Multiple spatial scale mapping of time-resolved brain network reconfiguration during evoked pain in patients with rheumatoid arthritis.

Functional brain networks and the perception of pain can fluctuate over time. However, how the time-dependent reconfiguration of functional brain networks contributes to chronic pain remains largely unexplained. Here, we explored time-varying changes in brain network integration and segregation during pain over a disease-affected area (joint) compared to a neutral site (thumbnail) in 28 patients with rheumatoid arthritis (RA) in comparison with 22 healthy controls (HC). During functional magnetic resonance imaging, all subjects received individually calibrated pain pressures corresponding to visual analog scale 50 mm at joint and thumbnail. We implemented a novel approach to track changes of task-based network connectivity over time. Within this framework, we quantified measures of integration (participation coefficient, PC) and segregation (within-module degree z-score). Using these network measures at multiple spatial scales, both at the level of single nodes (brain regions) and communities (clusters of nodes), we found that PC at the community level was generally higher in RA patients compared to HC during and after painful pressure over the inflamed joint and corresponding site in HC. This shows that all brain communities integrate more in RA patients than in HC for time points following painful stimulation to a disease-relevant body site. However, the elevated community-related integration seen in patients appeared to not pertain uniquely to painful stimulation at the inflamed joint, but also at the neutral thumbnail, as integration and segregation at the community level did not differ across body sites in patients. Moreover, there was no specific nodal contribution to brain network integration or segregation. Altogether, our findings indicate widespread and persistent changes in network interaction in RA patients compared to HC in response to painful stimulation.

Distinct aberrations in cerebral pain processing differentiating patients with fibromyalgia from patients with rheumatoid arthritis.

ABSTRACT: The current study used functional magnetic resonance imaging to directly compare disease-relevant cerebral pain processing in well-characterized patient cohorts of fibromyalgia (FM, nociplastic pain) and rheumatoid arthritis (RA, nociceptive pain). Secondary aims were to identify pain-related cerebral alterations related to the severity of clinical symptoms such as pain intensity, depression, and anxiety. Twenty-six patients with FM (without RA-comorbidity) and 31 patients with RA (without FM-comorbidity) underwent functional magnetic resonance imaging while stimulated with subjectively calibrated painful pressures corresponding to a pain sensation of 50 mm on a 100-mm visual analogue scale. Stimulation sites were at the most inflamed proximal interphalangeal joint in the left hand in patients with RA and the left thumbnail in patients with FM, 2 sites that have previously been shown to yield the same brain activation in healthy controls. The current results revealed disease-distinct differences during pain modulation in RA and FM. Specifically, in response to painful stimulation, patients with FM compared to patients with RA exhibited increased brain activation in bilateral inferior parietal lobe (IPL), left inferior frontal gyrus (IFG)/ventrolateral prefrontal cortex (vlPFC) encapsulating left dorsolateral prefrontal cortex, and right IFG/vlPFC. However, patients with RA compared to patients with FM exhibited increased functional connectivity (during painful stimulation) between right and left IPL and sensorimotor network and between left IPL and frontoparietal network. Within the FM group only, anxiety scores positively correlated with pain-related brain activation in left dorsolateral prefrontal cortex and right IFG/vlPFC, which further highlights the complex interaction between affective (ie, anxiety scores) and sensory (ie, cerebral pain processing) dimensions in this patient group.

Intrinsic Brain Connectivity in Chronic Pain: A Resting-State fMRI Study in Patients with Rheumatoid Arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is commonly accompanied by pain that is discordant with the degree of peripheral pathology. Very little is known about the cerebral processes involved in pain processing in RA. Here we investigated resting-state brain connectivity associated with prolonged pain in RA. METHODS: 24 RA subjects and 19 matched controls were compared with regard to both behavioral measures of pain perception and resting-resting state fMRI data acquired subsequently to fMRI sessions involving pain stimuli. The resting-state fMRI brain connectivity was investigated using 159 seed regions located in cardinal pain processing brain regions. Additional principal component based multivariate pattern analysis of the whole brain connectivity pattern was carried out in a data driven analysis to localize group differences in functional connectivity. RESULTS: When RA patients were compared to controls, we observed significantly lower pain resilience for pressure on the affected finger joints (i.e., P50-joint) and an overall heightened level of perceived global pain in RA patients. Relative to controls, RA patients displayed increased brain connectivity predominately for the supplementary motor areas, mid-cingulate cortex, and the primary sensorimotor cortex. Additionally, we observed an increase in brain connectivity between the insula and prefrontal cortex as well as between anterior cingulate cortex and occipital areas for RA patients. None of the group differences in brain connectivity were significantly correlated with behavioral parameters. CONCLUSION: Our study provides experimental evidence of increased connectivity between frontal midline regions that are implicated in affective pain processing and bilateral sensorimotor regions in RA patients.

Remaining Pain in Early Rheumatoid Arthritis Patients Treated With Methotrexate.

OBJECTIVE: To investigate the frequency of remaining pain in early rheumatoid arthritis (RA) after 3 months of treatment with methotrexate as the only disease modifying antirheumatic drug, with a special focus on patients with a good clinical response. METHODS: The study base was cases reported to a population-based early RA cohort who had followup data from the Swedish Rheumatology Quality Register (n = 1,241). The Disease Activity Score in 28 joints European League Against Rheumatism (EULAR) response criteria were used to evaluate clinical response to treatment as good, moderate, and no response. The primary end point was remaining pain at the 3-months followup visit, defined as pain >20 mm on a 100-mm visual analog scale (VAS). RESULTS: Remaining pain in spite of a EULAR good response at followup was associated with higher baseline disability, using the Health Assessment Questionnaire (adjusted odds ratio [OR] 2.2 [95% confidence interval (95% CI) 1.4-3.4] per unit increase), and less baseline inflammation, using the erythrocyte sedimentation rate (adjusted OR 0.81 [95% CI 0.70-0.93] per 10-mm increase). Similar associations were detected for remaining pain at followup in spite of low inflammatory activity, defined as a C-reactive protein level <10. Increase in VAS pain during the treatment period was observed in 19% of the whole cohort, with frequencies in the EULAR response groups of 9% (good response), 15% (moderate response), and 45% (no response). CONCLUSION: These results are in line with the hypothesis that a subgroup of early RA patients exhibits pain that is not inflammatory mediated, where alternative treatment strategies to traditional antiinflammatory medications need to be considered.

Evidence of different mediators of central inflammation in dysfunctional and inflammatory pain--interleukin-8 in fibromyalgia and interleukin-1 ß in rheumatoid arthritis.

The purpose of this study was to relate central inflammation to autonomic activity (heart rate variability (HRV)) in patients with rheumatoid arthritis (RA) and fibromyalgia (FM). RA patients had reduced parasympathetic activity and FM patients had increased sympathetic activity compared to healthy controls. Comparisons between RA and FM showed higher cerebrospinal fluid (CSF) interleukin (IL)-1ß inversely correlated to parasympathetic activity in RA. The FM patients had higher concentrations of CSF IL-8, IL-1Ra, IL-4 and IL-10, but none of these cytokines correlated with HRV. In conclusion, we found different profiles of central cytokines, i.e., elevated IL-1ß in inflammatory pain (RA) and elevated IL-8 in dysfunctional pain (FM).

Kinetics of neuronal contribution during the development of a contact allergic reaction.

The nervous system contributes to allergic contact dermatitis (ACD). Elucidation of the implication of the nervous system during different stages of ACD could be of therapeutic value. Our aim was to study the kinetics and contribution of the nervous system to ACD by investigating innervation and expression of neuropeptides in skin biopsies obtained at 0, 6, 24, 48 and 72 h post-challenge. Biopsies were stained using antisera against protein gene product (PGP) 9.5, growth associated protein (GAP)-43, substance P and its receptor (R) neurokinin (NK)-1, NKA and NK-2R, and calcitonin gene-related peptide (CGRP). GAP-43-immunoreactive (ir) nerves revealed a time-dependent increase that was more pronounced at 48 and 72 h, while PGP 9.5-ir nerves remained unaltered. Substance P-, NKA- and CGRP-ir nerves at 0 and 6 h were significantly higher compared to later time points, whereas NKA-, NK-1R- and NK-2R-ir cells were lower. A dramatic rise in cell numbers was noted at 24 h. Our findings demonstrate the implication of nerves and sensory neuropeptides during the kinetics of ACD and suggest a possibility to target this system at an early time point for therapy.