Brain Mechanisms in Acute and Chronic Depression Vary, According to New Research

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.

Notes for editors

The article is "MRI-Derived Markers of Acute and Chronic Inflammatory Processes in the VTA Associated with Depression," by Sarah Khalife, Steffen Bollmann, Andrew Zalesky, and Lena K.L. Oestreich (https://doi.org/10.1016/j.bpsc.2025.09.003). It appears online in online in advance of volume 11, issue 2 (February 2026) of Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, published by Elsevier.

The article is openly available athttps://www.biologicalpsychiatrycnni.org/article/S2451-9022(25)00267-8/fulltext.

Copies of this paper are also available to credentialed journalists upon request; please contact Rhiannon Bugno at [email protected]. Journalists wishing to interview the study’s authors should contact Lena K.L. Oestreich, PhD, School of Psychology, and the Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, at [email protected].

The authors’ affiliations and disclosures of financial and conflicts of interest are available in the article.

Cameron S. Carter, MD, is Chair of the Department of Psychiatry & Human Behavior at the University of California Irvine School of Medicine. His disclosures of financial and conflicts of interest are available here.

Lena Oestreich was supported by a National Health and Medical Research Council (NHMRC) Investigator grant (2007718), a strategic award from the School of Psychology, and a start-up fund from the Australian Institute for Bioengineering and Nanotechnolgy at the University of Queensland.

About Biological Psychiatry: Cognitive Neuroscience and Neuroimaging

Biological Psychiatry: Cognitive Neuroscience and Neuroimaging is an official journal of the Society of Biological Psychiatry, whose purpose is to promote excellence in scientific research and education in fields that investigate the nature, causes, mechanisms and treatments of disorders of thought, emotion, or behavior. In accord with this mission, this peer-reviewed, rapid-publication, international journal focuses on studies using the tools and constructs of cognitive neuroscience, including the full range of non-invasive neuroimaging and human extra- and intracranial physiological recording methodologies. It publishes both basic and clinical studies, including those that incorporate genetic data, pharmacological challenges, and computational modeling approaches. The 2024 Journal Impact Factor^TM score, from Clarivate, for Biological Psychiatry: Cognitive Neuroscience and Neuroimaging is 4.8.www.sobp.org/bpcnni

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