Cortical abnormalities in adults and adolescents with major depression based on brain scans from 20 cohorts worldwide in the ENIGMA Major Depressive Disorder Working Group

doi:10.1038/mp.2016.60

Meta-Analysis

. 2017 Jun;22(6):900-909.

doi: 10.1038/mp.2016.60. Epub 2016 May 3.

Cortical abnormalities in adults and adolescents with major depression based on brain scans from 20 cohorts worldwide in the ENIGMA Major Depressive Disorder Working Group

L Schmaal¹, D P Hibar², P G Sämann³, G B Hall⁴, B T Baune⁵, N Jahanshad², J W Cheung², T G M van Erp⁶, D Bos^{7

8}, M A Ikram^{7

8

9}, M W Vernooij^{7

8}, W J Niessen^{7

10

11}, H Tiemeier^{8

12}, A Hofman⁸, K Wittfeld¹³, H J Grabe^{13

14}, D Janowitz¹⁴, R Bülow¹⁵, M Selonke¹⁴, H Völzke^{16

17

18}, D Grotegerd¹⁹, U Dannlowski^{19

20}, V Arolt¹⁹, N Opel¹⁹, W Heindel²¹, H Kugel²¹, D Hoehn³, M Czisch³, B Couvy-Duchesne^{22

23

24}, M E Rentería²⁴, L T Strike²², M J Wright^{22

23}, N T Mills^{22

24}, G I de Zubicaray²⁵, K L McMahon²³, S E Medland²⁴, N G Martin²⁴, N A Gillespie²⁶, R Goya-Maldonado²⁷, O Gruber²⁸, B Krämer²⁸, S N Hatton²⁹, J Lagopoulos²⁹, I B Hickie²⁹, T Frodl^{30

31}, A Carballedo³¹, E M Frey³², L S van Velzen¹, B W J H Penninx¹, M-J van Tol³³, N J van der Wee³⁴, C G Davey^{35

36

37}, B J Harrison³⁷, B Mwangi³⁸, B Cao³⁸, J C Soares³⁸, I M Veer³⁹, H Walter³⁹, D Schoepf⁴⁰, B Zurowski⁴¹, C Konrad^{20

42}, E Schramm⁴³, C Normann⁴³, K Schnell²⁸, M D Sacchet⁴⁴, I H Gotlib⁴⁴, G M MacQueen⁴⁵, B R Godlewska⁴⁶, T Nickson⁴⁷, A M McIntosh^{47

48}, M Papmeyer^{47

49}, H C Whalley⁴⁷, J Hall^{47

50}, J E Sussmann^{47

51}, M Li⁵², M Walter^{52

53}, L Aftanas⁵⁴, I Brack⁵⁴, N A Bokhan^{55

56

57}, P M Thompson², D J Veltman¹

Affiliations

¹ Department of Psychiatry and Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
² Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine of USC, Marina del Rey, CA, USA.
³ Neuroimaging Core Unit, Max Planck Institute of Psychiatry, Munich, Germany.
⁴ Department of Psychology, Neuroscience and Behaviour, McMaster University, Hamilton, ON, Canada.
⁵ Discipline of Psychiatry, University of Adelaide, Adelaide, SA, Australia.
⁶ Department of Psychiatry and Human Behavior, University of California, Irvine, CA, USA.
⁷ Department of Radiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
⁸ Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
⁹ Department of Neurology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
¹⁰ Department of Medical Informatics, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
¹¹ Faculty of Applied Sciences, Delft University of Technology, Delft, The Netherlands.
¹² Department of Child and Adolescent Psychiatry, Erasmus University Medical Center-Sophia Children's Hospital, Rotterdam, The Netherlands.
¹³ German Center for Neurodegenerative Diseases (DZNE), Site Rostock/Greifswald, Germany.
¹⁴ Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany.
¹⁵ Institute for Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Greifswald, Germany.
¹⁶ Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
¹⁷ German Center for Cardiovascular Research (DZHK), partner site Griefswald, Greifswald, Germany.
¹⁸ German Center for Diabetes Research (DZD), partner site Griefswald, Greifswald, Germany.
¹⁹ Department of Psychiatry, University of Muenster, Muenster, Germany.
²⁰ Department of Psychiatry, University of Marburg, Marburg, Germany.
²¹ Department of Clinical Radiology, University of Muenster, Muenster, Germany.
²² Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.
²³ Center for Advanced Imaging, The University of Queensland, Brisbane, QLD, Australia.
²⁴ Queensland Institute of Medical Research Berghofer, Brisbane, QLD, Australia.
²⁵ Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD, Australia.
²⁶ Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Richmond, VA, USA.
²⁷ Centre for Translational Research in Systems Neuroscience and Psychiatry, Department of Psychiatry and Psychotherapy, University Medical Center (UMG), Georg-August-University, Göttingen, Germany.
²⁸ Section for Experimental Psychopathology and Neuroimaging, Department of General Psychiatry, Heidelberg University Hospital, Heidelberg, Germany.
²⁹ Clinical Research Unit, Brain and Mind Centre, University of Sydney, Camperdown, NSW, Australia.
³⁰ Department of Psychiatry and Psychotherapy, Otto von Guericke University, Magdeburg, Germany.
³¹ Department of Psychiatry and Institute of Neuroscience, Trinity College, Dublin, Ireland.
³² Department of Psychiatry and Psychotherapy, University of Regensburg, Regensburg, Germany.
³³ Neuroimaging Center, Section of Cognitive Neuropsychiatry, Department of Neuroscience, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
³⁴ Department of Psychiatry and Leiden Institute for Brain and Cognition, Leiden University Medical Center, Leiden, The Netherlands.
³⁵ Orygen, The National Centre of Excellence in Youth Mental Health, Melbourne, VIC, Australia.
³⁶ Centre for Youth Mental Health, The University of Melbourne, Melbourne, VIC, Australia.
³⁷ Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne, Melbourne, VIC, Australia.
³⁸ UT Center of Excellence on Mood Disoders, Department of Psychiatry and Behavioral Sciences, University of Texas Health Science Center at Houston, Houston, TX, USA.
³⁹ Department of Psychiatry and Psychotherapy, Charité Universitätsmedizin Berlin, Berlin, Germany.
⁴⁰ Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany.
⁴¹ Center for Integrative Psychiatry, University of Lübeck, Lübeck, Germany.
⁴² Department of Psychiatry and Psychotherapy, Agaplesion Diakonieklinikum Rotenburg, Rotenburg, Germany.
⁴³ Department of Psychiatry and Psychotherapy, University Medical Center Freiburg, Freiburg, Germany.
⁴⁴ Neurosciences Program and Department of Psychology, Stanford University, Stanford, CA, USA.
⁴⁵ Department of Psychiatry, University of Calgary, Calgary, AB, Canada.
⁴⁶ University Department of Psychiatry, Warneford Hospital, Oxford, UK.
⁴⁷ Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, UK.
⁴⁸ Centre for Cogntive Ageing and Cogntive Epidemiology, University of Edinburgh, Edinburg, UK.
⁴⁹ Division of Systems Neuroscience of Psychopathology, Translational Research Center, University Hospital of Psychiatry, University of Bern, Bern, Switzerland.
⁵⁰ Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, UK.
⁵¹ Department of Psychiatry, NHS Borders, Melrose, UK.
⁵² Leibniz Institute for Neurobiology, Magdeburg, Germany.
⁵³ Department of Psychiatry, University Tübingen, Tübingen, Germany.
⁵⁴ Department of Experimental and Clinical Neuroscience, Scientific Research Institute of Physiology and Basic Medicine, Novosibirsk, Russia.
⁵⁵ Mental Health Research Institute, Tomsk, Russia.
⁵⁶ Faculty of Psychology, National Research Tomsk State University, Tomsk, Russia.
⁵⁷ Department of General Medicine, Siberian State Medical University, Tomsk, Russia.

PMID: 27137745
PMCID: PMC5444023
DOI: 10.1038/mp.2016.60

Meta-Analysis

Cortical abnormalities in adults and adolescents with major depression based on brain scans from 20 cohorts worldwide in the ENIGMA Major Depressive Disorder Working Group

L Schmaal et al. Mol Psychiatry. 2017 Jun.

. 2017 Jun;22(6):900-909.

doi: 10.1038/mp.2016.60. Epub 2016 May 3.

Authors

Affiliations

¹ Department of Psychiatry and Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
² Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine of USC, Marina del Rey, CA, USA.
³ Neuroimaging Core Unit, Max Planck Institute of Psychiatry, Munich, Germany.
⁴ Department of Psychology, Neuroscience and Behaviour, McMaster University, Hamilton, ON, Canada.
⁵ Discipline of Psychiatry, University of Adelaide, Adelaide, SA, Australia.
⁶ Department of Psychiatry and Human Behavior, University of California, Irvine, CA, USA.
⁷ Department of Radiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
⁸ Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
⁹ Department of Neurology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
¹⁰ Department of Medical Informatics, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
¹¹ Faculty of Applied Sciences, Delft University of Technology, Delft, The Netherlands.
¹² Department of Child and Adolescent Psychiatry, Erasmus University Medical Center-Sophia Children's Hospital, Rotterdam, The Netherlands.
¹³ German Center for Neurodegenerative Diseases (DZNE), Site Rostock/Greifswald, Germany.
¹⁴ Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany.
¹⁵ Institute for Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Greifswald, Germany.
¹⁶ Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
¹⁷ German Center for Cardiovascular Research (DZHK), partner site Griefswald, Greifswald, Germany.
¹⁸ German Center for Diabetes Research (DZD), partner site Griefswald, Greifswald, Germany.
¹⁹ Department of Psychiatry, University of Muenster, Muenster, Germany.
²⁰ Department of Psychiatry, University of Marburg, Marburg, Germany.
²¹ Department of Clinical Radiology, University of Muenster, Muenster, Germany.
²² Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.
²³ Center for Advanced Imaging, The University of Queensland, Brisbane, QLD, Australia.
²⁴ Queensland Institute of Medical Research Berghofer, Brisbane, QLD, Australia.
²⁵ Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD, Australia.
²⁶ Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Richmond, VA, USA.
²⁷ Centre for Translational Research in Systems Neuroscience and Psychiatry, Department of Psychiatry and Psychotherapy, University Medical Center (UMG), Georg-August-University, Göttingen, Germany.
²⁸ Section for Experimental Psychopathology and Neuroimaging, Department of General Psychiatry, Heidelberg University Hospital, Heidelberg, Germany.
²⁹ Clinical Research Unit, Brain and Mind Centre, University of Sydney, Camperdown, NSW, Australia.
³⁰ Department of Psychiatry and Psychotherapy, Otto von Guericke University, Magdeburg, Germany.
³¹ Department of Psychiatry and Institute of Neuroscience, Trinity College, Dublin, Ireland.
³² Department of Psychiatry and Psychotherapy, University of Regensburg, Regensburg, Germany.
³³ Neuroimaging Center, Section of Cognitive Neuropsychiatry, Department of Neuroscience, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
³⁴ Department of Psychiatry and Leiden Institute for Brain and Cognition, Leiden University Medical Center, Leiden, The Netherlands.
³⁵ Orygen, The National Centre of Excellence in Youth Mental Health, Melbourne, VIC, Australia.
³⁶ Centre for Youth Mental Health, The University of Melbourne, Melbourne, VIC, Australia.
³⁷ Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne, Melbourne, VIC, Australia.
³⁸ UT Center of Excellence on Mood Disoders, Department of Psychiatry and Behavioral Sciences, University of Texas Health Science Center at Houston, Houston, TX, USA.
³⁹ Department of Psychiatry and Psychotherapy, Charité Universitätsmedizin Berlin, Berlin, Germany.
⁴⁰ Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany.
⁴¹ Center for Integrative Psychiatry, University of Lübeck, Lübeck, Germany.
⁴² Department of Psychiatry and Psychotherapy, Agaplesion Diakonieklinikum Rotenburg, Rotenburg, Germany.
⁴³ Department of Psychiatry and Psychotherapy, University Medical Center Freiburg, Freiburg, Germany.
⁴⁴ Neurosciences Program and Department of Psychology, Stanford University, Stanford, CA, USA.
⁴⁵ Department of Psychiatry, University of Calgary, Calgary, AB, Canada.
⁴⁶ University Department of Psychiatry, Warneford Hospital, Oxford, UK.
⁴⁷ Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, UK.
⁴⁸ Centre for Cogntive Ageing and Cogntive Epidemiology, University of Edinburgh, Edinburg, UK.
⁴⁹ Division of Systems Neuroscience of Psychopathology, Translational Research Center, University Hospital of Psychiatry, University of Bern, Bern, Switzerland.
⁵⁰ Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, UK.
⁵¹ Department of Psychiatry, NHS Borders, Melrose, UK.
⁵² Leibniz Institute for Neurobiology, Magdeburg, Germany.
⁵³ Department of Psychiatry, University Tübingen, Tübingen, Germany.
⁵⁴ Department of Experimental and Clinical Neuroscience, Scientific Research Institute of Physiology and Basic Medicine, Novosibirsk, Russia.
⁵⁵ Mental Health Research Institute, Tomsk, Russia.
⁵⁶ Faculty of Psychology, National Research Tomsk State University, Tomsk, Russia.
⁵⁷ Department of General Medicine, Siberian State Medical University, Tomsk, Russia.

PMID: 27137745
PMCID: PMC5444023
DOI: 10.1038/mp.2016.60

Abstract

The neuro-anatomical substrates of major depressive disorder (MDD) are still not well understood, despite many neuroimaging studies over the past few decades. Here we present the largest ever worldwide study by the ENIGMA (Enhancing Neuro Imaging Genetics through Meta-Analysis) Major Depressive Disorder Working Group on cortical structural alterations in MDD. Structural T1-weighted brain magnetic resonance imaging (MRI) scans from 2148 MDD patients and 7957 healthy controls were analysed with harmonized protocols at 20 sites around the world. To detect consistent effects of MDD and its modulators on cortical thickness and surface area estimates derived from MRI, statistical effects from sites were meta-analysed separately for adults and adolescents. Adults with MDD had thinner cortical gray matter than controls in the orbitofrontal cortex (OFC), anterior and posterior cingulate, insula and temporal lobes (Cohen's d effect sizes: -0.10 to -0.14). These effects were most pronounced in first episode and adult-onset patients (>21 years). Compared to matched controls, adolescents with MDD had lower total surface area (but no differences in cortical thickness) and regional reductions in frontal regions (medial OFC and superior frontal gyrus) and primary and higher-order visual, somatosensory and motor areas (d: -0.26 to -0.57). The strongest effects were found in recurrent adolescent patients. This highly powered global effort to identify consistent brain abnormalities showed widespread cortical alterations in MDD patients as compared to controls and suggests that MDD may impact brain structure in a highly dynamic way, with different patterns of alterations at different stages of life.

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Conflict of interest statement

The authors declare no conflict of interest. Jair Soares has participated in research funded by Forest, Merck, BMS, GSK and has been a speaker for Pfizer and Abbott. Andrew McIntosh has received support from Lilly, Janssen, Pfizer and Saccade Diagnostics. Carsten Konrad received fees for an educational program from Aristo Pharma, Janssen-Cilag, Lilly, MagVenture, Servier, and Trommsdorff as well as travel support and speakers honoraria from Janssen, Lundbeck and Servier. Theo G.M. van Erp has consulted for Roche Pharmaceuticals Ltd., and has a contract with Otsuka Phamaceutical Co., Ltd (OPCJ). Knut Schnell has consulted for Roche Pharmaceuticals and Servier Pharmaceuticals. Henrik Walter has received a speaker honorarium from Servier, 9987.

Figures

**Figure 1**
Meta-analysis effect sizes for regions with a significant (P_FDR<0.05) cortical thinning in adult major depressive disorder (MDD) patients compared to healthy controls. Negative effect sizes d indicate cortical thinning in MDD compared to controls.

**Figure 2**
Meta-analysed effect sizes for regions with a significant (P_FDR<0.05) decrease in cortical surface area in adolescent major depressive disorder (MDD) patients compared to healthy controls. Negative effect sizes d indicate lower cortical surface area in MDD compared to controls.

See this image and copyright information in PMC

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References

1. World Health Organization. Depression: a global public health concern, 2012. Available at: http://www.who.int/mental_health/management/depression/who_paper_depress... (accessed 2 October 2015).
1. Schmaal L, Veltman DJ, van Erp TGM, Sämann PG, Frodl T, Jahanshad N et al. Subcortical brain alterations in major depressive disorder: findings from the ENIGMA Major Depressive Disorder Working Group. Mol Psychiatry; e-pub ahead of print 30 June 2015; doi:10.1038/mp.2015.69. - PMC - PubMed
1. Kempton MJ. Structural neuroimaging studies in major depressive disorder. Arch Gen Psychiatry 2011; 68: 675–690. - PubMed
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1. Lai C. Gray matter volume in major depressive disorder: a meta-analysis of voxel-based morphometry studies. Psychiatry Res 2013; 211: 37–46. - PubMed

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[1] World Health Organization. Depression: a global public health concern, 2012. Available at: http://www.who.int/mental_health/management/depression/who_paper_depress... (accessed 2 October 2015).

[2] World Health Organization. Depression: a global public health concern, 2012. Available at: http://www.who.int/mental_health/management/depression/who_paper_depress... (accessed 2 October 2015).

[3] Schmaal L, Veltman DJ, van Erp TGM, Sämann PG, Frodl T, Jahanshad N et al. Subcortical brain alterations in major depressive disorder: findings from the ENIGMA Major Depressive Disorder Working Group. Mol Psychiatry; e-pub ahead of print 30 June 2015; doi:10.1038/mp.2015.69. - PMC - PubMed

[4] Schmaal L, Veltman DJ, van Erp TGM, Sämann PG, Frodl T, Jahanshad N et al. Subcortical brain alterations in major depressive disorder: findings from the ENIGMA Major Depressive Disorder Working Group. Mol Psychiatry; e-pub ahead of print 30 June 2015; doi:10.1038/mp.2015.69. - PMC - PubMed

[5] Kempton MJ. Structural neuroimaging studies in major depressive disorder. Arch Gen Psychiatry 2011; 68: 675–690. - PubMed

[6] Kempton MJ. Structural neuroimaging studies in major depressive disorder. Arch Gen Psychiatry 2011; 68: 675–690. - PubMed

[7] Bora E, Fornito A, Pantelis C, Yücel M. Gray matter abnormalities in major depressive disorder: a meta-analysis of voxel based morphometry studies. J Affect Disord 2012; 138: 9–18. - PubMed

[8] Bora E, Fornito A, Pantelis C, Yücel M. Gray matter abnormalities in major depressive disorder: a meta-analysis of voxel based morphometry studies. J Affect Disord 2012; 138: 9–18. - PubMed

[9] Lai C. Gray matter volume in major depressive disorder: a meta-analysis of voxel-based morphometry studies. Psychiatry Res 2013; 211: 37–46. - PubMed

[10] Lai C. Gray matter volume in major depressive disorder: a meta-analysis of voxel-based morphometry studies. Psychiatry Res 2013; 211: 37–46. - PubMed

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Cortical abnormalities in adults and adolescents with major depression based on brain scans from 20 cohorts worldwide in the ENIGMA Major Depressive Disorder Working Group

Affiliations

Cortical abnormalities in adults and adolescents with major depression based on brain scans from 20 cohorts worldwide in the ENIGMA Major Depressive Disorder Working Group

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Abstract

Conflict of interest statement

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