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Replicability and Generalizability of Gray Matter Reductions in Major Depression: A Voxel-Based Investigation of 4021 Individuals

23 Pages Posted: 7 Jun 2024

See all articles by Udo Dannlowski

Udo Dannlowski

University of Münster

Nils R. Winter

University of Münster

Susanne Meinert

University of Münster

Dominik Grotegerd

University of Münster

Anna Kraus

University of Münster

Kira Flinkenflügel

University of Münster

Elisabeth J. Leehr

University of Münster

Joscha Böhnlein

University of Münster

Tiana Borgers

University of Münster

Lukas Fisch

University of Münster

Michael Bauer

Dresden University of Technology

Andrea Pfennig

Dresden University of Technology

Maike Richter

University of Münster

Nils Opel

University of Münster

Jonathan Repple

University of Münster

Marius Gruber

University of Münster

Heike Minnerup

University of Münster

Marco Hermesdorf

University of Münster

Robert Nitsch

University of Münster

Joachim Groß

University of Münster - Institute for Biomagnetism and Biosignalanalysis

Andreas Jansen

University of Marburg

Nina Alexander

University of Marburg

Frederike Stein

University of Marburg

Igor Nenadić

University of Marburg, Faculty of Medicine, Department of Psychiatry and Psychotherapy

Klaus Berger

University of Münster

Tilo Kircher

University of Marburg

Tim Hahn

University of Münster

Janik Goltermann

University of Münster

More...

Abstract

Introduction: The neurobiology underlying Major Depressive Disorder (MDD) remains elusive. Contemporary neuroimaging research focusing on gray matter correlates has produced inconsistent outcomes with marginal effect sizes. Furthermore, the credibility of brain-psychopathology associations is under scrutiny, attributable to inadequately powered sample sizes, inflated effect sizes, and diminished replicability. The present study aims to examine the effect sizes, replicability, and generalizability of gray matter correlates of MDD.

Methods: Three large, independent clinical cohorts totaling n=4021 comprehensively characterized participants (age 15-65 years), encompassing patients with MDD (n=1764), and healthy controls (HC; n=2257) with individual T1-weighted MRI data were jointly analyzed. Diagnosis was based on structured clinical interviews. Brain-wide case-control differences in voxel-based morphometry (VBM) were tested. We conducted pooled analyses to maximize statistical power, and further investigated cross-cohort replicability and generalizability by inspecting 1) correlations between t-maps derived from each cohort, 2) converging significance across the three cohorts, and 3) by using a cross-validation framework, iterating through cohorts as independent test sets.

Results: Pooling all individuals together yielded reduced gray matter volumes in patients with MDD in widespread bilateral clusters, covering the insula, thalamus, orbitofrontal cortex, and a parahippocampal-fusiform-lingual complex. The largest effect size was found in the bilateral anterior insula (partial R2=0·01). Analyzing cohorts separately yielded 1) substantial t-map correlations between cohorts (r=0·212 to r=0·281), 2) converging significance in multiple areas exceeding thresholds in each single cohort, and 3) generalizability of case-control differences in clusters that were deemed non-significant in single cohorts, implicating further frontal, temporal and cerebellar regions.

Discussion: Gray matter correlates of MDD are subtle, however nevertheless replicable and generalizable. These alterations are localized in an array of regions involved in emotion regulation and sensory processing. Our investigation underscores the need to investigate replicability and generalizability in psychiatric neuroimaging and provides a tangible framework for this endeavor.

Funding: The MACS and MNC studies are funded by the German Research Foundation (DFG, grant FOR2107 DA1151/5-1 and DA1151/5-2 to UD; SFB-TRR58, Projects C09 and Z02 to UD), the Interdisciplinary Center for Clinical Research (IZKF) of the medical faculty of Munster (grant Dan3/012/17 to UD), IMF Munster RE 22 17 07 to JR and the Deanery of the Medical Faculty of the University of Munster. SM received funding by the IMF (ME122205) and the Else-Kröner Fresenius Stiftung (EKFS; 2023_EKEA.153). TH was supported by the German Research Foundation (DFG grants HA7070/2-2, HA7070/3, HA7070/4). The BiDirect study is funded by German Federal Ministry of Education and Research Grant Nos. 01ER0816, 01ER1506, and 01ER1205.

Declaration of Interest: TK received unrestricted educational grants from Servier, Janssen, Recordati, Aristo, Otsuka, neuraxpharm.

Ethical Approval: This study was conducted in strict accordance with the ethical guidelines provided by the Declaration of Helsinki. All utilized cohort studies were approved by the local Institutional Review Boards of the Medical Faculty at the University of Münster (MACS: AZ 2014-422-b-S; MNC: AZ 2007-307-f-S; BiDirect: AZ 2009-391-f-S) and by the Medical Faculty of the University of Marburg (MACS: 07/14). Prior to their participation, all subjects provided informed written consent."

Keywords: MDD, depression, depressive, MRI, VBM, gray matter, neuroimaging, replicability, generalizability, cross-validation

Suggested Citation

Dannlowski, Udo and Winter, Nils R. and Meinert, Susanne and Grotegerd, Dominik and Kraus, Anna and Flinkenflügel, Kira and Leehr, Elisabeth J. and Böhnlein, Joscha and Borgers, Tiana and Fisch, Lukas and Bauer, Michael and Pfennig, Andrea and Richter, Maike and Opel, Nils and Repple, Jonathan and Gruber, Marius and Minnerup, Heike and Hermesdorf, Marco and Nitsch, Robert and Groß, Joachim and Jansen, Andreas and Alexander, Nina and Stein, Frederike and Nenadić, Igor and Berger, Klaus and Kircher, Tilo and Hahn, Tim and Goltermann, Janik, Replicability and Generalizability of Gray Matter Reductions in Major Depression: A Voxel-Based Investigation of 4021 Individuals. Available at SSRN: https://ssrn.com/abstract=4854882 or http://dx.doi.org/10.2139/ssrn.4854882

Udo Dannlowski

University of Münster ( email )

Universitätsstraße 14-16
Münster, 48143
Germany

Nils R. Winter

University of Münster ( email )

Universitätsstraße 14-16
Münster, 48143
Germany

Susanne Meinert

University of Münster ( email )

Universitätsstraße 14-16
Münster, 48143
Germany

Dominik Grotegerd

University of Münster ( email )

Universitätsstraße 14-16
Münster, 48143
Germany

Anna Kraus

University of Münster ( email )

Universitätsstraße 14-16
Münster, 48143
Germany

Kira Flinkenflügel

University of Münster ( email )

Universitätsstraße 14-16
Münster, 48143
Germany

Elisabeth J. Leehr

University of Münster ( email )

Universitätsstraße 14-16
Münster, 48143
Germany

Joscha Böhnlein

University of Münster ( email )

Universitätsstraße 14-16
Münster, 48143
Germany

Tiana Borgers

University of Münster ( email )

Universitätsstraße 14-16
Münster, 48143
Germany

Lukas Fisch

University of Münster ( email )

Universitätsstraße 14-16
Münster, 48143
Germany

Michael Bauer

Dresden University of Technology ( email )

Andrea Pfennig

Dresden University of Technology ( email )

Maike Richter

University of Münster ( email )

Universitätsstraße 14-16
Münster, 48143
Germany

Nils Opel

University of Münster ( email )

Universitätsstraße 14-16
Münster, 48143
Germany

Jonathan Repple

University of Münster ( email )

Universitätsstraße 14-16
Münster, 48143
Germany

Marius Gruber

University of Münster ( email )

Universitätsstraße 14-16
Münster, 48143
Germany

Heike Minnerup

University of Münster ( email )

Universitätsstraße 14-16
Münster, 48143
Germany

Marco Hermesdorf

University of Münster ( email )

Robert Nitsch

University of Münster ( email )

Universitätsstraße 14-16
Münster, 48143
Germany

Joachim Groß

University of Münster - Institute for Biomagnetism and Biosignalanalysis ( email )

Andreas Jansen

University of Marburg ( email )

Universitätsstrasse 24
D-35032 Marburg, D-35032
Germany

Nina Alexander

University of Marburg ( email )

Universitätsstrasse 24
D-35032 Marburg, D-35032
Germany

Frederike Stein

University of Marburg ( email )

Universitätsstrasse 24
D-35032 Marburg, D-35032
Germany

Igor Nenadić

University of Marburg, Faculty of Medicine, Department of Psychiatry and Psychotherapy ( email )

Klaus Berger

University of Münster ( email )

Universitätsstraße 14-16
Münster, 48143
Germany

Tilo Kircher

University of Marburg ( email )

Universitätsstrasse 24
D-35032 Marburg, D-35032
Germany

Tim Hahn

University of Münster ( email )

Universitätsstraße 14-16
Münster, 48143
Germany

Janik Goltermann (Contact Author)

University of Münster ( email )

Universitätsstraße 14-16
Münster, 48143
Germany

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