Approved research

Identifying risk factors for chronic musculoskeletal pain: a multifactorial approach combining brain imaging and genetics

Lay summary

Chronic musculoskeletal pain (CMP) affects up to 47% of individuals worldwide. However, the processes underlying the development of CMP are poorly understood, precluding the development of novel preventative therapeutics. Increasing evidence suggests that the size and shapes of both the hippocampi, a brain region involved in memory and learning, and amygdala, a brain region involved in fear memory, can predict whether an individual will transition from acute musculoskeletal injury (such as a strain) and/or stress/trauma exposure to CMP. Current evidence indicates that individuals with a smaller hippocampus and amygdala are more susceptible to co-morbid neuropsychiatric outcomes. However, the size and role of the hippocampus and amygdala in CMP development remains unknown. Further, the underlying mechanisms that lead to individual differences in hippocampal/amygdala volume remain unknown. Current evidence indicates that abnormalities in hippocampal and amygdala volume precede injury and co-occur with measures of stress. E.g. chronic exposure to stress hormones have been shown to correlate with hippocampal and amygdala volume, with high levels of stress related to smaller hippocampi. However, this association has not been connected to CMP severity and individual vulnerabilities and molecular mechanisms responsible for this association have not been identified. Preliminary data from our group suggests that the FKBP5 gene/protein, a critical mediator of the stress response, influences susceptibility to chronic pain and is a key mediator driving smaller hippocampi/amygdala in individuals with CMP. In the proposed study we aim to understand a) whether common genetic variants in the FKBP5 gene are associated with CMP severity in the UK Biobank cohort, b) whether hippocampal and amygdalar volumes are associated with CMP in the same study cohort and c) whether there is a mediating relationship between FKBP5 variants, hippocampal/amygdalar volume, and CMP. We will also investigate stress-related, and pain-related genes and how they interact with brain volumes and CMP severity. Together this data will identify novel risk factors for CMP and will provide preliminary evidence indicating that interactions between the stress and nervous system might be a key mechanism driving CMP development. Future studies that translate these findings to pre-clinical mechanistic studies have the potential to lead to novel targets for therapeutic intervention.