White matter disturbances in major depressive disorder: a coordinated analysis across 20 international cohorts in the ENIGMA MDD working group

Abstract

Alterations in white matter (WM) microstructure have been implicated in the pathophysiology of major depressive disorder (MDD). However, previous findings have been inconsistent, partially due to low statistical power and the heterogeneity of depression. In the largest multi-site study to date, we examined WM anisotropy and diffusivity in 1305 MDD patients and 1602 healthy controls (age range 12-88 years) from 20 samples worldwide, which included both adults and adolescents, within the MDD Working Group of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) consortium. Processing of diffusion tensor imaging (DTI) data and statistical analyses were harmonized across sites and effects were meta-analyzed across studies. We observed subtle, but widespread, lower fractional anisotropy (FA) in adult MDD patients compared with controls in 16 out of 25 WM tracts of interest (Cohen's d between 0.12 and 0.26). The largest differences were observed in the corpus callosum and corona radiata. Widespread higher radial diffusivity (RD) was also observed (all Cohen's d between 0.12 and 0.18). Findings appeared to be driven by patients with recurrent MDD and an adult age of onset of depression. White matter microstructural differences in a smaller sample of adolescent MDD patients and controls did not survive correction for multiple testing. In this coordinated and harmonized multisite DTI study, we showed subtle, but widespread differences in WM microstructure in adult MDD, which may suggest structural disconnectivity in MDD.

Age‐related structural and functional variations in 5,967 individuals across the adult lifespan

“…Fourth, the resolution of the fMRI images is sub‐optimal (3.75 × 3.75 × 4.55 mm) compared to the newer multi‐band sequences (2–3 mm isotropic). In addition, there are some existing large N datasets, for example, ENIGMA (Favre et al, ; Hoogman et al, ; van Velzen et al, ), 10 K in 1 day (van den Heuvel et al, ) and morphometric similarity networks (Seidlitz et al, ), which introduce several new network features that can be used to investigate age‐related variations in both healthy as well as disease.…”

ENIGMA and global neuroscience: A decade of large-scale studies of the brain in health and disease across more than 40 countries

“…While effect sizes varied by tract and included significant reductions in the anterior corona radiata (d = 0.40) and corpus callosum (d = 0.39, specifically its body (d = 0.39) and genu (d = 0.37)), effects were observed throughout the brain, with peak reductions observed for the entire WM skeleton (d = 0.42). Figure 6 shows these findings alongside data from two other disorders for which ENIGMA published largescale DTI analyses, MDD 67 , and 22q11DS 17 . Fig.…”

“…b Independent work by the Japanese Consortium, COCORO, found a very similar set of effect sizes for group differences in subcortical volumes between schizophrenia patients and matched controls. [Data adapted, with permission of the authors and publishers, from Kelly et al 56 , van Velzen et al 67 , and Villalón-Reina et al 17 ; a key to the tract names appears in the original papers; some tracts (i.e. the hippocampal portion of the cingulum) were omitted from the 22q11DS analysis as they were not consistently in the field of view for some cohorts of the working group].…”

“…In addition to these investigations of gray matter in MDD, a large-scale analysis of WM microstructure with DTI has also been completed, comparing 1305 adults and adolescents with MDD to 1602 healthy controls from 20 samples worldwide 67 . In adults with MDD, widespread lower FA values were found in 16 out of 25 WM tracts of interest (d's = 0.12-0.26), with the largest differences in the corpus callosum and corona radiata.…”

“…Hibar et al 2,68 Volumetric reductions in hippocampus and thalamus and enlarged lateral ventricles in patients; thinner cortical gray matter in bilateral frontal, temporal and parietal regions; strongest effects on left pars opercularis, fusiform gyrus and rostral middle frontal cortex in BD. 67 ; Tozzi et al 75 ; Han et al 72 ; Frodl et al 74 ; Renteria et al 172 ;…”