MRI-Derived Markers of Acute and Chronic Inflammatory Processes in the VTA Associated with Depression

Background 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 MRI-derived markers sensitive to neuroinflammation and microstructure in the VTA are associated with depression diagnosis and symptom severity. Methods We analyzed diffusion weighted imaging and quantitative susceptibility mapping data from 32,495 UK Biobank participants, including 3,807 individuals with ICD-10 diagnosed depression. 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 major depression group and BMI, sex, and age-matched healthy controls were assessed using ANOVAs and linear regression was used to predict acute symptom severity based on Recent Depressive Symptoms scores. Results Participants with depression diagnosis had significantly higher FW ( p < 0.001) and ISOVF ( p = 0.001) compared to HCs, indicating increased extracellular processes such as inflammation in the VTA. Lower ISOVF ( β = -0.46, p = 0.017) and higher ICVF ( β = 0.34, p = 0.007) and ODI ( β = 0.49, p = 0.004) were associated with higher depression severity, independent of depressive diagnosis history. Conclusions Our findings reveal distinct patterns of VTA microstructural changes associated with 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.