The effects of childhood maltreatment on brain structure, function and connectivity

Journal name:
Nature Reviews Neuroscience
Volume:
17,
Pages:
652–666
Year published:
DOI:
doi:10.1038/nrn.2016.111
Published online

Abstract

Maltreatment-related childhood adversity is the leading preventable risk factor for mental illness and substance abuse. Although the association between maltreatment and psychopathology is compelling, there is a pressing need to understand how maltreatment increases the risk of psychiatric disorders. Emerging evidence suggests that maltreatment alters trajectories of brain development to affect sensory systems, network architecture and circuits involved in threat detection, emotional regulation and reward anticipation. This Review explores whether these alterations reflect toxic effects of early-life stress or potentially adaptive modifications, the relationship between psychopathology and brain changes, and the distinction between resilience, susceptibility and compensation.

At a glance

Figures

  1. Abuse type-specific effects on the developing brain.
    Figure 1: Abuse type-specific effects on the developing brain.

    Images depicting the potential effects of exposure to specific types of childhood maltreatment on grey-matter volume (GMV) or thickness and fibre-tract integrity. Exposure to parental verbal abuse was associated with increased GMV in the auditory cortex portion of the left superior temporal gyrus25 (part a) and decreased integrity of the left arcuate fasciculus (AF) interconnecting Wernicke's area and Broca's area26 (part b). Visually witnessing multiple episodes of domestic violence was associated with reduced GMV in right lingual gyrus, left occipital pole and bilateral secondary visual cortex (V2)27 (part c) and decreased integrity of the left inferior longitudinal fasciculus (ILF), which serves as a visual–limbic pathway28 (part d). Adults reporting exposure to multiple episodes of childhood forced-contact sexual abuse were found to have reduced GMV in right and left primary visual cortex (V1) and visual association cortices, as well as reduced thickness in right lingual, left fusiform and left middle occipital gyri29 (part e) and portions of the somatosensory cortex representing the clitoris and surrounding genital area30 (part f). Part a is adapted with permission from Ref. 25, Elsevier. Part b is adapted with permission from Ref. 26, Elsevier. Part c is adapted from Ref. 27. Part d is adapted with permission from Ref. 28, Elsevier. Part e is adapted with permission from Ref. 29, Elsevier. Part f is adapted from an image courtesy of C. Heim, Charité Universitätsmedizin Berlin, Germany, and J. Pruessner, McGill University, Canada.

  2. Circuitry underlying threat detection and response.
    Figure 2: Circuitry underlying threat detection and response.

    Simplified component diagram delineating brain regions found to be involved in detecting and responding to threatening sights and sounds. The figure is based primarily on work of LeDoux38, 39, with updates from translational studies2, 40, 41, 42, 43. Regions and pathways labelled in red have been reported to be altered in volume or integrity by childhood maltreatment. Visual information from the eyes is relayed to the superior colliculus (SC) and lateral geniculate nucleus (LG). From the SC, information can go to the LG or to the parabigeminal nucleus (PBG) and then to the amygdala. From the LG, information is projected to the visual cortex. Auditory information from the ears is relayed to the inferior colliculus (IC) or the medial geniculate nucleus (MG), with output from the IC projecting to the MG. From the MG, information can go to the auditory cortex or to the paraventricular thalamus (PVT) and then to the amygdala. Blue arrows delineate pathways through which information coding threatening sights or sounds can rapidly reach the amygdala without conscious awareness. Sensory cortical regions project to the amygdala, prefrontal cortex (PFC) and hippocampus. The PFC modulates the amygdala response, with the dorsal anterior cingulate cortex (dACC) amplifying this response (in the image, indicated by '+') and the ventromedial PFC (vmPFC) attenuating it (in the image, indicated by '−'). The dorsomedial PFC (dmPFC) helps to regulate the degree of dACC and vmPFC involvement. The hippocampus provides contextual information to the amygdala. The amygdala, in turn, projects to the paraventricular nucleus of the hypothalamus (PVN), which helps to regulate autonomic responses as well as pituitary adrenal and locus coeruleus (LC) responses. The PVN is also regulated by information from the hippocampus, via the subiculum and the bed nucleus of the stria terminalis (BNST). ACTH, adrenocorticotropic hormone; AF, arcuate fasciculus; ANS, autonomic nervous system; CRF, corticotropin-releasing factor; ILF, inferior longitudinal fasciculus; NA, noradrenaline; UF, uncinate fasciculus.

  3. Maltreatment-associated changes in functional connectivity.
    Figure 3: Maltreatment-associated changes in functional connectivity.

    Summary of alterations in resting-state functional connectivity reported in individuals with histories of childhood maltreatment58, 60, 91, 121, 171. Alterations are expressed in relationship to the degree and direction of connectivity in unexposed controls. Decreased correlation indicates that there were positive correlations in blood-oxygen-level-dependent (BOLD) signal fluctuations between regions in controls and that the degree of correlation was reduced to a less positive or negative degree in maltreated individuals. Decreased anti-correlation indicates that there was an inverse correlation in BOLD signal between regions in controls and that this was reduced to a less negative or positive degree in maltreated subjects. Increased correlation and increased anti-correlation indicate that the correlation between regions was in the same direction in maltreated subjects as in controls but was present to a greater — more positive or more negative — degree, respectively. Multiple arrows between regions indicate discrepant findings, which probably stem from methodological differences between studies in the way that global signals related to blood flow or movements were handled. Reports of both decreased correlation and decreased anti-correlation suggest that the regions are less coupled in maltreated individuals. Decreased correlation and increased anti-correlation suggest that the coupling is shifting from a positive relationship to a negative (reciprocal) relationship in maltreated subjects. These studies provide evidence for reduced coupling of the amygdala with medial–orbital prefrontal cortex (PFC), anterior cingulate cortex, posterior cingulate cortex (PCC) or precuneus, hippocampus and insula, as well as a shift in the direction of coupling of the amygdala with lateral PFC and putamen, plus increased connectivity of the amygdala with locus coeruleus (LC) and cerebellum. These studies also indicate that maltreatment is associated with reduced coupling of the hippocampus with the medial–orbital PFC and anterior cingulate cortex, but increased positive or negative coupling of the hippocampus with the PCC or precuneus, cerebellum and lateral PFC. Overall, these findings are indicative of reduced top-down regulation of the amygdala by prefrontal regions, reduced contextual input to the amygdala from hippocampus, and increased connectivity of the amygdala with LC and cerebellum that may result in a more rapid noradrenergic and postural response following amygdala activation.

  4. Maltreatment-sensitivity periods for different brain areas.
    Figure 4: Maltreatment-sensitivity periods for different brain areas.

    Developmental differences in sensitivity to effects of specific forms of childhood maltreatment on grey-matter measures or fibre-tract integrity (fractional anisotropy (FA)) show that different regions and pathways are maximally susceptible to maltreatment at different ages. a | Ages of exposure to sexual abuse in females are inversely correlated to reductions in hippocampal volume50. b | Predictive importance of visually witnessing domestic violence at specific ages and FA in the inferior longitudinal fasciculus, as assessed using predictive analytics and machine learning28. c | Predictive importance of maltreatment (composite score) at specific ages on reduction of the grey-matter volume of the right amygdala67. d | Predictive importance of visually witnessing domestic violence at specific ages on thinning of the secondary visual cortex (V2)27. e | Ages at exposure to sexual abuse in females show inverse correlation with grey-matter volume of the prefrontal cortex (PFC)50.

  5. The dopaminergic reward system.
    Figure 5: The dopaminergic reward system.

    Anatomical location of key structures that make up the reward system and mesocorticolimbic (red) and nigrostriatal (black) ascending dopaminergic pathways. Dopamine-neuron cell bodies for these ascending pathways are located primarily in the ventral tegmental area and substantia nigra. Dopaminergic neurons in the substantia nigra project to dorsal portions of the striatum (caudate and putamen), whereas dopaminergic neurons in the ventral tegmental area project to ventral portions of the striatum (particularly the nucleus accumbens and more ventral aspects of the caudate and putamen), as well as limbic regions (that is, the amygdala) and cortical regions (particularly the orbitofrontal cortex and anterior cingulate cortex). Childhood maltreatment has been reported to be associated with alterations in blood flow to the caudate, putamen, portions of prefrontal cortex, substantia nigra and nucleus accumbens48, 172, as well as reductions in size of the striatum37, 49, 75, alterations in developmental trajectory of the nucleus accumbens173, and reduced volume, thickness or connectivity of the anterior cingulate cortex30, 45, 75, 89, 90, 91 and orbitofrontal cortex53, 89, 92. Maltreatment is also consistently associated with an attenuated striatal response to anticipation or receipt of reward in functional MRI tasks82, 83, 84, 85, 86, 87. Green-shaded regions represent cell body regions or primary target regions of the ascending dopamine system.

  6. Network changes associated with childhood maltreatment.
    Figure 6: Network changes associated with childhood maltreatment.

    Maltreatment during childhood has been found to be associated with changes in structural connectivity at the network level. Here, the entire cerebral cortex of young adults with (n = 142) or without (n = 123) histories of childhood maltreatment was divided into 112 regional nodes. Within each group, between-subject correlations in the cortical thicknesses of each nodal pairing were used to infer connectivity, as brain regions that co-vary reliably in size between subjects are either structurally or functionally interconnected90. Network architecture and the centrality of each node were then determined by applying graph theory to the 112 × 112-node maltreated and non-maltreated cross-correlation matrices. Three key differences in structural nodal centrality between maltreated and non-maltreated groups are shown here. Green circles indicate nodal centres (the regions of interest) in each case for the left anterior cingulate cortex (left), the right anterior insula (middle) and the right precuneus (right). Red circles indicate primary nodes, which are regions with direct connections to the nodal centre. Blue circles delineate secondary nodes, which have direct connections with the primary nodes but do not have direct connections with the nodal centre. Childhood maltreatment was associated with a marked decrease in the centrality of the left anterior cingulate, as indicated by a substantial decrease in primary and secondary connections. Conversely, maltreatment was associated with a significant increase in the centrality of the right anterior insula and the right precuneus, as indicated by the greater number of primary and secondary nodal connections in these regions in the maltreated group. Adapted with permission from Ref. 90, Elsevier.

References

  1. Takesian, A. E. & Hensch, T. K. Balancing plasticity/stability across brain development. Prog. Brain Res. 207, 334 (2013).
  2. Teicher, M. H. & Samson, J. A. Childhood maltreatment and psychopathology: a case for ecophenotypic variants as clinically and neurobiologically distinct subtypes. Am. J. Psychiatry 170, 11141133 (2013).
    This article argues that psychiatric disorders need to be subtyped based on maltreatment history.
  3. Dube, S. R., Felitti, V. J., Dong, M., Giles, W. H. & Anda, R. F. The impact of adverse childhood experiences on health problems: evidence from four birth cohorts dating back to 1900. Prev. Med. 37, 268277 (2003).
  4. Dube, S. R. et al. Childhood abuse, neglect, and household dysfunction and the risk of illicit drug use: the adverse childhood experiences study. Pediatrics 111, 564572 (2003).
  5. Anda, R. F. et al. Adverse childhood experiences and prescribed psychotropic medications in adults. Am. J. Prev. Med. 32, 389394 (2007).
  6. Brown, D. W. et al. Adverse childhood experiences and the risk of premature mortality. Am. J. Prev. Med. 37, 389396 (2009).
  7. Price, L. H., Kao, H. T., Burgers, D. E., Carpenter, L. L. & Tyrka, A. R. Telomeres and early-life stress: an overview. Biol. Psychiatry 73, 1523 (2013).
  8. Ito, Y. et al. Increased prevalence of electrophysiological abnormalities in children with psychological, physical, and sexual abuse. J. Neuropsychiatry Clin. Neurosci. 5, 401408 (1993).
  9. Schiffer, F., Teicher, M. H. & Papanicolaou, A. C. Evoked potential evidence for right brain activity during the recall of traumatic memories. J. Neuropsychiatry Clin. Neurosci. 7, 169175 (1995).
  10. Teicher, M. H. Wounds that time won't heal: the neurobiology of child abuse. Cerebrum 4, 5067 (2000).
  11. Teicher, M. H. & Samson, J. A. Annual research review: enduring neurobiological effects of childhood abuse and neglect. J. Child Psychol. Psychiatry 57, 241266 (2016).
  12. Tottenham, N. The importance of early experiences for neuro-affective development. Curr. Top. Behav. Neurosci. 16, 109129 (2014).
  13. McLaughlin, K. A., Sheridan, M. A. & Lambert, H. K. Childhood adversity and neural development: deprivation and threat as distinct dimensions of early experience. Neurosci. Biobehav. Rev. 47, 578591 (2014).
  14. Brewin, C. R., Andrews, B. & Gotlib, I. H. Psychopathology and early experience: a reappraisal of retrospective reports. Psychol. Bull. 113, 8298 (1993).
  15. De Bellis, M. D. et al. Brain structures in pediatric maltreatment-related posttraumatic stress disorder: a sociodemographically matched study. Biol. Psychiatry 52, 10661078 (2002).
  16. Teicher, M. H., Tomoda, A. & Andersen, S. L. Neurobiological consequences of early stress and childhood maltreatment: are results from human and animal studies comparable? Ann. NY Acad. Sci. 1071, 313323 (2006).
  17. National Scientific Council on the Developing Child. Excessive stress disrupts the architecture of the developing brain: working paper #3 (Center on the Developing Child Harvard Univ., 2005).
  18. Lupien, S. J., McEwen, B. S., Gunnar, M. R. & Heim, C. Effects of stress throughout the lifespan on the brain, behaviour and cognition. Nat. Rev. Neurosci. 10, 434445 (2009).
  19. Teicher, M. H. Scars that won't heal: the neurobiology of child abuse. Sci. Am. 286, 6875 (2002).
  20. Teicher, M. H. et al. The neurobiological consequences of early stress and childhood maltreatment. Neurosci. Biobehav. Rev. 27, 3344 (2003).
  21. Gibb, B. E., Schofield, C. A. & Coles, M. E. Reported history of childhood abuse and young adults' information-processing biases for facial displays of emotion. Child Maltreat. 14, 148156 (2009).
  22. Pollak, S. D. Experience-dependent affective learning and risk for psychopathology in children. Ann. NY Acad. Sci. 1008, 102111 (2003).
  23. Rutter, M. Achievements and challenges in the biology of environmental effects. Proc. Natl Acad. Sci. USA 109, 1714917153 (2012).
  24. Belsky, J. & Pluess, M. Beyond risk, resilience, and dysregulation: phenotypic plasticity and human development. Dev. Psychopathol. 25, 12431261 (2013).
  25. Tomoda, A. et al. Exposure to parental verbal abuse is associated with increased gray matter volume in superior temporal gyrus. Neuroimage 54, S280S286 (2011).
  26. Choi, J., Jeong, B., Rohan, M. L., Polcari, A. M. & Teicher, M. H. Preliminary evidence for white matter tract abnormalities in young adults exposed to parental verbal abuse. Biol. Psychiatry 65, 227234 (2009).
  27. Tomoda, A., Polcari, A., Anderson, C. M. & Teicher, M. H. Reduced visual cortex gray matter volume and thickness in young adults who witnessed domestic violence during childhood. PLoS ONE 7, e52528 (2012).
  28. Choi, J., Jeong, B., Polcari, A., Rohan, M. L. & Teicher, M. H. Reduced fractional anisotropy in the visual limbic pathway of young adults witnessing domestic violence in childhood. Neuroimage 59, 10711079 (2012).
  29. Tomoda, A., Navalta, C. P., Polcari, A., Sadato, N. & Teicher, M. H. Childhood sexual abuse is associated with reduced gray matter volume in visual cortex of young women. Biol. Psychiatry 66, 642648 (2009).
  30. Heim, C. M., Mayberg, H. S., Mletzko, T., Nemeroff, C. B. & Pruessner, J. C. Decreased cortical representation of genital somatosensory field after childhood sexual abuse. Am. J. Psychiatry 170, 616623 (2013).
    This study provides evidence for sensory-specific damage after exposure to childhood sexual abuse.
  31. Tottenham, N. et al. Elevated amygdala response to faces following early deprivation. Dev. Sci. 14, 190204 (2011).
  32. McCrory, E. J. et al. Heightened neural reactivity to threat in child victims of family violence. Curr. Biol. 21, R947R948 (2011).
  33. Garrett, A. S. et al. Brain activation to facial expressions in youth with PTSD symptoms. Depress. Anxiety 29, 449459 (2012).
  34. Grant, M. M., Cannistraci, C., Hollon, S. D., Gore, J. & Shelton, R. Childhood trauma history differentiates amygdala response to sad faces within MDD. J. Psychiatr. Res. 45, 886895 (2011).
  35. Bogdan, R., Williamson, D. E. & Hariri, A. R. Mineralocorticoid receptor Iso/Val (rs5522) genotype moderates the association between previous childhood emotional neglect and amygdala reactivity. Am. J. Psychiatry 169, 515522 (2012).
  36. van Harmelen, A. L. et al. Enhanced amygdala reactivity to emotional faces in adults reporting childhood emotional maltreatment. Soc. Cogn. Affect. Neurosci. 8, 362369 (2013).
  37. Dannlowski, U. et al. Limbic scars: long-term consequences of childhood maltreatment revealed by functional and structural magnetic resonance imaging. Biol. Psychiatry 71, 286293 (2012).
    This paper shows evidence of morphometric abnormalities and amygdala hyperreactivity in maltreated subjects without psychopathology.
  38. LeDoux, J. Emotional networks and motor control: a fearful view. Prog. Brain Res. 107, 437446 (1996).
  39. LeDoux, J. Synaptic Self: How Our Brains Become Who We Are (Viking Penguin, 2002).
  40. Herman, J. P. & Mueller, N. K. Role of the ventral subiculum in stress integration. Behav. Brain Res. 174, 215224 (2006).
  41. Maren, S., Phan, K. L. & Liberzon, I. The contextual brain: implications for fear conditioning, extinction and psychopathology. Nat. Rev. Neurosci. 14, 417428 (2013).
  42. Linke, R., Braune, G. & Schwegler, H. Differential projection of the posterior paralaminar thalamic nuclei to the amygdaloid complex in the rat. Exp. Brain Res. 134, 520532 (2000).
  43. Shang, C. et al. A parvalbumin-positive excitatory visual pathway to trigger fear responses in mice. Science 348, 14721477 (2015).
  44. De Bellis, M. D., Keshavan, M. S., Spencer, S. & Hall, J. N-Acetylaspartate concentration in the anterior cingulate of maltreated children and adolescents with PTSD. Am. J. Psychiatry 157, 11751177 (2000).
  45. Cohen, R. A. et al. Early life stress and morphometry of the adult anterior cingulate cortex and caudate nuclei. Biol. Psychiatry 59, 975982 (2006).
  46. Kelly, P. A. et al. Cortical thickness, surface area, and gyrification abnormalities in children exposed to maltreatment: neural markers of vulnerability? Biol. Psychiatry 74, 845852 (2013).
  47. Jensen, S. K. et al. Effect of early adversity and childhood internalizing symptoms on brain structure in young men. JAMA Pediatr. 169, 938946 (2015).
  48. Chugani, H. T. et al. Local brain functional activity following early deprivation: a study of postinstitutionalized Romanian orphans. Neuroimage 14, 12901301 (2001).
  49. Edmiston, E. E. et al. Corticostriatal-limbic gray matter morphology in adolescents with self-reported exposure to childhood maltreatment. Arch. Pediatr. Adolesc. Med. 165, 10691077 (2011).
  50. Andersen, S. L. et al. Preliminary evidence for sensitive periods in the effect of childhood sexual abuse on regional brain development. J. Neuropsychiatry Clin. Neurosci. 20, 292301 (2008).
    This study provides the initial evidence for sensitive periods in the hippocampus, corpus callosum and PFC.
  51. Opel, N. et al. Hippocampal atrophy in major depression: a function of childhood maltreatment rather than diagnosis? Neuropsychopharmacology 39, 27232731 (2014).
    This paper shows that hippocampal volume abnormalities are associated more directly with maltreatment than with major depression.
  52. Teicher, M. H., Anderson, C. M. & Polcari, A. Childhood maltreatment is associated with reduced volume in the hippocampal subfields CA3, dentate gyrus, and subiculum. Proc. Natl Acad. Sci. USA 109, E563E572 (2012).
  53. Hanson, J. L. et al. Early stress is associated with alterations in the orbitofrontal cortex: a tensor-based morphometry investigation of brain structure and behavioral risk. J. Neurosci. 30, 74667472 (2010).
  54. Kumari, V. et al. Reduced thalamic volume in men with antisocial personality disorder or schizophrenia and a history of serious violence and childhood abuse. Eur. Psychiatry 28, 225234 (2013).
  55. Huang, H., Gundapuneedi, T. & Rao, U. White matter disruptions in adolescents exposed to childhood maltreatment and vulnerability to psychopathology. Neuropsychopharmacology 37, 26932701 (2012).
  56. Benedetti, F. et al. Adverse childhood experiences influence white matter microstructure in patients with bipolar disorder. Psychol. Med. 44, 30693082 (2014).
  57. Eluvathingal, T. J. et al. Abnormal brain connectivity in children after early severe socioemotional deprivation: a diffusion tensor imaging study. Pediatrics 117, 20932100 (2006).
  58. Birn, R. M., Patriat, R., Phillips, M. L., Germain, A. & Herringa, R. J. Childhood maltreatment and combat posttraumatic stress differentially predict fear-related fronto-subcortical connectivity. Depress. Anxiety 31, 880892 (2014).
  59. Cisler, J. M. et al. Differential functional connectivity within an emotion regulation neural network among individuals resilient and susceptible to the depressogenic effects of early life stress. Psychol. Med. 43, 507518 (2013).
  60. Herringa, R. J. et al. Childhood maltreatment is associated with altered fear circuitry and increased internalizing symptoms by late adolescence. Proc. Natl Acad. Sci. USA 110, 1911919124 (2013).
  61. Wang, L. et al. Overlapping and segregated resting-state functional connectivity in patients with major depressive disorder with and without childhood neglect. Hum. Brain Mapp. 35, 11541166 (2014).
    This study demonstrates functional connectivity abnormalities in depressed individuals with and without histories of maltreatment.
  62. Morris, J. S., Ohman, A. & Dolan, R. J. A subcortical pathway to the right amygdala mediating “unseen” fear. Proc. Natl Acad. Sci. USA 96, 16801685 (1999).
  63. Dannlowski, U. et al. Childhood maltreatment is associated with an automatic negative emotion processing bias in the amygdala. Hum. Brain Mapp. 34, 28992909 (2013).
  64. Mehta, M. A. et al. Amygdala, hippocampal and corpus callosum size following severe early institutional deprivation: the English and Romanian Adoptees Study Pilot. J. Child Psychol. Psychiatry 50, 943951 (2009).
  65. Tottenham, N. et al. Prolonged institutional rearing is associated with atypically large amygdala volume and difficulties in emotion regulation. Dev. Sci. 13, 4661 (2010).
  66. 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, 1432414329 (2011).
  67. Pechtel, P., Lyons-Ruth, K., Anderson, C. M. & Teicher, M. H. Sensitive periods of amygdala development: the role of maltreatment in preadolescence. Neuroimage 97, 236244 (2014).
  68. Whittle, S. et al. Childhood maltreatment and psychopathology affect brain development during adolescence. J. Am. Acad. Child Adolesc. Psychiatry 52, 940952.e1 (2013).
  69. Kuo, J. R., Kaloupek, D. G. & Woodward, S. H. Amygdala volume in combat-exposed veterans with and without posttraumatic stress disorder: a cross-sectional study. Arch. Gen. Psychiatry 69, 10801086 (2012).
  70. Hanson, J. L. et al. Behavioral problems after early life stress: contributions of the hippocampus and amygdala. Biol. Psychiatry 77, 314323 (2015).
  71. Lyons-Ruth, K., Pechtel, P., Yoon, S. A., Anderson, C. M. & Teicher, M. H. Disorganized attachment in infancy predicts greater amygdala volume in adulthood. Behav. Brain Res. 308, 8393 (2016).
  72. Fetterman, A. K., Ode, S. & Robinson, M. D. For which side the bell tolls: the laterality of approach-avoidance associative networks. Motiv. Emot. 37, 3338 (2013).
  73. Kolb, B. & Gibb, R. Searching for the principles of brain plasticity and behavior. Cortex 58, 251260 (2014).
  74. Caldji, C., Diorio, J. & Meaney, M. J. Variations in maternal care alter GABAA receptor subunit expression in brain regions associated with fear. Neuropsychopharmacology 28, 19501959 (2003).
  75. Baker, L. M. et al. Impact of early versus late childhood early life stress on brain morphometrics. Brain Imag. Behav. 7, 196203 (2013).
  76. Hodel, A. S. et al. Duration of early adversity and structural brain development in post-institutionalized adolescents. Neuroimage 105, 112119 (2015).
  77. Riem, M. M., Alink, L. R., Out, D., Van Ijzendoorn, M. H. & Bakermans-Kranenburg, M. J. Beating the brain about abuse: empirical and meta-analytic studies of the association between maltreatment and hippocampal volume across childhood and adolescence. Dev. Psychopathol. 27, 507520 (2015).
  78. Masten, C. L. et al. Recognition of facial emotions among maltreated children with high rates of post-traumatic stress disorder. Child Abuse Negl. 32, 139153 (2008).
  79. Gorka, A. X., Hanson, J. L., Radtke, S. R. & Hariri, A. R. 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. Biol. Mood Anxiety Disord. 4, 12 (2014).
  80. Whittle, S. et al. Hippocampal volume and sensitivity to maternal aggressive behavior: a prospective study of adolescent depressive symptoms. Dev. Psychopathol. 23, 115129 (2011).
  81. Morey, R. A., Haswell, C. C., Hooper, S. R. & De Bellis, M. D. Amygdala, hippocampus, and ventral medial prefrontal cortex volumes differ in maltreated youth with and without chronic posttraumatic stress disorder. Neuropsychopharmacology 41, 791801 (2016).
  82. Takiguchi, S. et al. Ventral striatum dysfunction in children and adolescents with reactive attachment disorder: a functional MRI Study. BJPsych Open 1, 121128 (2015).
  83. Hanson, J. L., Hariri, A. R. & Williamson, D. E. Blunted ventral striatum development in adolescence reflects emotional neglect and predicts depressive symptoms. Biol. Psychiatry 78, 598605 (2015).
    This study shows an association between childhood emotional neglect, reduced ventral striatal reward activation and depression.
  84. Mehta, M. A. et al. Hyporesponsive reward anticipation in the basal ganglia following severe institutional deprivation early in life. J. Cogn. Neurosci. 22, 23162325 (2010).
  85. Boecker, R. et al. Impact of early life adversity on reward processing in young adults: EEG-fMRI results from a prospective study over 25 years. PLoS ONE 9, e104185 (2014).
  86. Hanson, J. L. et al. Cumulative stress in childhood is associated with blunted reward-related brain activity in adulthood. Soc. Cogn. Affect. Neurosci. 11, 405412 (2015).
  87. Dillon, D. G. et al. Childhood adversity is associated with left basal ganglia dysfunction during reward anticipation in adulthood. Biol. Psychiatry 66, 206213 (2009).
  88. Haber, S. N. & Knutson, B. The reward circuit: linking primate anatomy and human imaging. Neuropsychopharmacology 35, 426 (2010).
  89. Thomaes, K. et al. Reduced anterior cingulate and orbitofrontal volumes in child abuse-related complex PTSD. J. Clin. Psychiatry 71, 16361644 (2010).
  90. Teicher, M. H., Anderson, C. M., Ohashi, K. & Polcari, A. Childhood maltreatment: altered network centrality of cingulate, precuneus, temporal pole and insula. Biol. Psychiatry 76, 297305 (2014).
    This study shows maltreatment-associated cortical network abnormalities in the cingulate, precuneus and insula.
  91. van der Werff, S. J. et al. Resting-state functional connectivity in adults with childhood emotional maltreatment. Psychol. Med. 43, 18251836 (2013).
  92. Gerritsen, L. et al. BDNF Val66Met genotype modulates the effect of childhood adversity on subgenual anterior cingulate cortex volume in healthy subjects. Mol. Psychiatry 17, 597603 (2012).
  93. Balodis, I. M. & Potenza, M. N. Anticipatory reward processing in addicted populations: a focus on the monetary incentive delay task. Biol. Psychiatry 77, 434444 (2015).
  94. De Bellis, M. D. et al. Developmental traumatology part II: brain development. Biol. Psychiatry 45, 12711284 (1999).
    A classic study on childhood trauma, PTSD and altered brain morphology in children.
  95. Teicher, M. H. et al. Childhood neglect is associated with reduced corpus callosum area. Biol. Psychiatry 56, 8085 (2004).
  96. Teicher, M. H., Samson, J. A., Sheu, Y. S., Polcari, A. & McGreenery, C. E. Hurtful words: association of exposure to peer verbal abuse with elevated psychiatric symptom scores and corpus callosum abnormalities. Am. J. Psychiatry 167, 14641471 (2010).
  97. Bucker, J. et al. Childhood maltreatment and corpus callosum volume in recently diagnosed patients with bipolar I disorder: data from the Systematic Treatment Optimization Program for Early Mania (STOP-EM). J. Psychiatr. Res. 48, 6572 (2014).
  98. Paul, R. et al. The relationship between early life stress and microstructural integrity of the corpus callosum in a non-clinical population. Neuropsychiatr. Dis. Treat. 4, 193201 (2008).
  99. Luders, E., Thompson, P. M. & Toga, A. W. The development of the corpus callosum in the healthy human brain. J. Neurosci. 30, 1098510990 (2010).
  100. Luders, E. et al. Positive correlations between corpus callosum thickness and intelligence. Neuroimage 37, 14571464 (2007).
  101. Teicher, M. H. et al. Preliminary evidence for abnormal cortical development in physically and sexually abused children using EEG coherence and MRI. Ann. NY Acad. Sci. 821, 160175 (1997).
  102. De Bellis, M. D. & Keshavan, M. S. Sex differences in brain maturation in maltreatment-related pediatric posttraumatic stress disorder. Neurosci. Biobehav. Rev. 27, 103117 (2003).
  103. Juraska, J. M. & Kopcik, J. R. Sex and environmental influences on the size and ultrastructure of the rat corpus callosum. Brain Res. 450, 18 (1988).
  104. Galinowski, A. et al. Resilience and corpus callosum microstructure in adolescence. Psychol. Med. 45, 22852294 (2015).
  105. Sheridan, M. A., Fox, N. A., Zeanah, C. H., McLaughlin, K. A. & Nelson, C. A. III. Variation in neural development as a result of exposure to institutionalization early in childhood. Proc. Natl Acad. Sci. USA 109, 1292712932 (2012).
  106. Rauch, S. L. et al. A symptom provocation study of posttraumatic stress disorder using positron emission tomography and script-driven imagery. Arch. Gen. Psychiatry 53, 380387 (1996).
  107. Schutter, D. J. & Harmon-Jones, E. The corpus callosum: a commissural road to anger and aggression. Neurosci. Biobehav. Rev. 37, 24812488 (2013).
  108. van den Heuvel, M. P. & Hulshoff Pol, H. E. Exploring the brain network: a review on resting-state fMRI functional connectivity. Eur. Neuropsychopharmacol. 20, 519534 (2010).
  109. He, Y. & Evans, A. Graph theoretical modeling of brain connectivity. Curr. Opin. Neurol. 23, 341350 (2010).
  110. Stevens, F. L., Hurley, R. A. & Taber, K. H. Anterior cingulate cortex: unique role in cognition and emotion. J. Neuropsychiatry Clin. Neurosci. 23, 121125 (2011).
  111. Ross, L. A. & Olson, I. R. Social cognition and the anterior temporal lobes. Neuroimage 49, 34523462 (2010).
  112. Amodio, D. M. & Frith, C. D. Meeting of minds: the medial frontal cortex and social cognition. Nat. Rev. Neurosci. 7, 268277 (2006).
  113. Cavanna, A. E. & Trimble, M. R. The precuneus: a review of its functional anatomy and behavioural correlates. Brain 129, 564583 (2006).
  114. Li, B. et al. A treatment-resistant default mode subnetwork in major depression. Biol. Psychiatry 74, 4854 (2013).
  115. Craig, A. D. How do you feel — now? The anterior insula and human awareness. Nat. Rev. Neurosci. 10, 5970 (2009).
  116. Philip, N. S. et al. Early life stress is associated with greater default network deactivation during working memory in healthy controls: a preliminary report. Brain Imag. Behav. 7, 204212 (2013).
  117. Sripada, R. K., Swain, J. E., Evans, G. W., Welsh, R. C. & Liberzon, I. Childhood poverty and stress reactivity are associated with aberrant functional connectivity in default mode network. Neuropsychopharmacology 39, 22442251 (2014).
  118. Bluhm, R. L. et al. Alterations in default network connectivity in posttraumatic stress disorder related to early-life trauma. J. Psychiatry Neurosci. 34, 187194 (2009).
  119. Krause-Utz, A. et al. Amygdala and anterior cingulate resting-state functional connectivity in borderline personality disorder patients with a history of interpersonal trauma. Psychol. Med. 44, 28892901 (2014).
  120. Marusak, H. A., Etkin, A. & Thomason, M. E. Disrupted insula-based neural circuit organization and conflict interference in trauma-exposed youth. Neuroimage Clin. 8, 516525 (2015).
  121. Philip, N. S. et al. Decreased default network connectivity is associated with early life stress in medication-free healthy adults. Eur. Neuropsychopharmacol. 23, 2432 (2013).
  122. Graham, A. M., Pfeifer, J. H., Fisher, P. A., Carpenter, S. & Fair, D. A. Early life stress is associated with default system integrity and emotionality during infancy. J. Child Psychol. Psychiatry 56, 12121222 (2015).
  123. Tursich, M. et al. Distinct intrinsic network connectivity patterns of post-traumatic stress disorder symptom clusters. Acta Psychiatr. Scand. 132, 2938 (2015).
  124. Cole, J., Costafreda, S. G., McGuffin, P. & Fu, C. H. Hippocampal atrophy in first episode depression: a meta-analysis of magnetic resonance imaging studies. J. Affect. Disord. 134, 483487 (2011).
  125. Vythilingam, M. et al. Childhood trauma associated with smaller hippocampal volume in women with major depression. Am. J. Psychiatry 159, 20722080 (2002).
  126. Chaney, A. et al. Effect of childhood maltreatment on brain structure in adult patients with major depressive disorder and healthy participants. J. Psychiatry Neurosci. 39, 5059 (2014).
  127. Gerritsen, L. et al. Childhood maltreatment modifies the relationship of depression with hippocampal volume. Psychol. Med. 45, 35173526 (2015).
  128. Samplin, E., Ikuta, T., Malhotra, A. K., Szeszko, P. R. & Derosse, P. Sex differences in resilience to childhood maltreatment: effects of trauma history on hippocampal volume, general cognition and subclinical psychosis in healthy adults. J. Psychiatr. Res. 47, 11741179 (2013).
  129. Geuze, E., Vermetten, E. & Bremner, J. D. MR-based in vivo hippocampal volumetrics: 2. Findings in neuropsychiatric disorders. Mol. Psychiatry 10, 160184 (2005).
  130. Malykhin, N. V., Carter, R., Hegadoren, K. M., Seres, P. & Coupland, N. J. Fronto-limbic volumetric changes in major depressive disorder. J. Affect. Disord. 136, 11041113 (2012).
  131. Kumari, V. et al. Lower anterior cingulate volume in seriously violent men with antisocial personality disorder or schizophrenia and a history of childhood abuse. Aust. N. Z. J. Psychiatry 48, 153161 (2014).
  132. Sheffield, J. M., Williams, L. E., Woodward, N. D. & Heckers, S. Reduced gray matter volume in psychotic disorder patients with a history of childhood sexual abuse. Schizophr. Res. 143, 185191 (2013).
  133. Bremner, J. D. et al. MRI and PET study of deficits in hippocampal structure and function in women with childhood sexual abuse and posttraumatic stress disorder. Am. J. Psychiatry 160, 924932 (2003).
  134. Shin, L. M. et al. Regional cerebral blood flow during script-driven imagery in childhood sexual abuse-related PTSD: a PET investigation. Am. J. Psychiatry 156, 575584 (1999).
  135. De Bellis, M. D. et al. Posterior structural brain volumes differ in maltreated youth with and without chronic posttraumatic stress disorder. Dev. Psychopathol. 27, 15551576 (2015).
  136. van Harmelen, A. L. et al. Reduced medial prefrontal cortex volume in adults reporting childhood emotional maltreatment. Biol. Psychiatry 68, 832838 (2010).
  137. Van Dam, N. T., Rando, K., Potenza, M. N., Tuit, K. & Sinha, R. Childhood maltreatment, altered limbic neurobiology, and substance use relapse severity via trauma-specific reductions in limbic gray matter volume. JAMA Psychiatry 71, 917925 (2014).
  138. van Harmelen, A. L. et al. Hypoactive medial prefrontal cortex functioning in adults reporting childhood emotional maltreatment. Soc. Cogn. Affect. Neurosci. 9, 20262033 (2014).
  139. Ugwu, I. D., Amico, F., Carballedo, A., Fagan, A. J. & Frodl, T. Childhood adversity, depression, age and gender effects on white matter microstructure: a DTI study. Brain Struct. Funct. 220, 19972009 (2015).
  140. Seckfort, D. L. et al. Early life stress on brain structure and function across the lifespan: a preliminary study. Brain Imag. Behav. 2, 4958 (2008).
  141. Carballedo, A. et al. Early life adversity is associated with brain changes in subjects at family risk for depression. World J. Biol. Psychiatry 13, 569578 (2012).
  142. Everaerd, D. et al. Sex modulates the interactive effect of the serotonin transporter gene polymorphism and childhood adversity on hippocampal volume. Neuropsychopharmacology 37, 18481855 (2012).
  143. Frodl, T. et al. Effects of early-life adversity on white matter diffusivity changes in patients at risk for major depression. J. Psychiatry Neurosci. 37, 3745 (2012).
  144. Teicher, M. H., Ohashi, K., Lowen, S. B., Polcari, A. & Fitzmaurice, G. M. Mood dysregulation and affective instability in emerging adults with childhood maltreatment: an ecological momentary assessment study. J. Psychiatr. Res. 70, 18 (2015).
  145. van der Werff, S. J. et al. Resilience to childhood maltreatment is associated with increased resting-state functional connectivity of the salience network with the lingual gyrus. Child Abuse Negl. 37, 10211029 (2013).
  146. Pagliaccio, D. et al. Stress-system genes and life stress predict cortisol levels and amygdala and hippocampal volumes in children. Neuropsychopharmacology 39, 12451253 (2014).
  147. Walsh, N. D. et al. General and specific effects of early-life psychosocial adversities on adolescent grey matter volume. Neuroimage Clin. 4, 308318 (2014).
  148. White, M. G. et al. FKBP5 and emotional neglect interact to predict individual differences in amygdala reactivity. Genes Brain Behav. 11, 869878 (2012).
  149. Hyman, S. E. How adversity gets under the skin. Nat. Neurosci. 12, 241243 (2009).
  150. Perroud, N. et al. Methylation of serotonin receptor 3A in ADHD, borderline personality, and bipolar disorders: link with severity of the disorders and childhood maltreatment. Depress. Anxiety 33, 4555 (2016).
  151. Plotsky, P. M. & Meaney, M. J. Early, postnatal experience alters hypothalamic corticotropin-releasing factor (CRF) mRNA, median eminence CRF content and stress-induced release in adult rats. Brain Res. Mol. Brain Res. 18, 195200 (1993).
  152. Barr, C. S. et al. Serotonin transporter gene variation is associated with alcohol sensitivity in rhesus macaques exposed to early-life stress. Alcohol Clin. Exp. Res. 27, 812817 (2003).
  153. Jackowski, A. et al. Early-life stress, corpus callosum development, hippocampal volumetrics, and anxious behavior in male nonhuman primates. Psychiatry Res. 192, 3744 (2011).
  154. Weaver, I. C. et al. Epigenetic programming by maternal behavior. Nat. Neurosci. 7, 847854 (2004).
  155. Maestripieri, D., Lindell, S. G., Ayala, A., Gold, P. W. & Higley, J. D. Neurobiological characteristics of rhesus macaque abusive mothers and their relation to social and maternal behavior. Neurosci. Biobehav. Rev. 29, 5157 (2005).
  156. Meaney, M. J., Brake, W. & Gratton, A. Environmental regulation of the development of mesolimbic dopamine systems: a neurobiological mechanism for vulnerability to drug abuse? Psychoneuroendocrinology 27, 127138 (2002).
  157. Suderman, M. et al. Conserved epigenetic sensitivity to early life experience in the rat and human hippocampus. Proc. Natl Acad. Sci. USA 109, 1726617272 (2012).
  158. Berrebi, A. S. et al. Corpus callosum: region-specific effects of sex, early experience and age. Brain Res. 438, 216224 (1988).
  159. Sapolsky, R. M. Stress, glucocorticoids, and damage to the nervous system: the current state of confusion. Stress 1, 119 (1996).
  160. Andersen, S. L. & Teicher, M. H. Delayed effects of early stress on hippocampal development. Neuropsychopharmacology 29, 19881993 (2004).
  161. Andersen, S. L. & Teicher, M. H. Stress, sensitive periods and maturational events in adolescent depression. Trends Neurosci. 31, 183191 (2008).
  162. Bock, J., Gruss, M., Becker, S. & Braun, K. Experience-induced changes of dendritic spine densities in the prefrontal and sensory cortex: correlation with developmental time windows. Cereb. Cortex 15, 802808 (2005).
  163. McEwen, B. S. Sex, stress and the hippocampus: allostasis, allostatic load and the aging process. Neurobiol. Aging 23, 921939 (2002).
  164. Champagne, D. L. et al. Maternal care and hippocampal plasticity: evidence for experience-dependent structural plasticity, altered synaptic functioning, and differential responsiveness to glucocorticoids and stress. J. Neurosci. 28, 60376045 (2008).
  165. Sanchez, M. M., Hearn, E. F., Do, D., Rilling, J. K. & Herndon, J. G. Differential rearing affects corpus callosum size and cognitive function of rhesus monkeys. Brain Res. 812, 3849 (1998).
  166. Howell, B. R. et al. Early adverse experience increases emotional reactivity in juvenile rhesus macaques: relation to amygdala volume. Dev. Psychobiol. 56, 17351746 (2014).
  167. Jackowski, A. P. et al. Corpus callosum in maltreated children with posttraumatic stress disorder: a diffusion tensor imaging study. Psychiatry Res. 162, 256261 (2008).
  168. Carrion, V. G. et al. Converging evidence for abnormalities of the prefrontal cortex and evaluation of midsagittal structures in pediatric posttraumatic stress disorder: an MRI study. Psychiatry Res. 172, 226234 (2009).
  169. Moutsiana, C. et al. Insecure attachment during infancy predicts greater amygdala volumes in early adulthood. J. Child Psychol. Psychiatry 56, 540548 (2015).
  170. Carrion, V. G., Weems, C. F. & Reiss, A. L. Stress predicts brain changes in children: a pilot longitudinal study on youth stress, posttraumatic stress disorder, and the hippocampus. Pediatrics 119, 509516 (2007).
  171. Thomason, M. E. et al. Altered amygdala connectivity in urban youth exposed to trauma. Soc. Cogn. Affect. Neurosci. 10, 14601468 (2015).
  172. Sheu, Y. S., Polcari, A., Anderson, C. M. & Teicher, M. H. Harsh corporal punishment is associated with increased T2 relaxation time in dopamine-rich regions. Neuroimage 53, 412419 (2010).
  173. Whittle, S. et al. Observed measures of negative parenting predict brain development during adolescence. PLoS ONE 11, e0147774 (2016).

Download references

Author information

Affiliations

  1. Department of Psychiatry, Harvard Medical School, 401 Park Drive, Boston, Massachusetts 02215, USA.

    • Martin H. Teicher,
    • Jacqueline A. Samson,
    • Carl M. Anderson &
    • Kyoko Ohashi
  2. Developmental Biopsychiatry Research Program, McLean Hospital, 115 Mill Street, Belmont, Massachusetts 02478, USA.

    • Martin H. Teicher,
    • Jacqueline A. Samson,
    • Carl M. Anderson &
    • Kyoko Ohashi

Competing interests statement

The authors declare no competing interests.

Corresponding author

Correspondence to:

Author details

  • Martin H. Teicher

    Martin H. Teicher is Director of the Developmental Biopsychiatry Research Program at McLean Hospital and an associate professor of psychiatry at Harvard Medical School, Boston, Massachusetts, USA. He has spent nearly 40 years studying the influence of early experience on the brain, behavioural development and psychopathology in humans and animal models.

  • Jacqueline A. Samson

    Jacqueline A. Samson is a clinical psychologist at McLean Hospital and an assistant professor of psychology in the Department of Psychiatry at Harvard Medical School, Boston, Massachusetts, USA. Her chief research interests involve understanding the biopsychosocial underpinnings of depressive illnesses, particularly the contributions of developmental trauma to psychopathology.

  • Carl M. Anderson

    Carl M. Anderson was an assistant professor at Harvard Medical School and an assistant psychobiologist at McLean Hospital, Boston, Massachusetts, USA, and has just accepted a position as Research Director at CooperRiis, a healing community in Mill Spring, North Carolina, USA. His interests include brain morphometry, the cerebellar vermis, neurofeedback and complementary medicine, and he is actively seeking to integrate these within psychiatry.

  • Kyoko Ohashi

    Kyoko Ohashi is an instructor of psychiatry at Harvard Medical School and an assistant neuroscientist at McLean Hospital, Boston, Massachusetts, USA. She received her doctorate from University of Tokyo, Japan, and currently focuses on the influence of childhood adversity on brain connectivity and network architecture, and the relationship between alterations in network architecture and psychopathology.

Supplementary information

PDF files

  1. Supplementary information (6.73 MB)

    Supplementary Box and tables

Additional data