Profound and reproducible patterns of reduced regional gray matter characterize major depressive disorder

Sarah C Hellewell, Thomas Welton, Jerome J Maller, Matthew Lyon, Mayuresh S Korgaonkar, Stephen H Koslow, Leanne M Williams, A John Rush, Evian Gordon, Stuart M Grieve, Sarah C Hellewell, Thomas Welton, Jerome J Maller, Matthew Lyon, Mayuresh S Korgaonkar, Stephen H Koslow, Leanne M Williams, A John Rush, Evian Gordon, Stuart M Grieve

Abstract

Reduced gray matter (GM) volume may represent a hallmark of major depressive disorder (MDD) neuropathology, typified by wide-ranging distribution of structural alteration. In the study, we aimed to replicate and extend our previous finding of profound and widespread GM loss in MDD, and evaluate the diagnostic accuracy of a structural biomarker derived from GM volume in an interconnected pattern across the brain. In a sub-study of the International Study to Predict Optimized Treatment in Depression (iSPOT-D), two cohorts of clinically defined MDD participants "Test" (n = 98) and "Replication" (n = 131) were assessed alongside healthy controls (n = 66). Using 3T MRI T1-weighted volumes, GM volume differences were evaluated using voxel-based morphometry. Sensitivity, specificity, and area under the receiver operating characteristic curve were used to evaluate an MDD diagnostic biomarker based on a precise spatial pattern of GM loss constructed using principal component analysis. We demonstrated a highly conserved symmetric widespread pattern of reduced GM volume in MDD, replicating our previous findings. Three bilateral dominant clusters were observed: Cluster 1: midline/cingulate (GM reduction: Test: 6.4%, Replication: 5.3%), Cluster 2: medial temporal lobe (GM reduction: Test: 8.2%, Replication: 11.9%), Cluster 3: prefrontal cortex (GM reduction: Test: 12.1%, Replication: 23.2%). We developed a biomarker reflecting the global pattern of GM reduction, achieving good diagnostic classification performance (AUC: Test = 0.75, Replication = 0.84). This study establishes that a highly specific pattern of reduced GM volume is a feature of MDD, suggestive of a structural basis for this disease. We introduce and validate a novel diagnostic biomarker based on this pattern.

Trial registration: ClinicalTrials.gov NCT00693849.

Conflict of interest statement

S.H. has no disclosures to declare. T.W. has no disclosures to declare. J.J.M. is an employee of General Electric Healthcare but has no conflict of interest. M.L. has no disclosures to declare. E.G. is the CEO of Brain Resource Ltd and has significant equity and stock options in the company. S.H.K. serves as a consultant and has stock options with Brain Resource Ltd.

Figures

Fig. 1. Whole-brain voxel-based morphometry revealed significant…
Fig. 1. Whole-brain voxel-based morphometry revealed significant clusters of reduced GM in MDD.
a Statistical parametric T-score maps of all clusters in the Test (top) and Replication (bottom) MDD cohorts, where MDD volume is significantly reduced versus control. b Top 10 clusters observed in the Test cohort that were successfully reproduced in the Replication MDD cohort
Fig. 2. Three dominant bilateral clusters of…
Fig. 2. Three dominant bilateral clusters of GM alteration between MDD and control groups.
Test (a) and Replication (b) cohorts. The three predominant clusters are demonstrated in columns 1–3, representing the midline structures including the cingulate bundle (Cluster 1), medial temporal lobe (Cluster 2), and prefrontal cortex (Cluster 3). The fourth column for each group shows the location of the cluster superimposed on a 3D rendering of a standard brain
Fig. 3. Performance of the structural biomarker…
Fig. 3. Performance of the structural biomarker in the Test and Replication MDD cohorts.
a Normalized Z-scores from candidate ROIs were combined to a single structural biomarker and assessed for discriminative power in the Test MDD cohort. MDD participants had significantly lower biomarker scores compared with control participants. This finding was then reproduced in the Replication cohort (b), with the biomarker also demonstrating discriminative capacity in this separate patient group. Performance of the biomarker was then assessed via ROC analysis in the Test and Replication cohorts (c) to assess sensitivity and specificity of the biomarker

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