This perspective is astonishingly naive. Even among the most impressive reports of axonal growth to date, the overall restitution of axon number is far below normal innervation density. Extensive restoration of function may require restitution of neural circuitry to pre-lesion patterns

that, during development, formed as a result of a precise orchestration of genetic and epigenetic events sequentially over time. This collective set of developmental events included both intracellular mechanisms in the neuron and environmental learn more expression of diffusible guidance cues, extracellular matrix molecules and cell adhesion molecules in precise temporal and spatial gradients. Moreover, remyelination of every new axon segment may be required to overcome conduction block. This set of restorative events is unlikely to occur after adult injury. Accordingly, the extent to which nondirected or partially directed growth can be functionally beneficial, as opposed to deleterious (causing spasticity or cause pain),

remains to be determined. We have only recently reached the point that this question can even be addressed because, finally, there are manipulations that produce at least some growth past the lesion. Directed rehabilitation, trophic gradients and other means may be required to shape the nature of circuit reformation, but even under these circumstances, will the number, topography, and remyelination of newly growing axons be sufficient to improve function? Moreover, we must also

ask whether our most commonly used functional measures are relevant to humans. For example, is restoration Pramipexole of MK-1775 supplier walking ability in a quadrupedal rodent relevant to the bipedal locomotion of humans that requires fine control of posture and balance? Nonetheless, partial improvements in behavior (often optimistically referred to as “functional recovery” in the literature) can be meaningful and informative regarding cellular and systems-level mechanisms that are required to improve function. Screening tools such as the Basso-Beattie-Bresnahan (BBB) scale (Basso et al., 1995) provide a convenient starting point, but quantifiable ordinate measures that are directly related to particular axon systems are needed to definitively relate axon growth with recovery. The requirement that experiments pass the criterion of demonstrating “functional benefit” to be considered of major importance in the spinal cord injury field should be soundly rejected by investigators, reviewers, and journal editors. We remain at a stage of spinal cord injury research in which discovery of fundamental mechanisms contributing to new axonal growth is critical: from new mechanistic discoveries that lead to significant axonal sprouting and regeneration, we will sequentially amplify the number of growing axons, the distance over which they grow, and their guidance to and connection with appropriate targets.