Deficits in the thalamocortical pathway associated with hypersensitivity to pain in patients with frozen shoulder

Abstract

Background and purpose: Frozen shoulder (FS) is a chronic pain condition and has been shown to be associated with pain sensitization. However, the underyling brain mechanisms remain unclear. Here, we aimed to explore brain alterations and their association with pain sensitization in patients with FS.

Materials and methods: A total of 54 FS patients and 52 healthy controls (HCs) were included in this study. Here, we applied both structural and functional magnetic resonance imaging (MRI) techniques to investigate brain abnormalities in FS patients. Voxel-wise comparisons were performed to reveal the differences in the gray matter volume (GMV) and amplitude of low-frequency fluctuation (ALFF) between FS patients and HCs. Furthermore, the region of interest (ROI) to whole-brain functional connectivity (FC) was calculated and compared between groups. Finally, Pearson's correlation coefficients were computed to reveal the association between clinical data and brain alterations.

Results: Four main findings were observed: (1) FS patients exhibited decreased thalamus GMV, which correlated with pain intensity and pain threshold; (2) relative to HCs, FS patients exhibited a higher level of ALFF within the anterior cingulate cortex (ACC) and the thalamus; (3) FS patients exhibited a significant increase in Tha-S1 FC compared to HCs; and (4) the effect of thalamus GMV on pain intensity was mediated by pain threshold in FS patients.

Conclusion: The dysfunctional thalamus might induce pain hypersensitivity, which further aggravates the pain in FS patients.

Keywords: amplitude of low frequency fluctuation; chronic pain; frozen shoulder; functional connectivity; functional magnetic resonance imaging; gray matter volume.

Figure 1

(A) Differences in the Pain Catastrophic Scale (PCS), Pain Vigilance and Awareness Questionnaire (PVAQ), and pain threshold (PT) between frozen shoulder (FS) and healthy controls (HC). ****P < 0.001. (B) left. Heat map for association among PCS, PVAQ, PT, and pain intensity (NRS) in FS patients. (B) right. Heat map for association among PCS, PVAQ, and PT in HC patients. (C) Scatter plots for the significant correlation between PT and pain intensity, between PVAQ and PCS, and between PVAQ and pain intensity.

Figure 2

(A) Brain regions exhibited decreased gray matter volume (GMV) in the frozen shoulder (FS) patients relative to healthy controls (HC). (B) Brain regions exhibited increased amplitude of low-frequency fluctuation (ALFF) in FS relative to HC. (C) Intersection for structural and functional alterations in thalamus. The intersection was used for functional connectivity (FC) analysis. (D) Brain regions exhibited increased FC in the frozen shoulder (FS) patients relative to healthy controls (HC).

Figure 3

Association between brain alterations and clinical measurements. (A) Scatter plot for a positive association between thalamus gray matter volume (GMV) and pain threshold (PT). (B) Scatter plot for a negative association between the thalamus GMV and pain intensity. (C) Scatter plot for a negative association between the thalamus GMV and amplitude of low-frequency fluctuation (ALFF). (A) Scatter plot for a positive association between the anterior cingulate cortex (ACC), ALFF, and pain vigilance and awareness questionnaire (PVAQ).

Figure 4

(A) Medication analyses. The effect of GMV on pain intensity was mediated by pain threshold in FS patients. (B) The possible assumption for pain hypersensitivity in FS patients based on our current findings.