Chronic pain does not cause depression in everyone

A team of researchers from the University of Warwick has discovered a brain mechanism that explains why some people with chronic pain become depressed, while others remain emotionally stable. The hippocampus, a region of the brain known for its role in memory formation, plays a crucial role in this process. In the early stages of chronic pain, the brain attempts to compensate for the stress by increasing activity in this area, but over time, some patients’ defense systems become compromised due to inflammation caused by immune cells in the brain, known as microglia. The results of the work, published in the journal Science, open up prospects for early prevention of depression in people living with persistent pain.

Chronic pain affects more than 20% of the world’s adult population, and a significant number of these individuals develop anxiety and depression over time, although not everyone does. The biological reasons for this disparity remained unclear until the publication of a new study by researchers from the University of Warwick, led by Professor Jianfeng Feng.

His team combined the analysis of large-scale neuroimaging data, including images from the UK Biobank database, with a series of animal experiments, and focused on the hippocampus, where they discovered a curious pattern. People who lived with chronic pain but did not suffer from depression had slightly larger hippocampi, increased activity in this area, and performed better on learning and memory tests, indicating that the brain was triggering a protective response in response to prolonged stress.

In patients with chronic pain and concomitant depression, the picture was reversed: a reduced hippocampus, weakened neural activity, and reduced cognitive performance, all of which increased gradually as the pain persisted for months and years. “The brain reacts to prolonged pain, and this is not an innate predisposition, but a process that unfolds over time,” Professor Feng explained.

Parallel experiments on animals with a neuropathic pain model confirmed this dynamic in detail. At first, the subjects became more sensitive to pain stimuli, then they displayed anxious behavior, and only in the later stages did the researchers observe signs of depression, which allowed them to establish a clear timeline of the transition from resilience to vulnerability.
The dentate gyrus, a small region of the hippocampus and one of the few areas in the adult brain where new neurons continue to form, played a crucial role in this transition.

In the early stages of chronic pain, these young neurons became activated, and the brain used them to adapt to the increasing stress. But then the microglia got involved: in some animals, these immune cells entered a pathological activation mode, disrupting normal interactions with neurons and turning the adaptive response into dysfunction. This was the turning point.

When the researchers suppressed the abnormal microglia activity, the animals’ depressive behavior subsided, while their other brain functions remained stable, confirming the role of inflammation as a key factor in the transition from pain to depression.

Professor Feng believes that the brain does not simply give up under the onslaught of pain, but actively fights for emotional balance. As long as the hippocampus’s defense system remains balanced, individuals remain resilient, but when inflammation disrupts this balance, depression takes over. If doctors can identify early signs of dysfunction and block the microglia’s inflammatory response before it causes irreversible damage, millions of individuals with chronic pain may have a better chance of avoiding depression.