Resting-state fMRI in Major Depressive Disorder: findings from the ENIGMA Major Depressive Disorder working group

Brisbane Convention & Exhibition Centre 

Major depressive disorder (MDD) is a leading contributor to the global burden of disease and disability. Despite extensive research, the neurobiological mechanisms underlying MDD remain poorly understood. Accumulating evidence suggests that MDD is characterised by alterations in functional connectivity, which may underlie the phenotypic manifestations of the disorder. However, findings from individual studies are often inconsistent, limiting the ability to draw definitive conclusions about patterns of connectivity alterations in MDD. These inconsistencies are likely due to the small sample sizes typical of neuroimaging studies, which result in limited statistical power, as well as substantial variability in the methods used to process fMRI data. In this talk, findings on functional alterations in MDD are presented, leveraging large-scale data from the ENIGMA MDD Consortium using standardised pipelines provided by the ENIGMA framework. The data includes resting-state fMRI scans from 25 cohorts worldwide analysed using a harmonised protocol (ENIGMA HALFpipe) to derive resting-state first-level features. These include connectivity metrics for specific seed regions (e.g., amygdala), large-scale networks (e.g., Default Mode Network), and measures of intrinsic neural activity (e.g., ReHo, fALFF). The resulting features were pooled using a mega-analysis framework to examine differences in resting-state functional connectivity between individuals with MDD and healthy controls. To account for variability across sites, linear mixed-effects models were employed with site included as a random effect. Results will be presented for the entire sample (MDD: N=2045, HC: N=2322, mean age = 39.7, SD = 17.14) as well as separately for adults (aged ≥25; MDD: N=1385, HC: N=1711) and youth (aged <25; MDD: N=660, HC: N=611). Across the whole sample, individuals with MDD showed lower connectivity compared to controls in specific regions, including the dorsolateral prefrontal cortex, posterior insula, thalamus, and fALFF. However, these differences were more pronounced when analysing adults and youth separately. Compared to controls, adults with MDD exhibited reduced connectivity between several seed regions (e.g., dorsomedial prefrontal cortex, precuneus, ventrolateral prefrontal cortex) and posterior brain regions (occipital cortex, lingual gyrus). In contrast, youth with MDD exhibited alterations predominantly in limbic and subcortical regions, including reduced connectivity between the amygdala and the insular cortex, the anterior insula and central operculum, the posterior insula and thalamus, and the thalamus and the precentral gyrus and anterior cingulate cortex. This comprehensive analysis highlights distinct connectivity alterations that vary by stage of development, providing new insights into the neurobiological underpinnings of MDD. The observed differences between adults and youth suggest that age-specific patterns of functional connectivity alterations may play a pivotal role in the neurobiology of MDD, highlighting the potential for tailoring neuromodulation treatments to target these distinct neural profiles more effectively. I will present these findings, and discuss the challenges and opportunities of large-scale multi-site rsfMRI harmonisation as well as potential implications of this work.