The neuroanatomical-functional paradox in spinal cord injury

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.

Fig. 1 |. Non-linear relationship between anatomical lesion severity and outcome.

After spinal cord injury, the severity of neurological deficit does not homogenously correlate with the size of the lesion (blue line). Thus, functional recovery cannot be predicted by assuming a linear correlation with lesion size (red line). This non-linear correlation results in ranges of lesion size that are ‘sensitive’ or ‘insensitive’ to experimental intervention. Diverging injury models produce different lesions with likewise diverging sensitivity to detect outcome modifying effects. The varying degree of functional relevance of a lesion is referred to as functional eloquence. Axes represent arbitrary scales from 0–100%.

Fig. 2 |. The neuroanatomical–functional paradox of recovery after spinal cord injury.

An example of mismatch between lesion size and functional outcome is illustrated for spinal cord lesions located at thoracic level Th8 in two rats. a | In this animal, the lesion (shown in grey) covered 54% of the cross-sectional area of the spinal cord. b | In this animal, the lesion covered 84% of the cross-sectional area of the spinal cord. A similar degree of locomotor recovery, measured with the Basso, Beattie and Bresnahan (BBB) open-field locomotor scale or grid-walking test, was achieved by both animals (a and b), despite the substantial differences in lesion size. Figure adapted with permission from REF., Elsevier.

Fig. 3 |. Reversible axonal injury and transient recovery.

The underlying causes of dissociated longitudinal outcomes after spinal cord injury (SCI) include reversible (transient) axonal injury and transient recovery. Predicted functional recovery based on lesion size is indicated by the dotted line, whereas actual observed recovery is indicated by the solid line. a | The observed functional recovery can be greater than the predicted functional recovery. This mismatch (green) can be accounted for by the presence of reversible (transient) axonal injury that resolves during the early part of recovery^,. b | Transient recovery can result in a mismatch (red) between the degree of recovery predicted from the initial lesion size and the final degree of recovery observed both after experimental SCI and human SCI^,,. This transient recovery can be caused by the delayed emergence of systemic disease modifiers^,,.

Fig. 4 |. Distinguishing between lesion-affected and recovery-related networks after spinal cord injury.

a | A horizontal lesion (blue) in the spinal cord damages central tracts (lesion-affected tracts, red solid lines) and spares some lateral tracts (green solid lines) that extend into the zone of partial preservation (ZPP; orange), and are able to sprout and re-connect with denervated circuitry (green dotted lines). b | A larger lesion but of a different orientation is associated with a better chance of recovery than the lesion illustrated in part a. The same tracts are affected in both scenarios; however, the ZPP in part b spares the segemental innervation of associated muscles and facilitates greater connectivity between the lesion-affected and recovery-related network (green solid and dotted lines) than is possible in the scenario illustrated in part a. Compared with lesions that leave no ZPPs, the presence of a ZPP after SCI is associated with a higher degree of motor score gain and a higher rate of conversion to less severe levels on the American Spinal Injury Association impairment scale^,. Despite measuring the number of lesion-affected tracts or recovery-related networks as solitary entities, the degree of connectivity and integration between both will determine the potential for recovery.

Fig. 5 |. Spared axonal fibres as outcome denominators independent of lesion size.

Spinal cord lesions of the same size can produce remarkably varied outcomes depending on the specific lesion-affected and recovery-related networks involved, as illustrated here in schematized coronal sections. Rodent spinal cord lesions that damage the corticospinal tract and reticulospinal tract (lesion 2, red) are more severe than lesions of the same size that spare reticulospinal fibres (lesion 1, blue) (left). In patients, sparing of the lateral rim of the cord would result in sacral sparing, as illustrated by lesion 1 (grey) (right). If the dorsolateral rim is spared, this will enable sacral motor sparing (voluntary anal contraction). If the ventrolateral rim of the cord is spared, this will enable sacral sensory sparing (feeling of deep anal pressure and/or sensation in S4/5 dermatomes). In humans, lesions of the same size can differ substantially in the amount of tissue from functionally relevant networks that is spared; either sensory or motor sparing are associated with better odds for recovery^,. These differences will not be mirrored in either serum or cerebrospinal fluid biomarker studies that assess volume of injured spinal cord tissue by measuring neuronal (for example, neurofilament) and glial (for example, GFAP) tissue damage, as the anatomical context of the injured tissue with regards to spared circuity (for example, the recovery-associated network) will be not reflected. In humans, the corticospinal tract is essential for fine motor control and has a more important role in locomotor control than in rodents. To date, rodent models are rarely used to assess changes in myotomes or dermatomes as indicators of sensory or motor level and, therefore, zones of partial preservation are not objectively quantified in rodent spinal cord injury models.

Fig. 6 |. Outcome variability and underlying causes.

The prediction of functional outcome of spinal cord injury (SCI) on the basis of initial injury severity only (dashed arrow) ignores the variability that is introduced after initial injury and can affect the lesion-affected (red) and recovery-related networks (green). This variability can be caused by transient functional modifiers that do not affect neuroanatomy, for example, variable diaschisis. Intraspinal modifiers (shaded grey box) can impair recovery via an effect on the neuroarchitecture, for example, haematoma formation or delayed haemorrhagic transformation is associated with increased intraspinal pressure, and thereby with progressive injury to the lesion-affected network, as well as with iron toxification that affects the recovery-related network^,. Post-SCI hyperglycaemia, hypotensive and hypertensive episodes^, also impair the capacity of the injured cord to repair. Additional outcome confounders are acquired infections and fever episodes^– that trigger sustained metabolic derangement, that is, a shifted glucose to lactate ratio, at the lesion site. SCI-associated gut dysbiosis and autoimmunity can also negatively affect functional outcome^–.