Severity of current depression and remission status are associated with structural connectome alterations in major depressive disorder

Jonathan Repple; Marco Mauritz; Susanne Meinert; Siemon C de Lange; Dominik Grotegerd; Nils Opel; Ronny Redlich; Tim Hahn; Katharina Förster; Elisabeth J Leehr; Nils Winter; Janik Goltermann; Verena Enneking; Stella M Fingas; Hannah Lemke; Lena Waltemate; Igor Nenadic; Axel Krug; Katharina Brosch; Simon Schmitt; Frederike Stein; Tina Meller; Andreas Jansen; Olaf Steinsträter; Bernhard T Baune; Tilo Kircher; Udo Dannlowski; Martijn P van den Heuvel

doi:10.1038/s41380-019-0603-1

Severity of current depression and remission status are associated with structural connectome alterations in major depressive disorder

Jonathan Repple, Marco Mauritz, Susanne Meinert, Siemon C de Lange, Dominik Grotegerd, Nils Opel, Ronny Redlich, Tim Hahn, Katharina Förster, Elisabeth J Leehr, Nils Winter, Janik Goltermann, Verena Enneking, Stella M Fingas, Hannah Lemke, Lena Waltemate, Igor Nenadic, Axel Krug, Katharina Brosch, Simon SchmittFrederike Stein, Tina Meller, Andreas Jansen, Olaf Steinsträter, Bernhard T Baune, Tilo Kircher, Udo Dannlowski, Martijn P van den Heuvel

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Abstract

Major depressive disorder (MDD) is associated to affected brain wiring. Little is known whether these changes are stable over time and hence might represent a biological predisposition, or whether these are state markers of current disease severity and recovery after a depressive episode. Human white matter network ("connectome") analysis via network science is a suitable tool to investigate the association between affected brain connectivity and MDD. This study examines structural connectome topology in 464 MDD patients (mean age: 36.6 years) and 432 healthy controls (35.6 years). MDD patients were stratified categorially by current disease status (acute vs. partial remission vs. full remission) based on DSM-IV criteria. Current symptom severity was assessed continuously via the Hamilton Depression Rating Scale (HAMD). Connectome matrices were created via a combination of T1-weighted magnetic resonance imaging (MRI) and tractography methods based on diffusion-weighted imaging. Global tract-based metrics were not found to show significant differences between disease status groups, suggesting conserved global brain connectivity in MDD. In contrast, reduced global fractional anisotropy (FA) was observed specifically in acute depressed patients compared to fully remitted patients and healthy controls. Within the MDD patients, FA in a subnetwork including frontal, temporal, insular, and parietal nodes was negatively associated with HAMD, an effect remaining when correcting for lifetime disease severity. Therefore, our findings provide new evidence of MDD to be associated with structural, yet dynamic, state-dependent connectome alterations, which covary with current disease severity and remission status after a depressive episode.

Original language	English
Pages (from-to)	1550-1558
Number of pages	9
Journal	Molecular Psychiatry
Volume	25
Issue number	7
Early online date	22 Nov 2019
DOIs	https://doi.org/10.1038/s41380-019-0603-1
Publication status	Published - Jul 2020

Funding

Acknowledgements This work is part of the German multicenter consortium “Neurobiology of Affective Disorders. A translational perspective on brain structure and function“, funded by the German Research Foundation (Deutsche Forschungsgemeinschaft DFG; For-schungsgruppe/Research Unit FOR2107). Principal investigators (PIs) with respective areas of responsibility in the FOR2107 consortium are: Work Package WP1, FOR2107/MACS cohort and brain imaging: Tilo Kircher (speaker FOR2107; DFG grant numbers KI 588/14-1, KI 588/ 14-2), Udo Dannlowski (co-speaker FOR2107; DA 1151/5-1, DA 1151/5-2), Axel Krug (KR 3822/5-1, KR 3822/7-2), Igor Nenadic (NE 2254/1-2), Carsten Konrad (KO 4291/3-1). CP1, biobank: Petra Pfefferle (PF 784/1-1, PF 784/1-2), Harald Renz (RE 737/20-1, 737/ 20-2). CP2, administration. Tilo Kircher (KI 588/15-1, KI 588/17-1), Udo Dannlowski (DA 1151/6-1), Carsten Konrad (KO 4291/4-1). Martijn van den Heuvel was supported by an ALW open (ALWOP.179), and VIDI (452-16-015) grant from the Netherlands Funding This work was funded by the German Research Foundation (DFG, grant FOR2107 DA 1151/5-1 and DA 1151/5-2 to UD; SFB-TRR58, Projects C09 and Z02 to UD), the Interdisciplinary Center for Clinical Research (IZKF) of the medical faculty of Münster (grant Dan3/012/17 to UD), IMF Münster RE111604 to RR und RE111722 to RR, IMF Münster RE 22 17 07 to Jonathan Repple and the Deanery of the Medical Faculty of the University of Münster. The FOR2107 cohort project (WP1) was approved by the Ethics Committees of the Medical Faculties, University of Marburg (AZ: 07/14), and University of Münster (AZ: 2014-422-b-S).

Funders	Funder number
IZKF	Dan3/012/17
Interdisciplinary Center for Clinical Research
Medical Faculty of the University of Münster
VIDI	452-16-015
International Monetary Fund	RE111604, RE111722
Deutsche Forschungsgemeinschaft	RR, FOR2107, FOR2107 DA 1151/5-1, DA 1151/5-2, Z02
German-Israeli Foundation for Scientific Research and Development
Astellas Pharma, Netherlands

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Severity of current depression and remission status are associated with structural connectome alterations in major depressive disorderFinal published version, 917 KBLicence: Article 25fa Dutch Copyright Act

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Repple, J., Mauritz, M., Meinert, S., de Lange, S. C., Grotegerd, D., Opel, N., Redlich, R., Hahn, T., Förster, K., Leehr, E. J., Winter, N., Goltermann, J., Enneking, V., Fingas, S. M., Lemke, H., Waltemate, L., Nenadic, I., Krug, A., Brosch, K., ... van den Heuvel, M. P. (2020). Severity of current depression and remission status are associated with structural connectome alterations in major depressive disorder. Molecular Psychiatry, 25(7), 1550-1558. https://doi.org/10.1038/s41380-019-0603-1

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abstract = "Major depressive disorder (MDD) is associated to affected brain wiring. Little is known whether these changes are stable over time and hence might represent a biological predisposition, or whether these are state markers of current disease severity and recovery after a depressive episode. Human white matter network ({"}connectome{"}) analysis via network science is a suitable tool to investigate the association between affected brain connectivity and MDD. This study examines structural connectome topology in 464 MDD patients (mean age: 36.6 years) and 432 healthy controls (35.6 years). MDD patients were stratified categorially by current disease status (acute vs. partial remission vs. full remission) based on DSM-IV criteria. Current symptom severity was assessed continuously via the Hamilton Depression Rating Scale (HAMD). Connectome matrices were created via a combination of T1-weighted magnetic resonance imaging (MRI) and tractography methods based on diffusion-weighted imaging. Global tract-based metrics were not found to show significant differences between disease status groups, suggesting conserved global brain connectivity in MDD. In contrast, reduced global fractional anisotropy (FA) was observed specifically in acute depressed patients compared to fully remitted patients and healthy controls. Within the MDD patients, FA in a subnetwork including frontal, temporal, insular, and parietal nodes was negatively associated with HAMD, an effect remaining when correcting for lifetime disease severity. Therefore, our findings provide new evidence of MDD to be associated with structural, yet dynamic, state-dependent connectome alterations, which covary with current disease severity and remission status after a depressive episode.",

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Repple, J, Mauritz, M, Meinert, S, de Lange, SC, Grotegerd, D, Opel, N, Redlich, R, Hahn, T, Förster, K, Leehr, EJ, Winter, N, Goltermann, J, Enneking, V, Fingas, SM, Lemke, H, Waltemate, L, Nenadic, I, Krug, A, Brosch, K, Schmitt, S, Stein, F, Meller, T, Jansen, A, Steinsträter, O, Baune, BT, Kircher, T, Dannlowski, U & van den Heuvel, MP 2020, 'Severity of current depression and remission status are associated with structural connectome alterations in major depressive disorder', Molecular Psychiatry, vol. 25, no. 7, pp. 1550-1558. https://doi.org/10.1038/s41380-019-0603-1

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AU - Repple, Jonathan

AU - Mauritz, Marco

AU - Meinert, Susanne

AU - de Lange, Siemon C

AU - Grotegerd, Dominik

AU - Opel, Nils

AU - Redlich, Ronny

AU - Hahn, Tim

AU - Förster, Katharina

AU - Leehr, Elisabeth J

AU - Winter, Nils

AU - Goltermann, Janik

AU - Enneking, Verena

AU - Fingas, Stella M

AU - Lemke, Hannah

AU - Waltemate, Lena

AU - Nenadic, Igor

AU - Krug, Axel

AU - Brosch, Katharina

AU - Schmitt, Simon

AU - Stein, Frederike

AU - Meller, Tina

AU - Jansen, Andreas

AU - Steinsträter, Olaf

AU - Baune, Bernhard T

AU - Kircher, Tilo

AU - Dannlowski, Udo

AU - van den Heuvel, Martijn P

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Severity of current depression and remission status are associated with structural connectome alterations in major depressive disorder

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