Physical Activity and Depressive Mood Share the Structural Connectivity Between Motor and Reward Networks

In various studies, exercise has been revealed to have a positive effect on alleviating depressive symptoms. However, the neural basis behind this phenomenon remains unknown, as well as its underlying biological mechanism. In this study, we used a large neuroimaging cohort [n = 1,027, major depressive disorder (MDD)/healthy controls (HCs) = 492/535] from the UK Biobank to identify structural connectivity (SC) patterns simultaneously linked with physical activity and depression, as well as the biological interpretation. An SC pattern linked with exercise was identified to be both significantly correlated with depressive mood and group discrimination between MDDs and HCs, primarily located between the motor-related regions and reward-related regions. This pattern was associated with multiple neurotransmitter receptors, such as serotonin and GABA receptors, and enriched in pathways like synaptic signaling and the astrocyte cell type. The SC pattern and genetic results were also replicated in another independent MDD dataset (n = 3,496) and present commonalities with bipolar disorder (n = 81). Overall, these findings not only initially identified a reproducible shared SC pattern between physical activity and depressive mood, but also elucidated the underlying biological mechanisms, which enhance our understanding of how exercise helps alleviate depression and may inform the development of novel neuromodulation targets.