03
Colich, N. L., Kircanski, K., Foland-Ross, L. C., & Gotlib, I. H. (2015). HPA-axis reactivity interacts with stage of pubertal development to predict the onset of depression. Psychoneuroendocrinology, 55, 94101.
Colich, N. L., Williams, E. S., Ho, T. C., King, L. S., Humphreys, K. L., Price, A. N., Ordaz, S. J., & Gotlib, I. H. (2017). The association between early life stress and prefrontal cortex activation during implicit emotion regulation is moderated by sex in early adolescence. Development and Psychopathology, 29, 18511864.
Conturo, T. E., Lori, N. F., Cull, T. S., Akbudak, E., Snyder, A. Z., Shimony, J. S., … Raichle, M. E. (1999). Tracking neuronal fiber pathways in the living human brain. Applied Physical Sciences: Neurobiology, 96, 1042210427. doi:10.1073/pnas.96.18.10422
Dahl, R. E. (2001). Affect regulation, brain development, and behavioral/emotional health in adolescence. CNS Spectrums, 6, 6072. doi:10.1017/S1092852900022884
Dannlowski, U., Stuhrmann, A., Beutelmann, V., Zwanzger, P., Lenzen, T., Grotegerd, D., … Kugel, H. (2012). Limbic scars: Long-term consequences of childhood maltreatment revealed by functional and structural magnetic resonance imaging. Biological Psychiatry, 71, 286293. doi:10.1016/j.biopsych.2011.10.021
DePasquale, C. E., Donzella, B., & Gunnar, M. R. (in press). Pubertal recalibration of cortisol reactivity following early life stress: A cross-sectional analysis. Journal of Child Psychology and Psychiatry. doi:10.1111/jcpp.12992
Desmangles, J. C., Lappe, J. M., Lipaczewski, G., & Haynatzki, G. (2006). Accuracy of pubertal Tanner staging self-reporting. Journal of Pediatric Endocrinology and Metabolism, 19, 213222. doi:10.1515/JPEM.2006.19.3.213
Destrieux, C., Fischl, B., Dale, A., & Halgren, E. (2010). Automatic parcellation of human cortical gyri and sulci using standard anatomical nomenclature. NeuroImage, 53, 115. doi:10.1016/j.neuroimage.2010.06.010
Doom, J. R., & Gunnar, M. R. (2013). Stress physiology and developmental psychopathology: Past, present and future. Development and Psychopathology, 25, 13591373. doi:10.1017/S0954579413000667
Eluvathingal, T. J. (2006). Abnormal brain connectivity in children after early severe socioemotional deprivation: A diffusion tensor imaging study. Pediatrics, 117, 20932100. doi:10.1542/peds.2005-1727
Fischl, B., Salat, D. H., Van Der Kouwe, A. J. W., Makris, N., Ségonne, F., Quinn, B. T., & Dale, A. M. (2004). Sequence-independent segmentation of magnetic resonance images. NeuroImage, 23, 6984. doi:10.1016/j.neuroimage.2004.07.016
Fries, E., Hesse, J., Hellhammer, J., & Hellhammer, D. H. (2005). A new view on hypocortisolism. Psychoneuroendocrinology, 30, 10101016. doi:10.1016/j.psyneuen.2005.04.006
Fuhrmann, D., Knoll, L. J., & Blakemore, S. J. (2015). Adolescence as a sensitive period of brain development. Trends in Cognitive Sciences, 19, 558566. doi:10.1016/j.tics.2015.07.008
Green, J. G., Mclaughlin, K. A., Berglund, P. A., Gruber, M. J., Sampson, N. A., Zaslavsky, A. M., & Kessler, R. C. (2010). Childhood adversities and adult psychiatric disorders in the national comorbidity survey replication I. American Medical Association, 67, 113123. doi:10.1001/archgenpsychiatry.2009.186
Haber, S. N., & Knutson, B. (2010). The reward circuit: Linking primate anatomy and human imaging. Neuropsychopharmacology, 35, 426. doi:10.1038/npp.2009.129
Hanson, J. L., Adluru, N., Chung, M. K., Alexander, A. L., Davidson, R. J., & Pollak, S. D. (2013). Early neglect is associated with alterations in white matter integrity and cognitive functioning. Child Development, 84, 15661578. doi:10.1111/cdev.12069
Hanson, J. L., Knodt, A. R., Brigidi, B. D., & Hariri, A. R. (2015). Lower structural integrity of the uncinate fasciculus is associated with a history of child maltreatment and future psychological vulnerability to stress. Development and Psychopathology, 27, 16111619. doi:10.1017/S0954579415000978
Hanson, J. L., Nacewicz, B. M., Sutterer, M. J., Cayo, A. A., Schaefer, S. M., Rudolph, K. D., … Davidson, R. J. (2015). Behavioral problems after early life stress: Contributions of the hippocampus and amygdala. Biological Psychiatry, 77, 314323. doi:10.1016/j.biopsych.2014.04.020
Harkness, K. L., Stewart, J. G., & Wynne-Edwards, K. E. (2011). Cortisol reactivity to social stress in adolescents: Role of depression severity and child maltreatment. Psychoneuroendocrinology, 36, 173181. doi:10.1016/j.psyneuen.2010.07.006
Ho, T. C., King, L. S., Leong, J. K., Colich, N. L., Humphreys, K. L., Ordaz, S. J., & Gotlib, I. H. (2017). Effects of sensitivity to life stress on uncinate fasciculus segments in early adolescence. Social Cognitive and Affective Neuroscience, 12, 14601469. doi:10.1093/scan/nsx065
Hua, K., Zhang, J., Wakana, S., Jiang, H., Li, X., Reich, D. S., … Mori, S. (2008). Tract probability maps in stereotaxic spaces: Analyses of white matter anatomy and tract-specific quantification. NeuroImage, 39, 336347. doi:10.1371/journal.pone.0128887
Huang, H., Gundapuneedi, T., & Rao, U. (2012). White matter disruptions in adolescents exposed to childhood maltreatment and vulnerability to psychopathology. Neuropsychopharmacology, 37, 26932701. doi:10.1038/npp.2012.133
Kessler, R. C. (2003). Epidemiology of women and depression. Journal of Affective Disorders, 74, 513. doi:10.1016/S0165-0327(02)00426-3
King, L. S., Colich, N. L., LeMoult, J., Humphreys, K. L., Ordaz, S. J., Price, A. N., & Gotlib, I. H. (2017). The impact of the severity of early life stress on diurnal cortisol: The role of puberty. Psychoneuroendocrinology, 77, 6874. doi:10.1016/j.psyneuen.2016.11.024
Kirschbaum, C., Pirke, K.-M., & Hellhammer, D. H. (1993). The Trier Social Stress Test—A tool for investigating psychobiological stress responses in a laboratory setting. Neuropychobiology, 28, 7681.
Koss, K. J., & Gunnar, M. R. (2018). Annual Research Review: Early adversity, the hypothalamic-pituitary-adrenocortical axis, and child psychopathology. Journal of Child Psychology and Psychiatry and Allied Disciplines, 4, 327346. doi:10.1111/jcpp.12784
Kovacs, M. (1985). The Children's Depression Inventory (CDI). Psychopharmocological Bulletin, 21, 995998.
Kovacs, M. (1992). The Children's Depression Inventory (CDI). Toronto, ON: Multi-Health Systems.
Kwong, A. S., Manley, D., Timpson, N. J., Pearson, R. M., Heron, J., Sallis, H., … Leckie, G. (in press). Identifying critical points of trajectories of depressive symptoms from childhood to young adulthood. Journal of Youth and Adolescence. doi:10.1007/s10964-018-0976-5
Lebel, C., Gee, M., Camicioli, R., Wieler, M., Martin, W., & Beaulieu, C. (2012). Diffusion tensor imaging of white matter tract evolution over the lifespan. NeuroImage, 60, 340352. doi:10.1016/j.neuroimage.2011.11.094
Leong, J. K., MacNiven, K. H., Samanez-Larkin, G. R., & Knutson, B. (2018). Distinct neural circuits support incentivized inhibition. NeuroImage, 178, 435444. doi:10.1016/j.neuroimage.2018.05.055
Leong, J., Pestilli, F., Wu, C., Samanez-Larkin, G., & Knutson, B. (2016). White-matter tract connecting anterior insula to nucleus accumbens correlates with reduced preference for positively skewed gambles. Neuron, 89, 6369. doi:10.1161/CIRCULATIONAHA.114.010270.
Lewinn, K. Z., Connolly, C. G., Wu, J., Drahos, M., Hoeft, F., Ho, T. C., … Yang, T. T. (2014). White matter correlates of adolescent depression: Structural evidence for frontolimbic disconnectivity. Journal of the American Academy of Child & Adolescent Psychiatry, 53, 899909. doi:10.1016/j.jaac.2014.04.021
Lupien, S. J., McEwen, B. S., Gunnar, M. R., & Heim, C. M. (2009). Effects of stress throughout the lifespan on the brain and behavior. In Pfaff, D. W. (Ed.), Hormones, brain and behavior (3rd ed., pp. 434445). San Diego, CA: Academic Press.
Marshall, W. A., & Tanner, J. M. (1968). Growth and physiological development during adolescence. Annual Review of Medicine, 19, 283300.
McEwen, B. S. (1998). Stress, adaptation, and disease: Allostasis and allostatic load. Annals of the New York Academy of Sciences, 840, 3344.
McEwen, B. S. (2004). Protection and damage from acute and chronic stress. Annals of the New York Academy of Sciences, 1032, 17.
McEwen, B. S., & Milner, T. (2007). Hippocampal formation: Shedding light on the influence of sex and stress on the brain. Brain Research Review, 55, 343355.
McLaughlin, K. A., Green, J. G., Gruber, M. J., Sampson, N. A., Zaslavsky, A. M., & Kessler, R. C. (2012). Childhood adversities and first onset of psychiatric disorders in a national sample of US adolescents. Archives of General Psychiatry, 69, 11511160. doi:10.1001/archgenpsychiatry.2011.2277
Messman-Moore, T. L., & Bhuptani, P. H. (2017). A review of the long-term impact of child maltreatment on posttraumatic stress disorder and its comorbidities: An emotion dysregulation perspective. Clinical Psychology Science and Practice, 24, 154169. doi:10.1111/cpsp.12193
Morris, M. C., Kouros, C. D., Mielock, A. S., & Rao, U. (2017). Depressive symptom composites associated with cortisol stress reactivity in adolescents. Journal of Affective Disorders, 210, 181188. doi:10.1016/j.jad.2016.12.023
Negriff, S., & Susman, E. J. (2011). Pubertal timing, depression, and externalizing problems: A framework, review, and examination of gender differences. Journal of Research on Adolescence, 21, 717746. doi:10.1111/j.1532-7795.2010.00708.x
Olson, I. R., Von der Heide, R. J., Alm, K. H., & Vyas, G. (2015). Development of the uncinate fasciculus: Implications for theory and developmental disorders. Developmental Cognitive Neuroscience, 14, 5061. doi:10.1016/j.dcn.2015.06.003
O'Mahen, H. A., Karl, A., Moberly, N., & Fedock, G. (2015). The association between childhood maltreatment and emotion regulation: Two different mechanisms contributing to depression? Journal of Affective Disorders, 174, 287295. doi:10.1016/j.jad.2014.11.028
Ordaz, S. J., & Luna, B. (2012). Sex differences in physiological reactivity to acute psychosocial stress in adolescence. Psychoneuroendocrinology, 37, 11351157. doi:10.1016/j.psyneuen.2012.01.002
Palacios-Barrios, E. E., & Hanson, J. (2019). Poverty and self-regulation: Integrating psychosocial processes and neurobiology to understand risk for psychopathology. Comprehensive Psychiatry, 90, 5264. doi:10.1016/j.comppsych.2018.12.012
Powell, D. J., & Schlotz, W. (2012). Daily life stress and the cortisol awakening response: testing the anticipation hypothesis. PLOS ONE, 7. doi:10.1371/journal.pone.0052067
Pruessner, J. C., Kirschbaum, C., Meinlschmid, G., & Hellhammer, D. H. (2003). Two formulas for computation of the area under the curve represent measures of total hormone concentration versus time-dependent change. Psychoneuroendocrinology, 28, 916931. doi:10.1016/S0306-4530(02)00108-7
Quevedo, K., Johnson, A., Loman, M., Lafavor, T., & Gunnar, M. (2012). The confluence of adverse early experience and puberty on the cortisol awakening response. International Journal of Behavioral Development, 36, 1928. doi:10.1177/0165025411406860
Rao, U., Hammen, C., Ortiz, L. R., Chen, L. A., & Poland, R. E. (2008). Effects of early and recent adverse experiences on adrenal response to psychosocial stress in depressed adolescents. Biological Psychiatry, 64, 521526. doi:10.1016/j.biopsych.2008.05.012
Raymond, C., Marin, M. F., Majeur, D., & Lupien, S. (2018). Early child adversity and psychopathology in adulthood: HPA axis and cognitive dysregulations as potential mechanisms. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 85, 152160. doi:10.1016/j.pnpbp.2017.07.015
R Core Team. (2017). R: A language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing.
Ribbe, D. (1996). Psychometric review of Traumatic Event Screening Instrument for Children (TESI-C). In Stamm, B. H. (Ed.), Measurement of stress, trauma, and adaptation (pp. 386387). Lutherville, MD: Sidran Press.
Rohde, G. K., Barnett, A. S., Basser, P. J., Marenco, S., & Pierpaoli, C. (2004). Comprehensive approach for correction of motion and distortion in diffusion-weighted MRI. Magnetic Resonance in Medicine, 51, 103114. doi:10.1002/mrm.10677
Romeo, R. D. (2010). Adolescence: A central event in shaping stress reactivity. Developmental Psychobiology, 52, 244253. doi:10.1002/dev.20437
Romeo, R. D., & McEwen, B. S. (2006). Stress and the adolescent brain. Annals of the New York Academy of Sciences, 1094, 202214. doi:10.1196/annals.1376.022
Rudolph, K. D., Hammen, C., Burge, D., Lindberg, N., Herzberg, D., & Daley, S. E. (2000). Toward an interpersonal life-stress model of depression: The developmental context of stress generation. Development and Psychopathology, 12, 215234
Sheikh, H. I., Joanisse, M. F., Mackrell, S. M., Kryski, K. R., Smith, H. J., Singh, S. M., & Hayden, E. P. (2014). Links between white matter microstructure and cortisol reactivity to stress in early childhood: Evidence for moderation by parenting. NeuroImage: Clinical, 6, 7785. doi:10.1016/j.nicl.2014.08.013
Shirtcliff, E. A., Dahl, R. E., & Pollak, S. D. (2009). Pubertal development: Correspondence between hormonal and physical development. Child Development, 80, 327337. doi:10.1111/j.1467-8624.2009.01263.x.Pubertal
Simmonds, D. J., Hallquist, M. N., Asato, M., & Luna, B. (2014). Developmental stages and sex differences of white matter and behavioral development through adolescence: A longitudinal diffusion tensor imaging (DTI) study. Neuroimage, 92, 356368. doi:10.1038/jid.2014.371
Stalder, T., Kirschbaum, C., Kudielka, B. M., Adam, E. K., Pruessner, J. C., Wüst, S., … Clow, A. (2016). Assessment of the cortisol awakening response: Expert consensus guidelines. Psychoneuroendocrinology, 63, 414432. doi:10.1016/j.psyneuen.2015.10.010
Teicher, M. H., Samson, J. A., Anderson, C. M., & Ohashi, K. (2016). The effects of childhood maltreatment on brain structure, function and connectivity. Nature Reviews Neuroscience, 17, 652666. doi:10.1038/nrn.2016.111
Teicher, M. H., Tomoda, A., & Andersen, S. E. (2006). Neurobiological consequences of early stress and childhood maltreatment: Are results from human and animal studies comparable? Annals of the New York Academy of Sciences, 1071, 313323. doi:10.1196/annals.1364.024
Tournier, J. D., Calamante, F., & Connelly, A. (2007). Robust determination of the fibre orientation distribution in diffusion MRI: Non-negativity constrained super-resolved spherical deconvolution. NeuroImage, 35, 14591472. doi:10.1016/j.neuroimage.2007.02.016
Trickett, P. K., Gordis, E., Peckins, M. K., & Susman, E. J. (2014). Stress reactivity in maltreated and comparison male and female young adolescents. Child Maltreatment, 19, 2737. doi:10.1177/1077559513520466
Ursache, A., Noble, K., & Blair, C. (2015). Socioeconomic status, subjective social status, and perceived stress: Associations with stress physiology and executive functioning. Journal of Behavioral Medicine, 41, 145154. doi:10.1161/CIRCULATIONAHA.114.010270.Hospital
Wakana, S., Jiang, H., & van Zijl, P. C. M. (2004). Fiber tract–based atlas of human white matter anatomy. Radiology, 230, 7787. doi:10.1148/radiol.2301021640
Yeatman, J. D., Dougherty, R. F., Myall, N. J., Wandell, B. A., & Feldman, H. M. (2012). Tract profiles of white matter properties: Automating fiber-tract quantification. PLOS ONE, 7. doi:10.1371/journal.pone.0049790
Zhang, W., Olivi, A., Hertig, S. J., van Zijl, P., & Mori, S. (2008). Automated fiber tracking of human brain white matter using diffusion tensor imaging. NeuroImage, 42, 771777. doi:10.1016/j.neuroimage.2008.04.241


Early life stress, cortisol, frontolimbic connectivity, and depressive symptoms during puberty

  • Katharina Kircanski (a1), Lucinda M. Sisk (a2), Tiffany C. Ho (a2), Kathryn L. Humphreys (a3), Lucy S. King (a2), Natalie L. Colich (a4), Sarah J. Ordaz (a2) and Ian H. Gotlib (a2)...


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