A functional and structural MRI study of patients with rheumatoid arthritis (RA) now published in Nature Communications may begin to explain how chronic systemic inflammation changes brain function. “Two regions of the brain, the inferior parietal lobule and the medial prefrontal cortex, become more strongly connected to multiple brain networks in patients with higher levels of inflammation,” says corresponding author Andrew Schrepf.

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Inflammation is known to affect brain connectivity and patients with chronic inflammatory conditions are susceptible to fatigue and hyperalgesia. However, previous analyses of the link between inflammation and brain function were reliant on animal models or acute inflammatory induction by lipopolysaccharide injection into human volunteers. “We naturally wanted to know what happens to the brain in a chronic inflammatory condition,” explains Schrepf. For this purpose, patients with RA are ideal candidates, as natural fluctuations in the degree of systemic inflammation can be used as correlates, without the need to ‘artificially’ induce acute inflammatory responses with immunogens.

The researchers measured erythrocyte sedimentation rate and serum C-reactive protein concentration as markers of inflammation in 54 patients with RA. These patients then underwent functional MRI and structural neuroimaging while they performed a basic cognitive test of continuously adding numbers. Data at baseline were compared against a 6-month follow-up.

The authors visualized a decrease in grey matter in the inferior parietal lobule by voxel-based morphometry, but the data were not statistically significant and the loss was not detected in the medial prefrontal cortex; longer term follow-up may be needed.

Using seed-based correlation analyses to infer functional connections, the researchers found strong linkage to some well characterized seed networks, including the default mode network, dorsal attention network, salience network, and the medial visual network.

“We looked at a huge number of possible connections – every connection between every pair of regions after dividing up the brain into 264 areas,” explains Schrepf.

Aside from linking inflammation with increased connectivity to these networks, intriguingly, the researchers also noticed odd patterning correlations with patient-reported fatigue and severity of pain. “It looked as if the brains of patients with higher inflammation were drawing on resources from the default mode network,” specifies Schrepf, “which is usually thought of as being ‘quiet’ during tasks like the one patients were performing.” He thinks this unusual requisition of the brain’s computing power might be necessary for these patients to complete the mathematical task given, which hints at a basis for explaining cognitive dysfunction in patients with chronic inflammatory diseases.

“We are planning analyses in several other cohorts of patients with autoimmune disease and chronic pain to see how these findings hold up,” says Schrepf “but to really understand these mechanisms we need to see if they change with successful treatment.”