, Volume 59, Issue 7, pp 699–708 | Cite as

Schizophrenia symptomatic associations with diffusion tensor imaging measured fractional anisotropy of brain: a meta-analysis

Functional Neuroradiology



Several studies have examined the relationships between diffusion tensor imaging (DTI)-measured fractional anisotropy (FA) and the symptoms of schizophrenia, but results vary across the studies. The aim of this study was to carry out a meta-analysis of correlation coefficients reported by relevant studies to evaluate the correlative relationships between FA of various parts of the brain and schizophrenia symptomatic assessments.


Literature was searched in several electronic databases, and study selection was based on précised eligibility criteria. Correlation coefficients between FA of a part of the brain and schizophrenia symptom were first converted into Fisher’s z-scores for meta-analyses, and then overall effect sizes were back transformed to correlation coefficients.


Thirty-three studies (1121 schizophrenia patients; age 32.66 years [95% confidence interval (CI) 30.19, 35.13]; 65.95 % [57.63, 74.28] males) were included in this meta-analysis. Age was inversely associated with brain FA (z-scores [95% CI] −0.23 [−0.14, −0.32]; p ˂ 0.00001). Brain FA of various areas was inversely associated with negative symptoms of schizophrenia (z-score −0.30 [−0.23, −0.36]; p ˂ 0.00001) but was positively associated with positive symptoms of schizophrenia (z-score 0.16 [0.04, 0.27]; p = 0.007) and general psychopathology of schizophrenia (z-score 0.26 [0.15, 0.37]; p = 0.00001).


Although, DTI-measured brain FA is found to be inversely associated with negative symptoms and positively associated with positive symptoms and general psychopathology of schizophrenia, the effect sizes of these correlations are low and may not be clinically significant. Moreover, brain FA was also negatively associated with age of patients.


Diffusion tensor imaging Fractional anisotropy Schizophrenia Psychosis Correlation 


Compliance with ethical standards


No funding was received for this study.

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Informed consent

Informed consent was not required from the individual participants included in this study.


  1. 1.
    Basser PJ, Mattiello J, LeBihan D (1994) MR diffusion tensor spectroscopy and imaging. Biophys J 66:259–267CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Mori S, Zhang J (2006) Principles of diffusion tensor imaging and its applications to basic neuroscience research. Neuron 51:527–539CrossRefPubMedGoogle Scholar
  3. 3.
    Le Bihan D, Mangin JF, Poupon C, Clark CA, Pappata S, Molko N, Chabriat H (2001) Diffusion tensor imaging: concepts and applications. J Magn Reson Imaging 13:534–546CrossRefPubMedGoogle Scholar
  4. 4.
    Le Bihan D (2003) Looking into the functional architecture of the brain with diffusion MRI. Nat Rev Neurosci 4:469–480CrossRefPubMedGoogle Scholar
  5. 5.
    Basser PJ, Jones DK (2002) Diffusion-tensor MRI: theory, experimental design and data analysis—a technical review. NMR Biomed 5:456–467CrossRefGoogle Scholar
  6. 6.
    Cercignani M, Horsfield MA (2001) The physical basis of diffusion weighted MRI. J Neurol Sci 186(Suppl. 1):S11–S14CrossRefPubMedGoogle Scholar
  7. 7.
    Gulani V, Webb AG, Duncan ID, Lauterbur PC (2001) Apparent diffusion tensor measurements in myelin-deficient rat spinal cords. Magn Reson Med 45:191–195CrossRefPubMedGoogle Scholar
  8. 8.
    Bennett IJ, Madden DJ, Vaidya CJ, Howard DV, Howard JH Jr (2010) Age-related differences in multiple measures of white matter integrity: a diffusion tensor imaging study of healthy aging. Hum Brain Mapp 31:378–390PubMedPubMedCentralGoogle Scholar
  9. 9.
    Cookey J, Bernier D, Tibbo PG (2014) White matter changes in early phase schizophrenia and cannabis use: an update and systematic review of diffusion tensor imaging studies. Schizophr Res 156:137–142CrossRefPubMedGoogle Scholar
  10. 10.
    Kubicki M, Shenton ME (2014) Diffusion tensor imaging findings and their implications in schizophrenia. Curr Opin Psychiatry 27:179–184CrossRefPubMedGoogle Scholar
  11. 11.
    DeLisi LE, Szulc KU, Bertisch H, Majcher M, Brown K, Bappal A, Branch CA, Ardekani BA (2006) Early detection of schizophrenia by diffusion weighted imaging. Psychiatry Res 148:61–66CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Konrad A, Winterer G (2008) Disturbed structural connectivity in schizophrenia—primary factor in pathology or epiphenomenon? Schizophr Bull 34:72–92CrossRefPubMedGoogle Scholar
  13. 13.
    Clark KA, Nuechterlein KH, Asarnow RF, Hamilton LS, Phillips OR, Hageman NS, Woods RP, Alger JR, Toga AW, Narr KL (2011) Mean diffusivity and fractional anisotropy as indicators of disease and genetic liability to schizophrenia. J Psychiatr Res 45:980–988CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Peters BD, Blaas J, de Haan L (2010) Diffusion tensor imaging in the early phase of schizophrenia: what have we learned? J Psychiatr Res 44(15):993–1004CrossRefPubMedGoogle Scholar
  15. 15.
    Boos HBM, Mandl RCW, van Haren NEM, Cahn W, van Baal GCM, Kahn RS, Hulshoff Pol HE (2013) Tract-based diffusion tensor imaging in patients with schizophrenia and their non-psychotic siblings. Eur Neuropsychopharmacol 23:295–304CrossRefPubMedGoogle Scholar
  16. 16.
    Ellison-Wright I, Bullmore E (2009) Meta-analysis of diffusion tensor imaging studies in schizophrenia. Schizophr Res 108:3–10CrossRefPubMedGoogle Scholar
  17. 17.
    Yao L, Lui S, Liao Y, Du MY, Hu N, Thomas JA, Gong QY (2013) White matter deficits in first episode schizophrenia: an activation likelihood estimation meta-analysis. Prog Neuro-Psychopharmacol Biol Psychiatry 45:100–106CrossRefGoogle Scholar
  18. 18.
    Bora E, Fornito A, Radua J, Walterfang M, Seal M, Wood SJ, Yücel M, Velakoulis D, Pantelis C (2011) Neuroanatomical abnormalities in schizophrenia: a multimodal voxelwise meta-analysis and meta-regression analysis. Schizophr Res 127:46–57CrossRefPubMedGoogle Scholar
  19. 19.
    Patel S, Mahon K, Wellington R, Zhang J, Chaplin W, Szeszko PR (2011) A meta-analysis of diffusion tensor imaging studies of the corpus callosum in schizophrenia. Schizophr Res 129:149–155CrossRefPubMedGoogle Scholar
  20. 20.
    Geoffroy PA, Houenou J, Duhamel A, Amad A, De Weijer AD, Curčić-Blake B, Linden DE, Thomas P, Jardri R (2014) The arcuate fasciculus in auditory-verbal hallucinations: a meta-analysis of diffusion-tensor-imaging studies. Schizophr Res 159:234–247CrossRefPubMedGoogle Scholar
  21. 21.
    Samartzis L, Dima D, Fusar-Poli P, Kyriakopoulos M (2014) White matter alterations in early stages of schizophrenia: a systematic review of diffusion tensor imaging studies. J Neuroimaging 24:101–110CrossRefPubMedGoogle Scholar
  22. 22.
    Higgins JPT, Green S (2011) Cochrane handbook for systematic reviews of interventions version 5.1.0. Cochrane Collab. Available from
  23. 23.
    Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 6:e1000097. doi: 10.1371/journal.pmed.1000097 CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Bai YM, Chou KH, Lin CP, Chen IY, Li CT, Yang KC, Chou YH, Su TP (2009) White matter abnormalities in schizophrenia patients with tardive dyskinesia: a diffusion tensor image study. Schizophr Res 109:167–181CrossRefPubMedGoogle Scholar
  25. 25.
    Balevich EC, Haznedar MM, Wang E, Newmark RE, Bloom R, Schneiderman JS, Aronowitz J, Tang CY, Chu KW, Byne W, Buchsbaum MS, Hazlett EA (2015) Corpus callosum size and diffusion tensor anisotropy in adolescents and adults with schizophrenia. Psychiatry Res 231:244–251CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Buchy L, Luck D, Czechowska Y, Malla A, Joober R, Lepage M (2012) Diffusion tensor imaging tractography of the fornix and belief confidence in first-episode psychosis. Schizophr Res 137:80–84CrossRefPubMedGoogle Scholar
  27. 27.
    Caprihan A, Jones T, Chen H, Lemke N, Abbott C, Qualls C, Canive J, Gasparovic C, Bustillo JR (2015) The paradoxical relationship between white matter, psychopathology and cognition in schizophrenia: a diffusion tensor and proton spectroscopic imaging study. Neuropsychopharmacology 40:2248–2257CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Chan WY, Yang GL, Chia MY, Lau IY, Sitoh YY, Nowinski WL, Sim K (2010) White matter abnormalities in first-episode schizophrenia: a combined structural MRI and DTI study. Schizophr Res 119:52–60CrossRefPubMedGoogle Scholar
  29. 29.
    Chiappelli J, Hong LE, Wijtenburg SA, Du X, Gaston F, Kochunov P, Rowland LM (2015) Alterations in frontal white matter neurochemistry and microstructure in schizophrenia: implications for neuroinflammation. Transl Psychiatry 5:e548. doi: 10.1038/tp.2015.43 CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Choi H, Kubicki M, Whitford TJ, Alvarado JL, Terry DP, Niznikiewicz M, McCarley RW, Kwon JS, Shenton ME (2011) Diffusion tensor imaging of anterior commissural fibers in patients with schizophrenia. Schizophr Res 130:78–85CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Fitzsimmons J, Kubicki M, Smith K, Bushell G, Estepar RS, Westin CF, Nestor PG, Niznikiewicz MA, Kikinis R, McCarley RW, Shenton ME (2009) Diffusion tractography of the fornix in schizophrenia. Schizophr Res 107:39–46CrossRefPubMedGoogle Scholar
  32. 32.
    Friedman JI, Tang C, Carpenter D, Buchsbaum M, Schmeidler J, Flanagan L, Golembo S, Kanellopoulou I, Ng J, Hof PR, Harvey PD, Tsopelas ND, Stewart D, Davis KL (2008) Diffusion tensor imaging findings in first-episode and chronic schizophrenia patients. Am J Psychiatr 165:1024–1032CrossRefPubMedGoogle Scholar
  33. 33.
    Gu C, Zhang Y, Wei F, Cheng Y, Cao Y, Hou H (2016) Magnetic resonance imaging DTI-FT study on schizophrenic patients with typical negative first symptoms. Exp Ther Med 12:1450–1454PubMedPubMedCentralGoogle Scholar
  34. 34.
    Fujiwara H, Namiki C, Hirao K, Miyata J, Shimizu M, Fukuyama H, Sawamoto N, Hayashi T, Murai T (2007) Anterior and posterior cingulum abnormalities and their association with psychopathology in schizophrenia: a diffusion tensor imaging study. Schizophr Res 95:215–222CrossRefPubMedGoogle Scholar
  35. 35.
    Kawashima T, Nakamura M, Bouix S, Kubicki M, Salisbury DF, Westin CF, McCarley RW, Shenton ME (2009) Uncinate fasciculus abnormalities in recent onset schizophrenia and affective psychosis: a diffusion tensor imaging study. Schizophr Res 110:119–126CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Kumra S, Ashtari M, Cervellione KL, Henderson I, Kester H, Roofeh D, Wu J, Clarke T, Thaden E, Kane JM, Rhinewine J, Lencz T, Diamond A, Ardekani BA, Szeszko PR (2005) White matter abnormalities in early-onset schizophrenia: a voxel-based diffusion tensor imaging study. J Am Acad Child Adolesc Psychiatry 44:934–941CrossRefPubMedGoogle Scholar
  37. 37.
    Lee SH, Kubicki M, Asami T, Seidman LJ, Goldstein JM, Mesholam-Gately RI, McCarley RW, Shenton ME (2013) Extensive white matter abnormalities in patients with first-episode schizophrenia: a diffusion tensor imaging (DTI) study. Schizophr Res 143:231–238CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Leroux E, Delcroix N, Dollfus S (2015) Left-hemisphere lateralization for language and interhemispheric fiber tracking in patients with schizophrenia. Schizophr Res 165:30–37CrossRefPubMedGoogle Scholar
  39. 39.
    Levitt JJ, Kubicki M, Nestor PG, Ersner-Hershfield H, Westin CF, Alvarado JL, Kikinis R, Jolesz FA, McCarley RW, Shenton ME (2010) A diffusion tensor imaging study of the anterior limb of the internal capsule in schizophrenia. Psychiatry Res 184(3):143–150CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Levitt JJ, Alvarado JL, Nestor PG, Rosow L, Pelavin PE, McCarley RW, Kubicki M, Shenton ME Fractional anisotropy and radial diffusivity: diffusion measures of white matter abnormalities in the anterior limb of the internal capsule in schizophrenia. Schizophr Res 136:55–62Google Scholar
  41. 41.
    Liu X, Lai Y, Wang X, Hao C, Chen L, Zhou Z, Yu X, Hong N (2013) Reduced white matter integrity and cognitive deficit in never-medicated chronic schizophrenia: a diffusion tensor study using TBSS. Behav Brain Res 252:157–163CrossRefPubMedGoogle Scholar
  42. 42.
    Luck D, Buchy L, Czechowska Y, Bodnar M, Pike GB, Campbell JS, Achim A, Malla A, Joober R, Lepage M (2011) Fronto-temporal disconnectivity and clinical short-term outcome in first episode psychosis: a DTI-tractography study. J Psychiatry Res 45:369–377CrossRefGoogle Scholar
  43. 43.
    Okugawa G, Nobuhara K, Minami T, Takase K, Sugimoto T, Saito Y, Yoshimura M, Kinoshita T (2006) Neural disorganization in the superior cerebellar peduncle and cognitive abnormality in patients with schizophrenia: a diffusion tensor imaging study. Prog Neuro-Psychopharmacol Biol Psychiatry 30:1408–1412CrossRefGoogle Scholar
  44. 44.
    Ou J, Lyu H, Hu M, Li J, Guo W, Guo X, Li L, Zheng J, Wei Q, Liu F, He Z, Wang J, Liu F, Wu R, Chen J, Li L, Hu B, Chen H, Zhao J (2016) Decreased white matter FA values in the left inferior frontal gyrus is a possible intermediate phenotype of schizophrenia: evidences from a novel group strategy. Eur Arch Psychiatry Clin Neurosci. doi: 10.1007/s00406-016-0752-z
  45. 45.
    Ozcelik-Eroglu E, Ertugrul A, Oguz KK, Has AC, Karahan S, Yazici MK (2014) Effect of clozapine on white matter integrity in patients with schizophrenia: a diffusion tensor imaging study. Psychiatry Res 223:226–235CrossRefPubMedGoogle Scholar
  46. 46.
    Rametti G, Junqué C, Falcón C, Bargalló N, Catalán R, Penadés R, Garzón B, Bernardo M (2009) A voxel-based diffusion tensor imaging study of temporal white matter in patients with schizophrenia. Psychiatry Res 171:166–177CrossRefPubMedGoogle Scholar
  47. 47.
    Rosenberger G, Kubicki M, Nestor PG, Connor E, Bushell GB, Markant D, Niznikiewicz M, Westin CF, Kikinis R, Saykin AJ, McCarley RW, Shenton ME (2008) Age-related deficits in fronto-temporal connections in schizophrenia: a diffusion tensor imaging study. Schizophr Res 102:181–188CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Sim K, Yang GL, Loh D, Poon LY, Sitoh YY, Verma S, Keefe R, Collinson S, Chong SA, Heckers S, Nowinski W, Pantelis C (2009) White matter abnormalities and neurocognitive deficits associated with the passivity phenomenon in schizophrenia: a diffusion tensor imaging study. Psychiatry Res 172:121–127CrossRefPubMedGoogle Scholar
  49. 49.
    Singh S, Singh K, Trivedi R, Goyal S, Kaur P, Singh N, Bhatia T, Deshpande SN, Khushu S (2016) Microstructural abnormalities of uncinate fasciculus as a function of impaired cognition in schizophrenia: a DTI study. J Biosci 41:419–426CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Sun H, Lui S, Yao L, Deng W, Xiao Y, Zhang W, Huang X, Hu J, Bi F, Li T, Sweeney JA, Gong Q (2015) Two patterns of white matter abnormalities in medication-naive patients with first-episode schizophrenia revealed by diffusion tensor imaging and cluster analysis. JAMA Psychiatry 72:678–686CrossRefPubMedGoogle Scholar
  51. 51.
    Szeszko PR, Robinson DG, Ashtari M, Vogel J, Betensky J, Sevy S, Ardekani BA, Lencz T, Malhotra AK, McCormack J, Miller R, Lim KO, Gunduz-Bruce H, Kane JM, Bilder RM (2008) Clinical and neuropsychological correlates of white matter abnormalities in recent onset schizophrenia. Neuropsychopharmacology 33:976–984CrossRefPubMedGoogle Scholar
  52. 52.
    White T, Magnotta VA, Bockholt HJ, Williams S, Wallace S, Ehrlich S, Mueller BA, Ho BC, Jung RE, Clark VP, Lauriello J, Bustillo JR, Schulz SC, Gollub RL, Andreasen NC, Calhoun VD, Lim KO (2011) Global white matter abnormalities in schizophrenia: a multisite diffusion tensor imaging study. Schizophr Bull 37:222–232CrossRefPubMedGoogle Scholar
  53. 53.
    Whitford TJ, Lee SW, Oh JS, de Luis-Garcia R, Savadjiev P, Alvarado JL, Westin CF, Niznikiewicz M, Nestor PG, McCarley RW, Kubicki M, Shenton ME (2014) Localized abnormalities in the cingulum bundle in patients with schizophrenia: a diffusion tensor tractography study. Neuroimage Clin 5:93–99CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Wolkin A, Choi SJ, Szilagyi S, Sanfilipo M, Rotrosen JP, Lim KO (2003) Inferior frontal white matter anisotropy and negative symptoms of schizophrenia: a diffusion tensor imaging study. Am J Psychiatr 160:572–584CrossRefPubMedGoogle Scholar
  55. 55.
    Wu CH, Hwang TJ, Chen PJ, Chou TL, Hsu YC, Liu CM, Wang HL, Chen CM, Hua MS, Hwu HG, Tseng WY (2014) Reduced structural integrity and functional lateralization of the dorsal language pathway correlate with hallucinations in schizophrenia: a combined diffusion spectrum imaging and functional magnetic resonance imaging study. Psychiatry Res 224:303–310CrossRefPubMedGoogle Scholar
  56. 56.
    Zhang XY, Fan FM, Chen DC, Tan YL, Tan SP, Hu K, Salas R, Kosten TR, Zunta-Soares G, Soares JC (2016) Extensive white matter abnormalities and clinical symptoms in drug-naive patients with first-episode schizophrenia: a voxel-based diffusion tensor imaging study. J Clin Psychiatry 77:205–211CrossRefPubMedGoogle Scholar
  57. 57.
    Alexander AL, Lee JE, Lazar M, Field AS (2007) Diffusion tensor imaging of the brain. Neurotherapeutics 4:316–329CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Grieve SM, Williams LM, Paul RH, Clark CR, Gordon E (2007) Cognitive aging, executive function, and fractional anisotropy: a diffusion tensor MR imaging study. AJNR Am J Neuroradiol 28:226–235PubMedGoogle Scholar
  59. 59.
    Frodl T, Amico F (2014) Is there an association between peripheral immune markers and structural/functional neuroimaging findings? Prog Neuro-Psychopharmacol Biol Psychiatry 48:295–303CrossRefGoogle Scholar
  60. 60.
    Clemm von Hohenberg C, Pasternak O, Kubicki M, Ballinger T, Vu MA, Swisher T, Green K, Giwerc M, Dahlben B, Goldstein JM, Woo TU, Petryshen TL, Mesholam-Gately RI, Woodberry KA, Thermenos HW, Mulert C, McCarley RW, Seidman LJ, Shenton ME (2014) White matter microstructure in individuals at clinical high risk of psychosis: a whole-brain diffusion tensor imaging study. Schizophr Bull 40:895–903CrossRefGoogle Scholar
  61. 61.
    Prasad KM, Upton CH, Nimgaonkar VL, Keshavan MS (2015) Differential susceptibility of white matter tracts to inflammatory mediators in schizophrenia: an integrated DTI study. Schizophr Res 161:119–125CrossRefPubMedGoogle Scholar
  62. 62.
    Whitford TJ, Kubicki M, Schneiderman JS, O’Donnell LJ, King R, Alvarado JL, Khan U, Markant D, Nestor PG, Niznikiewicz M, McCarley RW, Westin CF, Shenton ME (2010) Corpus callosum abnormalities and their association with psychotic symptoms in patients with schizophrenia. Biol Psychiatry 68:70–77CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Meyer U, Schwarz MJ, Müller N (2011) Inflammatory processes in schizophrenia: a promising neuroimmunological target for the treatment of negative/cognitive symptoms and beyond. Pharmacol Ther 132:96–110CrossRefPubMedGoogle Scholar
  64. 64.
    Drexhage RC, Knijff EM, Padmos RC, Heul-Nieuwenhuijzen L, Beumer W, Versnel MA, Drexhage HA (2010) The mononuclear phagocyte system and its cytokine inflammatory networks in schizophrenia and bipolar disorder. Expert Rev Neurother 10:59–76CrossRefPubMedGoogle Scholar
  65. 65.
    Fujiwara H, Murai T (2007) Anterior and posterior cingulum abnormalities and their association with psychopathology in schizophrenia: a diffusion tensor imaging study. Schizophr Res 95:215–222CrossRefPubMedGoogle Scholar
  66. 66.
    Takei K, Yamasue H, Abe O, Yamada H, Inoue H, Suga M, Moroi M, Sasaki H, Aoki S, Kasai K (2009) Structural disruption of the dorsal cingulum bundle is associated with impaired Stroop performance in patients with schizophrenia. Schizophr Res 114:119–127CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Xu Yang
    • 1
    • 2
  • Ding Cao
    • 3
  • Xiumei Liang
    • 2
  • Jiannong Zhao
    • 1
  1. 1.Department of Medical Imaging, the Second Affiliated HospitalChongqing Medical UniversityChongqingChina
  2. 2.Department of Medical Imagingthe Fifth People’s Hospital of ChongqingChongqingChina
  3. 3.Department of Hepatobiliary Surgery, the Second Affiliated HospitalChongqing Medical UniversityChongqingChina

Personalised recommendations