Importance: Multiple sclerosis (MS) is an immune-mediated neurological disorder that affects 2.4 million people world-wide, and up to 60% experience anxiety. Objective: We investigated how anxiety in MS is associated with white matter lesion burden in the uncinate fasciculus (UF). Design: Retrospective case-control study of participants who received research-quality 3-tesla (3T) neuroimaging as part of MS clinical care from 2010-2018. Analyses were performed from June 1st to September 30th, 2024. Setting: Single-center academic medical specialty MS clinic. Participants: Participants were identified from the electronic medical record. All participants were diagnosed by an MS specialist and completed research-quality MRI at 3T. After excluding participants with poor image quality, 372 were stratified into three groups which were balanced for age and sex: 1) MS without anxiety (MS+noA, n=99); 2) MS with mild anxiety (MS+mildA, n=249); and 3) MS with severe anxiety (MS+severeA, n=24). Exposure: Anxiety diagnosis and anxiolytic medication. Main Outcome and Measure: We first evaluated whether MS+severeA patients had greater lesion burden in the UF than MS+noA. Next, we examined whether increasing anxiety severity was associated with greater UF lesion burden. Generalized additive models were employed, with the burden of lesions (e.g. proportion of fascicle impacted) within the UF as the outcome measure and sex and spline of age as covariates. Results: UF burden was higher in MS+severeA as compared to MS+noA (T=2.02, P=0.045, Cohen f2=0.19). A dose-response effect was also found, where higher mean UF burden was associated with higher anxiety severity (T=2.08, P=0.038, Cohen f2=0.10). Conclusions and Relevance: We demonstrate that overall lesion burden in UF was associated with the presence and severity of anxiety in patients with MS. Future studies linking white matter lesion burden in UF with treatment prognosis are warranted.

The authors have declared no competing interest.

This work was supported by grants from the National Institute of Mental Health (K23MH133118 to EBB; R01MH112847 to TDS and RTS; R01MH120482 and R01MH113550 to TDS; R01MH123550 to RTS), Brain and Behavior Research Foundation (NARSAD Young Investigator Award #31319 to EBB), the National Institute for Neurological Disorder and Stroke (R01NS085211 and R01NS112274 to RTS), and the National Multiple Sclerosis Society. Additional support was provided by the Penn-CHOP Lifespan Brain Institute.

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The University of Pennsylvania Institutional Review Board gave ethical approval for this work.

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Patient data are HIPAA-protected and cannot be shared publicly. Code and instructions for replicating all analyses can be found at: https://baller-lab.github.io/msanxiety/.

https://baller-lab.github.io/msanxiety/