Cortical abnormalities in adults and adolescents with major depression based on brain scans from 20 cohorts worldwide in the ENIGMA Major Depressive Disorder Working Group

Abstract

The neuro-anatomical substrates of major depressive disorder (MDD) are still not well understood, despite many neuroimaging studies over the past few decades. Here we present the largest ever worldwide study by the ENIGMA (Enhancing Neuro Imaging Genetics through Meta-Analysis) Major Depressive Disorder Working Group on cortical structural alterations in MDD. Structural T1-weighted brain magnetic resonance imaging (MRI) scans from 2148 MDD patients and 7957 healthy controls were analysed with harmonized protocols at 20 sites around the world. To detect consistent effects of MDD and its modulators on cortical thickness and surface area estimates derived from MRI, statistical effects from sites were meta-analysed separately for adults and adolescents. Adults with MDD had thinner cortical gray matter than controls in the orbitofrontal cortex (OFC), anterior and posterior cingulate, insula and temporal lobes (Cohen's d effect sizes: −0.10 to −0.14). These effects were most pronounced in first episode and adult-onset patients (>21 years). Compared to matched controls, adolescents with MDD had lower total surface area (but no differences in cortical thickness) and regional reductions in frontal regions (medial OFC and superior frontal gyrus) and primary and higher-order visual, somatosensory and motor areas (d: −0.26 to −0.57). The strongest effects were found in recurrent adolescent patients. This highly powered global effort to identify consistent brain abnormalities showed widespread cortical alterations in MDD patients as compared to controls and suggests that MDD may impact brain structure in a highly dynamic way, with different patterns of alterations at different stages of life.

Studying neuroanatomy using MRI

“…Here the inside and outside surfaces of the cortex are segmented using deformable models and measures such as cortical thickness and surface area are extracted [12][13][14] . The diverse anatomical metrics that can be extracted from threedimensional models of the cortical surface capture different developmental processes, and show dissociable correlations with demographic 15,16 , genetic 17,18 , environmental 19 , and clinical 20,21 variables -highlighting the value in moving classical volumetric approaches to anatomical analysis. Surface based methods also provide an improved coordinate system for the cerebral cortex, allowing for smoothing of signal on the cortical sheet and surface based alignment to bring individuals into closer correspondence for statistical comparisons 13,22 .…”

612. Hippocampal Subfield Volumes in Mood Disorders

“…22,40,41 To be brief, any outlier (five standard deviations) of any hippocampal subfield was excluded. Then each segmented image, overlaid on the corresponding brain structural image, was visually inspected by two co-authors independently (BC and HT), in order to exclude segmentations with poor registration to the hippocampus location or with apparent wrong assignment of the subfields.…”

Breaking down the genetics of depression using brain endophenotypes

“…In Chapter 7, we detail the steps of sample extraction and data preparation that aimed at harmonise study design across groups within the consortium. In addition, we briefly summarise the main findings of the two publications on the subcortical and cortical signatures of MDD [68,69].…”

“…The second publication studied cortical differences between cases and controls in a combined sample from 20 sites (10,105 scans, 2,148 MDD cases) [68]. The slightly smaller sample size can be attributed to more scan exclusions in the cortical analysis, which is a consequence of the greater number of MRI artefacts around the edge of the field of view.…”

“…There has been an explosion of proposed brain endophenotypes for depression, with most publications reporting unreplicated phenotypic associations based on small sample sizes (see [400][401][402] for reviews). To overcome publication bias and propose robust candidate endophenotypes, the Major Depressive Disorder (MDD) group of the ENIGMA consortium [386] has conducted large-scale exploratory case-control comparisons, which reported several structural brain phenotypes associated with MDD [68,385], but somewhat conflicting cortical signatures of depression when stratifying the analysis by age (cut-off 21 yrs.). In addition, another large voxel-wise meta-analysis of cortical density reported several volume changes associated with MDD [403].…”