Khaberni - Scientists have discovered a brain mechanism that may explain why chronic pain leads to depression in some people and not others, challenging the notion that depression is an inevitable result of long-term pain, according to research published in the journal Science.
By combining wide-scale brain imaging in humans and animal experiments, researchers found that persistent pain leads to gradual changes in the hippocampus (an area of the brain known for its role in memory), which shapes whether people become depressed over time or remain emotionally resilient.
Professor Jianfeng Feng from the University of Warwick, one of the co-authors of the study, said: "Chronic pain often develops into depression or anxiety, but until now we did not understand why this happens to some people and not others. Our findings suggest that the hippocampus acts as a control center that helps the brain regulate emotional responses to prolonged pain. Depression is not inevitable—it depends on how this system responds over time."
Chronic pain affects over 20% of adults worldwide and is closely linked to anxiety and depression. However, many people suffering from persistent pain do not develop these conditions, and the biological reasons for this variation have remained unclear.
To investigate, researchers analyzed brain scans from large population groups, including data from the UK Biobank. They found that people who suffer from chronic pain, but not depression, tend to show a slightly larger hippocampus size and increased activity in this brain region.
These changes were accompanied by better performance in some learning and memory tasks, suggesting that the brain may initially respond with a compensatory response to persistent pain.
In contrast, individuals suffering from both chronic pain and depression showed a reduced hippocampus size, disrupted activity, and poorer cognitive performance. Longitudinal analyses suggested that these changes gradually evolved over time.
Professor Feng added, "The fact that these changes appear gradually indicates that they are driven by the prolonged pain experience itself. It is not just a pre-existing weakness; it is something the brain does in response to persistent pain."
To understand how these changes evolve, researchers conducted parallel studies in animal models of chronic neuropathic pain. They observed a clear progression in behavioral effects. Increased pain sensitivity appeared first, followed by anxiety-like behaviors, and then depressive-like symptoms. These behavioral changes were accompanied by gradual changes in the structure and activity of the hippocampus, illustrating how prolonged pain can reshape brain circuits involved in emotional regulation.
A small subregion of the hippocampus known as the dentate gyrus— one of the few areas in the adult brain where new neurons continue to form— emerged as a major regulatory center.
Early in the course of chronic pain, newly formed neurons in the dentate gyrus became very active, suggesting that the brain initially tries to adapt to the ongoing stress.
However, over time, immune cells in the brain called microglia became abnormally active. This disruption in normal communication between neurons and microglia marked a shift from adaptive brain responses to disordered signals.
When researchers inhibited this abnormal activity of microglia in animal models, depressive-like behaviors improved while overall brain function remained stable. The findings suggest that targeting microglial inflammation in the hippocampus could help prevent depression in people suffering from persistent pain, especially if treatment is administered early.
Professor Feng concluded, saying, "What this shows is that the brain is not simply overwhelmed by chronic pain. It actively tries to regulate emotional wellbeing. When this regulatory system remains balanced, people can remain resilient. When this system is disrupted, especially due to inflammation in the hippocampus, depression can occur. Understanding this process opens up new possibilities for early intervention."
