It is unknown how chronic inflammation impacts the brain. Here, we examined whether higher levels of peripheral inflammation were associated with brain connectivity and structure in 54 rheumatoid arthritis patients using functional and structural MRI. We show that higher levels of inflammation are associated with more positive connections between the inferior parietal lobule (IPL), medial prefrontal cortex, and multiple brain networks, as well as reduced IPL grey matter, and that these patterns of connectivity predicted fatigue, pain and cognitive dysfunction. At a second scan 6 months later, some of the same patterns of connectivity were again associated with higher peripheral inflammation. A graph theoretical analysis of whole-brain functional connectivity revealed a pattern of connections spanning 49 regions, including the IPL and medial frontal cortex, that are associated with peripheral inflammation. These regions may play a critical role in transducing peripheral inflammatory signals to the central changes seen in rheumatoid arthritis.
Chronic overlapping pain conditions (COPCs) are characterized by aberrant central nervous system processing of pain. This "centralized pain" phenotype has been described using a large and diverse set of symptom domains, including the spatial distribution of pain, pain intensity, fatigue, mood imbalances, cognitive dysfunction, altered somatic sensations, and hypersensitivity to external stimuli. Here, we used 3 cohorts, including patients with urologic chronic pelvic pain syndrome, a mixed pain cohort with other COPCs, and healthy individuals (total n = 1039) from the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network to explore the factor structure of symptoms of centralized pain. Using exploratory and confirmatory factor analysis, we identified 2 general factors in all 3 cohorts, one characterized by a broad increased sensitivity to internal somatic sensations,environmental stimuli, and diffuse pain, termed Generalized Sensory Sensitivity, and one characterized by constitutional symptoms-Sleep, Pain, Affect, Cognition, Energy (SPACE). Longitudinal analyses in the urologic chronic pelvic pain syndrome cohort found the same 2-factor structure at month 6 and 1 year, suggesting that the 2-factor structure is reproducible over time. In secondary analyses, we found that Generalized Sensory Sensitivity particularly is associated with the presence of comorbid COPCs, whereas SPACE shows modest associations with measures of disability and urinary symptoms. These factors may represent an important and distinct continuum of symptoms that are indicative of the centralized pain phenotype at high levels. Future research of COPCs should accommodate the measurement of each factor.
Fibromyalgia (FM) is a chronic widespread pain condition characterized by augmented multi-modal sensory sensitivity. Although the mechanisms underlying this sensitivity are thought to involve an imbalance in excitatory and inhibitory activity throughout the brain, the underlying neural network properties associated with hypersensitivity to pain stimuli are largely unknown. In network science, explosive synchronization (ES) was introduced as a mechanism of hypersensitivity in diverse biological and physical systems that display explosive and global propagations with small perturbations. We hypothesized that ES may also be a mechanism of the hypersensitivity in FM brains. To test this hypothesis, we analyzed resting state electroencephalogram (EEG) of 10 FM patients. First, we examined theoretically well-known ES conditions within functional brain networks reconstructed from EEG, then tested whether a brain network model with ES conditions identified in the EEG data is sensitive to an external perturbation. We demonstrate for the first time that the FM brain displays characteristics of ES conditions, and that these factors significantly correlate with chronic pain intensity. The simulation data support the conclusion that networks with ES conditions are more sensitive to perturbation compared to non-ES network. The model and empirical data analysis provide convergent evidence that ES may be a network mechanism of FM hypersensitivity.
Supplemental Digital Content is Available in the Text.Hub topology is altered in fibromyalgia, and disruption of the excitatory tone within the insula influences hub status and is associated with clinical pain intensity.
RA patients who have increased levels of FMness appear to share neurobiologic features consistently observed in FM patients. This study is the first to provide neuroimaging evidence that RA is a mixed pain state, with many patients' symptoms being related to the central nervous system rather than to classic inflammatory mechanisms.
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