HIGHER lesion burden in the uncinate fasciculus (UF), a key brain pathway linking emotional regulation regions, is associated with increased anxiety severity in multiple sclerosis (MS) patients, according to a retrospective case-control study of 372 individuals.
MS, an immune-mediated neurological disorder affecting 2.4 million people globally, is frequently accompanied by anxiety, with up to 60% of patients experiencing symptoms. Despite its prevalence, the neural mechanisms underlying anxiety in MS remain poorly understood. This study investigated whether white matter lesions in the UF—a tract connecting the orbitofrontal cortex and amygdala, critical for emotional processing—correlate with anxiety severity. Participants were stratified into three groups: 99 without anxiety (MS+noA), 249 with mild anxiety (MS+mildA), and 24 with severe anxiety (MS+severeA), all balanced for age and sex. Researchers analysed 3T MRI scans performed between 2010–2018, using generalised additive models to assess UF lesion burden while adjusting for age, sex, and total brain volume.
Patients with severe anxiety exhibited significantly higher UF lesion burden compared to those without anxiety (T=2.01, P=0.047; Cohen’s f²=0.19, 95% CI 0.08–0.52). A dose-response relationship emerged, with greater UF lesion burden linked to worsening anxiety severity (T=2.09, P=0.04; f²=0.10, 95% CI 0.05–0.21). Sensitivity analyses confirmed specificity to the UF, as no associations were found with fornix lesions or depression diagnoses. Notably, 79% of severe anxiety patients were female, reflecting MS’s higher prevalence in women.
These findings suggest UF lesions may disrupt neural circuits governing fear and emotional regulation, contributing to anxiety in MS. Clinicians should consider neuroimaging assessments of UF integrity when managing anxiety in MS patients, particularly those unresponsive to standard therapies. Future research should explore whether reducing UF lesion burden through disease-modifying therapies alleviates anxiety symptoms and investigate targeted interventions for this high-risk subgroup.
Reference
Baller EB et al. Uncinate fasciculus lesion burden and anxiety in multiple sclerosis. JAMA Netw Open. 2025;8(4):e254751.
