Magnetic Resonance Imaging-Derived Markers of Acute and Chronic Inflammatory Processes in the Ventral Tegmental Area...

Depression is a leading cause of disability worldwide, with inflammation increasingly recognized as a contributing factor. Inflammatory processes can disrupt the brain's reward circuitry, particularly the ventral tegmental area (VTA), which is central to dopamine-mediated motivation and reward. This study investigates whether magnetic resonance imaging-derived markers sensitive to neuroinflammation and microstructure in the VTA are associated with depression diagnosis and symptom severity.

We analyzed diffusion-weighted imaging and quantitative susceptibility mapping data from 32,495 UK Biobank participants, including 3807 individuals with ICD-10-diagnosed major depressive disorder (MDD). Metrics sensitive to neuroinflammation (free water [FW], isotropic volume fraction [ISOVF], magnetic susceptibility) and microstructure (intracellular volume fraction [ICVF], orientation dispersion index [ODI], volume) were extracted from the VTA. Group differences between the MDD group and healthy control (HC) group matched on body mass index, sex, and age were assessed using analysis of variance. Linear regression was used to predict acute symptom severity based on Recent Depressive Symptoms scores.

Participants with an MDD diagnosis had significantly higher FW (p < .001) and ISOVF (p = .001) compared with HCs, indicating increased extracellular processes such as inflammation in the VTA. Lower ISOVF (β = -0.28, p = .033) and higher ICVF (β = 0.29, p = .017) and ODI (β = 0.4, p = .007) were associated with higher depression severity, independent of depressive diagnosis history.

Our findings reveal distinct patterns of VTA microstructural changes associated with major depression history versus acute depressive symptom severity, suggesting different underlying pathophysiological mechanisms. Distinct patterns of neuroinflammation may differentiate acute from chronic depression, informing targeted interventions.