Hill, et al. (2001): Degeneration and sprouting of identified descending supraspinal axons after contusive spinal cord injury in the rat

[Wise Young]

• Hill CE, Beattie MS and Bresnahan JC (2001). Degeneration and sprouting of identified descending supraspinal axons after contusive spinal cord injury in the rat. Exp Neurol. 171 (1): 153-69. Summary: Contusive spinal cord injury (SCI) results in the formation of a chronic lesion cavity surrounded by a rim of spared fibers. Tissue bridges containing axons extend from the spared rim into the cavity dividing it into chambers. Whether descending axons can grow into these trabeculae or whether fibers within the trabeculae are spared fibers remains unclear. The purposes of the present study were (1) to describe the initial axonal response to contusion injury in an identified axonal population, (2) to determine whether and when sprouts grow in the face of the expanding contusion cavity, and (3) in the long term, to see whether any of these sprouts might contribute to the axonal bundles that have been seen within the chronic contusion lesion cavity. The design of the experiment also allowed us to further characterize the development of the lesion cavity after injury. The corticospinal tract (CST) underwent extensive dieback after contusive SCI, with retraction bulbs present from 1 day to 8 months postinjury. CST sprouting occurred between 3 weeks and 3 months, with penetration of CST axons into the lesion matrix occurring over an even longer time course. Collateralization and penetration of reticulospinal fibers were observed at 3 months and were more extensive at later time points. This suggests that these two descending systems show a delayed regenerative response and do extend axons into the lesion cavity and that the endogenous repair can continue for a very long time after SCI. Copyright 2001 Academic Press. <http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&dopt=r&uid=11520130> Department of Neuroscience, The Ohio State University, Columbus, Ohio, 43210

[This message was edited by Wise Young on September 23, 2001 at 10:18 PM.]

[Wise Young]

This is a very important paper. In 1997, Beattie and Bresnahan at Ohio State, using some 600 spinal cords studied as part of the Multicenter Animal Spinal Cord Injury Study (MASCIS) showed that as much as 70% of the spinal cords showed remarkable numbers of axons growing into the cavity that remained at the injury site after injury. The origins and destinations of these fibers were unclear. Nevetheless, it was clear that they were newly grown fibers and that they were penetrating into the injury site and, in some cases, apparently growing to the other side. The cystic cavity at the injury site appears to be filled with a loose matrix of cells that may have been produced by endogenous stem cells. The functional effects of these cells and axons that appear to be growing on them (in untreated rats) are not known.

They have now conducted a detailed study of two major descending spinal tract systems and determined that many of the fibers in the central cystic area come from the corticospinal and the brainstem-to-spinal cord tracts. They further showed that the corticospinal tract dies back some distance and then regrows towards the injury site. This finding, in itself is rather surprising because it means that the corticospinal tract is growing some distance in the proximal spinal cord through area that most scientists would consider to be inhibitory of growth.

Another aspect of this study that is surprising is the slow rate of growth of the axons. The dieback of the axons occur relatively quickly and the axons die back perhaps 2-3 cm at most. However, it took these axons several months to grow this distance. In rats, things usually occur several times faster than in humans. Therefore, one might expect growth to be slower in humans. For a while now, I have been talking about the slow rate of axonal growth... suggesting that it might be on the order of 1 mm per day. However, the slow rate of growth of the spontaneous axons suggest that the growth may be as slow as 1-2 mm per week.

If such a phenomenon occurred in humans, it may account for the fact that most patients recover at least 1-2 segments below the injury, often 6 or more months after injury. It may also explain the slow recovery of some people as long as 5-10 years after spinal cord injury. Christopher Reeve, for example, has been slowly recovering more and more sensation over time and may even be getting some motor function back with time.

One may then ask why there is not more recovery after spinal cord injury. Well, one possibility is that many of the patients may have growth back but their neurons below the injury site may have shut off due to "learned non-use" and inactivity for several years. As you can recognize, the above are radical ideas and definitely not in the mainstream of thinking regarding spinal cord injury.

In summary, this study suggests that there is much more spontaneous growth of axons in the spinal cord of rats than hitherto suspected and that such growth can include corticospinal and brainstem-spinal tracts. The axons appear to grow from the point of dieback back to the injury site and the axons grow into the matrix of loose cells in the cystic cavity remaining at the injury site. It is not clear from this study whether the axons penetrate to the other side of the injury site and grow on down the spinal cord.

Wise.

[Carl R]

Dr. Young, I had seen you mentioned Christopher Reeve several times with regard to the amount of improvement he has had. Are there any specific therapies that you can point to, that could be the reason for his recovery? How much sensation as he actually recovered?

Just curious as well, had you ever invited him here?

[Wise Young]

I am not sure what other therapies Christopher Reeve is receiving for his breathing but, to my knowledge, he has been going through daily standing and pedalling exercises, as well as FES. He of course got methylprednisolone very early after spinal cord injury. Wise.