The neuroanatomical–functional paradox in spinal cord injury

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. In this Perspective, the authors discuss the mechanisms underlying the complex relationship between lesion size and functional recovery after spinal cord injury, highlighting various complications that can limit the accuracy of outcome prediction in patients and in animal models.