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. 2018 May;23(5):1261-1269.
doi: 10.1038/mp.2017.170. Epub 2017 Oct 17.

Widespread White Matter Microstructural Differences in Schizophrenia Across 4322 Individuals: Results From the ENIGMA Schizophrenia DTI Working Group

S Kelly  1   2 N Jahanshad  1 A Zalesky  3 P Kochunov  4 I Agartz  5   6   7 C Alloza  8 O A Andreassen  9 C Arango  10 N Banaj  11 S Bouix  12 C A Bousman  3   13   14   15 R M Brouwer  16 J Bruggemann  17 J Bustillo  18 W Cahn  16 V Calhoun  19   20 D Cannon  21 V Carr  17 S Catts  22 J Chen  23 J-X Chen  24 X Chen  25 C Chiapponi  26 Kl K Cho  27 V Ciullo  11 A S Corvin  28 B Crespo-Facorro  29   30 V Cropley  3 P De Rossi  11   31   32 C M Diaz-Caneja  10 E W Dickie  33 S Ehrlich  34 F-M Fan  24 J Faskowitz  1 H Fatouros-Bergman  6 L Flyckt  35   36 J M Ford  37 J-P Fouche  38 M Fukunaga  39 M Gill  28 D C Glahn  40 R Gollub  2   41 E D Goudzwaard  42 H Guo  43 R E Gur  44 R C Gur  44 T P Gurholt  5 R Hashimoto  45   46 S N Hatton  47 F A Henskens  48   49   50 D P Hibar  1 I B Hickie  47 L E Hong  4 J Horacek  51   52 F M Howells  38 H E Hulshoff Pol  16 C L Hyde  25 D Isaev  1 A Jablensky  53 P R Jansen  54 J Janssen  16   10 E G Jönsson  5   6 L A Jung  55 R S Kahn  16 Z Kikinis  12 K Liu  3 P Klauser  3   56   57 C Knöchel  55 M Kubicki  58 J Lagopoulos  59 C Langen  54 S Lawrie  8 R K Lenroot  17 K O Lim  60 C Lopez-Jaramillo  61 A Lyall  12   62 V Magnotta  63 R C W Mandl  16 D H Mathalon  37 R W McCarley  64 S McCarthy-Jones  65 C McDonald  21 S McEwen  66 A McIntosh  8 T Melicher  67   52 R I Mesholam-Gately  68 P T Michie  69   70   50 B Mowry  71 B A Mueller  60 D T Newell  12 P O'Donnell  25 V Oertel-Knöchel  55 L Oestreich  71 S A Paciga  25 C Pantelis  3   13   72   70 O Pasternak  58 G Pearlson  40 G R Pellicano  11 A Pereira  73 J Pineda Zapata  74 F Piras  11   75 S G Potkin  42 A Preda  42 P E Rasser  50   76 D R Roalf  44 R Roiz  29   30 A Roos  77 D Rotenberg  33 T D Satterthwaite  44 P Savadjiev  58 U Schall  50   76 R J Scott  50   75 M L Seal  78 L J Seidman  2   62   68 C Shannon Weickert  70   79   80 C D Whelan  1 M E Shenton  58   81 J S Kwon  27 G Spalletta  11   82 F Spaniel  51   52 E Sprooten  40 M Stäblein  55 D J Stein  38   83 S Sundram  13   84 Y Tan  24 S Tan  24 S Tang  85 H S Temmingh  38 L T Westlye  5   86 S Tønnesen  5 D Tordesillas-Gutierrez  30   87 N T Doan  5 J Vaidya  88 N E M van Haren  16 C D Vargas  89 D Vecchio  11 D Velakoulis  90 A Voineskos  91 J Q Voyvodic  16 Z Wang  24 P Wan  43 D Wei  92 T W Weickert  70   79   80 H Whalley  8 T White  54 T J Whitford  35 J D Wojcik  68 H Xiang  85 Z Xie  25 H Yamamori  46 F Yang  24 N Yao  93 G Zhang  94 J Zhao  21   95 T G M van Erp  42 J Turner  96 P M Thompson  1 G Donohoe  21
Free PMC article

Widespread White Matter Microstructural Differences in Schizophrenia Across 4322 Individuals: Results From the ENIGMA Schizophrenia DTI Working Group

S Kelly et al. Mol Psychiatry. .
Free PMC article


The regional distribution of white matter (WM) abnormalities in schizophrenia remains poorly understood, and reported disease effects on the brain vary widely between studies. In an effort to identify commonalities across studies, we perform what we believe is the first ever large-scale coordinated study of WM microstructural differences in schizophrenia. Our analysis consisted of 2359 healthy controls and 1963 schizophrenia patients from 29 independent international studies; we harmonized the processing and statistical analyses of diffusion tensor imaging (DTI) data across sites and meta-analyzed effects across studies. Significant reductions in fractional anisotropy (FA) in schizophrenia patients were widespread, and detected in 20 of 25 regions of interest within a WM skeleton representing all major WM fasciculi. Effect sizes varied by region, peaking at (d=0.42) for the entire WM skeleton, driven more by peripheral areas as opposed to the core WM where regions of interest were defined. The anterior corona radiata (d=0.40) and corpus callosum (d=0.39), specifically its body (d=0.39) and genu (d=0.37), showed greatest effects. Significant decreases, to lesser degrees, were observed in almost all regions analyzed. Larger effect sizes were observed for FA than diffusivity measures; significantly higher mean and radial diffusivity was observed for schizophrenia patients compared with controls. No significant effects of age at onset of schizophrenia or medication dosage were detected. As the largest coordinated analysis of WM differences in a psychiatric disorder to date, the present study provides a robust profile of widespread WM abnormalities in schizophrenia patients worldwide. Interactive three-dimensional visualization of the results is available at

Conflict of interest statement

CSW is on an advisory board for Lundbeck, Australia Pty Ltd and in collaboration with Astellas Pharma Inc., Japan (no conflict of interest). The remaining authors declare no conflict of interest.


Figure 1
Figure 1
(a) Fractional anisotropy (FA) differences between schizophrenia patients and healthy controls for 25 white matter (WM) regions representing major fasciculi. Gradient bar indicates Cohen’s d effect sizes after meta-analysis. (b) Cohen’s d effect sizes after meta-analysis, sorted in increasing magnitude of Cohen’s d effect sizes across 29 cohorts for FA differences in schizophrenia patients (N=1963) versus healthy controls (N=2359), after including age, sex, age × sex, age2 and age2 × sex as covariates. Error bars represent 95% confidence intervals. Significant regions after adjusting for multiple regions tested (P<0.05/25=0.002) are highlighted in orange. (c) Forest plot of effect sizes for 29 cohorts. Interactive three-dimensional (3D) visualization of the results is available at
Figure 2
Figure 2
(a) Cohen’s d effect sizes, after meta-analysis, for fractional anisotropy (FA), mean diffusivity (MD) and radial diffusivity (RD) differences in schizophrenia patients versus healthy controls, after including age, sex, age × sex, age2 and age2 × sex as covariates for the top four regions of interest (ROIs) showing the largest FA effects (average FA, body of corpus callosum (BCC), corpus callosum (CC), anterior corona radiata (ACR) and genu of corpus callosum (GCC)). Error bars represent the 95% confidence intervals. The corpus callosum, ACR and FA across the whole brain are among the measures that show most robust effects in cohorts worldwide. (b) Relationship between FA and diffusivity (mean, axial and radial) Cohen’s d effect sizes after meta-analysis for differences between schizophrenia patients and healthy controls. The effect of RD is highly correlated, whereas axial diffusivity (AD) shows no correlation and low effect sizes.

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