Scientists have uncovered a brain mechanism that may explain why chronic pain leads to depression in some people but not others, according to research published in Science . The findings challenge the idea that depression is an inevitable consequence of long-term pain.
By combining large-scale human brain imaging with animal experiments, the researchers found that persistent pain drives progressive changes in the hippocampus (a brain region best known for its role in memory), which shapes whether people develop depression over time or remain emotionally resilient.
"Chronic pain frequently develops into depression or anxiety, but until now we haven't understood why this happens to some people and not others," said co-lead author Professor Jianfeng Feng of the University of Warwick.
"Our findings suggest that the hippocampus acts as a control centre that helps the brain regulate emotional responses to long-term pain. Depression is not inevitable - it depends on how this system responds over time."
The brain's early response to pain
Chronic pain affects more than 20% of adults worldwide and is strongly associated with anxiety and depression. Yet many people with persistent pain do not develop these conditions, and the biological reasons for this difference have remained unclear.
To investigate, the researchers analysed brain scans from large population cohorts, including data from the UK Biobank. They found that people living with chronic pain but without depression tended to show slightly larger hippocampal volume and increased activity in this brain region. These changes were accompanied by better performance in certain learning and memory tasks, suggesting the brain may initially mount a compensatory response to persistent pain.
In contrast, individuals experiencing both chronic pain and depression showed reduced hippocampal volume, disrupted activity, and poorer cognitive performance. Longitudinal analyses indicated that these changes developed progressively over time.
"The fact that these changes emerge gradually suggests they are driven by the experience of prolonged pain itself," Professor Feng added. "This isn't simply a pre-existing vulnerability; it's something the brain is doing in response to ongoing pain."
From resilience to vulnerability
To understand how these changes unfold, the researchers conducted parallel studies in animal models of chronic neuropathic pain.
They observed a clear progression of behavioural effects. Increased pain sensitivity appeared first, followed by anxiety-like behaviour, and later by depression-like symptoms. These behavioural changes were accompanied by gradual alterations in hippocampal structure and activity, showing 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 of the adult brain where new neurons continue to form - emerged as a key regulatory hub.
Early in the course of chronic pain, newly generated neurons in the dentate gyrus became highly active, suggesting the brain initially attempts to adapt to ongoing stress. Over time, however, immune cells in the brain called microglia became abnormally activated. This disrupted normal communication between neurons and microglia marked a tipping point from adaptive brain responses to dysfunctional signalling.
When the researchers suppressed this abnormal microglial activity in animal models, depression-like behaviours improved while overall brain function remained stable. The findings suggest that targeting microglial inflammation in the hippocampus could help prevent depression in people living with persistent pain, particularly if treatment is introduced early.
"What this shows is that the brain is not simply overwhelmed by chronic pain," Professor Feng concluded. "It actively tries to regulate emotional wellbeing. When that regulatory system remains balanced, people can stay resilient. When it becomes disrupted, particularly by inflammation in the hippocampus, depression can emerge. Understanding this process opens new possibilities for early intervention."
