Childhood adversity impacts on brain subcortical structures relevant to depression

doi:10.1016/j.jpsychires.2016.11.010

Multicenter Study

. 2017 Mar:86:58-65.

doi: 10.1016/j.jpsychires.2016.11.010. Epub 2016 Nov 19.

Childhood adversity impacts on brain subcortical structures relevant to depression

Thomas Frodl¹, Deborah Janowitz², Lianne Schmaal³, Leonardo Tozzi⁴, Henrik Dobrowolny⁵, Dan J Stein⁶, Dick J Veltman⁷, Katharina Wittfeld⁸, Theo G M van Erp⁹, Neda Jahanshad¹⁰, Andrea Block¹¹, Katrin Hegenscheid¹², Henry Völzke¹³, Jim Lagopoulos¹⁴, Sean N Hatton¹⁵, Ian B Hickie¹⁵, Eva Maria Frey¹⁶, Angela Carballedo¹⁷, Samantha J Brooks⁶, Daniella Vuletic⁶, Anne Uhlmann⁶, Ilya M Veer¹⁸, Henrik Walter¹⁸, Knut Schnell¹⁹, Dominik Grotegerd²⁰, Volker Arolt²⁰, Harald Kugel²¹, Elisabeth Schramm²², Carsten Konrad²³, Bartosz Zurowski²⁴, Bernhard T Baune²⁵, Nic J A van der Wee²⁶, Marie-Jose van Tol²⁷, Brenda W J H Penninx⁷, Paul M Thompson¹⁰, Derrek P Hibar¹⁰, Udo Dannlowski²⁸, Hans J Grabe²⁹

Affiliations

¹ Department of Psychiatry and Psychotherapy, Otto von Guericke University of Magdeburg, Germany; Department of Psychiatry, University of Dublin, Trinity College, Dublin, Ireland. Electronic address: Thomas.Frodl@med.ovgu.de.
² Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Germany.
³ Department of Psychiatry and Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands; Orygen, The National Centre of Excellence in Youth Mental Health, Melbourne, Australia; Centre for Youth Mental Health, The University of Melbourne, Melbourne, Australia.
⁴ Department of Psychiatry and Psychotherapy, Otto von Guericke University of Magdeburg, Germany; Department of Psychiatry, University of Dublin, Trinity College, Dublin, Ireland.
⁵ Department of Psychiatry and Psychotherapy, Otto von Guericke University of Magdeburg, Germany.
⁶ Department of Psychiatry and Mental Health, University of Cape Town, South Africa.
⁷ Department of Psychiatry and Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
⁸ German Center for Neurodegenerative Diseases (DZNE), Rostock, Greifswald, Germany.
⁹ Department of Psychiatry and Human Behavior, University of California, Irvine, CA, USA.
¹⁰ Imaging Genetics Center, Department of Neurology, Keck School of Medicine, University of Southern California, Marina del Rey, CA, USA.
¹¹ Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Germany; Sociology of Physical Activity and Health, Department of Health Sciences, University of Potsdam, Germany.
¹² Institute of Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Germany.
¹³ Institute for Community Medicine, University Medicine Greifswald, Germany.
¹⁴ Brain and Mind Centre, University of Sydney, Camperdown, Australia; Sunshine Coast Mind and Neuroscience - Thompson Institute, University of The Sunshine Coast, QLD, Australia.
¹⁵ Brain and Mind Centre, University of Sydney, Camperdown, Australia.
¹⁶ Department of Psychiatry, University of Regensburg, Regensburg, Germany.
¹⁷ Department of Psychiatry and Psychotherapy, Otto von Guericke University of Magdeburg, Germany; Trinity College Institute of Neuroscience, Trinity College Dublin, Ireland.
¹⁸ Charité Universitätsmedizin Berlin, Department of Psychiatry and Psychotherapy, Division of Mind and Brain Research, Berlin, Germany.
¹⁹ Department of General Psychiatry, University Hospital Heidelberg, Germany.
²⁰ Department of Psychiatry and Psychotherapy, University of Münster, Germany.
²¹ Department of Clinical Radiology, University of Münster, Germany.
²² Department of Psychiatry and Psychotherapy, University Medical Center Freiburg, Germany; Psychiatric University Clinic, Basel, Switzerland.
²³ Department of Psychiatry and Psychotherapy, Agaplesion Diakoniklinikum, Rotenburg, Germany; Department of Psychiatry and Psychotherapy, Philipps-University Marburg, Germany.
²⁴ Center for Integrative Psychiatry, University of Lübeck, Lübeck, Germany.
²⁵ Discipline of Psychiatry, School of Medicine, University of Adelaide, SA 5005 Adelaide, Australia.
²⁶ Department of Psychiatry, Leiden Institute for Brain and Cognition and Leiden Center for Translational Neuroscience, Leiden, The Netherlands.
²⁷ Department of Neuroscience, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
²⁸ Department of Psychiatry and Psychotherapy, University of Münster, Germany; Department of Psychiatry, University of Marburg, Germany.
²⁹ Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Germany; German Center for Neurodegenerative Diseases (DZNE), Rostock, Greifswald, Germany; Helios Hospital Stralsund, Germany.

PMID: 27918926
PMCID: PMC5564511
DOI: 10.1016/j.jpsychires.2016.11.010

Multicenter Study

Childhood adversity impacts on brain subcortical structures relevant to depression

Thomas Frodl et al. J Psychiatr Res. 2017 Mar.

. 2017 Mar:86:58-65.

doi: 10.1016/j.jpsychires.2016.11.010. Epub 2016 Nov 19.

Authors

Affiliations

¹ Department of Psychiatry and Psychotherapy, Otto von Guericke University of Magdeburg, Germany; Department of Psychiatry, University of Dublin, Trinity College, Dublin, Ireland. Electronic address: Thomas.Frodl@med.ovgu.de.
² Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Germany.
³ Department of Psychiatry and Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands; Orygen, The National Centre of Excellence in Youth Mental Health, Melbourne, Australia; Centre for Youth Mental Health, The University of Melbourne, Melbourne, Australia.
⁴ Department of Psychiatry and Psychotherapy, Otto von Guericke University of Magdeburg, Germany; Department of Psychiatry, University of Dublin, Trinity College, Dublin, Ireland.
⁵ Department of Psychiatry and Psychotherapy, Otto von Guericke University of Magdeburg, Germany.
⁶ Department of Psychiatry and Mental Health, University of Cape Town, South Africa.
⁷ Department of Psychiatry and Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
⁸ German Center for Neurodegenerative Diseases (DZNE), Rostock, Greifswald, Germany.
⁹ Department of Psychiatry and Human Behavior, University of California, Irvine, CA, USA.
¹⁰ Imaging Genetics Center, Department of Neurology, Keck School of Medicine, University of Southern California, Marina del Rey, CA, USA.
¹¹ Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Germany; Sociology of Physical Activity and Health, Department of Health Sciences, University of Potsdam, Germany.
¹² Institute of Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Germany.
¹³ Institute for Community Medicine, University Medicine Greifswald, Germany.
¹⁴ Brain and Mind Centre, University of Sydney, Camperdown, Australia; Sunshine Coast Mind and Neuroscience - Thompson Institute, University of The Sunshine Coast, QLD, Australia.
¹⁵ Brain and Mind Centre, University of Sydney, Camperdown, Australia.
¹⁶ Department of Psychiatry, University of Regensburg, Regensburg, Germany.
¹⁷ Department of Psychiatry and Psychotherapy, Otto von Guericke University of Magdeburg, Germany; Trinity College Institute of Neuroscience, Trinity College Dublin, Ireland.
¹⁸ Charité Universitätsmedizin Berlin, Department of Psychiatry and Psychotherapy, Division of Mind and Brain Research, Berlin, Germany.
¹⁹ Department of General Psychiatry, University Hospital Heidelberg, Germany.
²⁰ Department of Psychiatry and Psychotherapy, University of Münster, Germany.
²¹ Department of Clinical Radiology, University of Münster, Germany.
²² Department of Psychiatry and Psychotherapy, University Medical Center Freiburg, Germany; Psychiatric University Clinic, Basel, Switzerland.
²³ Department of Psychiatry and Psychotherapy, Agaplesion Diakoniklinikum, Rotenburg, Germany; Department of Psychiatry and Psychotherapy, Philipps-University Marburg, Germany.
²⁴ Center for Integrative Psychiatry, University of Lübeck, Lübeck, Germany.
²⁵ Discipline of Psychiatry, School of Medicine, University of Adelaide, SA 5005 Adelaide, Australia.
²⁶ Department of Psychiatry, Leiden Institute for Brain and Cognition and Leiden Center for Translational Neuroscience, Leiden, The Netherlands.
²⁷ Department of Neuroscience, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
²⁸ Department of Psychiatry and Psychotherapy, University of Münster, Germany; Department of Psychiatry, University of Marburg, Germany.
²⁹ Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Germany; German Center for Neurodegenerative Diseases (DZNE), Rostock, Greifswald, Germany; Helios Hospital Stralsund, Germany.

PMID: 27918926
PMCID: PMC5564511
DOI: 10.1016/j.jpsychires.2016.11.010

Abstract

Childhood adversity plays an important role for development of major depressive disorder (MDD). There are differences in subcortical brain structures between patients with MDD and healthy controls, but the specific impact of childhood adversity on such structures in MDD remains unclear. Thus, aim of the present study was to investigate whether childhood adversity is associated with subcortical volumes and how it interacts with a diagnosis of MDD and sex. Within the ENIGMA-MDD network, nine university partner sites, which assessed childhood adversity and magnetic resonance imaging in patients with MDD and controls, took part in the current joint mega-analysis. In this largest effort world-wide to identify subcortical brain structure differences related to childhood adversity, 3036 participants were analyzed for subcortical brain volumes using FreeSurfer. A significant interaction was evident between childhood adversity, MDD diagnosis, sex, and region. Increased exposure to childhood adversity was associated with smaller caudate volumes in females independent of MDD. All subcategories of childhood adversity were negatively associated with caudate volumes in females - in particular emotional neglect and physical neglect (independently from age, ICV, imaging site and MDD diagnosis). There was no interaction effect between childhood adversity and MDD diagnosis on subcortical brain volumes. Childhood adversity is one of the contributors to brain structural abnormalities. It is associated with subcortical brain abnormalities that are relevant to psychiatric disorders such as depression.

Keywords: Caudate; Childhood adversity; Depression; ENIGMA; Hippocampus; MRI.

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Conflict of interest statement

Conflicts of interest

All authors have no conflicts of interest related to this study. Dr. Stein has received research grants and/or consultancy honoraria from AMBRF, Biocodex, Cipla, Lundbeck, National Responsible Gambling Foundation, Novartis, Servier, and Sun.

Professor Ian Hickie is a Commissioner in Australia’s new National Mental Health Commission from 2012. He is the Co-Director, Health and Policy at the Brain and Mind Centre which operates two early-intervention youth services under contract to headspace. Professor Hickie has led a range of community-based and pharmaceutical industry-supported depression awareness and education and training programs. He has led projects for health professionals and the community supported by governmental, community agency and pharmaceutical industry partners (Wyeth, Eli Lily, Servier, Pfizer, AstraZeneca) for the identification and management of depression and anxiety. He has received honoraria for presentations of his own work at educational seminars supported by a number of non-government organisations and the pharmaceutical industry (including Servier, Pfizer, AstraZeneca, and Eli Lilly). He is a member of the Medical Advisory Panel for Medibank Private and also a Board Member of Psychosis Australia Trust. He leads an investigator-initiated study of the effects of agomelatine on circadian parameters (supported in part by Servier) and has participated in a multicentre clinical trial of the effects of agomelatine on sleep architecture in depression and a Servier-supported study of major depression and sleep disturbance in primary care settings.

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 Aristo Pharma, Janssen, Lundbeck and Servier.

Professor Thomas Frodl received fees for presentations and scientific organisation of a conference from Janssen-Cilag, Lund-beck and Servier.

Dr. Van Erp has a contract with Otsuka Pharmaceutical, Inc.

Figures

**Fig. 1**
Association between childhood adversity and caudate volumes (mean of left and right) in females and males. Shown are quintiles (quintiles of the population, with mean of quintiles labeled) for the different severities of childhood adversity and predicted values after correction for covariates, age, ICV, imaging site as well as the standard error.

**Fig. 2**
Association between emotional neglect, physical neglect and physical abuse and subcortical volumes of nucleus caudate in females. Shown are quintiles/quantiles (with mean of quintiles/quantiles/tertiles labeled) for the different severities of childhood adversity and residual values after correction for covariates, age, ICV, imaging site as well as the standard error. Left for association with left caudate, Right for association with right caudate. The distribution of physical neglect was obtained in quantiles).

**Fig. 3**
Bar diagram shows means and standard deviations (estimated values using age, sex, field strength and site as covariates) for MDD patients currently taking antidepressants compared to those MDD patients currently unmedicated and compared to controls. Patients currently taking antidepressants had significantly larger thalamus volumes compared to controls and patients not taking antidepressants. Patients not taking antidepressants had significantly smaller hippocampal volumes compared to controls and patients taking antidepressants.

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References

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1. Alexander GE, DeLong MR, Strick PL. Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Annu Rev Neurosci. 1986;9:357–381. - PubMed
1. Arnone D, Job D, Selvaraj S, Abe O, Amico F, Cheng Y, Colloby SJ, O’Brien JT, Frodl T, Gotlib IH, Ham BJ, Kim MJ, Koolschijn PC, Perico CA, Salvadore G, Thomas AJ, Van Tol MJ, van der Wee NJ, Veltman DJ, Wagner G, McIntosh AM. Computational meta-analysis of statistical parametric maps in major depression. Hum Brain Mapp. 2016;37(4):1393–1404. - PMC - PubMed
1. Bernstein DP, Fink L, Handelsman L, Foote J, Lovejoy M, Wenzel K, Sapareto E, Ruggiero J. Initial reliability and validity of a new retrospective measure of child abuse and neglect. Am J Psychiatry. 1994;151(8):1132–1136. - PubMed
1. Bernstein DP, Stein JA, Newcomb MD, Walker E, Pogge D, Ahluvalia T, Stokes J, Handelsman L, Medrano M, Desmond D, Zule W. Development and validation of a brief screening version of the Childhood Trauma Questionnaire. Child Abuse Negl. 2003;27(2):169–190. - PubMed

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[1] Ahdidan J, Hviid LB, Chakravarty MM, Ravnkilde B, Rosenberg R, Rodell A, Stodkilde-Jorgensen H, Videbech P. Longitudinal MR study of brain structure and hippocampus volume in major depressive disorder. Acta Psychiatr Scand. 2011;123(3):211–219. - PubMed

[2] Ahdidan J, Hviid LB, Chakravarty MM, Ravnkilde B, Rosenberg R, Rodell A, Stodkilde-Jorgensen H, Videbech P. Longitudinal MR study of brain structure and hippocampus volume in major depressive disorder. Acta Psychiatr Scand. 2011;123(3):211–219. - PubMed

[3] Alexander GE, DeLong MR, Strick PL. Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Annu Rev Neurosci. 1986;9:357–381. - PubMed

[4] Alexander GE, DeLong MR, Strick PL. Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Annu Rev Neurosci. 1986;9:357–381. - PubMed

[5] Arnone D, Job D, Selvaraj S, Abe O, Amico F, Cheng Y, Colloby SJ, O’Brien JT, Frodl T, Gotlib IH, Ham BJ, Kim MJ, Koolschijn PC, Perico CA, Salvadore G, Thomas AJ, Van Tol MJ, van der Wee NJ, Veltman DJ, Wagner G, McIntosh AM. Computational meta-analysis of statistical parametric maps in major depression. Hum Brain Mapp. 2016;37(4):1393–1404. - PMC - PubMed

[6] Arnone D, Job D, Selvaraj S, Abe O, Amico F, Cheng Y, Colloby SJ, O’Brien JT, Frodl T, Gotlib IH, Ham BJ, Kim MJ, Koolschijn PC, Perico CA, Salvadore G, Thomas AJ, Van Tol MJ, van der Wee NJ, Veltman DJ, Wagner G, McIntosh AM. Computational meta-analysis of statistical parametric maps in major depression. Hum Brain Mapp. 2016;37(4):1393–1404. - PMC - PubMed

[7] Bernstein DP, Fink L, Handelsman L, Foote J, Lovejoy M, Wenzel K, Sapareto E, Ruggiero J. Initial reliability and validity of a new retrospective measure of child abuse and neglect. Am J Psychiatry. 1994;151(8):1132–1136. - PubMed

[8] Bernstein DP, Fink L, Handelsman L, Foote J, Lovejoy M, Wenzel K, Sapareto E, Ruggiero J. Initial reliability and validity of a new retrospective measure of child abuse and neglect. Am J Psychiatry. 1994;151(8):1132–1136. - PubMed

[9] Bernstein DP, Stein JA, Newcomb MD, Walker E, Pogge D, Ahluvalia T, Stokes J, Handelsman L, Medrano M, Desmond D, Zule W. Development and validation of a brief screening version of the Childhood Trauma Questionnaire. Child Abuse Negl. 2003;27(2):169–190. - PubMed

[10] Bernstein DP, Stein JA, Newcomb MD, Walker E, Pogge D, Ahluvalia T, Stokes J, Handelsman L, Medrano M, Desmond D, Zule W. Development and validation of a brief screening version of the Childhood Trauma Questionnaire. Child Abuse Negl. 2003;27(2):169–190. - PubMed

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Childhood adversity impacts on brain subcortical structures relevant to depression

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Childhood adversity impacts on brain subcortical structures relevant to depression

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