Skip to main content

Lower structural integrity of the uncinate fasciculus is associated with a history of child maltreatment and future psychological vulnerability to stress

  • Jamie L. Hanson (a1) (a2), Annchen R. Knodt (a1), Bartholomew D. Brigidi (a1) and Ahmad R. Hariri (a1)

The experience of child maltreatment is a significant risk factor for the development of later internalizing disorders such as depression and anxiety. This risk is particularly heightened after exposure to additional, more contemporaneous stress. While behavioral evidence exists for such “stress sensitization,” little is known about the mechanisms mediating such relationships, particularly within the brain. Here we report that the experience of child maltreatment independent of recent life stress, gender, and age is associated with reduced structural integrity of the uncinate fasciculus, a major white matter pathway between the amygdala and ventromedial prefrontal cortex, in young adults. We further demonstrate that individuals with lower uncinate fasciculus integrity at baseline who subsequently experience stressful life events report higher levels of internalizing symptomatology at follow-up. Our findings suggest a novel neurobiological mechanism linking child maltreatment with later internalizing symptoms, specifically altered structural connectivity within the brain's threat-detection and emotion-regulation circuitry.

Corresponding author
Address correspondence and reprint requests to: Jamie Hanson, Laboratory of NeuroGenetics, Duke University, 417 Chapel Drive, Duke West Campus, Sociology–Psychology Building, Room 07A, Durham, NC 27710; E-mail:
Hide All
Amaral, D. G., & Price, J. L. (1984). Amygdalo-cortical projections in the monkey (Macaca fascicularis). Journal of Comparative Neurology, 230, 465496.
Barbas, H., & De Olmos, J. (1990). Projections from the amygdala to basoventral and mediodorsal prefrontal regions in the rhesus monkey. Journal of Comparative Neurology, 300, 549571.
Barnett, D., Manly, J. T., & Cicchetti, D. (1993). Defining child maltreatment: The interface between policy and research. In Cicchetti, D. & Toth, S. L. (Eds.), Child abuse, child development, and social policy (pp. 773). Norwood, NJ: Ablex.
Bernstein, D. P., Ahluvalia, T., Pogge, D., & Handelsman, L. (1997). Validity of the Childhood Trauma Questionnaire in an adolescent psychiatric population. Journal of the American Academy of Child & Adolescent Psychiatry, 36, 340348.
Bishop, S. J. (2007). Neurocognitive mechanisms of anxiety: An integrative account. Trends in Cognitive Sciences, 11, 307316.
Bogdan, R., Perlis, R. H., Fagerness, J., & Pizzagalli, D. A. (2010). The impact of mineralocorticoid receptor ISO/VAL genotype (rs5522) and stress on reward learning. Genes, Brain and Behavior, 9, 658667.
Burke, K. C., Burke, J. D., Regier, D. A., & Rae, D. S. (1990). Age at onset of selected mental disorders in five community populations. Archives of General Psychiatry, 47, 511518.
Chapman, D. P., Whitfield, C. L., Felitti, V. J., Dube, S. R., Edwards, V. J., & Anda, R. F. (2004). Adverse childhood experiences and the risk of depressive disorders in adulthood. Journal of Affective Disorders, 82, 217225.
Choi, J., Jeong, B., Polcari, A., Rohan, M. L., & Teicher, M. H. (2012). Reduced fractional anisotropy in the visual limbic pathway of young adults witnessing domestic violence in childhood. NeuroImage, 59, 10711079.
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.
Cicchetti, D., & Gunnar, M. R. (2008). Integrating biological measures into the design and evaluation of preventive interventions. Development and Psychopathology, 20, 737743.
Cicchetti, D., & Tucker, D. (1994). Development and self-regulatory structures of the mind. Development and Psychopathology, 6, 533549.
Clark, L. A., & Watson, D. (1991). Tripartite model of anxiety and depression: Psychometric evidence and taxonomic implications. Journal of Abnormal Psychology, 100, 316336.
Clements, K., & Turpin, G. (1996). The life events scale for students: Validation for use with British samples. Personality and Individual Differences, 20, 747751.
Covault, J., Tennen, H., Armeli, S., Conner, T. S., Herman, A. I., Cillessen, A. H. N., et al. (2007). Interactive effects of the serotonin transporter 5-HTTLPR polymorphism and stressful life events on college student drinking and drug use. Biological Psychiatry, 61, 609616.
Danese, A., Moffitt, T. E., Harrington, H., Milne, B. J., Polanczyk, G., Pariante, C. M., et al. (2009). Adverse childhood experiences and adult risk factors for age-related disease: Depression, inflammation, and clustering of metabolic risk markers. Archives of Pediatrics & Adolescent Medicine, 163, 11351143.
Dannlowski, U., Stuhrmann, A., Beutelmann, V., Zwanzger, P., Lenzen, T., Grotegerd, D., et al. (2012). Limbic scars: Long-term consequences of childhood maltreatment revealed by functional and structural magnetic resonance imaging. Biological Psychiatry, 71, 286293.
Davidson, R. J., Putnam, K. M., & Larson, C. L. (2000). Dysfunction in the neural circuitry of emotion regulation—A possible prelude to violence. Science, 289, 591594.
Davis, M., & Whalen, P. J. (2001). The amygdala: Vigilance and emotion. Molecular Psychiatry, 6, 1334.
De Brito, S. A., Viding, E., Sebastian, C. L., Kelly, P. A., Mechelli, A., Maris, H., et al. (2013). Reduced orbitofrontal and temporal grey matter in a community sample of maltreated children. Journal of Child Psychology and Psychiatry, 54, 105112.
Eluvathingal, T. J., Chugani, H. T., Behen, M. E., Juhász, C., Muzik, O., Maqbool, M., et al. (2006). Abnormal brain connectivity in children after early severe socioemotional deprivation: A diffusion tensor imaging study. Pediatrics, 117, 20932100.
Espejo, E. P., Hammen, C. L., Connolly, N. P., Brennan, P. A., Najman, J. M., & Bor, W. (2007). Stress sensitization and adolescent depressive severity as a function of childhood adversity: A link to anxiety disorders. Journal of Abnormal Child Psychology, 35, 287299.
Etkin, A., Prater, K. E., Hoeft, F., Menon, V., & Schatzberg, A. F. (2010). Failure of anterior cingulate activation and connectivity with the amygdala during implicit regulation of emotional processing in generalized anxiety disorder. American Journal of Psychiatry, 167, 545554.
Fink, L. A., Bernstein, D., Handelsman, L., Foote, J., & Lovejoy, M. (1995). Initial reliability and validity of the childhood trauma interview: A new multidimensional measure of childhood interpersonal trauma. American Journal of Psychiatry, 152, 13291335.
First, M. B., Spitzer, R. L., Gibbon, M., & Williams, J. (1996). Structured Clinical Interview for DSM-IV Axis I disorders: Research version, non-patient edition (pp. 12). New York: New York State Psychiatric Institute.
Ghashghaei, H. T., & Barbas, H. (2002). Pathways for emotion: Interactions of prefrontal and anterior temporal pathways in the amygdala of the rhesus monkey. Neuroscience, 115, 12611279.
Glaser, J.-P., van Os, J., Portegijs, P. J. M., & Myin-Germeys, I. (2006). Childhood trauma and emotional reactivity to daily life stress in adult frequent attenders of general practitioners. Journal of Psychosomatic Research, 61, 229236.
Gooding, H. C., Milliren, C. E., Austin, S. B., Sheridan, M. A., & McLaughlin, K. A. (2015). Child abuse, resting blood pressure, and blood pressure reactivity to psychosocial stress. Journal of Pediatric Psychology. Advance online publication. doi:10.1093/jpepsy/jsv040
Gorka, A. X., Hanson, J. L., Radtke, S. R., & Hariri, A. R. (2014). Reduced hippocampal and medial prefrontal gray matter mediate the association between reported childhood maltreatment and trait anxiety in adulthood and predict sensitivity to future life stress. Biology of Mood & Anxiety Disorders, 4, 12.
Govindan, R. M., Behen, M. E., Helder, E., Makki, M. I., & Chugani, H. T. (2010). Altered water diffusivity in cortical association tracts in children with early deprivation identified with tract-based spatial statistics (TBSS). Cerebral Cortex, 20, 561569.
Green, J. G., McLaughlin, K. A., Berglund, P. A., Gruber, M. J., Sampson, N. A., Zaslavsky, A. M., et al. (2010). Childhood adversities and adult psychiatric disorders in the national comorbidity survey replication: I. Associations with first onset of DSM-IV disorders. Archives of General Psychiatry, 67, 113123.
Hammen, C. (2005). Stress and depression. Annual Review of Clinical Psychology, 1, 293319.
Hammen, C., Henry, R., & Daley, S. E. (2000). Depression and sensitization to stressors among young women as a function of childhood adversity. Journal of Consulting and Clinical Psychology, 68, 782787.
Hanson, J. L., Chung, M. K., Avants, B. B., Shirtcliff, E. A., Gee, J. C., Davidson, R. J., et al. (2010). Early stress is associated with alterations in the orbitofrontal cortex: A tensor-based morphometry investigation of brain structure and behavioral risk. Journal of Neuroscience, 30, 74667472.
Hanson, J. L., Nacewicz, B. M., Sutterer, M. J., Cayo, A. A., Schaefer, S. M., Rudolph, K. D., et al. (2015). Behavioral problems after early life stress: Contributions of the hippocampus and amygdala. Biological Psychiatry, 77, 314323.
Hariri, A. R. (2009). The neurobiology of individual differences in complex behavioral traits. Annual Review of Neuroscience, 32, 225247.
Harkness, K. L., Bruce, A. E., & Lumley, M. N. (2006). The role of childhood abuse and neglect in the sensitization to stressful life events in adolescent depression. Journal of Abnormal Psychology, 115, 730741.
Heim, C., Newport, D. J., Mletzko, T., Miller, A. H., & Nemeroff, C. B. (2008). The link between childhood trauma and depression: Insights from HPA axis studies in humans. Psychoneuroendocrinology, 33, 693710.
Herringa, R. J., Birn, R. M., Ruttle, P. L., Burghy, C. A., Stodola, D. E., Davidson, R. J., et al. (2013). Childhood maltreatment is associated with altered fear circuitry and increased internalizing symptoms by late adolescence. Proceedings of the National Academy of Sciences, 110, 1911919124.
Herts, K. L., McLaughlin, K. A., & Hatzenbuehler, M. L. (2012). Emotion dysregulation as a mechanism linking stress exposure to adolescent aggressive behavior. Journal of Abnormal Child Psychology, 40, 11111122.
Huang, H., Gundapuneedi, T., & Rao, U. (2012). White matter disruptions in adolescents exposed to childhood maltreatment and vulnerability to psychopathology. Neuropsychopharmacology, 37, 26932701.
Jahanshad, N., Kochunov, P. V., Sprooten, E., Mandl, R. C., Nichols, T. E., Almasy, L., et al. (2013). Multi-site genetic analysis of diffusion images and voxelwise heritability analysis: A pilot project of the ENIGMA-DTI working group. NeuroImage, 81, 455469.
Kessler, R. C. (1997). The effects of stressful life events on depression. Annual Review of Psychology, 48, 191214.
Kessler, R. C., Berglund, P., Demler, O., Jin, R., Merikangas, K. R., & Walters, E. E. (2005). Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Archives of General Psychiatry, 62, 593602.
Kim, J., & Cicchetti, D. (2010). Longitudinal pathways linking child maltreatment, emotion regulation, peer relations, and psychopathology. Journal of Child Psychology and Psychiatry, 51, 706716.
Ledoux, J. E. (2000). Emotion circuits in the brain. Annual Review of Neuroscience, 23, 155184.
Leitzke, B. T., Hilt, L. M., & Pollak, S. D. (2015). Maltreated youth display a blunted blood pressure response to an acute interpersonal stressor. Journal of Clinical Child and Adolescent Psychology, 44, 305313.
Manly, J. T., Kim, J. E., Rogosch, F. A., & Cicchetti, D. (2001). Dimensions of child maltreatment and children's adjustment: Contributions of developmental timing and subtype. Development and Psychopathology, 13, 759782.
McCrory, E. J., & Viding, E. (2015). The theory of latent vulnerability: Reconceptualizing the link between childhood maltreatment and psychiatric disorder. Development and Psychopathology, 27, 493505.
McGrath, C. L., Kelley, M. E., Holtzheimer, P. E., Dunlop, B. W., Craighead, W. E., Franco, A. R., et al. (2013). Toward a neuroimaging treatment selection biomarker for major depressive disorder. JAMA Psychiatry, 70, 821829.
McLaughlin, K. A., Conron, K. J., Koenen, K. C., & Gilman, S. E. (2010). Childhood adversity, adult stressful life events, and risk of past-year psychiatric disorder: A test of the stress sensitization hypothesis in a population-based sample of adults. Psychological Medicine, 40, 16471658.
McLaughlin, K. A., Koenen, K. C., Hill, E. D., Petukhova, M., Sampson, N. A., Zaslavsky, A. M., et al. (2013). Trauma exposure and posttraumatic stress disorder in a national sample of adolescents. Journal of the American Academy of Child & Adolescent Psychiatry, 52, 815830.
McLaughlin, K. A., Sheridan, M. A., Alves, S., & Mendes, W. B. (2014). Child maltreatment and autonomic nervous system reactivity: Identifying dysregulated stress reactivity patterns by using the biopsychosocial model of challenge and threat. Psychosomatic Medicine, 76, 538546.
Milad, M. R., & Quirk, G. J. (2012). Fear extinction as a model for translational neuroscience: Ten years of progress. Annual Review of Psychology, 63, 129151.
Monroe, S., & Reid, M. (2008). Gene-environment interactions in depression research. Psychological Science, 19, 947.
Morecraft, R. J., Geula, C., & Mesulam, M. M. (1992). Cytoarchitecture and neural afferents of orbitofrontal cortex in the brain of the monkey. Journal of Comparative Neurology, 323, 341358.
Mori, S., Wakana, S., Van Zijl, P. C., & Nagae-Poetscher, L. M. (2005). MRI atlas of human white matter. Amsterdam: Elsevier.
Paykel, E. S. (2003). Life events and affective disorders. Acta Psychiatrica Scandinavica, 108(Suppl.), 6166.
Petrides, M., & Pandya, D. N. (1988). Association fiber pathways to the frontal-cortex from the superior temporal region in the rhesus-monkey. Journal of Comparative Neurology, 273, 5266.
Porrino, L. J., Crane, A. M., & Goldman-Rakic, P. S. (1981). Direct and indirect pathways from the amygdala to the frontal lobe in rhesus monkeys. Journal of Comparative Neurology, 198, 121136.
Quirk, G. J., & Beer, J. S. (2006). Prefrontal involvement in the regulation of emotion: Convergence of rat and human studies. Current Opinion in Neurobiology, 16, 723727.
R Core Team. (2014). R: A language and environment for statistical computing [Computer software]. Vienna: R Foundation for Statistical Computing.
Rutter, M. (1998). Developmental catch-up, and deficit, following adoption after severe global early privation. Journal of Child Psychology and Psychiatry and Allied Disciplines, 39, 465476.
Scher, C. D., Stein, M. B., Asmundson, G. J., McCreary, D. R., & Forde, D. R. (2001). The Childhood Trauma Questionnaire in a community sample: Psychometric properties and normative data. Journal of Traumatic Stress, 14, 843857.
Shapero, B. G., Black, S. K., Liu, R. T., Klugman, J., Bender, R. E., Abramson, L. Y., et al. (2013). Stressful life events and depression symptoms: The effect of childhood emotional abuse on stress reactivity. Journal of Clinical Psychology, 70, 209223.
Sheehan, D. V., Lecrubier, Y., Sheehan, K. H., Amorim, P., Janavs, J., Weiller, E., et al. (1998). The Mini-International Neuropsychiatric Interview (M.I.N.I.): The development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. Journal of Clinical Psychiatry, 59, 2233; quiz, 34–57.
Smith, S. M., Jenkinson, M., Johansen-Berg, H., Rueckert, D., Nichols, T. E., Mackay, C. E., et al. (2006). Tract-based spatial statistics: Voxelwise analysis of multi-subject diffusion data. NeuroImage, 31, 14871505.
Swartz, J. R., Knodt, A. R., Radtke, S. R., & Hariri, A. R. (2015). A neural biomarker of psychological vulnerability to future life stress. Neuron, 85, 505511.
Tarullo, A. R., & Gunnar, M. R. (2006). Child maltreatment and the developing HPA axis. Hormones and Behavior, 50, 632639.
Teicher, M. H., Anderson, C. M., & Polcari, A. (2012). Childhood maltreatment is associated with reduced volume in the hippocampal subfields CA3, dentate gyrus, and subiculum. Proceedings of the National Academy of Sciences, 109, E563E572.
Tottenham, N., Hare, T. A., Millner, A., Gilhooly, T., Zevin, J. D., & Casey, B. J. (2011). Elevated amygdala response to faces following early deprivation. Developmental Science, 14, 190204.
Tromp, D. P. M., Grupe, D. W., Oathes, D. J., McFarlin, D. R., Hernandez, P. J., Kral, T. R. A., et al. (2012). Reduced structural connectivity of a major frontolimbic pathway in generalized anxiety disorder. Archives of General Psychiatry, 69, 925934.
Walsh, W. A., Dawson, J., & Mattingly, M. J. (2010). How are we measuring resilience following childhood maltreatment? Is the research adequate and consistent? What is the impact on research, practice, and policy? Trauma, Violence & Abuse, 11, 2741.
Wildeman, C., Emanuel, N., Leventhal, J. M., Putnam-Hornstein, E., Waldfogel, J., & Lee, H. (2014). The prevalence of confirmed maltreatment among US children, 2004 to 2011. JAMA Pediatrics, 168, 706713.
Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Development and Psychopathology
  • ISSN: 0954-5794
  • EISSN: 1469-2198
  • URL: /core/journals/development-and-psychopathology
Please enter your name
Please enter a valid email address
Who would you like to send this to? *


Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed