Neil Basu

Objective Chronic fatigue is a major clinical unmet need among patients with rheumatoid arthritis (RA). Current therapies are limited to nonpharmacological interventions, such as personalized exercise programs (PEPs) and cognitive–behavioral approaches (CBAs); however, most patients still continue to report severe fatigue. To inform more effective therapies, we conducted a magnetic resonance imaging (MRI) brain study of PEPs and CBAs, nested within a randomized controlled trial (RCT), to identify their neurobiological mechanisms of fatigue reduction in RA. Methods A subgroup of patients with RA (n = 90), participating in an RCT of PEPs and CBAs for fatigue, undertook a multimodal MRI brain scan following randomization to either usual care (UC) alone or in addition to PEPs and CBAs and again after the intervention (six 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). Results Several structural and functional connections were identified as mediators of fatigue improvement in both PEPs and CBAs compared to UC. PEPs had a more pronounced effect on functional connectivity than CBAs; 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 PEPs and CBAs (ß Average = −0.46, SD 0.61; ß Average = −0.32, SD 0.47, respectively). Conclusion The structural connection between the L‐ICC and L‐PCL appears to be a dominant mechanism for how both PEPs and CBAs reduce fatigue among patients with RA. This supports its potential as a substrate of fatigue neurobiology and a putative candidate for future targeting.