Brain Structure and Function

, Volume 220, Issue 4, pp 1997–2009 | Cite as

Childhood adversity, depression, age and gender effects on white matter microstructure: a DTI study

  • Izuchukwu D. Ugwu
  • Francesco Amico
  • Angela Carballedo
  • Andrew J. Fagan
  • Thomas Frodl
Original Article


Previous diffusion tensor imaging (DTI) studies have shown that various factors can affect white matter (WM) tract diffusivity. The aim of the present study was to investigate the effects of childhood adversity (CA), age and gender on WM diffusivity in tracts that are thought to be involved in emotional regulation in individuals with major depressive disorder (MDD) and healthy controls (HC). DTI was obtained from 46 subjects with MDD and 46 HC subjects. Data were pre-processed and deterministic tractography was applied in the cingulum, uncinate fasciculus (UF), fornix, superior longitudinal fasciculus (SLF) and fronto-occipital fasciculus (FOF). In subjects with a history of CA, fractional anisotropy (FA) was greater in the rostral cingulum (RC) and dorsal cingulum, whereas radial diffusivity (RD) was smaller in the RC when compared with subjects with no history of CA. In the UF, FOF and parahippocampal cingulum, FA was greater in the left hemisphere in the subjects with CA when compared with those without CA. Age affected FA, longitudinal diffusivity and RD in the UF, fornix, FOF and SLF, reflecting axonal and myelin degeneration with increasing age. Depression or gender did not have any effects on the diffusivity measures. Due to the cross-sectional nature of the study, a recall bias for CA and possible effects of medical treatment on diffusivity measures could have played a role. CA and age could increase the likelihood to develop WM microstructural anomalies in the brain affective network. Moreover, subjects with CA could be more vulnerable to FA changes.


Childhood adversity Age White matter Major depressive disorder DTI Childhood adversity 


  1. Aaro LE, Herbec A et al (2011) Depressive episodes and depressive tendencies among a sample of adults in Kielce, south-eastern Poland. Ann Agric Environ Med 18(2):273–278PubMedGoogle Scholar
  2. Aguilera M, Arias B et al (2009) Early adversity and 5-HTT/BDNF genes: new evidence of gene-environment interactions on depressive symptoms in a general population. Psychol Med 39(9):1425–1432PubMedCrossRefGoogle Scholar
  3. American Psychiatric Association (2000) Diagnostic and statistical manual of mental disorders, 4th edn, text rev. Author, Washington, DCGoogle Scholar
  4. Bae JN, MacFall JR et al (2006) Dorsolateral prefrontal cortex and anterior cingulate cortex white matter alterations in late-life depression. Biol Psychiatry 60(12):1356–1363PubMedCrossRefGoogle Scholar
  5. Basser PJ, Mattiello J et al (1994) Estimation of the effective self-diffusion tensor from the NMR spin echo. J Magn Reson B 103(3):247–254PubMedCrossRefGoogle Scholar
  6. Beaulieu C (2002) The basis of anisotropic water diffusion in the nervous system—a technical review. NMR Biomed 15(7–8):435–455PubMedCrossRefGoogle Scholar
  7. Beck AT, Steer RA et al (1996) Comparison of Beck Depression Inventories-IA and -II in psychiatric outpatients. J Pers Assess 67(3):588–597PubMedCrossRefGoogle Scholar
  8. Bernstein DP, Stein JA et al (2003) Development and validation of a brief screening version of the Childhood Trauma Questionnaire. Child Abuse Negl 27(2):169–190PubMedCrossRefGoogle Scholar
  9. Burgel U, Amunts K et al (2006) White matter fiber tracts of the human brain: three-dimensional mapping at microscopic resolution, topography and intersubject variability. Neuroimage 29(4):1092–1105PubMedCrossRefGoogle Scholar
  10. Carballedo A, Morris D et al (2013) Brain-derived neurotrophic factor Val66Met polymorphism and early life adversity affect hippocampal volume. Am J Med Genet B Neuropsychiatr Genet 162(2):183–190CrossRefGoogle Scholar
  11. Carli V, Mandelli L et al (2011) A protective genetic variant for adverse environments? The role of childhood traumas and serotonin transporter gene on resilience and depressive severity in a high-risk population. Eur Psychiatry 26(8):471–478PubMedCrossRefGoogle Scholar
  12. Catani M, Howard RJ et al (2002) Virtual in vivo interactive dissection of white matter fasciculi in the human brain. Neuroimage 17(1):77–94PubMedCrossRefGoogle Scholar
  13. Chanraud S, Zahr N et al (2010) MR diffusion tensor imaging: a window into white matter integrity of the working brain. Neuropsychol Rev 20(2):209–225PubMedCentralPubMedCrossRefGoogle Scholar
  14. Chen S, Conwell Y et al (2012) Prevalence and natural course of late-life depression in China primary care: a population based study from an urban community. J Affect Disord 141(1):86–93PubMedCentralPubMedCrossRefGoogle Scholar
  15. Choi J, Jeong B et al (2009) Preliminary evidence for white matter tract abnormalities in young adults exposed to parental verbal abuse. Biol Psychiatry 65(3):227–234PubMedCentralPubMedCrossRefGoogle Scholar
  16. Claes SJ (2004) CRH, stress, and major depression: a psychobiological interplay. Vitam Horm 69:117–150PubMedCrossRefGoogle Scholar
  17. Cullen KR, Klimes-Dougan B et al (2010) Altered white matter microstructure in adolescents with major depression: a preliminary study. J Am Acad Child Adolesc Psychiatry 49(2):173–183 e171Google Scholar
  18. Dalby RB, Frandsen J et al (2010) Depression severity is correlated to the integrity of white matter fiber tracts in late-onset major depression. Psychiatry Res 184(1):38–48PubMedCrossRefGoogle Scholar
  19. Dalton VS, Kolshus E et al (2014) Epigenetics and depression: return of the repressed. J Affect Disord 155:1–12PubMedCrossRefGoogle Scholar
  20. Daniels JK, Lamke JP et al (2013) White matter integrity and its relationship to ptsd and childhood trauma-a systematic review and meta-analysis. Depress Anxiety 30(3):207–216PubMedCrossRefGoogle Scholar
  21. Das D, Cherbuin N et al (2011) DRD4-exonIII-VNTR moderates the effect of childhood adversities on emotional resilience in young-adults. PLoS ONE 6(5):e20177PubMedCentralPubMedCrossRefGoogle Scholar
  22. Davis SW, Dennis NA et al (2009) Assessing the effects of age on long white matter tracts using diffusion tensor tractography. Neuroimage 46(2):530–541PubMedCentralPubMedCrossRefGoogle Scholar
  23. First MB, Spitzer RL et al (2002) Structured clinical interview for DSM-IV-TR axis I disorders, research version, patient edition (SCID-I/P). Biometrics Research, New York State Psychiatric Institute, New YorkGoogle Scholar
  24. Frodl T, Carballedo A et al (2012) Effects of early-life adversity on white matter diffusivity changes in patients at risk for major depression. J Psychiatry Neurosci 37:37–45PubMedCentralPubMedCrossRefGoogle Scholar
  25. Gatt JM, Williams LM et al (2010) Impact of the HTR3A gene with early life trauma on emotional brain networks and depressed mood. Depress Anxiety 27(8):752–759PubMedCrossRefGoogle Scholar
  26. Ghashghaei HT, Barbas H (2002) Pathways for emotion: interactions of prefrontal and anterior temporal pathways in the amygdala of the rhesus monkey. Neuroscience 115(4):1261–1279PubMedCrossRefGoogle Scholar
  27. Gong G, He Y et al (2011) Brain connectivity: gender makes a difference. Neuroscientist 17:575–591PubMedCrossRefGoogle Scholar
  28. Grabe HJ, Schwahn C et al (2012) Genetic epistasis between the brain-derived neurotrophic factor Val66Met polymorphism and the 5-HTT promoter polymorphism moderates the susceptibility to depressive disorders after childhood abuse. Prog Neuropsychopharmacol Biol Psychiatry 36(2):264–270PubMedCrossRefGoogle Scholar
  29. Hamilton M (1969) Standardised assessment and recording of depressive symptoms. Psychiatr Neurol Neurochir 72(2):201–205PubMedGoogle Scholar
  30. Hasan KM, Iftikhar A et al (2009) Development and aging of the healthy human brain uncinate fasciculus across the lifespan using diffusion tensor tractography. Brain Res 1276:67–76PubMedCentralPubMedCrossRefGoogle Scholar
  31. Herting MM, Maxwell EC et al (2012) The impact of sex, puberty, and hormones on white matter microstructure in adolescents. Cereb Cortex 22(9):1979–1992PubMedCentralPubMedCrossRefGoogle Scholar
  32. Hsu JL, Leemans A et al (2008) Gender differences and age-related white matter changes of the human brain: a diffusion tensor imaging study. Neuroimage 39(2):566–577PubMedCrossRefGoogle Scholar
  33. Huang H, Gundapuneedi T et al (2012) White matter disruptions in adolescents exposed to childhood maltreatment and vulnerability to psychopathology. Neuropsychopharmacology 37(12):2693–2701PubMedCentralPubMedCrossRefGoogle Scholar
  34. Inano S, Takao H et al (2011) Effects of age and gender on white matter integrity. AJNR Am J Neuroradiol 32(11):2103–2109PubMedCrossRefGoogle Scholar
  35. Infrasca R (2003) Childhood adversities and adult depression: an experimental study on childhood depressogenic markers. J Affect Disord 76(1–3):103–111PubMedCrossRefGoogle Scholar
  36. Jackson DC, Mueller CJ et al (2003) Now you feel it, now you don’t: frontal brain electrical asymmetry and individual differences in emotion regulation. Psychol Sci 14(6):612–617PubMedCrossRefGoogle Scholar
  37. Johansen-Berg H, Gutman DA et al (2008) Anatomical connectivity of the subgenual cingulate region targeted with deep brain stimulation for treatment-resistant depression. Cereb Cortex 18(6):1374–1383PubMedCrossRefGoogle Scholar
  38. Kaufman J, Yang BZ et al (2006) Brain-derived neurotrophic factor-5-HTTLPR gene interactions and environmental modifiers of depression in children. Biol Psychiatry 59(8):673–680PubMedCrossRefGoogle Scholar
  39. Kessler RC, Berglund P et al (2003) The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). JAMA 289(23):3095–3105PubMedCrossRefGoogle Scholar
  40. Kieseppa T, Eerola M et al (2010) Major depressive disorder and white matter abnormalities: a diffusion tensor imaging study with tract-based spatial statistics. J Affect Disord 120(1–3):240–244PubMedCrossRefGoogle Scholar
  41. Kim KJ, Bell MA (2006) Frontal EEG asymmetry and regulation during childhood. Ann N Y Acad Sci 1094:308–312PubMedCrossRefGoogle Scholar
  42. Kim SH, Cornwell B et al (2012) Individual differences in emotion regulation and hemispheric metabolic asymmetry. Biol Psychol 89(2):382–386PubMedCrossRefGoogle Scholar
  43. Klein DN, Arnow BA et al (2009) Early adversity in chronic depression: clinical correlates and response to pharmacotherapy. Depress Anxiety 26(8):701–710PubMedCentralPubMedCrossRefGoogle Scholar
  44. Kvickstrom P, Eriksson B et al (2011) Selective frontal neurodegeneration of the inferior fronto-occipital fasciculus in progressive supranuclear palsy (PSP) demonstrated by diffusion tensor tractography. BMC Neurol 11:13PubMedCentralPubMedCrossRefGoogle Scholar
  45. Laitinen LV (1979) Emotional responses to subcortical electrical stimulation in psychiatric patients. Clin Neurol Neurosurg 81(3):148–157PubMedCrossRefGoogle Scholar
  46. Leemans A, Jones DK (2009) The B-matrix must be rotated when correcting for subject motion in DTI data. Magn Reson Med 61(6):1336–1349PubMedCrossRefGoogle Scholar
  47. Leemans A, Jeurissen B, Sijbers J et al (2009) Explore DTI: a graphical toolbox for processing, analysing, and visualising diffusion MR data. 17th annual meeting of Intl Soc Mag Reson Med, HawaiiGoogle Scholar
  48. Levine B, Black SE et al (1998) Episodic memory and the self in a case of isolated retrograde amnesia. Brain 121(Pt 10):1951–1973PubMedCrossRefGoogle Scholar
  49. Li L, Ma N et al (2007) Prefrontal white matter abnormalities in young adult with major depressive disorder: a diffusion tensor imaging study. Brain Res 1168:124–128PubMedCrossRefGoogle Scholar
  50. Lim KO, Helpern JA (2002) Neuropsychiatric applications of DTI—a review. NMR Biomed 15(7–8):587–593PubMedCrossRefGoogle Scholar
  51. Lovden M, Bodammer NC et al (2010) Experience-dependent plasticity of white-matter microstructure extends into old age. Neuropsychologia 48(13):3878–3883PubMedCrossRefGoogle Scholar
  52. Lu C, Teng S et al (2010) A neuronal fiber tracking study for major depressive disorder using MR diffusion tensor imaging with fiber tractography. International conference on bioinformatics and biomedical technology (ICBBT). IEEE, Piscataway, pp 106–110Google Scholar
  53. Luck D, Buchy L et al (2011) Fronto-temporal disconnectivity and clinical short-term outcome in first episode psychosis: a DTI-tractography study. J Psychiatr Res 45(3):369–377PubMedCrossRefGoogle Scholar
  54. Mabbott DJ, Rovet J et al (2009) The relations between white matter and declarative memory in older children and adolescents. Brain Res 1294:80–90PubMedCrossRefGoogle Scholar
  55. Malykhin N, Concha L et al (2008) Diffusion tensor imaging tractography and reliability analysis for limbic and paralimbic white matter tracts. Psychiatry Res 164(2):132–142PubMedCrossRefGoogle Scholar
  56. Mayberg HS, Lozano AM et al (2005) Deep brain stimulation for treatment-resistant depression. Neuron 45(5):651–660PubMedCrossRefGoogle Scholar
  57. Menzler K, Belke M et al (2011) Men and women are different: diffusion tensor imaging reveals sexual dimorphism in the microstructure of the thalamus, corpus callosum and cingulum. Neuroimage 54(4):2557–2562PubMedCrossRefGoogle Scholar
  58. Michielse S, Coupland N et al (2010) Selective effects of aging on brain white matter microstructure: a diffusion tensor imaging tractography study. Neuroimage 52(4):1190–1201PubMedCrossRefGoogle Scholar
  59. Mori S, Kaufmann WE et al (2002) Imaging cortical association tracts in the human brain using diffusion-tensor-based axonal tracking. Magn Reson Med 47(2):215–223PubMedCrossRefGoogle Scholar
  60. Mostert JP, Sijens PE et al (2006) Fluoxetine increases cerebral white matter NAA/Cr ratio in patients with multiple sclerosis. Neurosci Lett 402(1–2):22–24PubMedCrossRefGoogle Scholar
  61. Murphy ML, Frodl T (2011) Meta-analysis of diffusion tensor imaging studies shows altered fractional anisotropy occurring in distinct brain areas in association with depression. Biol Mood Anxiety Disord 1(1):3PubMedCentralPubMedCrossRefGoogle Scholar
  62. Murphy CF, Gunning-Dixon FM et al (2007) White-matter integrity predicts stroop performance in patients with geriatric depression. Biol Psychiatry 61(8):1007–1010PubMedCentralPubMedCrossRefGoogle Scholar
  63. Nobuhara K, Okugawa G et al (2006) Frontal white matter anisotropy and symptom severity of late-life depression: a magnetic resonance diffusion tensor imaging study. J Neurol Neurosurg Psychiatry 77(1):120–122PubMedCentralPubMedCrossRefGoogle Scholar
  64. Pal D, Trivedi R et al (2011) Quantification of age- and gender-related changes in diffusion tensor imaging indices in deep grey matter of the normal human brain. J Clin Neurosci 18(2):193–196PubMedCrossRefGoogle Scholar
  65. Paul R, Henry L et al (2008) The relationship between early life stress and microstructural integrity of the corpus callosum in a non-clinical population. Neuropsychiatr Dis Treat 4(1):193–201PubMedCentralPubMedCrossRefGoogle Scholar
  66. Paus T, Nawaz-Khan I et al (2010) Sexual dimorphism in the adolescent brain: role of testosterone and androgen receptor in global and local volumes of grey and white matter. Horm Behav 57(1):63–75PubMedCrossRefGoogle Scholar
  67. Perrin JS, Herve PY et al (2008) Growth of white matter in the adolescent brain: role of testosterone and androgen receptor. J Neurosci 28(38):9519–9524PubMedCrossRefGoogle Scholar
  68. Pfefferbaum A, Sullivan EV et al (2000) Age-related decline in brain white matter anisotropy measured with spatially corrected echo-planar diffusion tensor imaging. Magn Reson Med 44(2):259–268PubMedCrossRefGoogle Scholar
  69. Ramnani N, Behrens TE et al (2004) New approaches for exploring anatomical and functional connectivity in the human brain. Biol Psychiatry 56(9):613–619PubMedCrossRefGoogle Scholar
  70. Roberts AC, Wallis JD (2000) Inhibitory control and affective processing in the prefrontal cortex: neuropsychological studies in the common marmoset. Cereb Cortex 10(3):252–262PubMedCrossRefGoogle Scholar
  71. Russell D, Springer KW et al (2010) Witnessing domestic abuse in childhood as an independent risk factor for depressive symptoms in young adulthood. Child Abuse Negl 34(6):448–453PubMedCentralPubMedCrossRefGoogle Scholar
  72. Sachdev PS, Chen X et al (2008) Light to moderate alcohol use is associated with increased cortical gray matter in middle-aged men: a voxel-based morphometric study. Psychiatry Res 163(1):61–69PubMedCrossRefGoogle Scholar
  73. Sadeghirad B, Haghdoost AA et al (2010) Epidemiology of major depressive disorder in Iran: a systematic review and meta-analysis. Int J Prev Med 1(2):81–91PubMedCentralPubMedGoogle Scholar
  74. Sadowski H, Ugarte B et al (1999) Early life family disadvantages and major depression in adulthood. Br J Psychiatry 174:112–120PubMedCrossRefGoogle Scholar
  75. Salat DH, Tuch DS et al (2005) Age-related alterations in white matter microstructure measured by diffusion tensor imaging. Neurobiol Aging 26(8):1215–1227PubMedCrossRefGoogle Scholar
  76. Scholz J, Klein MC et al (2009) Training induces changes in white-matter architecture. Nat Neurosci 12(11):1370–1371PubMedCentralPubMedCrossRefGoogle Scholar
  77. Shaffer A, Huston L et al (2008) Identification of child maltreatment using prospective and self-report methodologies: a comparison of maltreatment incidence and relation to later psychopathology. Child Abuse Negl 32(7):682–692PubMedCentralPubMedCrossRefGoogle Scholar
  78. Shimony JS, Sheline YI et al (2009) Diffuse microstructural abnormalities of normal-appearing white matter in late life depression: a diffusion tensor imaging study. Biol Psychiatry 66(3):245–252PubMedCentralPubMedCrossRefGoogle Scholar
  79. Solano-Castiella E, Anwander A et al (2010) Diffusion tensor imaging segments the human amygdala in vivo. Neuroimage 49(4):2958–2965PubMedCrossRefGoogle Scholar
  80. Song SK, Sun SW et al (2002) Dysmyelination revealed through MRI as increased radial (but unchanged axial) diffusion of water. Neuroimage 17(3):1429–1436PubMedCrossRefGoogle Scholar
  81. Song SK, Sun SW et al (2003) Diffusion tensor imaging detects and differentiates axon and myelin degeneration in mouse optic nerve after retinal ischemia. Neuroimage 20(3):1714–1722PubMedCrossRefGoogle Scholar
  82. Song SK, Yoshino J et al (2005) Demyelination increases radial diffusivity in corpus callosum of mouse brain. Neuroimage 26(1):132–140PubMedCrossRefGoogle Scholar
  83. Spinhoven P, Elzinga BM et al (2010) The specificity of childhood adversities and negative life events across the life span to anxiety and depressive disorders. J Affect Disord 126(1–2):103–112PubMedCrossRefGoogle Scholar
  84. Steffens DC, Chung H et al (2008) Antidepressant treatment and worsening white matter on serial cranial magnetic resonance imaging in the elderly: the Cardiovascular Health Study. Stroke 39(3):857–862PubMedCrossRefGoogle Scholar
  85. Sun SW, Song SK et al (2005) Detection of age-dependent brain injury in a mouse model of brain amyloidosis associated with Alzheimer’s disease using magnetic resonance diffusion tensor imaging. Exp Neurol 191(1):77–85PubMedCrossRefGoogle Scholar
  86. Taylor WD, MacFall JR et al (2007) Structural integrity of the uncinate fasciculus in geriatric depression: relationship with age of onset. Neuropsychiatr Dis Treat 3(5):669–674PubMedCentralPubMedGoogle Scholar
  87. Thiebaut de Schotten M, Dell’Acqua F et al (2012) Monkey to human comparative anatomy of the frontal lobe association tracts. Cortex 48(1):82–96PubMedCrossRefGoogle Scholar
  88. Tuch DS, Reese TG et al (2003) Diffusion MRI of complex neural architecture. Neuron 40(5):885–895PubMedCrossRefGoogle Scholar
  89. Ustun TB, Ayuso-Mateos JL et al (2004) Global burden of depressive disorders in the year 2000. Br J Psychiatry 184:386–392PubMedCrossRefGoogle Scholar
  90. Wager TD et al (2008) Neural mechanisms of emotion regulation: evidence for two independent prefrontal-subcortical pathways. Natl Inst Health Public Access 59(6):1037–1050Google Scholar
  91. Williams VJ, Leritz EC et al (2013) Interindividual variation in serum cholesterol is associated with regional white matter tissue integrity in older adults. Hum Brain Mapp 34(8):1826–1841PubMedCentralPubMedCrossRefGoogle Scholar
  92. Wu YC, Field AS et al (2011) Age- and gender-related changes in the normal human brain using hybrid diffusion imaging (HYDI). Neuroimage 54(3):1840–1853PubMedCentralPubMedCrossRefGoogle Scholar
  93. Yang Q, Huang X et al (2007) White matter microstructural abnormalities in late-life depression. Int Psychogeriatr 19(4):757–766PubMedCrossRefGoogle Scholar
  94. Yoo SY, Jang JH et al (2007) White matter abnormalities in drug-naive patients with obsessive-compulsive disorder: a diffusion tensor study before and after citalopram treatment. Acta Psychiatr Scand 116(3):211–219PubMedCrossRefGoogle Scholar
  95. Zhu X, Wang X et al (2011) Altered white matter integrity in first-episode, treatment-naive young adults with major depressive disorder: a tract-based spatial statistics study. Brain Res 1369:223–229PubMedCrossRefGoogle Scholar
  96. Zou K, Huang X et al (2008) Alterations of white matter integrity in adults with major depressive disorder: a magnetic resonance imaging study. J Psychiatry Neurosci 33(6):525–530PubMedCentralPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Izuchukwu D. Ugwu
    • 1
    • 5
  • Francesco Amico
    • 2
    • 3
  • Angela Carballedo
    • 1
    • 2
  • Andrew J. Fagan
    • 4
  • Thomas Frodl
    • 1
    • 2
    • 3
    • 4
  1. 1.Adelaide and Meath Hospital Incorporating the National Children’s HospitalDublinIreland
  2. 2.Department of Psychiatry, School of MedicineTrinity College Dublin, College GreenDublin 2Ireland
  3. 3.Research Group Integrated NeuroimagingTrinity College Institute of Neuroscience, Trinity CollegeDublinIreland
  4. 4.St. James’s Hospital, Centre of Advanced Medical Imaging (CAMI)DublinIreland
  5. 5.Department of Old Age PsychiatryJulian HospitalNorwichUK

Personalised recommendations