Motor tract lesion mapping from brain to lower spinal cord in people with relapsing remitting multiple sclerosis: exploring the association between lesion severity and functional consequences by limb

Abstract Motor deficits in people with multiple sclerosis (pwMS) are often asymmetrical, suggesting an important role of focal lesions affecting the corresponding motor pathways. However, only a modest relationship has been established between lesion load and physical disability. One hypothesis could be that only heavily demyelinated lesions along the corticospinal tract (CST) would be associated with functional consequences. To test this hypothesis, we reconstructed the whole CST from the cortex to the bottom of the spinal cord and linked its structural damage with its functional consequences as measured clinically (with the American Spinal Injury Association motor [mASIA] score) and electrophysiologically (with the central motor conduction time [CMCT]) by limb. We prospectively included 60 relapsing remitting pwMS and 33 healthy controls. The CSTs were reconstructed using probabilistic atlases. Lesion volume fraction and myelin content (approximated through the magnetisation transfer ratio [MTR] and quantitative T1 [qT1]) were calculated by side on the different portions of the CST. Voxelwise MTR z-score maps were also produced to detect lesions severely demyelinated (z-score < −1.96 SD) along the whole CST. Forty-six pwMS and 28 healthy controls were included in the analyses. In the upper limb, CMCT was associated with both cervical lesion load (p < .001) and cervical MTR (p = .02) in the CST. In the lower limb, CMCT was associated with cervical lesion load and brain and thoracic MTR (all p < .001) in the CST. The EDSS score was associated with brainstem lesion load and thoracic MTR (all p < .01) in the CST. No association was found with the mASIA score per limb. Twenty-six percent of the lesions were classified as severe, mainly in the cervical CST. In patients with at least one severe lesion, extra-lesional MTR along the CST was lower than in those without severe lesions (p < .001). The presence of a severe lesion in the spinal cord CST was the only explanatory variable associated with an increased risk of having an abnormal lower limb CMCT (OR [95%CI]: 1.74 [1.36–2.24], p < .001). The main results were replicated with qT1. In this study, we describe varying levels of microstructural damage in lesions along the CST, with associations observed between lesion severity and both extra-lesional damage and CMCT. These findings highlight the critical role of severe lesions along the CST—particularly at the cervical level—beyond overall lesion load, and underscore the need to develop therapies that promote remyelination and to evaluate their effects at the cervical spinal cord level.