Many people and animals recover from devastating injuries that must have destroyed as much as 90% of the spinal tracts at the injury site. I have long felt that if we understood and can implement the mechanisms by which people and animals recover from spinal cord injury, we would have a cure. How and why do people and animals recover from spinal cord injury?
The importance of the spinal cord to survival is clear from the evolution of the complex, beautiful, and flexible vertebral column that protects the spinal cord against trauma. As many as a million people suffer trauma to the spinal column every year in the United States but only 1% (10,000 people) have serious neurological deficits. We have many names for spinal injuries that produce only transient neurological deficits: whiplash, stingers, burners, etc. Although most clinicians assume that the spinal cord has not been damaged in such accidents, it is possible that many people may have suffer some spinal cord injury but simply recovered. Over 60% of people with severe spinal cord injuries have some residual motor or sensory function below the injury site shortly after injury. Most of these patients recover locomotor, sensory, bladder, and other functions over a period of many months.
My first encounter with a person who recovered from spinal cord injury was in 1981. Carey Erickson was a well-known choreographer in New York. He injured his cervical spinal cord at C4-5 and had no function below his injury site except for a patch of sensation on his left leg when he was admitted. I did weekly somatosensory evoked potentials on him for 72 days and saw his response improve from almost nothing to virtually normal in amplitude and latency. Over several months, he recovered his legs first and then his arms. At 2 years after injury, he walked into my office and, to most casual observers, appeared to have recovered completely. He, however, told me that his strength, coordination, and endurance were only 50% of what they were before his injury.
Another example is a young woman who fell off a horse and had a C5 cervical spinal cord injury. Although her father noted that she had some sensation in the legs when she was loaded into the ambulance, she had no movement or feeling in all four limbs for weeks. Over a period of 3 months, however, she recovered substantially. When I saw her 3 months after injury, she walked into the room with a cane. Later, she accompanied me on a visit to a lecture hall and we walked up a steep hill together. Although she still had to be careful when she walked, her endurance and strength was good. She has recovered virtually completely.
Many athletes have made remarkable recoveries after spinal cord injury. For example, Dennis Byrd of the New York Jets walked out of the hospital. He, like Carey Erickson, had only a patch of sensation on one leg at the time of admission to hospital. Reggie Brown of the Detroit Lions is another football player who walked out of the hospital after a cervical spinal cord injury that had paralyzed his arms and legs. I met him at a function several year later and, if I did not know his story, I would not have suspected that he had spinal cord injury. More recently, Adam Taliaferro, a freshman cornerback for Penn State, had a cervical spinal cord injury that paralyzed his arms and legs for several weeks. He is walking.
Dozens of people have come to me and told me of their recovery from quadriplegia to normality. Most had some residual motor or sensory function during the first 24 hours after injury. Almost all received methylprednisolone shortly after injury. The recovery took place over weeks, months, or even years after injury. There have not been any rigorous studies of the incidence of dramatic recoveries after spinal cord injury. In 1992, I surveyed some 400 patients whom we cared for at Bellevue Hospital in the 1980s. During those years, we were already treating people with methylprednisolone. Some 17% of the patients walked out of the hospital. Admittedly, most were incomplete injuries. But, some were complete spinal cord injuries.
In the NASCIS 2 trial carried out in the late 1980s, over 60% of the patients had complete loss of motor function and untreated patients recovered on average 8% of the motor score that they had lost, compared to 21% in patients that received methylprednisolone with 8 hours. So-called incomplete untreated patients recovered 59% of what they had lost by 6 months, compared to 75% in methylprednisolone-treated patients. In the recent study by Geisler, et al., (2001), 29% of nearly 800 patients showed "marked recovery" (i.e. a 2-category improvement on the Benzel score). Approximately 17% of the ASIA A ("complete" spinal cord injuries) patients had "marked recovery" by 52 weeks after injury. By comparison, about 40% of ASIA B ("sensory preservation only") and about 75% of ASIA C ("some motor and sensory preservation) patients had "marked recovery".
Thus, it is fair to say that recovery is the rule and not the exception in spinal cord injury. The observation that 17% of patients with so-called "complete" spinal cord injury had "marked recovery" of 2 categories on the Benzel scale is impressive. Close to 40% of patients with only minor sensory preservation had marked recovery. Finally, over 75% of patients with some motor and sensory preservation recovered walking. As pointed out above, many people recover almost completely from apparently severe spinal cord injuries that left them quadriplegic for weeks or even months. These data contrast sharply with the deep pessimism that the general public and many clinicians view the likelihood of recovery from spinal cord injury.
The ability of the spinal cord to recover from injury is truly amazing if you consider that animals (and humans) will usually recover almost completely from a lateral hemisection, i.e. cutting a half of the spinal cord on one side. A hemisection eliminates half of the connections to and from the brain. In humans, this type of injury produces a Brown-Sequard syndrome, named after a British neurologist who described the syndrome in patients who had been punished by the Mafia with a stiletto inserted into the spinal cord to cut half the spinal cord on one side. There is an initial period of paralysis and sensory loss on the side of the cut, with loss of pain and temperature sensation on the other side. Over a period of several months, most people will recover ability to walk with both legs although sensory recovery may take many years and, in some patients, do not recover.
In animals, a hemisection likewise causes an initial period of neurological loss but most rats will recover ability to walk with both hindlimbs 2 weeks after a lateral hemisection. In an relatively little-known paper published, Kato, et al. (1985) described the remarkable recovery of cats from bilateral hemisections. They hemisected the spinal cord at T12, waited 0-126 days, and then hemisected the other side of the spinal cord at T7. Incredibly, when the hemisections were separated by 10 or more days, the cats recovered walking even though all the tracts between the brain and spinal cord have been severed. If the two hemisections were carried out in one surgery, the cats remained permanently paralyzed. If the hemisections were separated by 1-7 days, the cats required an average of 43 days to recover standing. If the second hemisection occurred 10-126 days after the first, the cats required an average of 15 days to recover standing. Over a period of several months, most of the latter recover bipedal walking. Bilateral hemisections should eliminate all long tracts between the brain and the lower spinal cord.
What are some of the mechanisms of recovery that could be playing a role in recovery? Animal studies suggest at least two mechanisms of recovery:
Sprouting for preserved contralateral spinal tracts. In 1994, Saruhashi, et al. examined the locomotor recovery in rats after hemisection, looking specifically at serotonergic fibers that crossed the midline from the intact side. All the rats recovered bipedal locomotion within 2-4 weeks and the extent of recovery correlated linearly with growth of serotonergic fibers from the intact side to the lesioned side. Similar correlations of forelimb recovery with sprouting of the contralateral corticospinal tract occur after a unilateral corticospinal tract lesion (Z'Graggen, et al., 2000) or sprouting of the ventral corticospinal tract after a bilateral corticospinal tract lesion (Weidner, et al. 2001).
Multisynaptic pathways. In the 1980's, Alstermark examined the recovery of forepaw function in cats after cutting various spinal tracts (summarized in Peterson, et al. 1997). They found that the cats would recover almost completely from lesions of every individual tract, as long as they left the propriospinal tract (which mediates multisynaptic connections within the spinal cord) intact. However, when they combined lesions of the propriospinal tract with other tracts, they found deficits.
Probably a combination of both mechanisms play a role in recovery of locomotion after bilateral hemisection. The remarkable results of Kato, et al. (1985) could be explained by sprouting of axons across the midline which then activate locomotor centers in the lower spinal cord through multisynaptic propriospinal pathways. In 1990, Kato, et al. not only hemisected the spinal cord at L2-3 but also did a mid-line myelotomy (cutting the spinal cord down the midline) which isolated the lower left lumbar cord. After the lesion, the cats initially recovered ability to stand on three legs. However, two days later, the leg innervated by the isolated lower left lumbar cord recovered walking capabilities. Although the phase relationships of the walking were more variable than normal, the two legs stepped alternatively. Kato did not report histological examinations of the spinal cords but one possibility is sprouting across the midline.
The vast majority of human spinal cord injury involve contusion or compression rather than physical transection. Contusion injury produces a stereotyped central hemorrhagic necrosis that usually leaves a thin rim of white matter at the injury site. In 1986, Blight & DeCrescito did a detailed and quantitative analysis of the surviving axons that are necessary and sufficient to support locomotor recovery in cats after a severe contusion injury. A 20 gram weight dropped 20 cm onto the thoracic spinal cord of a cat typically left a thin rim of less than 0.3 mm white matter. Quantitative counts of the axons revealed that cats with as little as 10% of their axons were able to recover independent locomotion. Since central hemorrhagic necrosis eliminated all deeper tracts, including the propriospinal tracts, the mechanism of recovery likely involved axons close to the pial surface.
Basso, et al. (1996) carried out a similar morphological correlation with locomotor recovery in rats after contusion injuries. Using the newly developed BBB locomotor scale, they showed that the degree of spinal cord white matter sparing correlated linearly with the BBB scores. Of interest, however, was the fact that when BBB scores were plotted against spared white matter (X-axis), the line intersected the Y-axis at a BBB score of about 8. A BBB score of 10 signifies a rat that is able to stand and take steps. Rats with only 10% spared white matter were able to walk. This is consistent with the experience of many other investigators.
In 1997, Beattie, et al. examined the spinal cords of several hundred rats that had received contusion injuries. Over 70% of the rats had cysts at the contusion site that was filled with a cellular matrix. Thousand of axons were growing on the cellular matrix. Although the origin and destination of the axons were not known, they were clearly regenerating axons. More recently, Hill, et al. (2001) showed that some of the fibers came from the corticospinal tract and reticulospinal tract. The extent to which these regenerating axons contributed to locomotor recovery is not clear. However, in earlier studies, Beattie, et al. transected the spinal cord and found that rats recovered BBB scores of 3-4. These scores imply that the rats were able to move 1 or 2 joints.
Could spontaneous regeneration be occurring in the rat spinal cord? Clearly, some regeneration did occur even though the functional significance of the regeneration has not yet been proven. Substantial and convincing data support an important role of axonal sprouting unilateral and across the midline in both forelimb and hindlimb recovery after hemisections. The spinal cord is clearly able to activate locomotor centers with less than 10% of the white matter. The remarkable capability of the spinal cord to recover locomotion after a bilateral hemisection and even after a hemisection plus midline myelotomy provide strong evidence of the robust capabilities of sprouting. If such amazing recovery can occur through sprouting under such adverse conditions, why can't we consider regeneration as a possibility?
What is the evidence that the spinal cord cannot regenerate? This dogma arose many decades ago when scientists were transecting the spinal cord. When the spinal cord is transected, the tension in the spinal cord usually forces the cut ends of the spinal cords apart. Few researchers took the trouble or had the ability to re-oppose the cut ends of the spinal cord. It is not so surprising that none of these studies revealed regeneration. After all, if there is one obstacle that axons are unlikely to surmount, it is the presence of a gap of several mm. The contusion model of spinal cord injury leaves continuous tissue. Studies of the contusion model indicate that axons are growing into and probably across the injury site. Thus, the possibility of spontaneous regeneration contributing to functional recovery after spinal cord injury should be seriously considered.
Finally, many people with spinal cord injury recover sensation and even motor function years after spinal cord injury. For example, Christopher Reeve suffered a C1/2 injury. He was examined by dozens of doctors and was as "complete" a spinal cord injury as ever documented. Yet, at about two years after injury, he recovered light touch sensation in his arms and hands, extending all the way to the lowest sacral levels. He is now able to go off the ventilator for several hours at a time, can shrug his shoulders (indicative of some C4 function), and apparently has shown some hand motion. The last appeared more than five years after injury. This kind of recovery occurring steadily and starting with more proximal levels and extending distally over time is strongly suggestive of regeneration. The timing of the recovery is consistent with the slow growth of axons in the spinal cord. We should keep our minds open to the possibility of spontaneous regeneration even in humans.
Kato M, Murakami S, Hirayama H and Hikino K (1985). Recovery of postural control following chronic bilateral hemisections at different spinal cord levels in adult cats. Exp Neurol. 90 (2): 350-64. Summary: Chronic cats with double hemisections of the spinal cord, first at a lower thoracic level followed by a contralateral midthoracic cord at intervals of 0 to 126 days (T-T preparations) or first at an upper cervical followed by a midthoracic at intervals of 15 to 74 days (C-T preparations), eventually recovered quadrupedal standing 7 to 53 days after the second hemisection. For about 7 days following the first hemisection at a lower thoracic level, floor reaction force (FRF) of the hind limb of the hemisected side decreased to 25 to 30% of the normal value, then recovered to the control value. A group of cats whose second hemisection was done within 7 days after the first hemisection needed 24 to 53 (mean 43) days to recover quadrupedal standing, whereas cats whose second hemisection occurred after 10 to 126 days needed 7 to 22 (mean 15) days. During the recovery period many unusual reflexes were elicited which eventually disappeared as the cats resumed standing and walking. Lateral stability of the double-hemisected cats deteriorated significantly, whereas segmental reflexes were augmented. These results indicate the importance of descending impulses over the segmental motoneuron pools to control standing posture and locomotion. It was assumed that the descending impulses were conveyed by polysynaptic pathways which had minimal functions before the hemisections. <http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=4054289>
Saruhashi Y, Young W and Perkins R (1996). The recovery of 5-HT immunoreactivity in lumbosacral spinal cord and locomotor function after thoracic hemisection. Exp Neurol. 139 (2): 203-13. Summary: To determine the role of serotonin (5-HT) in recovery from spinal cord injury, we examined spinal cord 5-HT immunohistologically and assessed locomotor recovery after thoracic (T8) spinal cord hemisection in 68 rats. Forty eight rats had laminectomy and hemisection, while the remaining 20 rats received laminectomy only. All rats were evaluated every other day for 4 weeks, using a 0-14 point scale open field test. Hemisection markedly reduced mean hindlimbs scores from 14 to 1.5 +/- 0.32 and 5.6 +/- 0.31 (mean +/- standard error of mean) in the ipsilateral and contralateral side, respectively. The rats all recovered apparently normal walking by 4 weeks. The 5-HT immunohistological study revealed a marked reduction of 5-HT-containing terminals in the ipsilateral but not the contralateral lumbosacral cord by 1 week after hemisection. By 4 weeks after hemisection, 5-HT immunoreactive fibers and terminals returned to the ipsilateral lumbosacral cord, with many 5-HT fibers crossing over the central canal at thoracic level. We estimated the recovery of 5-HT neural elements in lumbosacral ventral horn by ranking 5-HT staining intensity and counting 5-HT terminals. The return of 5-HT immunoreactivity of the lumbosacral ventral horn correlated with locomotor recovery. Locomotory recovery invariably occurred when the density of 5-HT terminals approached 20% of control values. These results indicate that return of 5-HT fibers and terminals predict the time course and extent of locomotory recovery after thoracic spinal cord hemisection. <http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=8654523> Department of Neurosurgery, New York University Medical Center, New York 10016, USA.
Z'Graggen WJ, Fouad K, Raineteau O, Metz GA, Schwab ME and Kartje GL (2000). Compensatory sprouting and impulse rerouting after unilateral pyramidal tract lesion in neonatal rats. J Neurosci. 20 (17): 6561-9. Summary: After lesions of the developing mammalian CNS, structural plasticity and functional recovery are much more pronounced than in the mature CNS. We investigated the anatomical reorganization of the corticofugal projections rostral to a unilateral lesion of the corticospinal tract at the level of the medullary pyramid (pyramidotomy) and the contribution of this reorganization and other descending systems to functional recovery. Two-day-old (P2) and adult rats underwent a unilateral pyramidotomy. Three months later the corticofugal projections to the red nucleus and the pons were analyzed; a relatively large number of corticorubral and corticopontine fibers from the lesioned side had crossed the midline and established an additional contralateral innervation of the red nucleus and the pons. Such anatomical changes were not seen after adult lesions. Intracortical microstimulation of the primary motor cortex with EMG recordings of the elbow flexor muscles were used to investigate possible new functional connections from the motor cortex of the pyramidotomy side to the periphery. In rats lesioned as adults, stimulation of the motor cortex ipsilateral to the pyramidotomy never elicited EMG activity. In contrast, in P2 lesioned rats bilateral forelimb EMGs were found. EMG latencies were comparable for the ipsilateral and contralateral responses but were significantly longer than in unlesioned animals. Transient inactivation of both red nuclei with the GABA receptor agonist muscimol led to a complete loss of these bilateral movements. Movements and EMGs reappeared after wash-out of the drug. These results suggest an important role of the red nucleus in the reconnection of the cortex to the periphery after pyramidotomy. <http://www.jneurosci.org/cgi/content/full/20/17/6561
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10964961> Brain Research Institute, University of Zurich and Swiss Federal Institute of Technology Zurich, CH-8057 Zurich, Switzerland. email@example.com
Weidner N, Ner A, Salimi N and Tuszynski MH (2001). Spontaneous corticospinal axonal plasticity and functional recovery after adult central nervous system injury. Proc Natl Acad Sci U S A. 98 (6): 3513-8. Summary: Although it is believed that little recovery occurs after adult mammalian spinal cord injury, in fact significant spontaneous functional improvement commonly occurs after spinal cord injury in humans. To investigate potential mechanisms underlying spontaneous recovery, lesions of defined components of the corticospinal motor pathway were made in adult rats in the rostral cervical spinal cord or caudal medulla. Following complete lesions of the dorsal corticospinal motor pathway, which contains more than 95% of all corticospinal axons, spontaneous sprouting from the ventral corticospinal tract occurred onto medial motoneuron pools in the cervical spinal cord; this sprouting was paralleled by functional recovery. Combined lesions of both dorsal and ventral corticospinal tract components eliminated sprouting and functional recovery. In addition, functional recovery was also abolished if dorsal corticospinal tract lesions were followed 5 weeks later by ventral corticospinal tract lesions. We found extensive spontaneous structural plasticity as a mechanism correlating with functional recovery in motor systems in the adult central nervous system. Experimental enhancement of spontaneous plasticity may be useful to promote further recovery after adult central nervous system injury. <http://www.pnas.org/cgi/content/full/98/6/3513
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11248109> Department of Neurosciences, University of California at San Diego, La Jolla, CA 92093, USA.
Pettersson LG, Lundberg A, Alstermark B, Isa T and Tantisira B (1997). Effect of spinal cord lesions on forelimb target-reaching and on visually guided switching of target-reaching in the cat. Neurosci Res. 29 (3): 241-56. Summary: Cats were trained to reach to an illuminated tube placed horizontally at shoulder level and retrieve food with the forepaw. The trajectory of an infrared light emitting diode, taped to the wrist dorsum, was recorded with a SELSPOT-like recording system. Movement paths and velocity profiles were compared before and after lesions: (1) in dorsal C5, transecting cortico- and rubrospinal pathways to the forelimb segments so that the cats could only use the C3-C4 propriospinal neurones (PNs) to command reaching, (2) in the ventral part of the lateral funicle in C5, transecting the axons of C3-C4 PNs so that the cats had to use circuitry in the forelimb segments to command reaching. Comparison of trajectories and velocity profiles before and after lesion 1 did not reveal any major qualitative change. After lesion 2, the last third of the movement was fragmented with separate lifting and protraction. Switching of target-reaching occurred when illumination was shifted to another tube during the ongoing movement. The switching latency measured from the time of illumination shift to the earliest change in movement trajectory had a minimal value of 50-60 ms. Short latencies were present after lesion 1 as well as lesion 2 which suggest that fast switching mediated by the C3-C4 PNs and the interneuronal system in the forelimb segments is controlled in parallel by the brain. In order to test a hypothesis that fast switching depends on the tectospinal and tecto-reticulospinal pathways (the tecto-reticulo-spinal system) a ventral lesion was made in C2 aiming at interrupting these pathways. Large ventral C2 lesions tended to block conduction in the more dorsally located rubrospinal (less in corticospinal) axons probably due to compression during surgery. When conduction in the rubrospinal tract was completely interrupted by a ventral C2 lesion which also completely transected the axons of the tecto-reticulo-spinal system, then there was a prolongation of the switching latency with 10-20 ms. After a similar large ventral lesion with remaining conduction in the rubrospinal tract the switching latencies were unchanged. It is postulated that fast visually governed switching does not depend on the tecto-reticulo-spinal system alone but on more dorsally located pathways, presumably the rubrospinal tract, either acting alone or together with the tecto-reticulo-spinal system. It is further postulated that the delayed switching after interruption of conduction both in the rubrospinal tract and the tecto-reticulo-spinal system depends on the corticospinal tract. Visual control of rubrospinal and of corticospinal neurones is considered. It is postulated that target-reaching normally depends on signals in the cortico- and rubrospinal tracts and mechanisms for co-ordination of activity in them as required during switching is discussed in view of the findings now reported. <http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9436650> Institute of Physiology and Pharmacology, Department of Physiology, Goteborg University, Sweden.
Kato M (1990). Chronically isolated lumbar half spinal cord generates locomotor activities in the ipsilateral hindlimb of the cat. Neurosci Res. 9 (1): 22-34. Summary: The lumbar spinal cord of the cat was both hemisected (at L2 or L3) and longitudinally myelotomized in order to make half lumbar cord isolated from descending as well as contralateral impulses. The chronic cats recovered the ability to stand with their two forelimbs and a hindlimb, contralateral to the hemisection, 17.2 +/- 10.8 days after the operations. Two days later the hindlimb innervated by the isolated half lumbar cord regained walking capability. Phase relationships between the fore- and hindlimb muscles during locomotion were studied by recording EMGs from bilateral triceps brachii, vastus lateris and tibialis anterior muscles. Phase relationships between bilateral triceps brachii were 0.97 +/- 0.13 pi to 1.09 +/- 0.12 pi, indicating that the two forelimbs were stepping alternately and rhythmically. Phase relationships between bilateral vastus lateralis muscles were highly variable step by step, suggesting that the stepping of the hindlimb innervated by the isolated half lumbar cord was independently carried out, possibly evoked by peripheral receptors such as joint, muscle and cutaneous receptors. <http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=2175864> Department of Physiology, Hokkaido University School of Medicine, Sapporo, Japan.
Blight AR and Decrescito V (1986). Morphometric analysis of experimental spinal cord injury in the cat: the relation of injury intensity to survival of myelinated axons. Neuroscience. 19 (1): 321-41. Summary: The pattern of axonal destruction and demyelination that occurs in experimental contusion injury of cat thoracic spinal cord was studied by line sampling of axons in 1 micron thick plastic sections with the light microscope. Injuries were produced by a weight-drop apparatus, with the vertebral body (T9) below the impact stabilized by supports under the transverse processes. The effects of two combinations of weight and height were examined: 10 or 13 g dropped 20 cm onto an impact area of 5 mm diameter. Animals were kept for 3-5 months after injury, then fixed by perfusion for histological analysis. The number of surviving myelinated axons was found to vary both with the weight used and with the size of the spinal cord. A measure of impact intensity was derived from the calculated momentum of the weight at impact divided by the cross sectional area of the cord (interpolated from dimensions measured rostral and caudal of the lesion following fixation). At impact intensities greater than 0.02 kg-m/s/cm2 there was practically no survival of axons at the center of the injury site, combined with almost complete breakdown of the pial margin. Between 0.08 and 0.2 kg-m/s/cm2 the number of surviving axons varied between 100,000 and 2,000, approximating a negative exponential function (r = -0.88). The number of axons surviving in the outer 100 microns of the cord varied practically linearly (r = -0.82) between near normal and less than 1% of normal over the same range of injury intensity. The number of surviving axons decreased with depth from the pia, also approximating a negative exponential function, with a 10-fold decrease in density over approximately 500 microns. The average slope of this relation with depth remained similar over the range of injury intensity examined, though the slope appeared inversely related to variation in axonal survival for different individuals at a given intensity. It is argued that the loss of axons is probably determined primarily by mechanical stretch at the time of impact. Its centrifugal pattern may be explained by longitudinal displacement of the central contents of the cord, reflecting the viscoelastic "boundary layer" properties of parenchymal flow within the meningeal tube. This is illustrated with reference to the behavior of a gelatin model under compression. The preferential loss of large caliber axons and the characteristic shift to abnormally thin myelin sheaths (resulting from post-traumatic demyelination) both varied in extent independently of injury intensity and overall axonal survival.(ABSTRACT TRUNCATED AT 400 WORDS). <http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=3785669>
Basso DM, Beattie MS and Bresnahan JC (1996). Graded histological and locomotor outcomes after spinal cord contusion using the NYU weight-drop device versus transection. Exp Neurol. 139 (2): 244-56. Summary: Injury reproducibility is an important characteristic of experimental models of spinal cord injuries (SCI) because it limits the variability in locomotor and anatomical outcome measures. Recently, a more sensitive locomotor rating scale, the Basso, Beattie, and Bresnahan scale (BBB), was developed but had not been tested on rats with severe SCI complete transection. Rats had a 10-g rod dropped from heights of 6.25, 12.5, 25, and 50 mm onto the exposed cord at Tl 0 using the NYU device. A subset of rats with 25 and 50 mm SCI had subsequent spinal cord transection (SCI + TX) and were compared to rats with transection only (TX) in order to ascertain the dependence of recovery on descending systems. After 7-9 weeks of locomotor testing, the percentage of white matter measured from myelin-stained cross sections through the lesion center was significantly different between all the groups with the exception of 12.5 vs 25 mm and 25 vs 50 mm groups. Locomotor recovery was greatest for the 6.25-mm group and least for the 50-mm group and was correlated positively to the amount of tissue sparing at the lesion center (p < 0.0001). BBB scale sensitivity was sufficient to discriminate significant locomotor differences between the most severe SCI (50 mm) and complete TX (p < 0.01). Transection following SCI resulted in a drop in locomotor scores and rats were unable to step or support weight with their hindlimbs (p < 0.01), suggesting that locomotor recovery depends on spared descending systems. The SCI + TX group had a significantly greater frequency of HL movements during open field testing than the TX group (p < 0.005). There was also a trend for the SCI + TX group to have higher locomotor scores than the TX group (p > 0.05). Thus, spared descending systems appear to modify segmental systems which produce greater behavioral improvements than isolated cord systems. <http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=8654527> Ohio State University, Columbus, Ohio 43210, USA.
Beattie MS, Bresnahan JC, Komon J, Tovar CA, Van Meter M, Anderson DK, Faden AI, Hsu CY, Noble LJ, Salzman S and Young W (1997). Endogenous repair after spinal cord contusion injuries in the rat. Exp Neurol. 148 (2): 453-63. Summary: Contusion injuries of the rat thoracic spinal cord were made using a standardized device developed for the Multicenter Animal Spinal Cord Injury Study (MASCIS). Lesions of different severity were studied for signs of endogenous repair at times up to 6 weeks following injury. Contusion injuries produced a typical picture of secondary damage resulting in the destruction of the cord center and the chronic sparing of a peripheral rim of fibers which varied in amount depending upon the injury magnitude. It was noted that the cavities often developed a dense cellular matrix that became partially filled with nerve fibers and associated Schwann cells. The amount of fiber and Schwann cell ingrowth was inversely related to the severity of injury and amount of peripheral fiber sparing. The source of the ingrowing fibers was not determined, but many of them clearly originated in the dorsal roots. In addition to signs of regeneration, we noted evidence for the proliferation of cells located in the ependymal zone surrounding the central canal at early times following contusion injuries. These cells may contribute to the development of cellular trabeculae that provide a scaffolding within the lesion cavity that provides the substrates for cellular infiltration and regeneration of axons. Together, these observations suggest that the endogenous reparative response to spinal contusion injury is substantial. Understanding the regulation and restrictions on the repair processes might lead to better ways in which to encourage spontaneous recovery after CNS injury. <http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9417825> Department of Cell Biology, Ohio State University College of Medicine, 333 West 10th Avenue, Columbus, Ohio 43210, USA.
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. <http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11520130> Department of Neuroscience, The Ohio State University, Columbus, Ohio 43210, USA.