Neuroimmune Links to White-matter Microstructure in Medication-naïve Children with Tic Disorder: A Mediation Analysis.
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OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.