Multimodal neuroimaging of pain and inflammation in the central nervous system in patients with fibromyalgia and rheumatoid arthritis

The prevalence of concomitant fibromyalgia (FM) is puzzlingly high among rheumatoid arthritis (RA) patients and a contemporary challenge is to resolve why some RA patients continue to report pain despite adequate treatment of their peripheral inflammation. While recent literature has concentrated on the link between cerebral and inflammatory mechanisms in RA patients with concomitant FM, little attention has been directed towards commonalities and divergences among these two patient groups when they are wellcharacterized. The overarching aim of the current thesis was to identify and filling contemporary gaps of knowledge related to cerebral pain processing and associated mechanisms (i.e. contextual influences and neuroinflammation) in patients with wellcharacterized rheumatoid arthritis (nociceptive pain) and well-characterized fibromyalgia (nociplastic pain) condition. In study I, multi-ligand positron-emission tomography (PET) was used to investigate brain glial activation (i.e. neural inflammation) in FM patients compared to healthy controls (HC). The results supported a role for glial activation in FM pathophysiology, as FM vs. HC exhibited wide-spread cortical elevations of translocator protein (TSPO) binding, a sign of activated glia. Increased subjective ratings of fatigue in FM correlated with increased TSPO binding in the midcingulate cortex. In study II, functional magnetic resonance imaging (fMRI) was used to Investigate cerebral pain processing in RA patients at disease-affected (most inflamed finger joint) and nonaffected (thumb nail) sites. Corresponding sites were used in HC. The results indicated normal pain sensitivity and cerebral pain processing in RA for non-affected sites, while disease-relevant pain processing was marked by a failed initiation of cortical top-down regulation. In study III, combined behavioral and fMRI data suggested that FM subjects display a predisposition to form new pain-related associations while simultaneously maintaining high-pain associations that are no longer relevant. Study IV extended these findings, and revealed that FM vs. HC exhibited reduced prefrontal activation during repeatedly violated high pain associations. These results may help explain why ratings of high pain persist in FM subjects despite that the subsequent pressure stimulation had been lowered (i.e. high pain replaced by a lower mid-intensity painful pressure). In study V, fMRI was used to directly compare cerebral pain processing in wellcharacterized RA and FM patients without comorbidities. The results suggested that cerebral pain processing in RA was associated with dysfunction in the early initiation of the pain modulatory system, i.e. reduced activation of the dorsolateral prefrontal cortex. Whereas, cerebral pain processing in FM was associated with reduced engagement of more medial structures such as medial prefrontal cortex and rostral anterior cingulate cortex. In FM patients only, disruptions in pain-related cerebral activation correlated with higher degrees of clinical pain, which indicate more pronounced disruptions in patients suffering from nociplastic pain. In conclusion, the results from the above-mentioned studies in the current thesis noted distinct aberrations in cerebral pain modulation between well-characterized FM and wellcharacterized RA. Specifically, while cerebral pain modulatory aberrations were restricted to affected sites (i.e. most inflamed finger joint) in RA, cerebral pain processing in FM was found to be marked by notably complex cognitive processes and associated with overall clinical pain. These results may indicate more prominent pain-related cerebral disruptions in patients suffering from nociplastic pain. However, it remains elusive to which extent contextual factors and pain catastrophizing interact with cerebral pain modulation (independent of mood) in RA