A multi-modal MRI study of the central response to inflammation in rheumatoid arthritis

Abstract

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.

Conflict of interest statement

Pfizer provided supplementary funding to N.B. for data acquisition. D.J.C. has consulted or served as an expert witness for Forest Laboratories, Pfizer, Inc, Cerephex Corp, Eli Lilly and Company, Merck & Co, Nuvo Research Inc, Tonix Pharmaceuticals, Johnson & Johnson, Pierre Fabre, Cypress Biosciences, Wyeth Pharmaceuticals, UCB, AstraZeneca, Jazz Pharmaceuticals, Abbott Laboratories, and Iroko Pharmaceuticals. R.E.H. has consulted for Pfizer, Inc. S.E.H. has received research funding from Aptinyx, Cerephex, Eli Lily, Forest Laboratories, and Merck and served as a consultant for Pfizer, Analgesic Solutions, Aptinyx, and deCode Genetics. A.S., C.M.K., S.E.H., R.E.H., T.L., E.I., and D.J.C. have all received funding from the National Institutes of Health. The remaining authors declare no competing interests.

Figures

Fig. 1

Box plots of clinical characteristics and symptoms at baseline and 6 months for 54 rheumatoid arthritis patients. The center line represents the median value, the lower bound of the box represents the 25th percentile, the upper bound of the box the 75th percentile, and the whiskers represent minimum and maximum values, or 1.5 times the interquartile range in the presence of outliers, which are indicated by dots or asterisks

Fig. 2

Inflammation-associated functional connectivity patterns. Brain regions (medial prefrontal cortex [mPFC], inferior parietal lobule [IPL]) showing positive connections to the default mode network (DMN; a), dorsal attention network (DAN; b, c), medial visual network (MVN; d), and salience network (SLN; e, f) at higher levels of peripheral inflammation. Scatterplots showing the strength connectivity and levels of erythrocyte sedimentation rate (ESR) are displayed below brain images. All associations were detected using seed networks identified by independent component analysis in a whole-brain search with ESR as the primary predictor of interest controlling for age and sex with p < 0.05 false discovery rate (FDR) cluster corrected for multiple comparisons

Fig. 3

Overlap of inflammation-associated functional connectivity changes. a Brain regions (medial prefrontal cortex [mPFC], inferior parietal lobule [IPL]) showing positive connectivity to the different networks (medial visual network [MVN], default mode network [DMN], dorsal attention network [DAN], salience network [SLN]) at higher levels of peripheral inflammation measured by erythrocyte sedimentation rate (ESR). Area of reduced grey matter volume is shown in light blue. This was identified by testing the association of ESR with grey matter volume derived through voxel-based morphometry (VBM) in 8 mm spheres extracted around the significant peak cluster coordinates from the session 1 network to whole-brain connectivity analyses, in multiple linear regression analyses controlling for age and sex at p < 0.05 uncorrected. b Scatterplot showing the association between ESR and grey matter volume. Displayed at p = 0.005 voxel threshold corrected for age and sex

Fig. 4

Overlap of inflammation-associated functional connectivity at both time points. a Positive connections between the default mode network (DMN) with the inferior parietal lobule (IPL), b dorsal attention network (DAN) and IPL, c the DAN and medial prefrontal cortex (mPFC) at baseline and 6 months that were associated with increased peripheral inflammation measured by erythrocyte sedimentation rate (ESR). Scatterplots showing the association between ESR and the strength of connectivity are displayed next to each brain region. Extracted average Fisher r values from 8 mm spheres derived from the significant peak cluster coordinates identified at session 1 (baseline) were used at session 2 (month 6) and these were correlated with concurrent ESR values using Pearson correlations at p < 0.05 uncorrected. Baseline regions are shown in orange, 6 months in blue. Displayed at p = 0.005 voxel threshold

Fig. 5

Summary of inflammation-associated functional connectivity changes. a Nodes and edges showing the Network-Based Statistic (NBS) inflammation configuration, with scatterplot showing the association (Pearson correlation) between erythrocyte sedimentation rate (ESR) and the average strength of connectivity across the 54 edges. Undirected and weighted Fisher z-transformed bivariate correlation matrices of connectivity were created for each subject from 10 mm diameter spheres at the 264 nodes of the Power atlas (264 × 264 matrices). Identified nodes and edges associated in aggregate with higher ESR are derived from permutation testing at family wise error corrected p < 0.05. b Overlap of regions of positive connectivity identified through seed network to whole-brain analyses and nodes identified through NBS analyses of higher inflammation