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Structural brain measures linked to clinical phenotypes in major depression replicate across clinical centres

Molecular Psychiatry volume 26, pages 2764–2775 (2021)Cite this article

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Abstract

Abnormalities in brain structural measures, such as cortical thickness and subcortical volumes, are observed in patients with major depressive disorder (MDD) who also often show heterogeneous clinical features. This study seeks to identify the multivariate associations between structural phenotypes and specific clinical symptoms, a novel area of investigation. T1-weighted magnetic resonance imaging measures were obtained using 3 T scanners for 178 unmedicated depressed patients at four academic medical centres. Cortical thickness and subcortical volumes were determined for the depressed patients and patients’ clinical presentation was characterized by 213 item-level clinical measures, which were grouped into several large, homogeneous categories by K-means clustering. The multivariate correlations between structural and cluster-level clinical-feature measures were examined using canonical correlation analysis (CCA) and confirmed with both 5-fold and leave-one-site-out cross-validation. Four broad types of clinical measures were detected based on clustering: an anxious misery composite (composed of item-level depression, anxiety, anhedonia, neuroticism and suicidality scores); positive personality traits (extraversion, openness, agreeableness and conscientiousness); reported history of physical/emotional trauma; and a reported history of sexual abuse. Responses on the item-level anxious misery measures were negatively associated with cortical thickness/subcortical volumes in the limbic system and frontal lobe; reported childhood history of physical/emotional trauma and sexual abuse measures were negatively correlated with entorhinal thickness and left hippocampal volume, respectively. In contrast, the positive traits measures were positively associated with hippocampal and amygdala volumes and cortical thickness of the highly-connected precuneus and cingulate cortex. Our findings suggest that structural brain measures may reflect neurobiological mechanisms underlying MDD features.

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Fig. 1: Correlations between structural measures and clinical variates.
Fig. 2: Contributions of symptom subsets to the first CCA mode.
Fig. 3: Cross-validation CCA analysis.
Fig. 4: Leave-one-site-out CCA analysis.

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Acknowledgements

We acknowledge the following support: U01 MH109991 (YIS); R01 NS085211, R01 NS060910, R01 MH112847 and RG-1707– 28586 (RTS); R01-MH111886 (DO); U01 MH092250 (MMW). TMM is supported by the Lifespan Brain Institute (LiBI) of the Children’s Hospital of Philadelphia. The content is solely the responsibility of the authors and does not necessarily represent the official views of any of the funding agencies. We thank Maria Prociuk for her assistance with the preparation and submission of the manuscript. We thank the EMBARC teams for collecting the data.

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  1. These authors contributed equally: Meichen Yu, Nicholas Cullen

Authors and Affiliations

  1. Center for Neuromodulation in Depression and Stress, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Meichen Yu, Kristin A. Linn, Desmond J. Oathes, Darsol Seok, Philip A. Cook, Romain Duprat, Irem Aselcioglu, Maria A. Oquendo, Russell T. Shinohara & Yvette I. Sheline

  2. Neuroscience Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Nicholas Cullen

  3. Penn Statistics in Imaging and Visualization Center, Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Kristin A. Linn & Russell T. Shinohara

  4. Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Philip A. Cook, Christos Davatzikos & Yvette I. Sheline

  5. Brain Behavior Laboratory, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Tyler M. Moore

  6. Department of Psychiatry, Columbia University, VAGELOS College of Physicians & Surgeons, New York Psychiatric Institute, New York, NY, USA

    Maria A. Oquendo & Myrna M. Weissman

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Correspondence to Yvette I. Sheline.

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Dr. Oquendo receives royalties for the use of the Columbia Suicide Severity Rating Scale and her family owns stock in Bristol-Myers Squibb. Dr. Weissman has received funding from the Interstitial Cystitis Association, NARSAD, the National Institute on Drug Abuse, NIMH, the Sackler Foundation, and the Templeton Foundation; and she receives royalties from American Psychiatric Publishing, MultiHealth Systems, Oxford University Press, and Perseus Press., Dr. Shinohara has received consulting income from Genentech/Roche and editorial/reviewership income from the American Medical Association and Research Square. All other authors report no financial relationships with commercial interests.

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Yu, M., Cullen, N., Linn, K.A. et al. Structural brain measures linked to clinical phenotypes in major depression replicate across clinical centres. Mol Psychiatry 26, 2764–2775 (2021). https://doi.org/10.1038/s41380-021-01039-8

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