Neuroimmune Links to White-matter Microstructure in Medication-naïve Children with Tic Disorder: A Mediation Analysis

To determine whether newly diagnosed pediatric tic disorder is associated with white-matter microstructural alterations on diffusion tensor imaging (DTI) relative to healthy controls, and whether these changes relate to tic severity and circulating pro-inflammatory cytokines.

Twenty-one medication-naïve children with tic disorder and 26 healthy controls underwent 3T DTI and blood sampling. Voxel-wise group differences in fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity, and radial diffusivity (RD) were examined using tract-based spatial statistics. In the tic group, correlations between DTI metrics, tic severity (Yale Global Tic Severity Scale scores), and cytokine levels were tested, followed by mediation analysis.

Patients showed lower FA and higher MD and RD across multiple tracts, including the corpus callosum, corticospinal tract, inferior longitudinal fasciculus (ILF), and inferior fronto-occipital fasciculus (IFOF). Elevated RD in the left ILF correlated with greater tic severity (ρ = 0.61, p = 0.004). Cytokine-DTI associations were region-specific: higher interleukin-1β was linked to lower FA in the left corticospinal tract and higher MD in the right IFOF, whereas higher tumor necrosis factor-α was associated with lower RD in the right IFOF.

Medication-naïve pediatric tic disorder is characterized by widespread white-matter abnormalities that relate to both clinical severity and peripheral inflammation. Integrating DTI and immune measures may facilitate biomarker development and guide neuroinflammation-targeted interventions in pediatric tic disorders.