Associations between fronto-limbic white matter connections and internalizing symptoms in pediatric demyelinating disease

Introduction: Children with neuroinflammatory disorders, such as multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), and myelin oligodendrocyte glycoprotein-associated disorder (MOGAD), have high rates of anxiety and depression. These symptoms may be linked to disruptions in fronto-limbic white matter (WM) tracts, including the cingulum bundle (CB), inferior fronto-occipital fasciculus (IFOF), and uncinate fasciculus (UF), which support emotional regulation. Methods: We studied 33 children with neuroinflammatory disorders and 28 healthy controls. Diffusion tensor imaging and white matter tract integrity maps were generated, focusing on WM tracts of interest (CB, IFOF, UF) and a control tract (acoustic radiation). We examined differences in WM microstructure and internalizing symptoms between high and low symptom groups. Results: Participants with MS (40%), MOGAD (28%), and NMOSD (25%) reported high levels of internalizing symptoms. MOGAD participants showed lower axonal water fraction compared to MS and controls. Both MS and MOGAD groups exhibited reduced intra-axonal diffusivity and increased extra-axonal diffusivity, indicating demyelination and axonal changes. No significant differences were found between high and low internalizing groups, but higher relapse rates were linked to less WM disruption in those with high internalizing symptoms. Limitations: The cross-sectional design limits causal interpretations, and medical covariates may affect WM structure. Conclusion: Neuroinflammatory disorders are linked to fronto-limbic WM changes and high internalizing symptoms. Relapse may influence WM structure and psychological resilience in this population.