Study in Biological Psychiatry: Cognitive Neuroscience and Neuroimaging illuminates the role of the ventral tegmental area in reward processing, motivation, and emotional regulation

November 18, 2025 – A new study investigating neuroinflammation in the ventral tegmental area (VTA) of the brain, a small, midbrain dopaminergic region, has found that acute and chronic depression are associated with distinct pathophysiological mechanisms. The findings from this new study in Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, published by Elsevier, help clarify the VTA’s role as a potential target for developing more targeted and state-specific treatments for depression.

Depression affects approximately 300 million individuals worldwide, making it a leading cause of disability. Inflammation has consistently been linked to depression in both clinical and population studies. Periods of prolonged stress, often preceding depression, can induce acute and, in severe cases, chronic inflammation in the brain. Previous research suggests that inflammatory processes can disrupt the synthesis, release, and reuptake of dopamine, the key neurotransmitter central to the brain’s reward system. Disruptions within this reward circuitry are thought to underlie core depressive symptoms such as anhedonia and low motivation.

“Our study focused on the VTA because it is at the core of the mesocortical and mesolimbic systems, which are both strongly associated with depression due to their central roles in reward processing, motivation, and emotional regulation. However, because of its small size and complex structure, the VTA has been relatively neglected in neuroimaging research,” notes co-lead investigator Lena K.L. Oestreich, PhD, School of Psychology, and the Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, Australia.

The researchers wanted to determine whether the VTA could reveal biological differences in individuals with a history of depression (chronic state) or current depressive symptoms (acute state). They analyzed MRI markers sensitive to inflammation and brain microstructure, specifically measures of extracellular and intracellular water content in the VTA, using a large and diverse sample from 32,495 UK Biobank participants, including 3,807 individuals with International Classification of Diseases (ICD-10)-diagnosed depression.

Co-lead investigator Sarah Khalife, PhD candidate, School of Psychology, The University of Queensland, Brisbane, Australia, explains, “We found that individuals with a history of major depression showed higher MRI markers associated with neuroinflammation (free water and isotropic volume fraction) in the VTA, suggesting increased extracellular inflammatory processes. In contrast, current depressive symptom severity was associated with distinct microstructural changes (higher intracellular volume fraction and orientation dispersion, but lower isotropic volume fraction), indicating that acute and chronic depression may involve different underlying pathophysiological mechanisms.”

Depression is a highly heterogeneous disorder influenced by numerous factors, including sex, lifestyle factors, genetic predisposition, and metabolic variables such as BMI. The results of this analysis underscore the complex interplay between neuroinflammation, lifestyle factors, and depressive symptoms, suggesting that future studies should consider these factors in more detail to fully understand the multifactorial nature of depression.

“By focusing on the VTA and using updated brainstem atlases, the investigators were able to map the VTA more precisely and contribute to the limited body of human imaging research on this region, illuminating the VTA’s role as a potential future therapeutic target for depression,” concludes Editor-in-Chief of Biological Psychiatry: Cognitive Neuroscience and Neuroimaging Cameron S. Carter, MD, University of California Irvine School of Medicine.