Characterising the neurobiological mechanisms of action of exercise and cognitive behavioural interventions for rheumatoid arthritis fatigue: an MRI brain study

Background Chronic Fatigue is a major clinical unmet need among patients with Rheumatoid Arthritis (RA). Current therapies are limited to non-pharmacological interventions, such as personalised exercise programmes (PEP) and cognitive behavioural approaches (CBA), however, still most patients continue to report severe fatigue. To inform more effective therapies, we conducted an MRI brain study of PEP and CBA, nested within a randomised controlled trial (RCT), to identify their neurobiological mechanisms of fatigue reduction in RA. Methods A sub-group of RA subjects (n=90), participating in a RCT of PEP/CBA for fatigue, undertook a multi-modal MRI brain scan following randomisation to either usual care (UC) alone or in addition to PEP/CBA, and again after the intervention (6 months). Brain regional volumetric, functional, and structural connectivity indices were curated and then computed employing a causal analysis framework. The primary outcome was fatigue improvement (Chalder Fatigue Scale). Findings Several structural and functional connections were identified as mediators of fatigue improvement in both PEP and CBA compared to UC. PEP had a more pronounced effect on functional connectivity than CBA, however, structural connectivity between the left isthmus cingulate cortex (L-ICC) and left paracentral lobule (L-PCL) was shared and the size of mediation effect ranked highly for both PEP/CBA (ß Average =-0·46, SD 0·61; ß Average =-0·32, SD 0·47, respectively). Interpretation The structural connection between the L-ICC and L-PCL appears to be a dominant mechanism for how both PEP/CBA reduces fatigue among RA patients. This supports its potential as a substrate of fatigue neurobiology and a putative candidate for future targeting.