Mild traumatic brain injury is associated with effect of inflammation on structural changes of default mode network in those developing chronic pain

Abstract

Background: Mild traumatic brain injury (mTBI) has a higher prevalence (more than 50%) of developing chronic posttraumatic headache (CPTH) compared with moderate or severe TBI. However, the underlying neural mechanism for CPTH remains unclear. This study aimed to investigate the inflammation level and cortical volume changes in patients with acute PTH (APTH) and further examine their potential in identifying patients who finally developed CPTH at follow-up.

Methods: Seventy-seven mTBI patients initially underwent neuropsychological measurements, 9-plex panel of serum cytokines and MRI scans within 7 days post-injury (T-1) and 54 (70.1%) of patients completed the same protocol at a 3-month follow-up (T-2). Forty-two matched healthy controls completed the same protocol at T-1 once.

Results: At baseline, mTBI patients with APTH presented significantly increased GM volume mainly in the right dorsal anterior cingulate cortex (dACC) and dorsal posterior cingulate cortex (dPCC), of which the dPCC volume can predict much worse impact of headache on patients' lives by HIT-6 (β = 0.389, P = 0.007) in acute stage. Serum levels of C-C motif chemokine ligand 2 (CCL2) were also elevated in these patients, and its effect on the impact of headache on quality of life was partially mediated by the dPCC volume (mean [SE] indirect effect, 0.088 [0.0462], 95% CI, 0.01-0.164). Longitudinal analysis showed that the dACC and dPCC volumes as well as CCL2 levels had persistently increased in patients developing CPTH 3 months postinjury.

Conclusion: The findings suggested that structural remodelling of DMN brain regions were involved in the progression from acute to chronic PTH following mTBI, which also mediated the effect of inflammation processes on pain modulation.

Trial registration: ClinicalTrial.gov ID: NCT02868684 ; registered 16 August 2016.

Keywords: Inflammation effect; Mild traumatic brain injury; Posttraumatic headache; Voxel-based morphometry.

Fig. 1

GM volume changes in mTBI + APTH. Areas showing GM volume changes in patients with mTBI + APTH, compared with HC and mTBI – APTH groups (conjunction p < 0.05, FWE corrected), represented on a high-resolution T1-weighited template. Regions of increased GM volume are represented in red (color-coded for their t value). dACC = dorsal anterior cingulate cortex, dPCC = dorsal posterior cingulate cortex, VLPFC = ventrolateral prefrontal cortex, OFC = orbitofrontal cortex. mTBI + APTH = mild traumatic brain injury and acute post-traumatic headache, mTBI – APTH = mild traumatic brain injury without acute post-traumatic headache, HCs = healthy controls

Fig. 2

GM volume changes in mTBI + CPTH. Areas showing GM volume changes in patients with mTBI + CPTH, compared with HC and mTBI – CPTH groups (conjunction p < 0.05, FWE corrected), represented on a high-resolution T1-weighited template. Regions of increased GM volume are represented in red (color-coded for their t value), and regions of decreased GM volume are shown in blue (color-coded for their t values). dACC = dorsal anterior cingulate cortex, dPCC = dorsal posterior cingulate cortex, M1 = primary motor cortex, ITG = inferior temporal gyrus, DLPFC = dorsolateral prefrontal cortex, OFC = orbitofrontal cortex. mTBI + CPTH = mild traumatic brain injury and chronic post-traumatic headache, mTBI – CPTH = mild traumatic brain injury without chronic post-traumatic headache, HCs = healthy controls

Fig. 3

Mediation model. The relationship among CCL2 level, GMV of dPCC from conjunction analysis and HIT scores. Alteration of gray matter volume in the dPCC mediates the relationship between CCL2 level and HIT scores in early mTBI patients. Covariates (age, sex, education, injury time) were included in the model. Abbreviations: dPCC = dorsal posterior cingulate cortex; CCL2 = C-C motif chemokine ligand 2; HIT = short form headache impact test

Fig. 4

CCL2 level changes at acute and chronic phase post-injury. The CCL2 level significantly increased between the acute and chronic phase post-injury in the mTBI + CPTH group (*p < 0.05, repeated measures analysis of covariance [RM-ANCOVA]), but not in the mTBI – CPTH group (p = 0.08, RM-ANCOVA). mTBI + CPTH = mild traumatic brain injury and chronic post-traumatic headache, mTBI – CPTH = mild traumatic brain injury without chronic post-traumatic headache