Acute and chronic depression appear differently in the brain

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Acute and chronic depression appear differently in the brain

New research finds differences in inflammation and microstructure in a mood-, motivation-, and reward-related brain region between acute and chronically depressed people.

23 January 2026

By Emma Young

Inflammation is known to play a role in depression. But there's debate about what, exactly, that role is — and whether it might be different for people with a long-term history of depression versus those in the throes of an acute depressive episode.

To explore this, Sarah Khalife at the University of Queensland, Australia and colleagues analysed markers of inflammation in MRI scans of the brains of 32,495 participants in the UK Biobank study. Of these, 3,807 had been diagnosed with depression.

Their work, in Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, focused specifically on a brain region called the ventral tegmental area (VTA). This area plays a critical role in regulating mood, motivation, and reward — all of which are altered in depression. But, because of the small size and complexity of the VTA, it has been relatively neglected in neuro-imaging research, the team writes.

When conducting their analysis, the team didn't just consider whether a participant had been diagnosed with depression or not. They also looked at the participants' scores on a survey of levels of depressive symptoms that they had completed on the day of their brain scan. This questionnaire asked about levels of depressed mood, a lack of enthusiasm/disinterest, tenseness/restlessness and tiredness/lethargy over the past fortnight.

The team used the participants' total scores on this survey to identify those with 'acute' depression — irrespective of whether they had ever been diagnosed with depression. This led them to compare VTA data on three main groups: healthy controls, participants with acute depression, and participants with chronic depression.

When the team then analysed the MRI data, they found that those with chronic depression had clear signs of neuro-inflammation in the VTA, compared with the healthy controls. There were no changes to the microstructure of the VTA, however.

The pattern of results for those with acute depression was different. Whether or not they had received a diagnosis of depression, they showed signs of VTA inflammation — though there were slight differences in the specific inflammation signals compared with those in the participants diagnosed with depression. There were also micro-structural changes within the VTA, with the MRI data suggesting a greater density of brain cells, for example.

"This dissociation suggests that these two states of depression — historical diagnosis of major depression versus acute depressive symptoms across the general population – may reflect distinct biological processes and inflammatory states," the researchers write.

Earlier work has shown that the VTA is highly susceptible to inflammation, they note, and that by interfering with dopamine signalling in this region, inflammatory chemicals may tip the balance in favour of prioritising the conservation of energy — perhaps triggering the withdrawal behaviours typical of depression, rather than reward-seeking behaviours — such as going out and meeting up with friends.

More work is clearly needed to elucidate how the VTA changes associated with acute versus chronic depression affect symptoms. Also, the cross-sectional design of the study means it cannot show that certain types of neuro-inflammation cause microstructure changes — longitudinal type studies would be needed to explore this.

But the identification of specific, and also different, changes in the VTA in people with acute versus chronic depression suggest new potential approaches to treatments. "These findings could ultimately inform more targeted therapeutic approaches that consider the distinct biological processes underlying depression," the team concludes.

Read the paper in full:
Khalife, S., Bollmann, S., Zalesky, A., & Oestreich, L. K. L. (2025). MRI-Derived Markers of Acute and Chronic Inflammatory Processes in the VTA Associated with Depression. Biological Psychiatry: Cognitive Neuroscience and Neuroimaging. https://doi.org/10.1016/j.bpsc.2025.09.003

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