BACKGROUND/OBJECTIVE: To investigate the modulatory effects of different physical exercise modalities on connectivity of amygdala subregions and its association with pain symptoms in patients with knee osteoarthritis (KOA). METHODS: 140 patients with KOA were randomly allocated either to the Tai Chi, Baduanjin, stationary cycling, or health education group and conducted a 12 week-long intervention in one of the four groups. The behavioral, magnetic resonance imaging (MRI), and blood data were collected at baseline and the end of the study. RESULTS: Compared to the control group, all physical exercise modalities lead to significant increases in Knee Injury and Osteoarthritis Outcome Score (KOOS) pain score (pain relief) and serum Programmed Death-1 (PD-1) levels. Additionally, all physical exercise modalities resulted in decreased resting state functional connectivity (rsFC) of the basolateral amygdala (BA)-temporal pole and BA-medial prefrontal cortex (mPFC). The overlapping BA-temporal pole rsFC observed in both Tai Chi and Baduanjin groups was significantly associated with pain relief, while the BA-mPFC rsFC was significantly associated with PD-1 levels. In addition, we found increased fractional anisotropy (FA) values, a measurement of water diffusion anisotropy of tissue that responded to changes in brain microstructure, within the mind-body exercise groups' BA-temporal pole pathway. The average FA value of this pathway was positively correlated with KOOS pain score at baseline across all subjects. CONCLUSIONS: Our findings suggest that physical exercise has the potential to modulate both functional and anatomical connectivity of the amygdala subregions, indicating a possible shared pathway for various physical exercise modalities.

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