Why does chronic pain often lead to depression? Our research shows the answer is in the brain

Researchers have long wondered why some people with chronic pain develop depression. yourphotopie/ Shutterstock Chronic pain has long been known to be associated with depression. Among adults with chronic pain, around 40% exhibit clinical symptoms of depression. But why is it that only some people with chronic pain develop depression? Researchers have long been wondering why this happens – and what goes on in the brain. If we can answer this question, we may be able to prevent depression from developing. Our recent article, published in Science, suggests the answer to this question does indeed lie in the brain. To conduct our study, we analysed neuroimaging brain scans from 14,462 participants from the UK Biobank cohort. We compared the following groups of participants: people with chronic pain for at least seven years who did not have symptoms of depression, and people with chronic pain who also developed depressive symptoms. For the latter, the depressive symptoms were present either for the entire seven-year period, or they developed after two years or four years. This enabled an analysis of the development of depression associated with chronic pain, using brain imaging. These neuroimaging analyses revealed something surprising was taking place in the brain – specifically in a structure called the hippocampus. The hippocampus has important functions in learning and memory. In the participants who reported chronic pain without depressive symptoms, they showed modest increases in hippocampal volume and improved memory performance. This is consistent with the brain attempting to cope with the stress of the pain. In contrast, people experiencing both chronic pain and depression exhibited reduced hippocampal volume and impaired cognitive performance. Further analyses of these scans suggested these changes developed progressively over time. This indicates that the hippocampus may initially adapt to persistent pain, but it gradually becomes vulnerable when pain continues over long periods. Importantly, similar patterns were observed across multiple categories of chronic pain – including back, stomach, knee and hip pain, as well as headaches. This suggests that the findings were not specific to a single type of chronic pain condition. We then studied how these brain changes unfolded in people with chronic pain by using rodent animal models. This research found that in animals there was a similar sequence of changes in the volume of the hippocampus, accompanied by increased neural activity. Moderate improvements in cognitive functioning occurred initially, but this was then followed by anxiety-like behaviour, which later transitioned to depressive-like symptoms and poorer memory. The hippocampus has long been known to be involved in emotional memories and is highly susceptible to chronic stress. The hippocampus’s plasticity (the ability to form new nerve cells) is known to be involved in coping with chronic stress. The hippocampus was shown to be the key area involved in the link between chronic pain and depression. MattL_Images/ Shutterstock

Chronic stress has also been implicated in exacerbating apoptosis (nerve cell death) and suppressing adult neurogenesis – the process of producing new nerve cells in the hippocampus. We found that a region of the hippocampus known as the dentate gyrus – one of the few areas where new brain cells continue to form in adulthood – emerged as the critical regulatory hub and the pivot for the transition from chronic pain to depression. Early in the pain process, newly generated neurons in the dentate gyrus showed increased activity – suggesting the brain initially mounts a protective response to persistent pain. Over time, however, immune cells, known as microglia, became abnormally activated and disrupted normal neural signalling in the hippocampus. This abnormal microglial activation appeared to mark the tipping point at which the brain’s initially protective response to pain began to fail. Importantly, an antibiotic treatment, minocycline, suppressed abnormal microglial activation and reduced depression-like behaviour in the animal models. This treatment also preserved the structure of the hippocampus and cognitive function. Treating pain and depression Our findings suggest that a treatment such as minocycline could help prevent depression in people living with persistent pain — particularly if treatment is introduced early. Of course, other psychosocial, socio-economic and genetic factors play a role in the perception of pain. Therefore, it’s likely that in some people these factors will exacerbate chronic stress and the experience of pain. However, there are other evidence-based ways to reduce the risk of depression. In another collaborative study between Fudan University and the University of Cambridge, it was shown that seven healthy lifestyle factors, including good sleep, exercise and diet, could reduce the risk of depression by 57%. Importantly, these lifestyle factors were also associated with increased hippocampal volume, consistent with our new study. Mindfulness training may be another strategy. This focuses on being present in the moment and minimising distraction from competing thoughts and memories. The practice is shown to improve working memory and increase hippocampal density. How mindfulness therapy could help those left behind by depression treatment

A recent review showed that mindfulness meditation experts have increased brain grey matter, including the hippocampus. Mindfulness meditation training was also shown to lead to increased hippocampal volume. Mindfulness practice has also been found to be beneficial for improving quality of life – not only when coping with chronic pain – and for reducing symptoms of stress and depression. Our discovery has answered an important question that has long puzzled researchers. We showed the key role the brain’s hippocampus plays in why some chronic pain sufferers develop depression. This discovery also points to potential treatments that may prevent depression in people with chronic pain. The brain’s coping mechanisms that we discovered may also apply more generally to other conditions where the brain has to cope with chronic stress – such as in psychological trauma.

Barbara Jacquelyn Sahakian receives funding from the Wellcome Trust and the Lundbeck Foundation. Her research work is conducted within the NIHR Cambridge Biomedical Research Centre (BRC) Mental Health and Neurodegeneration Themes. She receives Royalties from Cambridge University Press for Brain Boost: Healthy Habits for a Happier Life. Jianfeng Feng receives funding from nsfc Trevor Robbins he is a consultant for Cambridge Cognition, and Blandaris. Xiao Xiao receives funding from 2030 China Brain Project.