Corticospinal tract alterations after ankle sprain in adolescence: Insights from the mouse model

Abstract

Purpose: Lateral ankle sprains (LAS) are associated with corticospinal pathway deficits. Existing evidence is primarily based on cross-sectional investigations and noncausal speculations. This study aims to determine whether maladaptive corticospinal pathway alterations occur pre- and postligament transection in LAS mouse models. Additionally, this study explores whether the alterations are more pronounced in adolescent mice than adults.

Methods: Twenty-four 8-week-old adolescent and twenty-four 24-week-old adult mice were randomly assigned to lateral ankle ligament transection or sham surgery. Diffusion-weighted imaging of the corticospinal pathway was performed presurgery and 8 weeks postsurgery. Fractional anisotropy (FA) values, reflecting fiber integrity within the corticospinal subregions of the medulla, pons, midbrain, and cerebrum, were extracted.

Results: Overall, 41 mice completed repeated image acquisition. Before surgery, no significant group effects on FA within the four corticospinal subregions were detected in either adolescent or adult mice. Two months after surgery, the adolescent cohort displayed a significant reduction in FA in the medulla subregion following ankle ligament transection (β-baseline-adjusted = −0.083, 95% CI, −0.145 to −0.021, p-corrected = 0.048). Conversely, no significant effects of ankle ligament transection on corticospinal FA were observed in the adult cohort.

Conclusion: The maladaptive alterations in the corticospinal tract could be observed in the adolescent LAS mouse model, characterized by reduced fiber integrity in the medulla subregion. While these results are derived from an animal model, they provide a foundation for future investigations into the mechanisms underlying neurological deficits following musculoskeletal injuries.

Keywords

Ankle injuries / Magnetic resonance imaging / Neuronal plasticity / Animal models

Conflict of interest

The authors have no direct or indirect interests that are in direct conflict with the conduction of this study.

Ethical approval statement

The Animal Welfare and Ethics Group of the Department of Experimental Animal Sciences granted the necessary approvals for all animal experimentation procedures involved in the study (Approval ID: 2020-JS645).

Funding

This work was supported by the National Natural Science Foundation of China [No. 81871823, 8207090113, 82072510], National Key R&D Program of China [No. 2018YFC1312900], Shanghai Natural Science Foundation [No. 20ZR1406400], Science and Technology Commission of Shanghai Municipality [No. 18JC1410403], and Shanghai Municipal Science and Technology Major Project [No.2017SHZDZX01, 2018SHZDZX01].

Data statement

The extracted MRI outcomes are available upon reasonable request corresponding to the senior authors (Y.H., [e-mail]; H.W., [e-mail])

CRediT authorship contribution statement

Xiao’ao Xue: Conceptualization, Data curation, Formal analysis, Writing - original draft. Xicheng Gu: Conceptualization, Data curation, Formal analysis, Writing - original draft. Yuwen Zhang: Conceptualization, Data curation, Formal analysis, Writing - original draft. Xuejun Wu: Methodology, Writing - review & editing. Tian Xia: Investigation, Writing - review & editing. Rong Lu: Formal analysis, Methodology, Software, Writing - review & editing. He Wang: Funding acquisition, Supervision, Writing - review & editing. Yinghui Hua: Funding acquisition, Supervision, Writing - review & editing.

Acknowledgements

The authors would like to express their gratitude to EditSprings (https://www.editsprings.cn) for the expert linguistic services provided.

Appendix A. Supplementary data

Supplementary data to this article can be found online at https://doi.org/10.1016/j.smhs.2024.06.006https://doi.org/10.1016/j.smhs.2024.06.006.

References

[1] Herzog MM, Kerr ZY, Marshall SW, Wikstrom EA. Epidemiology of ankle sprains and chronic ankle instability. J Athl Train. 2019; 54(6):603-610. https://doi.org/10.4085/1062-6050-447-17.

[2] Hong CC, Calder J. The Burden of the “Simple ankle sprains”: a review of the epidemiology and long-term impact. Foot Ankle Clin. 2023; 28(2):187-200. https://doi.org/10.1016/j.fcl.2022.12.002.

[3] Needle AR, Lepley AS, Grooms DR. Central nervous system adaptation after ligamentous injury: a summary of theories, evidence, and clinical interpretation. Sports Med. 2017; 47(7):1271-1288. https://doi.org/10.1007/s40279-016-0666-y.

[4] Hopkins JT, Ingersoll CD. Arthrogenic muscle inhibition: 20 Years on. J Sport Rehabil. 2022; 31(6):665-666. https://doi.org/10.1123/jsr.9.2.135.

[5] Lepley AS, Lepley LK. Mechanisms of arthrogenic muscle inhibition. J Sport Rehabil. 2021; 31(6):707-716. https://doi.org/10.1123/jsr.2020-0479.

[6] Terada M, Kosik KB, McCann RS, Drinkard C, Gribble PA. Corticospinal activity during a single-leg stance in people with chronic ankle instability. J Sport Heal Sci. 2022; 11(1):58-66. https://doi.org/10.1016/j.jshs.2020.08.008.

[7] McLeod MM, Gribble PA, Pietrosimone BG. Chronic ankle instability and neural excitability of the lower extremity. J Athl Train. 2015; 50(8):847-853. https://doi.org/10.4085/1062-6050-50.4.06.

[8] Terada M, Bowker S, Thomas AC, Pietrosimone B, Hiller CE, Gribble PA. Corticospinal excitability and inhibition of the soleus in individuals with chronic ankle instability. Pharm Manag PM R. 2016; 8(11):1090-1096. https://doi.org/10.1016/j.pmrj.2016.04.006.

[9] Kosik KB, Terada M, Drinkard CP, McCann RS, Gribble PA. Potential corticomotor plasticity in those with and without chronic ankle instability. Med Sci Sports Exerc. 2017; 49(1):141-149. https://doi.org/10.1249/MSS.0000000000001066.

[10] Lepley AS, Ly MT, Grooms DR, Kinsella-Shaw JM, Lepley LK. Corticospinal tract structure and excitability in patients with anterior cruciate ligament reconstruction: a DTI and TMS study. NeuroImage Clin. 2020;25:102157. https://doi.org/10.1016/j.nicl.2019.102157.

[11] Xue X, Li YI, Wang Y, et al. Maladaptive neuroplasticity in corticospinal tract after ankle sprain: causal links established by mendelian randomization. Med Sci Sports Exerc. 2023; 55(6):1114-1120. https://doi.org/10.1249/MSS.0000000000003134.

[12] Wakana S, Caprihan A, Panzenboeck MM, et al. Reproducibility of quantitative tractography methods applied to cerebral white matter. Neuroimage. 2007; 36(3): 630-644. https://doi.org/10.1016/j.neuroimage.2007.02.049.

[13] Terada M, Johnson N, Kosik K, Gribble P. Quantifying brain white matter microstructure of people with lateral ankle sprain. Med Sci Sports Exerc. 2019; 51(4): 640-646. https://doi.org/10.1249/MSS.0000000000001848.

[14] Xue X, Li Q, Wang Y, et al. Impaired corticospinal tract in chronic ankle instability: a diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) study at 7.0 Tesla. J Sci Med Sport. 2022; 25(8):649-654. https://doi.org/10.1016/j.jsams.2022.05.003.

[15] Bleakley C, Wagemans J, Netterstr€om-Wedin F. Understanding chronic ankle instability: model rich, data poor. Br J Sports Med. 2021; 55(9):463-464. https://doi.org/10.1136/bjsports-2020-103311.

[16] Wikstrom EA, Hubbard-Turner T, Woods S, Guderian S, Turner MJ. Developing a mouse model of chronic ankle instability. Med Sci Sports Exerc. 2015; 47(4):866-872. https://doi.org/10.1249/MSS.0000000000000466.

[17] Wikstrom EA, Hubbard-Turner T, Guderian S, Turner MJ. Lateral ankle sprain in a mouse model: lifelong sensorimotor dysfunction. J Athl Train. 2018; 53(3):249-254. https://doi.org/10.4085/1062-6050-365-16.

[18] Wikstrom EA, Hubbard-Turner T, Duncan A, Cline J, Turner MJ. Prolonged rest, long-term dynamic balance, and gait in a mouse ankle-sprain model. J Athl Train. 2019; 54(7):801-807. https://doi.org/10.4085/1062-6050-38-18.

[19] Dutta S, Sengupta P. Men and mice: relating their ages. Life Sci. 2016; 152:244-248. https://doi.org/10.1016/j.lfs.2015.10.025.

[20] Chang SH, Yasui T, Taketomi S, et al. Comparison of mouse and human ankles and establishment of mouse ankle osteoarthritis models by surgically-induced instability. Osteoarthritis Cartilage. 2016; 24(4):688-697. https://doi.org/10.1016/j.joca.2015.11.008.

[21] Hubbard-Turner T, Wikstrom EA, Turner MJ. A 14-day recovery and physical activity levels after an ankle sprain in mice. J Athl Train. 2019; 54(7):796-800. https://doi.org/10.4085/1062-6050-135-18.

[22] Hubbard-Turner T, Wikstrom EA, Guderian S, Turner MJ. Acute ankle sprain in a mouse model: changes in knee-joint space. J Athl Train. 2017; 52(6):587-591. https://doi.org/10.4085/1062-6050-52.3.07.

[23] Hubbard-Turner T, Wikstrom EA, Guderian S, Turner MJ. Acute ankle sprain in a mouse model. Med Sci Sports Exerc. 2013; 45(8):1623-1628. https://doi.org/10.1249/MSS.0b013e3182897d25.

[24] Xue X, Zhang Y, Tao W, et al. Longitudinal neuroplasticity after ankle sprain in mice: a voxel-based morphometry study on 11.7T MRI. J Orthop Res. 2023; 41(6): 1291-1298. https://doi.org/10.1002/jor.25458.

[25] Yan CG, Rincón-Cortés M, Raineki C, et al. Aberrant development of intrinsic brain activity in a rat model of caregiver maltreatment of offspring. Transl Psychiatry. 2017; 7(1):e1005. https://doi.org/10.1038/tp.2016.276.

[26] Lemon RN. Descending pathways in motor control. Annu Rev Neurosci. 2008; 31: 195-218. https://doi.org/10.1146/annurev.neuro.31.060407.125547.

[27] Liu P, Chen K, Wang S, Hua C, Zhang H, Yu J. A mouse model of ankle-subtalar joint complex instability induced post-traumatic osteoarthritis. J Orthop Surg Res. 2021; 16(1):541. https://doi.org/10.1186/s13018-021-02683-0.

[28] Lepley LK, McKeon PO, Fitzpatrick SG, Beckemeyer CL, Uhl TL, Butterfield TA. Neuromuscular alterations after ankle sprains: an animal model to Establish causal links after injury. J Athl Train. 2016; 51(10):797-805. https://doi.org/10.4085/1062-6050-51.11.13.

[29] Kim K-M, Kim J-S, Cruz-Díaz D, Ryu S, Kang M, Taube W. Changes in spinal and corticospinal excitability in patients with chronic ankle instability: a systematic review with meta-analysis. J Clin Med. 2019; 8(7):1037. https://doi.org/10.3390/jcm8071037.

[30] Kosik KB, Terada M, Drinkard CP, McCann RS, Gribble PA. Potential corticomotor plasticity in those with and without chronic ankle instability. Med Sci Sports Exerc. 2017; 49(1):141-149. https://doi.org/10.1249/MSS.0000000000001066.

[31] Davidoff RA. The pyramidal tract. Neurology. 1990; 40(2):332-339. https://doi.org/10.1212/wnl.40.2.332.

[32] Waterman BR, Owens BD, Davey S, Zacchilli MA, Belmont PJ. The epidemiology of ankle sprains in the United States. J Bone Jt Surg - Ser A. 2010; 92(13):2279-2284. https://doi.org/10.2106/JBJS.I.01537.

[33] Burke SN, Barnes CA. Neural plasticity in the ageing brain. Nat Rev Neurosci. 2006; 7(1):30-40. https://doi.org/10.1038/nrn1809.

[34] Kosik KB, Johnson NF, Terada M, Thomas AC, Mattacola CG, Gribble PA. Decreased dynamic balance and dorsiflexion range of motion in young and middle-aged adults with chronic ankle instability. J Sci Med Sport. 2019; 22(9):976-980. https://doi.org/10.1016/j.jsams.2019.05.005.

[35] Gribble PA, Bain KA, Davidson CD, Hoch MC, Kosik KB. Yoga as a balance intervention for middle-age and older adults with history of lateral ankle sprain: an exploratory study. J Bodyw Mov Ther. 2023; 35:190-195. https://doi.org/10.1016/j.jbmt.2023.04.010.

[36] Bruce AS, Howard JS, Van Werkhoven H, McBride JM, Needle AR. The effects of transcranial direct current stimulation on chronic ankle instability. Med Sci Sports Exerc. 2020; 52(2):335-344. https://doi.org/10.1249/MSS.0000000000002129.

[37] Ching SH, Chiu YC, Liao YC, Yang SH, Tsai YJ. A new mouse model of ankle instability induced by multiple mechanical sprains with controlled inversion angle and speed. Front Bioeng Biotechnol. 2022; 10:927987. https://doi.org/10.3389/fbioe.2022.927987.