Maladaptive Neuroplasticity in Corticospinal Tract after Ankle Sprain: Causal Links Established by Mendelian Randomization

It has been hypothesized that the corticospinal tract (CST) is involved in the neural origins underlying muscular deficits after an ankle sprain. Microstructural differences in the CST have been reported in patients with and without a history of ankle sprain, but the causal links between the CST and the injuries have not been verified. This study aimed to explore whether genetically predisposed ankle sprains would impair the integrity and organization of CST neurites, manifesting as reduced fractional anisotropy (FA) and increased orientation dispersion index (ODI). Single-nucleotide polymorphisms (SNP) associated with ankle sprains were identified from genome-wide association studies (GWAS) in FinnGen based on hospital discharge records (7223 cases and 245,598 controls). Outcome statistics for CST microstructures were collected from the GWAS from diffusion-weighted-imaging outcomes in the UK Biobank (33,224 participants). Random-effect, inverse-variance weighted Mendelian randomization was used as the primary method. Eighteen SNP were selected as forming possible causal links between ankle sprains and CST structure; F value ranged from 755 to 1026. Ankle sprains were associated with a reduction in the FA of the right CST ( β = -0.033, P = 0.0439), whereas no significant effects were observed on the left side ( β = -0.029, 0.004; P = 0.0748). Ankle sprains significantly increased the ODI of the left CST ( β = 0.053, P = 0.0036) and the right CST ( β = 0.038, P = 0.0259). No significant pleiotropy or heterogeneity was observed in the analyses. A genetic predisposition to ankle sprains can lead to maladaptive neuroplasticity of the CST, manifesting as abnormally organized neurites.