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      Subcortical brain alterations in major depressive disorder: findings from the ENIGMA Major Depressive Disorder working group

      research-article
      1 , * , 1 , 2 , 3 , 4 , 5 , 6 , 7 , 7 , 8 , 7 , 9 , 10 , 7 , 9 , 7 , 9 , 11 , 12 , 12 , 13 , 14 , 13 , 15 , 16 , 3 , 3 , 17 , 17 , 17 , 18 , 18 , 18 , 19 , 20 , 21 , 22 , 19 , 20 , 21 , 22 , 23 ,   20 , 21 , 24 , 22 , 25 , 19 , 26 , 27 , 4 , 28 , 1 , 29 , 30 , 31 , 32 , 32 , 33 , 34 , 34 , 35 , 36 , 37 , 38 , 38 , 39 , 38 , 38 , 38 , 40 , 40 , 41 , 42 , 41 , 43 , 1 , 6 , 6
      Molecular Psychiatry
      Nature Publishing Group

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          Abstract

          The pattern of structural brain alterations associated with major depressive disorder (MDD) remains unresolved. This is in part due to small sample sizes of neuroimaging studies resulting in limited statistical power, disease heterogeneity and the complex interactions between clinical characteristics and brain morphology. To address this, we meta-analyzed three-dimensional brain magnetic resonance imaging data from 1728 MDD patients and 7199 controls from 15 research samples worldwide, to identify subcortical brain volumes that robustly discriminate MDD patients from healthy controls. Relative to controls, patients had significantly lower hippocampal volumes (Cohen's d=−0.14, % difference=−1.24). This effect was driven by patients with recurrent MDD (Cohen's d=−0.17, % difference=−1.44), and we detected no differences between first episode patients and controls. Age of onset ⩽21 was associated with a smaller hippocampus (Cohen's d=−0.20, % difference=−1.85) and a trend toward smaller amygdala (Cohen's d=−0.11, % difference=−1.23) and larger lateral ventricles (Cohen's d=0.12, % difference=5.11). Symptom severity at study inclusion was not associated with any regional brain volumes. Sample characteristics such as mean age, proportion of antidepressant users and proportion of remitted patients, and methodological characteristics did not significantly moderate alterations in brain volumes in MDD. Samples with a higher proportion of antipsychotic medication users showed larger caudate volumes in MDD patients compared with controls. This currently largest worldwide effort to identify subcortical brain alterations showed robust smaller hippocampal volumes in MDD patients, moderated by age of onset and first episode versus recurrent episode status.

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          Most cited references29

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          The role of the hippocampus in the pathophysiology of major depression.

          Converging lines of research suggest that the hippocampal complex (HC) may have a role in the pathophysiology of major depressive disorder (MDD). Although postmortem studies show little cellular death in the HC of depressed patients, animal studies suggest that elevated glucocorticoid levels associated with MDD may negatively affect neurogenesis, cause excitotoxic damage or be associated with reduced levels of key neurotrophins in the HC. Antidepressant medications may counter these effects, having been shown to increase HC neurogenesis and levels of brain-derived neurotrophic factor in animal studies. Neuropsychological studies have identified deficits in hippocampus-dependent recollection memory that may not abate with euthymia, and such memory impairment has been the most reliably documented cognitive abnormality in patients with MDD. Finally, data from imaging studies suggest both structural changes in the volume of the HC and functional alterations in frontotemporal and limbic circuits that may be critical for mood regulation. The extent to which such functional and structural changes determine clinical outcome in MDD remains unknown; a related, but also currently unanswered, question is whether the changes in HC function and structure observed in MDD are preventable or modifiable with effective treatment for the depressive illness.
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            A comparison of automated segmentation and manual tracing for quantifying hippocampal and amygdala volumes.

            Large databases of high-resolution structural MR images are being assembled to quantitatively examine the relationships between brain anatomy, disease progression, treatment regimens, and genetic influences upon brain structure. Quantifying brain structures in such large databases cannot be practically accomplished by expert neuroanatomists using hand-tracing. Rather, this research will depend upon automated methods that reliably and accurately segment and quantify dozens of brain regions. At present, there is little guidance available to help clinical research groups in choosing such tools. Thus, our goal was to compare the performance of two popular and fully automated tools, FSL/FIRST and FreeSurfer, to expert hand tracing in the measurement of the hippocampus and amygdala. Volumes derived from each automated measurement were compared to hand tracing for percent volume overlap, percent volume difference, across-sample correlation, and 3-D group-level shape analysis. In addition, sample size estimates for conducting between-group studies were computed for a range of effect sizes. Compared to hand tracing, hippocampal measurements with FreeSurfer exhibited greater volume overlap, smaller volume difference, and higher correlation than FIRST, and sample size estimates with FreeSurfer were closer to hand tracing. Amygdala measurement with FreeSurfer was also more highly correlated to hand tracing than FIRST, but exhibited a greater volume difference than FIRST. Both techniques had comparable volume overlap and similar sample size estimates. Compared to hand tracing, a 3-D shape analysis of the hippocampus showed FreeSurfer was more accurate than FIRST, particularly in the head and tail. However, FIRST more accurately represented the amygdala shape than FreeSurfer, which inflated its anterior and posterior surfaces.
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              Structural brain abnormalities in major depressive disorder: a selective review of recent MRI studies.

              While there is evidence to suggest that major depressive disorder (MDD) is associated with structural brain abnormalities, the precise nature of these abnormalities remains unclear. To review recent structural magnetic resonance imaging (MRI) research findings in MDD while considering the potential influence of key clinical and demographic variables. A selective review of all T1-weighted structural MRI studies published between 2000 and 2007 in adult samples of MDD patients. Volumetric reductions of the hippocampus, basal ganglia and OFC and SGPFC are consistently found in MDD patients, with more persistent forms of MDD (e.g., multiple episodes or repeated relapses, longer illness duration) being associated with greater impact on regional brain volumes. Gender, medication, stage of illness, and family history all affect the nature of the findings in a regionally specific manner. Overall, differences between the samples in factors such as illness severity, medication, gender and family history of mental illness makes difficult to identify their confounding effects on the observed neuroanatomical changes. Also, the tracing protocols used for particular brain regions were different amongst the reviewed studies, making difficult to compare their findings. The data support the notion that MDD involves pathological alterations of limbic and cortical structures, and that they are generally more apparent in patients with more severe or persistent forms of the illness.
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                Author and article information

                Journal
                Mol Psychiatry
                Mol. Psychiatry
                Molecular Psychiatry
                Nature Publishing Group
                1359-4184
                1476-5578
                June 2016
                30 June 2015
                : 21
                : 6
                : 806-812
                Affiliations
                [1 ]Department of Psychiatry and Neuroscience Campus Amsterdam, VU University Medical Center , Amsterdam, The Netherlands
                [2 ]Department of Psychiatry and Human Behavior, University of California , Irvine, CA, USA
                [3 ]Max Planck Institute of Psychiatry , Munich, Germany
                [4 ]Department of Psychiatry, University of Regensburg , Regensburg, Germany
                [5 ]Department of Psychiatry, University of Dublin, Trinity College , Dublin, Ireland
                [6 ]Imaging Genetics Center, Department of Neurology, Keck School of Medicine, University of Southern California , Marina del Rey, CA, USA
                [7 ]Department of Epidemiology, Erasmus MC University Medical Center , Rotterdam, The Netherlands
                [8 ]Department of Psychiatry, Erasmus MC University Medical Center , Rotterdam, The Netherlands
                [9 ]Departments of Radiology and Medical Informatics, Erasmus MC University Medical Center , Rotterdam, The Netherlands
                [10 ]Imaging Science and Technology, Faculty of Applied Sciences, Delft University of Technology , Delft, The Netherlands
                [11 ]Department of Neurology, Erasmus MC University Medical Center , Rotterdam, The Netherlands
                [12 ]German Center for Neurodegenerative Diseases (DZNE) , Rostock/Greifswald, Germany
                [13 ]Department of Psychiatry and Psychotherapy, University Medicine Greifswald , Greifswald, Germany
                [14 ]Helios Hospital Stralsund , Stralsund, Germany
                [15 ]Institute of Diagnostic Radiology and Neuroradiology, University Medicine Greifswald , Greifswald, Germany
                [16 ]Institute for Community Medicine, University Medicine Greifswald , Greifswald, Germany
                [17 ]Clinical Research Unit, Brain and Mind Research Institute, University of Sydney , Camperdown, Australia
                [18 ]Center for Translational Research in Systems Neuroscience and Psychiatry, Department of Psychiatry and Psychotherapy, University Medical Center , Goettingen, Germany
                [19 ]NeuroImaging Genetics, QIMR Berghofer Medical Research Institute , Brisbane, QLD, Australia
                [20 ]School of Psychology, University of Queensland , Brisbane, QLD, Australia
                [21 ]Center for Advanced Imaging, University of Queensland , Brisbane, QLD, Australia
                [22 ]Genetic Epidemiology, QIMR Berghofer Medical Research Institute , Brisbane, QLD, Australia
                [23 ]Queensland Brain Institute, University of Queensland , Brisbane, QLD, Australia
                [24 ]Quantitative Genetics, QIMR Berghofer Medical Research Institute , Brisbane, QLD, Australia
                [25 ]Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University , Richmond, VA, USA
                [26 ]Department of Psychology, Neuroscience and Behaviour, McMaster University , Hamilton, ON, Canada
                [27 ]Department of Psychiatry, Mathison Centre for Mental Health Research and Education, Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary , Calgary, AB, Canada
                [28 ]Department of Psychiatry and Institute of Neuroscience, University of Dublin, Trinity College Dublin , Dublin, Ireland
                [29 ]University of Groningen, University Medical Center Groningen, NeuroImaging Center , Groningen, The Netherlands
                [30 ]Department of Psychiatry, Leiden University Medical Center, Leiden University , Leiden, The Netherlands
                [31 ]Leiden Institute for Brain and Cognition , Leiden, The Netherlands
                [32 ]Department of Psychiatry and Psychotherapy, Division of Mind and Brain Research, Charité Universitätsmedizin Berlin , Berlin, Germany
                [33 ]Department of General Psychiatry, University Hospital Heidelberg , Heidelberg, Germany
                [34 ]Department of Psychiatry and Psychotherapy, University Medical Center Freiburg , Freiburg im Breisgau, Germany
                [35 ]Department of Psychiatry, University of Bonn , Bonn, Germany
                [36 ]Department of Psychiatry and Psychotherapy, Philipps-University Marburg, Marburg, Germany
                [37 ]Center for Integrative Psychiatry, University of Lübeck , Lübeck, Germany
                [38 ]Division of Psychiatry, University of Edinburgh , Edinburgh, UK
                [39 ]Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh , Edinburgh, UK
                [40 ]University Department of Psychiatry, Warneford Hospital , Oxford, UK
                [41 ]Department of Psychosomatic Medicine, Center for Internal Medicine and Dermatology, Charité Universitätsmedizin , Berlin, Germany
                [42 ]Institute for Social Medicine, Epidemology and Health Economics, Charité Universitätsmedizin , Berlin, Germany
                [43 ]Department of Quantitative Health Sciences, University of Massachusetts Medical School , Worcester, MA, USA
                Author notes
                [* ]Department of Psychiatry and Neuroscience Campus Amsterdam, VU University Medical Center , P.O. Box 74077, Amsterdam 1070 BB, The Netherlands. E-mail: l.schmaal@ 123456ggzingeest.nl
                [44]

                The members of the collaboration can be found in http://enigma.ini.usc.edu/ongoing/enigma-mdd-working-group/.

                Author information
                http://orcid.org/0000-0002-4395-1397
                Article
                mp201569
                10.1038/mp.2015.69
                4879183
                26122586
                0acf1e39-bb43-42a1-9119-19d36182779e
                Copyright © 2016 Macmillan Publishers Limited

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

                History
                : 27 October 2014
                : 13 March 2015
                : 01 April 2015
                Categories
                Original Article

                Molecular medicine
                Molecular medicine

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