Functional dysconnectivity and microstructural impairment of the cortico-thalamo-cortical network in women with rheumatoid arthritis: A multimodal MRI study

Abstract

Background: Cognitive deficits are common in rheumatoid arthritis (RA) patients, but the mechanisms remain unclear. We investigated the effective connectivity and structural alterations of the core brain regions in RA patients with cognitive impairment.

Methods: Twenty-four female patients with RA and twenty-four healthy controls were enrolled. We analyzed abnormal brain activity patterns using functional MRI during the Iowa gambling task (IGT) and core regions effective connectivity using dynamic causal model (DCM). Structural alterations of white matter volume (WMV) and gray matter volume (GMV) were detected using voxel-based morphometry (VBM).

Results: RA patients showed altered activation patterns of the cortico-thalamo-cortical network, increased coupling strength from the left ventromedial prefrontal gyrus to the anterior cingulate cortex (ACC), the ACC to the right thalamus, and decreased connectivity from the thalamus to left hippocampus. VBM structural analysis showed increased GMV in the bilateral orbital frontal gyrus, bilateral hippocampus and right putamen, and reduced GMV and WMV in the bilateral thalamus in RA patients. Right thalamic GMV and WMV were positively correlated with the right thalamus-to-hippocampus connective strength. Additionally, the bold signal, GMV and WMV of the right thalamus were positively correlated with cognitive performance (IGT score) in RA patients.

Conclusion: Results suggest a structural and functional deficiency in the cortico-thalamo-cortical network, which is characterized by increased ACC-to-thalamus strength and reduced thalamus-to-hippocampus coupling in RA patients. The cognitive dysfunction may be the result of compensatory measures against imbalanced cortico-thalamic-cortical coupling.

Keywords: Cognitive impairment; Cortico-thalamo-cortical network; DCM; Rheumatoid arthritis; VBM.

Fig. 1

Iowa Gambling Task (IGT) performance and activated brain regions in RA and HC groups. A. The total net IGT score was higher in healthy controls than in RA patients. B. There was no difference in the net score of blocks 1 and 2 between RA patients and healthy controls. The net score of blocks 3, 4, and 5 in healthy controls was higher than those of blocks 1 and 2, the score of block 5 was higher than that of block 3. RA patients did not show this learning trend. C. Enhanced activation in the left medial frontal gyrus, bilateral anterior cingulate, bilateral posterior cingulate, and left hippocampus and deactivation in right thalamus, right insula, right putamen and right middle temporal gyrus in RA patients compared to controls. D-E. In RA patients, the IGT net score was negatively correlated with the bold signal of the anterior cingulate (ACC) and positively correlated with the bold signal of the right thalamus (RTH).

Fig. 2

Differences in gray matter volume (GMV) and white matter volume (WMV) between the RA and HC groups. A. Compared to controls, the main GMV increases in RA patients were found in the bilateral orbital frontal cortex, bilateral hippocampus, and right putamen, whereas clusters of decreased GMV were found in the bilateral thalamus and left middle temporal gyrus. B. Decreased WMV was detected in the bilateral thalamus of RA patients. C-F. Total IGT net score was positively correlated with both GMV and WMV of right thalamus (RTH) in patients with RA, and the bold signal of the right thalamus was positively associated with GMV and WMV of the right thalamus.

Fig. 3

Effective connectivity between the right thalamus (RTH), left hippocampus (HIP), left thalamus (LTH), left ventromedial prefrontal gyrus (PFC) and anterior cingulate cortex (ACC). A. 20 models in which the brain regions in each model had bidirectional connections, and the decision-masking effect stimulation acted on effective connection in each of the two brain regions. B. DCM of healthy controls. C. DCM of RA patients. D. RA patients showed an abnormal effective connectivity between the right thalamus, left hippocampus, left thalamus, left PFC and ACC. E-F. In RA patients, both GMV and WMV of the right thalamus were positively correlated with the connective strength from the right thalamus to the hippocampus.