White matter microstructure and serum biomarkers of inflammation in psychogenic non-epileptic seizures

BACKGROUND: Neuroinflammation may contribute to the pathophysiology of psychogenic non-epileptic seizures (PNES). However, it is unclear whether and to what degree comorbid psychiatric symptoms explain this association. In this study, we investigated the neuroinflammatory signature of PNES and how it compares to that of people with psychiatric conditions (PwPCs). METHODS: We prospectively assessed differences in neurite density (NDI), orientation dispersion (ODI), and isotropic diffusion (F-ISO) in 23 participants with PNES and 27 PwPCs, and their relationships to serum levels of tumor necrosis factor (TNF)-α, TNF receptor 1 (TNF-R1), TNF-related apoptosis-inducing ligand (TRAIL), interleukin (IL)-6, intercellular adhesion molecule (ICAM)-1, and monocyte chemoattractant protein (MCP)-1 using voxelwise multiple linear regressions. Pearson correlations between serum biomarkers and clinical symptoms were also obtained. RESULTS: There were no white matter (WM) microstructural differences between groups. In PNES, TNF-R1 was negatively associated with NDI in the right uncinate fasciculus (UF) and positively associated with F-ISO in the left UF. IL-6 was positively associated with NDI and negatively with F-ISO in the left UF. ICAM-1 was positively associated with ODI in the left UF. TNF-α was negatively associated with ODI in the left cingulum bundle. The opposite relationships were observed in PwPCs. Higher TNF-R1 was associated with higher depression, anxiety, lower emotional quality of life, and higher levels of disability in PNES. CONCLUSIONS: For the first time, we report relationships between peripheral inflammatory biomarkers and WM integrity in PNES, including abnormalities in the UF and cingulum bundle. Our results suggest that serum biomarkers of inflammation may, with additional studies, become a useful aid to PNES diagnosis, especially in settings where video-EEG is not available. The lack of group differences in WM microstructure suggests that previously identified WM abnormalities in PNES versus healthy controls may be related to psychological comorbidities of PNES.