Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Perspective
  • Published:

The neuroanatomical–functional paradox in spinal cord injury

Nature Reviews Neurology volume 17, pages 53–62 (2021)Cite this article

Subjects

A Publisher Correction to this article was published on 08 August 2023

This article has been updated

Abstract

Although lesion size is widely considered to be the most reliable predictor of outcome after CNS injury, lesions of comparable size can produce vastly different magnitudes of functional impairment and subsequent recovery. This neuroanatomical–functional paradox is likely to contribute to the many failed attempts to independently replicate findings from animal models of neurotrauma. In humans, the analogous clinical–radiological paradox could explain why individuals with similar injuries can respond differently to rehabilitation. We describe the neuroanatomical–functional paradox in the context of traumatic spinal cord injury (SCI) and discuss the underlying mechanisms of the paradox, including the concepts of lesion-affected and recovery-related networks. We also consider the various secondary complications that further limit the accuracy of outcome prediction in SCI and provide suggestions for how to increase the predictive, translational value of preclinical SCI models.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Non-linear relationship between anatomical lesion severity and outcome.
Fig. 2: The neuroanatomical–functional paradox of recovery after spinal cord injury.
Fig. 3: Reversible axonal injury and transient recovery.
Fig. 4: Distinguishing between lesion-affected and recovery-related networks after spinal cord injury.
Fig. 5: Spared axonal fibres as outcome denominators independent of lesion size.
Fig. 6: Outcome variability and underlying causes.

Similar content being viewed by others

Change history

References

  1. Marino, R. J., Ditunno, J. F. Jr., Donovan, W. H. & Maynard, F. Jr. Neurologic recovery after traumatic spinal cord injury: data from the Model Spinal Cord Injury Systems. Arch. Phys. Med. Rehabil. 80, 1391–1396 (1999).

    Article  CAS  PubMed  Google Scholar 

  2. Fawcett, J. W. et al. Guidelines for the conduct of clinical trials for spinal cord injury as developed by the ICCP panel: spontaneous recovery after spinal cord injury and statistical power needed for therapeutic clinical trials. Spinal Cord 45, 190–205 (2007).

    Article  CAS  PubMed  Google Scholar 

  3. Schucht, P., Raineteau, O., Schwab, M. E. & Fouad, K. Anatomical correlates of locomotor recovery following dorsal and ventral lesions of the rat spinal cord. Exp. Neurol. 176, 143–153 (2002).

    Article  CAS  PubMed  Google Scholar 

  4. Hurd, C., Weishaupt, N. & Fouad, K. Anatomical correlates of recovery in single pellet reaching in spinal cord injured rats. Exp. Neurol. 247, 605–614 (2013).

    Article  CAS  PubMed  Google Scholar 

  5. Fouad, K., Hurd, C. & Magnuson, D. S. Functional testing in animal models of spinal cord injury: not as straight forward as one would think. Front. Integr. Neurosci. 7, 85 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  6. Steward, O., Popovich, P. G., Dietrich, W. D. & Kleitman, N. Replication and reproducibility in spinal cord injury research. Exp. Neurol. 233, 597–605 (2012).

    Article  PubMed  Google Scholar 

  7. Lam, C. J., Assinck, P., Liu, J., Tetzlaff, W. & Oxland, T. R. Impact depth and the interaction with impact speed affect the severity of contusion spinal cord injury in rats. J. Neurotrauma 31, 1985–1997 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  8. Ballermann, M. & Fouad, K. Spontaneous locomotor recovery in spinal cord injured rats is accompanied by anatomical plasticity of reticulospinal fibers. Eur. J. Neurosci. 23, 1988–1996 (2006).

    Article  PubMed  Google Scholar 

  9. Martinez, M., Delivet-Mongrain, H., Leblond, H. & Rossignol, S. Recovery of hindlimb locomotion after incomplete spinal cord injury in the cat involves spontaneous compensatory changes within the spinal locomotor circuitry. J. Neurophysiol. 106, 1969–1984 (2011).

    Article  PubMed  Google Scholar 

  10. Loy, D. N. et al. Functional redundancy of ventral spinal locomotor pathways. J. Neurosci. 22, 315–323 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Loy, D. N. et al. Both dorsal and ventral spinal cord pathways contribute to overground locomotion in the adult rat. Exp. Neurol. 177, 575–580 (2002).

    Article  PubMed  Google Scholar 

  12. Brustein, E. & Rossignol, S. Recovery of locomotion after ventral and ventrolateral spinal lesions in the cat. I. Deficits and adaptive mechanisms. J. Neurophysiol. 80, 1245–1267 (1998).

    Article  CAS  PubMed  Google Scholar 

  13. Filli, L. et al. Bridging the gap: a reticulo-propriospinal detour bypassing an incomplete spinal cord injury. J. Neurosci. 34, 13399–13410 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Aboul-Enein, F., Weiser, P., Höftberger, R., Lassmann, H. & Bradl, M. Transient axonal injury in the absence of demyelination: a correlate of clinical disease in acute experimental autoimmune encephalomyelitis. Acta Neuropathol. 111, 539–547 (2006).

    Article  PubMed  Google Scholar 

  15. Kerschensteiner, M., Schwab, M. E., Lichtman, J. W. & Misgeld, T. In vivo imaging of axonal degeneration and regeneration in the injured spinal cord. Nat. Med. 11, 572–577 (2005).

    Article  CAS  PubMed  Google Scholar 

  16. Duncan, G. J. et al. Locomotor recovery following contusive spinal cord injury does not require oligodendrocyte remyelination. Nat. Commun. 9, 3066 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  17. Bartus, K. et al. Neuregulin-1 controls an endogenous repair mechanism after spinal cord injury. Brain 139, 1394–1416 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  18. Pukos, N., Goodus, M. T., Sahinkaya, F. R. & McTigue, D. M. Myelin status and oligodendrocyte lineage cells over time after spinal cord injury: what do we know and what still needs to be unwrapped? Glia 67, 2178–2202 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Chen, H. S., Holmes, N., Liu, J., Tetzlaff, W. & Kozlowski, P. Validating myelin water imaging with transmission electron microscopy in a rat spinal cord injury model. Neuroimage 153, 122–130 (2017).

    Article  PubMed  Google Scholar 

  20. Goldstein, B., Hammond, M. C., Stiens, S. A. & Little, J. W. Posttraumatic syringomyelia: profound neuronal loss, yet preserved function. Arch. Phys. Med. Rehabil. 79, 107–112 (1998).

    Article  CAS  PubMed  Google Scholar 

  21. Dreizin, D. et al. Will the real SCIWORA please stand up? exploring clinicoradiologic mismatch in closed spinal cord injuries. AJR Am. J. Roentgenol. 205, 853–860 (2015).

    Article  PubMed  Google Scholar 

  22. Curt, A. The translational dialogue in spinal cord injury research. Spinal Cord 50, 352–357 (2012).

    Article  CAS  PubMed  Google Scholar 

  23. Popovich, P. G. et al. The neuropathological and behavioral consequences of intraspinal microglial/macrophage activation. J. Neuropathol. Exp. Neurol. 61, 623–633 (2002).

    Article  CAS  PubMed  Google Scholar 

  24. Pouratian, N. & Bookheimer, S. Y. The reliability of neuroanatomy as a predictor of eloquence: a review. Neurosurg. Focus. 28, E3 (2002).

    Article  Google Scholar 

  25. Levine, A. J. et al. Identification of a cellular node for motor control pathways. Nat. Neurosci. 17, 586–593 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Stepien, A. E., Tripodi, M. & Arber, S. Monosynaptic rabies virus reveals premotor network organization and synaptic specificity of cholinergic partition cells. Neuron 68, 456–472 (2010).

    Article  CAS  PubMed  Google Scholar 

  27. Conta, A. C. & Stelzner, D. J. Differential vulnerability of propriospinal tract neurons to spinal cord contusion injury. J. Comp. Neurol. 479, 347–359 (2004).

    Article  PubMed  Google Scholar 

  28. Filli, L. & Schwab, M. E. Structural and functional reorganization of propriospinal connections promotes functional recovery after spinal cord injury. Neural Regen. Res. 10, 509–513 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Miles, G. B., Hartley, R., Todd, A. J. & Brownstone, R. M. Spinal cholinergic interneurons regulate the excitability of motoneurons during locomotion. Proc. Natl Acad. Sci. USA 104, 2448–2453 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Liu, Y. et al. Touch and tactile neuropathic pain sensitivity are set by corticospinal projections. Nature 561, 547–550 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Kirshblum, S. et al. The impact of sacral sensory sparing in motor complete spinal cord injury. Arch. Phys. Med. Rehabil. 92, 376–383 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  32. Waters, R. L., Adkins, R. H. & Yakura, J. S. Definition of complete spinal cord injury. Paraplegia 29, 573–581 (1991).

    CAS  PubMed  Google Scholar 

  33. Zdunczyk, A. et al. The corticospinal reserve capacity: reorganization of motor area and excitability as a novel pathophysiological concept in cervical myelopathy. Neurosurgery 83, 810–818 (2018).

    Article  PubMed  Google Scholar 

  34. Torres-Espín, A. et al. Eliciting inflammation enables successful rehabilitative training in chronic spinal cord injury. Brain 141, 1946–1962 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  35. Kanagal, S. G. & Muir, G. D. Task-dependent compensation after pyramidal tract and dorsolateral spinal lesions in rats. Exp. Neurol. 216, 193–206 (2009).

    Article  PubMed  Google Scholar 

  36. Whishaw, I. Q., Gorny, B. & Sarna, J. Paw and limb use in skilled and spontaneous reaching after pyramidal tract, red nucleus and combined lesions in the rat: behavioral and anatomical dissociations. Behav. Brain Res. 93, 167–183 (1998).

    Article  CAS  PubMed  Google Scholar 

  37. Curt, A., Van Hedel, H. J. A., Klaus, D. & Dietz, V., EM-SCI Study Group. Recovery from a spinal cord injury: significance of compensation, neural plasticity, and repair. J. Neurotrauma. 25, 677–685 (2008).

    Article  PubMed  Google Scholar 

  38. Fouad, K., Pedersen, V., Schwab, M. E. & Brösamle, C. Cervical sprouting of corticospinal fibers after thoracic spinal cord injury accompanies shifts in evoked motor responses. Curr. Biol. 11, 1766–1770 (2001).

    Article  CAS  PubMed  Google Scholar 

  39. Bareyre, F. M. et al. The injured spinal cord spontaneously forms a new intraspinal circuit in adult rats. Nat. Neurosci. 7, 269–277 (2004).

    Article  CAS  PubMed  Google Scholar 

  40. Krajacic, A., Weishaupt, N., Girgis, J., Tetzlaff, W. & Fouad, K. Training-induced plasticity in rats with cervical spinal cord injury: effects and side effects. Behav. Brain Res. 214, 323–331 (2010).

    Article  PubMed  Google Scholar 

  41. van den Brand, R. et al. Restoring voluntary control of locomotion after paralyzing spinal cord injury. Science 336, 1182–1185 (2012).

    Article  PubMed  Google Scholar 

  42. Liu, K. et al. PTEN deletion enhances the regenerative ability of adult corticospinal neurons. Nat. Neurosci. 13, 1075–1081 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Wang, Z., Reynolds, A., Kirry, A., Nienhaus, C. & Blackmore, M. G. Overexpression of Sox11 promotes corticospinal tract regeneration after spinal injury while interfering with functional recovery. J. Neurosci. 35, 3139–3145 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Jayaprakash, N. et al. Optogenetic interrogation of functional synapse formation by corticospinal tract axons in the injured spinal cord. J. Neurosci. 36, 5877–5890 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Fouad, K., Ng, C. & Basso, D. M. Behavioral testing in animal models of spinal cord injury. Exp. Neurol. 333, 113410 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Popovich, P. G., Lemeshow, S., Gensel, J. C. & Tovar, C. A. Independent evaluation of the effects of glibenclamide on reducing progressive hemorrhagic necrosis after cervical spinal cord injury. Exp. Neurol. 233, 615–622 (2002).

    Article  Google Scholar 

  47. Simard, J. M., Popovich, P. G., Tsymbalyuk, O. & Gerzanich, V. Spinal cord injury with unilateral versus bilateral primary hemorrhage-effects of glibenclamide. Exp. Neurol. 233, 829–835 (2012).

    Article  CAS  PubMed  Google Scholar 

  48. Watzlawick, R. et al. Outcome heterogeneity and bias in acute experimental spinal cord injury: a meta-analysis. Neurology 93, e40–e51 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  49. Begley, C. G. & Ioannidis, J. P. Reproducibility in science: improving the standard for basic and preclinical research. Circ. Res. 116, 116–126 (2015).

    Article  CAS  PubMed  Google Scholar 

  50. Callahan, A. et al. Developing a data sharing community for spinal cord injury research. Exp. Neurol. 295, 135–143 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  51. Fouad, K. et al. FAIR SCI ahead: the evolution of the open data commons for pre-clinical spinal cord injury research. J. Neurotrauma 37, 831–838 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  52. Hotamisligil, G. S. Foundations of immunometabolism and implications for metabolic health and disease. Immunity 47, 406–420 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Hotamisligil, G. S. Inflammation, metaflammation and immunometabolic disorders. Nature 542, 177–185 (2017).

    Article  CAS  PubMed  Google Scholar 

  54. Failli, V. et al. Functional neurological recovery after spinal cord injury is impaired in patients with infections. Brain 135, 3238–3250 (2012).

    Article  PubMed  Google Scholar 

  55. Kopp, M. A. et al. Long-term functional outcome in patients with acquired infections after acute spinal cord injury. Neurology 88, 892–900 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  56. Jaja, B. N. R. et al. Association of pneumonia, wound infection, and sepsis with clinical outcomes after acute traumatic spinal cord injury. J. Neurotrauma 36, 3044–3050 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  57. Gallagher, M. J. et al. Markedly deranged injury site metabolism and impaired functional recovery in acute spinal cord injury patients with fever. Crit. Care Med. 46, 1150–1157 (2018).

    Article  PubMed  Google Scholar 

  58. Marik, P. E. & Bellomo, R. Stress hyperglycemia: an essential survival response! Crit. Care 17, 305 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  59. Kobayakawa, K. et al. Acute hyperglycemia impairs functional improvement after spinal cord injury in mice and humans. Sci. Transl Med. 6, 256ra137 (2014).

    Article  PubMed  Google Scholar 

  60. Ryken, T. C. et al. The acute cardiopulmonary management of patients with cervical spinal cord injuries. Neurosurgery 72 (Suppl. 2), 84–92 (2013).

    Article  PubMed  Google Scholar 

  61. Ehsanian, R. et al. Exploration of surgical blood pressure management and expected motor recovery in individuals with traumatic spinal cord injury. Spinal Cord 58, 377–386 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  62. Gallagher, M. J., Hogg, F. R. A., Zoumprouli, A., Papadopoulos, M. C. & Saadoun, S. Spinal cord blood flow in patients with acute spinal cord injuries. J. Neurotrauma 36, 919–929 (2019).

    Article  PubMed  Google Scholar 

  63. Kigerl, K. A. et al. Gut dysbiosis impairs recovery after spinal cord injury. J. Exp. Med. 213, 2603–2620 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Schmidt, E. K. A. et al. Fecal transplant prevents gut dysbiosis and anxiety-like behaviour after spinal cord injury in rats. PLoS ONE 15, e0226128 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Ankeny, D. P., Guan, Z. & Popovich, P. G. B cells produce pathogenic antibodies and impair recovery after spinal cord injury in mice. J. Clin. Invest. 119, 2990–2999 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Schwab, J. M., Zhang, Y., Kopp, M. A., Brommer, B. & Popovich, P. G. The paradox of chronic neuroinflammation, systemic immune suppression, autoimmunity after traumatic chronic spinal cord injury. Exp. Neurol. 258, 121–129 (2014).

    Article  CAS  PubMed  Google Scholar 

  67. Shibata, D., Cain, K., Tanzi, P., Zierath, D. & Becker, K. Myelin basic protein autoantibodies, white matter disease and stroke outcome. J. Neuroimmunol. 252, 106–112 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Doyle, K. P. et al. B-lymphocyte-mediated delayed cognitive impairment following stroke. J. Neurosci. 35, 2133–2145 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Diamond, B., Huerta, P. T., Mina-Osorio, P., Kowal, C. & Volpe, B. T. Losing your nerves? Maybe it’s the antibodies. Nat. Rev. Immunol. 9, 449–456 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Freund, P. et al. MRI investigation of the sensorimotor cortex and the corticospinal tract after acute spinal cord injury: a prospective longitudinal study. Lancet Neurol. 12, 873–881 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. James, N. D. et al. Conduction failure following spinal cord injury: functional and anatomical changes from acute to chronic stages. J. Neurosci. 31, 18543–18555 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Catalano, S. M. & Shatz, C. J. Activity-dependent cortical target selection by thalamic axons. Science 281, 559–562 (1998).

    Article  CAS  PubMed  Google Scholar 

  73. Zhang, L. I. & Poo, M. M. Electrical activity and development of neural circuits. Nat. Neurosci. 4 (Suppl.), 1207–1214 (2001).

    Article  CAS  PubMed  Google Scholar 

  74. Ditunno, J. F. Jr & Formal, C. S. Chronic spinal cord injury. N. Engl. J. Med. 330, 550–556 (1994).

    Article  PubMed  Google Scholar 

  75. Kirshblum, S., Millis, S., McKinley, W. & Tulsky, D. Late neurologic recovery after traumatic spinal cord injury. Arch. Phys. Med. Rehabil. 85, 1811–1817 (2004).

    Article  PubMed  Google Scholar 

  76. el Masry, W. S. Physiological instability of the spinal cord following injury. Paraplegia 31, 273–275 (1993).

    CAS  PubMed  Google Scholar 

  77. Chen, Q., Smith, G. M. & Shine, H. D. Immune activation is required for NT-3-induced axonal plasticity in chronic spinal cord injury. Exp. Neurol. 209, 497–509 (2008).

    Article  CAS  PubMed  Google Scholar 

  78. Beauparlant, J. et al. Undirected compensatory plasticity contributes to neuronal dysfunction after severe spinal cord injury. Brain 136, 3347–3361 (2013).

    Article  PubMed  Google Scholar 

  79. Li, Y. et al. Pericytes impair capillary blood flow and motor function after chronic spinal cord injury. Nat. Med. 23, 733–741 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. von Monakow, C. Lokalisation im Gehirn und funktionelle Stoerungen induziert durch kortikale Laesionen. (Bergmann JF, 1914).

  81. Carrera, E. & Tononi, G. Diaschisis: past, present, future. Brain 137, 2408–2422 (2014).

    Article  PubMed  Google Scholar 

  82. Seitz, R. J. et al. The role of diaschisis in stroke recovery. Stroke 30, 1844–1850 (1999).

    Article  CAS  PubMed  Google Scholar 

  83. Baldassarre, A. et al. Dissociated functional connectivity profiles for motor and attention deficits in acute right-hemisphere stroke. Brain 139, 2024–2038 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  84. Min, Y. S. et al. Alteration of resting-state brain sensorimotor connectivity following spinal cord injury: a resting-state functional magnetic resonance imaging study. J. Neurotrauma 32, 1422–1427 (2015).

    Article  PubMed  Google Scholar 

  85. Dietz, V. Behavior of spinal neurons deprived of supraspinal input. Nat. Rev. Neurol. 6, 167–174 (2010).

    Article  PubMed  Google Scholar 

  86. Vallotton, K. et al. Width and neurophysiologic properties of tissue bridges predict recovery after cervical injury. Neurology 92, e2793–e2802 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  87. Huber, E. et al. Dorsal and ventral horn atrophy is associated with clinical outcome after spinal cord injury. Neurology 90, e1510–e1522 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  88. Pfyffer, D., Huber, E., Sutter, R., Curt, A. & Freund, P. Tissue bridges predict recovery after traumatic and ischemic thoracic spinal cord injury. Neurology 93, e1550–e1560 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  89. Talbott, J. F. et al. The Brain and Spinal Injury Center score: a novel, simple, and reproducible method for assessing the severity of acute cervical spinal cord injury with axial T2-weighted MRI findings. J. Neurosurg. Spine 23, 495–504 (2015).

    Article  PubMed  Google Scholar 

  90. Wheeler-Kingshott, C. A. et al. The current state-of-the-art of spinal cord imaging: applications. Neuroimage 84, 1082–1093 (2014).

    Article  CAS  PubMed  Google Scholar 

  91. Stroman, P. W. et al. The current state-of-the-art of spinal cord imaging: methods. Neuroimage 84, 1070–1081 (2014).

    Article  CAS  PubMed  Google Scholar 

  92. Lang, B. T. et al. Modulation of the proteoglycan receptor PTPσ promotes recovery after spinal cord injury. Nature 518, 404–408 (2015).

    Article  CAS  PubMed  Google Scholar 

  93. Blesch, A. & Tuszynski, M. H. Spinal cord injury: plasticity, regeneration and the challenge of translational drug development. Trends Neurosci. 32, 41–47 (2009).

    Article  CAS  PubMed  Google Scholar 

  94. Filli, L. & Schwab, M. E. The rocky road to translation in spinal cord repair. Ann. Neurol. 72, 491–501 (2012).

    Article  PubMed  Google Scholar 

  95. Freria, C. M. et al. Deletion of the fractalkine receptor, CX3CR1, improves endogenous repair, axon sprouting, and synaptogenesis after spinal cord injury in mice. J. Neurosci. 37, 3568–3587 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Church, J. S., Kigerl, K. A., Lerch, J. K., Popovich, P. G. & McTigue, D. M. TLR4 deficiency impairs oligodendrocyte formation in the injured spinal cord. J. Neurosci. 36, 6352–6364 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Hansen, C. N. et al. Elevated MMP-9 in the lumbar cord early after thoracic spinal cord injury impedes motor relearning in mice. J. Neurosci. 33, 13101–13111 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Tanadini, L. G. et al. Identifying homogeneous subgroups in neurological disorders: unbiased recursive partitioning in cervical complete spinal cord injury. Neurorehabil. Neural Repair 28, 507–515 (2014).

    Article  PubMed  Google Scholar 

  99. Ghasemlou, N., Kerr, B. J. & David, S. Tissue displacement and impact force are important contributors to outcome after spinal cord contusion injury. Exp. Neurol. 196, 9–17 (2005).

    Article  PubMed  Google Scholar 

  100. Santos-Benito, F. F., Muñoz-Quiles, C. & Ramón-Cueto, A. Long-term care of paraplegic laboratory mammals. J. Neurotrauma 23, 521–536 (2006).

    Article  PubMed  Google Scholar 

  101. Kigerl, K. A., Mostacada, K. & Popovich, P. G. Gut microbiota are disease-modifying factors after traumatic spinal cord injury. Neurotherapeutics 15, 60–67 (2018).

    Article  PubMed  Google Scholar 

  102. Kigerl, K. A., Zane, K., Adams, K., Sullivan, M. B. & Popovich, P. G. The spinal cord-gut-immune axis as a master regulator of health and neurological function after spinal cord injury. Exp. Neurol. 323, 113085 (2020).

    Article  CAS  PubMed  Google Scholar 

  103. Levy, M., Kolodziejczyk, A. A., Thaiss, C. A. & Elinav, E. Dysbiosis and the immune system. Nat. Rev. Immunol. 17, 219–232 (2017).

    Article  CAS  PubMed  Google Scholar 

  104. Berer, K. et al. Commensal microbiota and myelin autoantigen cooperate to trigger autoimmune demyelination. Nature 479, 538–541 (2011).

    Article  CAS  PubMed  Google Scholar 

  105. Wiesel, T. N. & Hubel, D. H. Extent of recovery from the effects of visual deprivation in kittens. J. Neurophysiol. 28, 1060–1072 (1965).

    Article  CAS  PubMed  Google Scholar 

  106. Raineteau, O. & Schwab, M. E. Plasticity of motor systems after incomplete spinal cord injury. Nat. Rev. Neurosci. 2, 263–273 (2001).

    Article  CAS  PubMed  Google Scholar 

  107. May, Z., Fouad, K., Shum-Siu, A. & Magnuson, D. S. Challenges of animal models in SCI research: Effects of pre-injury task-specific training in adult rats before lesion. Behav. Brain Res. 291, 26–35 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  108. Caudle, K. L. et al. Hindlimb immobilization in a wheelchair alters functional recovery following contusive spinal cord injury in the adult rat. Neurorehabil. Neural Repair 25, 729–739 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  109. Basso, D. M., Beattie, M. S. & Bresnahan, J. C. A sensitive and reliable locomotor rating scale for open field testing in rats. J. Neurotrauma 12, 1–21 (1995).

    Article  CAS  PubMed  Google Scholar 

  110. Kirshblum, S. C. et al. Patterns of sacral sparing components on neurologic recovery in newly injured persons with traumatic spinal cord injury. Arch. Phys. Med. Rehabil. 97, 1647–1655 (2016).

    Article  PubMed  Google Scholar 

  111. Courtine, G. et al. Can experiments in nonhuman primates expedite the translation of treatments for spinal cord injury in humans? Nat. Med. 13, 561–566 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Farhadi, H. F. et al. Impact of admission imaging findings on neurological outcomes in acute cervical traumatic spinal cord injury. J. Neurotrauma 35, 1398–1406 (2018).

    Article  PubMed  Google Scholar 

  113. Bradbury, E. J. & McMahon, S. B. Spinal cord repair strategies: why do they work? Nat. Rev. Neurosci. 7, 644–653 (2006).

    Article  CAS  PubMed  Google Scholar 

  114. Kapur, N. Paradoxes in rehabilitation. Disabil. Rehabil. 42, 1495–1502 (2020).

    Article  PubMed  Google Scholar 

  115. Page, S. J., Gauthier, L. V. & White, S. Size doesn’t matter: cortical stroke lesion volume is not associated with upper extremity motor impairment and function in mild, chronic hemiparesis. Arch. Phys. Med. Rehabil. 94, 817–821 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  116. Price, C. J., Hope, T. M. & Seghier, M. L. Ten problems and solutions when predicting individual outcome from lesion site after stroke. Neuroimage 145, 200–208 (2017).

    Article  PubMed  Google Scholar 

  117. Rorden, C. & Karnath, H. O. Using human brain lesions to infer function: a relic from a past era in the fMRI age? Nat. Rev. Neurosci. 5, 813–819 (2004).

    Article  PubMed  Google Scholar 

  118. Inoue, K., Madhyastha, T., Rudrauf, D., Mehta, S. & Grabowski, T. What affects detectability of lesion-deficit relationships in lesion studies? Neuroimage Clin. 6, 388–397 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  119. Barkhof, F. The clinico-radiological paradox in multiple sclerosis revisited. Curr. Opin. Neurol. 15, 239–245 (2002).

    Article  PubMed  Google Scholar 

  120. Barkhof, F. MRI in multiple sclerosis: correlation with expanded disability status scale (EDSS). Mult. Scler. 5, 283–286 (1999).

    Article  CAS  PubMed  Google Scholar 

  121. Okuda, D. T. et al. Incidental MRI anomalies suggestive of multiple sclerosis: the radiologically isolated syndrome. Neurology 72, 800–805 (2009).

    Article  CAS  PubMed  Google Scholar 

  122. Wuerfel, J. et al. Mouse model mimics multiple sclerosis in the clinico-radiological paradox. Eur. J. Neurosci. 26, 190–198 (2007).

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The work of K.F. is supported by grants from the Canadian Health Research Council (CIHR), the Wings for Life Spinal Cord Research Foundation, the Craig H. Neilsen Foundation, the Canadian Research Chair Program. The work of P.G.P. is supported by the National Institutes of Neurological Disorders-NIH (Grants R01 NS083942, R01 NS099532 and R35 NS111582) and the Ray W. Poppleton Endowment. The work of J.M.S. is supported by the National Institute of Disability, Independent Living and Rehabilitation Research (NIDILRR Grant 90SI5020), the National Institutes of Neurological Disorders – NIH (Grant R01 NS118200), the European Union (EU Era Net – Neuron Program, SILENCE Grant 01EW170A), the Craig H. Neilsen Foundation (Grant 596764), the Wings for Life Spinal Cord Research Foundation and the William E. Hunt and Charlotte M. Curtis Endowment. J.M.S. is a Discovery Theme Initiative Scholar (Chronic Brain Injury) of Ohio State University.

Author information

Author notes

  1. These authors contributed equally: Karim Fouad, Phillip G. Popovich.

Authors and Affiliations

  1. Department of Physical Therapy, Faculty of Rehabilitation Medicine, University of Alberta, Edmonton, AB, Canada

    Karim Fouad

  2. Institute for Neuroscience and Mental Health, University of Alberta, Edmonton, AB, Canada

    Karim Fouad

  3. Belford Center for Spinal Cord Injury, The Ohio State University, Wexner Medical Center, Columbus, OH, USA

    Phillip G. Popovich & Jan M. Schwab

  4. Center for Brain and Spinal Cord Repair, The Ohio State University, Wexner Medical Center, Columbus, OH, USA

    Phillip G. Popovich & Jan M. Schwab

  5. Department of Neuroscience, The Ohio State University, Wexner Medical Center, Columbus, OH, USA

    Phillip G. Popovich & Jan M. Schwab

  6. The Neurological Institute, The Ohio State University, Wexner Medical Center, Columbus, OH, USA

    Phillip G. Popovich & Jan M. Schwab

  7. Clinical & Experimental Spinal Cord Injury Research, Department of Neurology with Experimental Neurology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany

    Marcel A. Kopp & Jan M. Schwab

  8. Berlin Institute of Health (QUEST-Center for Transforming Biomedical Research), Berlin, Germany

    Marcel A. Kopp

  9. Spinal Cord Injury Medicine (Neuroplegiology), Department of Neurology, The Ohio State University, Wexner Medical Center, Columbus, OH, USA

    Jan M. Schwab

  10. Department of Physical Medicine and Rehabilitation, The Ohio State University, Wexner Medical Center, Columbus, OH, USA

    Jan M. Schwab

Authors
  1. Karim Fouad
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Phillip G. Popovich
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Marcel A. Kopp
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jan M. Schwab
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

J.M.S., K.F. and P.G.P. researched data for the article, made a substantial contribution to the discussion of article content, wrote the article, and reviewed and edited the manuscript before submission. M.A.K. made a substantial contribution to the discussion of article content, wrote parts of the article, and reviewed and edited the manuscript before submission.

Corresponding author

Correspondence to Jan M. Schwab.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information

Nature Reviews Neurology thanks E. Bradbury, P. Freund, P. Reier and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

Corticospinal tract

(CST). Comprises axons of the descending pyramidal tract, which controls motor function.

External validity

The extent to which one can generalize the findings of an experimental study to reflect the situation in humans.

Propriospinal projections

Axons that relay information on deep sensitivity and joint position. Constitute an essential pathway for the recovery of neurological function after spinal cord injury.

Reticulospinal axons

Descending axons that relay information for extrapyramidal motor control.

Syngeneic

Genetically similar or identical and immunologically compatible.

Syringomyelia

Generic term referring to a fluid-formed cavity in the spinal cord that develops at the site of a lesion and can be present for a long time after the initial injury.

Unbiased recursive partitioning

A regression analysis method that enables the binary analysis of non-parametric data.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Fouad, K., Popovich, P.G., Kopp, M.A. et al. The neuroanatomical–functional paradox in spinal cord injury. Nat Rev Neurol 17, 53–62 (2021). https://doi.org/10.1038/s41582-020-00436-x

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41582-020-00436-x

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing