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Spinal Cord Injury Special Series |
DM Basso, PT, EdD, Assistant Professor, Division of Physical Therapy, School of Allied Medical Professions, The Ohio State University, 306 SAMP, 1583 Perry St, Columbus, OH 43210 (USA) (basso.2{at}osu.edu)
 | Abstract |
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Key Words: Experimental models • Flexor withdrawal reflex • Locomotion • Neuroplasticity • Treadmill training
| Introduction |
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 TopAbstract Introduction Lesion Development After SCIRelationship of Lesion Size...Identification of CNS Systems...Justification for Locomotor...SummaryReferences |
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| Lesion Development After SCI |
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TopAbstractIntroductionLesion Development After SCIRelationship of Lesion Size...Identification of CNS Systems...Justification for Locomotor...SummaryReferences |
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Thus, a clinically complete lesion does not necessarily indicate an anatomically complete SCI. A functionally or clinically complete lesion is typically described as the absence of sensory and motor function below the level of the lesion (American Spinal Injury Association [ASIA] Impairment Scale classification A).10 In contrast, an individual with an incomplete SCI has sensory and/or motor function below the lesion (ASIA B, C, and D).11 Thus, tissue sparing after complete SCI suggests that the remaining axons are available to possibly mediate some recovery of function but do not appear to be recruited using traditional rehabilitation approaches such as compensation. The emergence of the full capacity of these spared axons may depend on the type of therapeutic interventions that are used.
Several experimental models of SCI have been developed in order to understand factors that may facilitate recovery of function after SCI in humans. The advantages of using an animal model rather than studying humans with SCI are: (1) the severity of the lesion can be controlled and reproduced across animals and experiments, (2) direct neuroanatomical evidence of lesion development over time can be attained using invasive procedures, and (3) effective parameters of therapeutic interventions can be established and refined before translating them for human use. One of the most clinically relevant experimental models of SCI is the contusion injury in rats, created by rapid impact of the dorsal surface of the spinal cord using an electromagnetic device12,13 or a weight-drop device.14–16 These devices create a central core lesion and a peripheral rim of spared white matter similar to that reported in humans. The area of the cord with the greatest extent of damage is referred to as the "lesion epicenter." This review will focus on data gathered from contusion models of SCI primarily in rats.
Lesion development in SCI progresses over time and in neuroanatomical distribution. The primary phase of injury occurs during the first 18 hours and is typified by necrotic death of neurons and axons that were directly disrupted by the trauma.17–20 The secondary phase of tissue injury can last several weeks and progresses in rostral and caudal directions, away from the lesion epicenter. Recent work suggests that the immune system plays a primary role in initiating cellular cascades that contribute to the expansion of the lesion during the secondary phase of lesion development.21–23 In the secondary phase, immune system cells such as monocytes and macrophages are thought to emit chemical signals such as cytokines and chemokines.22 These substances act on neurons and oligodendrocytes and appear to trigger apoptosis or programmed cell death in which DNA in the nucleus of the cell is systematically broken down into fragments.24–26 Thus, intracellular processes in neurons and oligodendrocytes lead to destruction of their nuclei, causing cell death, despite no direct trauma to the cell. Apoptosis is known to occur after contusive SCI, especially in white matter tracts great distances away from the lesion (at least 4 spinal segments above and below the lesion epicenter).26,27 Oligodendrocytes appear to undergo programmed cell death, which results in demyelination of axons many segments away from the lesion epicenter.28 Thus, early after SCI, the injury is small, focal, and localized to the point of impact, but over time the lesion spreads to distant sites and may preferentially affect myelination of axons that are otherwise intact.
One critical issue in SCI research is whether lesion size and tissue sparing are important determinants of final functional outcome after contusion injury. If the size of the lesion is an important determinant of final functional outcome in patients with SCI, then interventions that attempt to bridge the central lesion or limit the secondary progression of the lesion would appear to be quite beneficial. The action of methylprednisolone, the standard treatment after SCI, is to reduce the inflammatory response and inhibit the immune system.29,30 Methylprednisolone, therefore, could limit lesion expansion, which might explain the marked improvement in functional outcome of those treated.29,30 As other pharmaceutical interventions are developed that limit or prevent the secondary lesion cascade, it is likely that the incidence of functionally complete lesions will decline.
| Relationship of Lesion Size and Behavioral Outcome |
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TopAbstractIntroductionLesion Development After SCIRelationship of Lesion Size...Identification of CNS Systems...Justification for Locomotor...SummaryReferences |
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As a gross behavioral outcome measure for use with animal models, my collaborators and I31 recently developed the semiquantitative Basso, Beattie, and Bresnahan (BBB) Locomotor Rating Scale to assess overground locomotion in the open field. The measure is a sensitive,31 reliable36 measure of overall locomotor performance. The ratings of the BBB Locomotor Rating Scale range from 0 to 21 and distinguish between locomotor features such as flaccid paralysis, isolated hind-limb joint movements, weight-supported plantar stepping, coordination, and fine details of locomotion (eg, toe clearance, paw position).
Does Tissue Sparing Mediate Behavioral Recovery?
In a series of experiments, my collaborators and I15,31 analyzed locomotor outcomes after mild, moderate, or severe spinal cord contusion in rats with extensive (>40%), intermediate (15%–40%), or minimal (1%–14%) tissue sparing at the lesion epicenter. We found differences in BBB Locomotor Rating Scale scores across groups. In general, locomotor recovery was extensive after mild SCI with extensive axonal sparing (>40%) but was quite limited after severe SCI with little sparing (as low as 1%–2%).15 The BBB Locomotor Rating Scale scores predicted the extent of underlying neuropathology, as indicated by a positive correlation between BBB Locomotor Rating Scale score and percentage of spared tissue at the epicenter (replicated across studies: r2=.79,15 r2=.8831; P<.001). Although there was a causal relationship between the extent of sparing and the extent of recovery, correlational data were insufficient to conclude that the spared axons directly mediated the recovery. Perhaps spinal cord systems below the level of the lesion were responsible for the locomotor recovery. Therefore, we took 2 groups that had recovered for 9 weeks after moderate and severe SCIs and transected the spared axons at the lesion epicenter.31 If functional recovery was due to segmental systems in the lumbar spinal cord, then transection of the spared tissue would have no behavioral effect. However, we found that severing the spared axons eliminated the behavioral recovery. The secondary transection resulted in a loss of locomotion such that the animals with SCI and spinal cord transection performed no differently within the first 5 days after transection than animals with spinal cord transection alone, based on BBB Locomotor Rating Scale scores. These findings suggest that tissue sparing at the lesion epicenter is responsible for behavioral recovery after experimental spinal cord contusion.
Can Minimal Sparing Improve Motor Function?
The study of rats with SCI and spinal cord transection31 yielded important information about reorganization within the spinal cord. We were surprised by our observation that the rats with SCI and spinal cord transection appeared to demonstrate some motor recovery 2 weeks after complete transection of the spinal cord, a finding that rarely or never occurs after complete transection alone in adult rats.12,31 Although the ability to locomote remained lost, the rats with SCI and spinal cord transection demonstrated more extensive hind-limb joint movements than the rats with transection alone, as measured by the BBB Locomotor Rating Scale scores. On closer examination of videotaped performance in the open field, we found that the rats that recovered from SCI and spinal cord transection performed more hind-limb movements than the rats that had recovered from a transection alone.31 This is an important finding because it shows that animals that recover in the presence of relatively few spared axons (<2% in some cases) have altered organization of systems below the lesion. This reorganization, presumably of segmental systems, is evident when the lumbar spinal cord functions in isolation of supraspinal systems after the transection. Reorganization of caudal segments may be in the form of anatomical changes such as synaptogenesis of primary afferent fibers into vacated synaptic sites,37 physiological changes that lower the threshold of postsynaptic neurons and render them more likely to produce an action potential,38 or loss of axo-axonic presynaptic inhibition.39,40 In summary, tissue sparing directly mediates recovery of function after experimental SCI, and sparing of as little as 1% to 2% is sufficient to facilitate reorganization within the lumbar spinal cord.
In another experiment, in which my collaborators and I studied the locomotion of opossums after spinal cord transection,41 we found further evidence that an incomplete complement of descending or ascending axons induced marked reorganization below the level of the lesion. The study was designed to examine the effects of complete spinal cord transection made early in development on adult motor function.41 Opossums are born 12 days after conception, crawl into the mother's pouch, and continue developing.42,43 Therefore, lesions can be made extremely early in development without using high-risk, in utero techniques. Previous work by Martin and colleagues44,45 established that, if the transection is made at postnatal day 26 in development, then at least a few axons from some supraspinal systems (primarily rubrospinal axons) grow across the lesion and travel into the lumbar spinal cord. However, in those studies, there was no examination of the behavioral effects of these axons.
In our study,41 a group of opossums had midthoracic transection on postnatal day 5 and grew to adulthood; a procedure that results in only a partial complement of axons growing across the lesion into the lumbar spinal cord. Despite less input to the lumbar spinal cord, these opossums developed nearly normal locomotion, as measured by the BBB Locomotor Rating Scale in adulthood. Three animals from this group were then given spinal cord retransection to determine whether supraspinal axons reaching the lumbar spinal cord contributed to the locomotor effects. At the end of the experiment, we used one of the most sensitive silver staining methods46 to detect axons as small as 1 µm in diameter that may have been spared after retransection. Based on our post-mortem findings that the cut ends of the spinal cord separated 5 to 10 mm and that no axons traversed the lesion site, we confirmed that the retransection was complete. Thus, any hind-limb motor function would be mediated solely by the isolated lumbar spinal cord after retransection.
As observed in the study of rats with SCI and transection,31 severing the partial complement of axons that reach the lumbar spinal cord in the opossum eliminated locomotion immediately and hind-limb movements were similar to those exhibited by opossums that had spinal cord transection in adulthood.41 More importantly, the opossums with retransection demonstrated dramatic rebound in hind-limb motor function over time, a pattern seen in rats with SCI and transection. By 6 weeks following retransection, each of the animals was able to take several bouts of consecutive weight-supported stepping with the hind limbs. The hind limbs often stepped in a rhythmic, alternating manner. In contrast, it is well documented that complete transection of the spinal cord in adult animals (rat,12,47 cat,48,49 opossum,50 review51) results in hind-limb paralysis during over-ground locomotion. Thus, the only difference between opossums with spinal cord transection in adulthood and those with retransection in adulthood is that the lumbar spinal cord of the animals with retransection developed in the presence of an incomplete complement of descending systems. The remarkable stepping exhibited by the animals with retransection is evidence of substantial reorganization of lumbar systems during development.
In summary, the rat and opossum studies present dramatic evidence in both adult and developing animals that a great deal of reorganization of lumbar circuits takes place in the presence of a partial complement of descending systems. In terms of clinical application, it remains to be seen whether this reorganization can be shaped or molded through therapeutic interventions such as exercise training or constraint-induced movement of the affected extremities.
Are Segmental Reflexes Modified According to the Amount of Tissue Sparing?
In our studies, we determined that tissue sparing facilitates recovery of locomotion after contusion but we did not know whether the amount of sparing would differentially affect other motor behaviors such as reflexes. In another set of experiments, my collaborators and I52 compared the performance of the flexor withdrawal reflex in animals with substantial sparing (mild SCI) or minimal sparing (moderate SCI). The flexor withdrawal reflex was elicited by pinching the intrinsic muscles of the paw with our fingers, which elicited rapid flexion of the hip, knee, and ankle. By using our fingers rather than an implement, we were able to release the paw immediately at the onset of movement so that the motion was not impeded. We rated the pressure of the pinch on a scale from 1 to 3, with 1 being almost no pressure, 2 being the pressure necessary to elicit a response in an animal without a lesion, and 3 being a large amount of pressure. In order to assess the movement characteristics of the hind limb after stimulation, we videotaped the performance and used frame-by-frame kinematic analysis. We focused our analysis on the ankle because it appeared to have greater deficits than the other joints during locomotion.
Examination of stimulus threshold for the animals with moderate SCI showed an initial increase above normal 1 week after SCI, which decreased to below-normal levels by 4 weeks after SCI. Over time, very little pinch pressure was required to elicit a robust flexor withdrawal response. Given the manner in which we measured stimulus intensity, we have recently replicated these findings in animals with moderate SCI under blinded conditions and found a decrease in stimulus threshold compared with animals with laminectomy that served as controls.53 Due to technological problems in which verbal statements of stimulus intensity recorded on videotape were erased, no stimulus data could be recovered for the animals with mild SCI. Therefore, we quantified the stimulus intensity after mild SCI (n=12) in several other studies in our laboratory and present these data as representative of animals with mild SCI (unpublished observation). One week after mild SCI, the stimulus intensity was slightly less than normal but had returned to normal levels by 4 weeks after SCI. In summary, animals with less sparing required a much lower stimulus intensity to elicit the reflex than animals with more tissue sparing and animals without lesions.
The reflex response was more robust after moderate SCI but not after mild SCI, as was evident by: (1) incorporation of pronounced trunk flexion and rotation, (2) rapid, repetitive hind-limb flexion to a single stimulus, and (3) brisk, full extension of the unstimulated hind limb. These qualitative observations suggest that hyperreflexia may have developed after moderate SCI, an interpretation also supported by precise quantitative measurements of hind-limb movement. Although flexor excursion of the ankle was unchanged for the animals with mild and moderate SCI, we found that movement speed and timing were different between groups. There was a trend that peak angular velocity of the ankle was consistently higher for animals with moderate SCI than for animals with mild SCI at 2, 3, and 4 weeks after SCI. We also found that the animals with moderate SCI had faster movement times and reached peak flexion sooner than the animals with mild SCI (Figure). Our data suggest that pronounced hyperreflexia of segmental systems in the lumbar spinal cord developed when the lesion was extensive and tissue sparing was minimal.
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| Identification of CNS Systems Spared After SCI |
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TopAbstractIntroductionLesion Development After SCIRelationship of Lesion Size...Identification of CNS Systems...Justification for Locomotor...SummaryReferences |
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In general, retrograde tracing demonstrated greater cell labeling after mild SCI than after moderate SCI. Despite differential sparing, both groups had labeled neurons in most of the movement-related nuclei in the CNS, including the red nucleus, medullary reticular formation, raphe nuclei, and lateral vestibular nucleus. However, there were 2 areas that had little or no labeling in either group: the sensorimotor cortex and lamina 8 of the gray matter of the cervical spinal cord. Thus, it appears that corticospinal and long-descending propriospinal tracts to the anterior horn are lost after spinal cord contusion, regardless of lesion severity. It is likely that the central position of these tracts in the rat spinal cord rendered them more susceptible to damage after contusion than tracts located at the peripheral edge of the spinal cord. Although the human corticospinal tract runs in the anterior and lateral funiculi of the spinal cord, the corticospinal tract in the rat travels in the base of the dorsal funiculus.61
In summary, the spared tissue at the lesion center following mild or moderate spinal cord contusion is composed of at least rubro-, reticulo-, vestibulo-, and raphe-spinal tracts. Given that locomotor recovery depends on tissue sparing, these descending brain-stem systems must play an important role, whereas cortico-spinal and propriospinal tracts probably play little or no role. Anatomically intact axons may not be physiologically active. However, in our model, at least some of these intact axons appear to be functional, given that transection of the spared axons results in a loss of previously recovered locomotion. Further studies are being conducted to determine whether individual descending pathways contribute to the recovery of specific features of locomotion. Alternatively, the spared systems may function as a unit, modulating descending drive to the reorganized spinal cord systems below the injury.
| Justification for Locomotor Training After SCI |
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TopAbstractIntroductionLesion Development After SCIRelationship of Lesion Size...Identification of CNS Systems...Justification for Locomotor...SummaryReferences |
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One of the first attempts to convert neuroanatomical principles from the laboratory into a therapeutic treatment approach is based on evidence of central pattern generators (CPGs) in the spinal cord. Central pattern generators produce rhythmic, oscillating activity of limb flexor and extensor muscle groups independent of any supraspinal or afferent input.62–64 Thus, CPGs appear to be interneuron-motoneuron circuits within the spinal cord of vertebrates. It is widely held that such CPGs are located in the lumbar segments of the spinal cord in rats, cats, and dogs.62–65 These CPGs are multifunctional and can produce a variety of locomotor behaviors. Normally, CPGs that produce overground locomotion are activated by descending supraspinal input; however, in the absence of this input, the CPGs can be triggered by an external stimulus such as a moving treadmill belt. Thus, the neural control of overground locomotion is distinct from the control of reflex locomotion on a treadmill. Animals that are unable to locomote overground after complete transection of the spinal cord perform nearly normal stepping on the treadmill.48,49,66
Scientists have taken advantage of the principles of CPG activation to examine the capacity of the isolated lumbar spinal cord to learn. Edgerton and colleagues67,68 have carried out a series of studies in which animals with complete, low-thoracic transection of the spinal cord were trained to step or stand with their hind limbs and their performance was compared with the spontaneous recovery of untrained animals with SCI that served as controls. The animals in the experimental group were placed in a body support sling on a treadmill and underwent extensive training to either stand in a stationary position with the treadmill turned off or to step with their hind limbs on the moving treadmill belt. Initially, the hind limbs of the animals in the step training group were manually assisted, when necessary, to complete the step. During training, the amount of body weight supported by the hind limbs and treadmill speeds were varied.
The animals in the standing group were trained by increasing afferent input to the spinal cord via cutaneous stimulation of the tail or paw. By 3 months, the animals in the standing group could stand independently and support their full body weight for 30 minutes, whereas the untrained animals were unable to stand. The animals in the stepping group were able to walk on the treadmill at relatively high speeds without assistance. Although the untrained animals had some spontaneous recovery of treadmill stepping, these animals could only tolerate treadmill speeds nearly 3 times lower than the treadmill speeds tolerated by the trained animals. Thus, each group of animals learned to perform the task on which they were trained to a higher competency than animals relying on only spontaneous recovery. More importantly, these findings demonstrate that the isolated lumbar spinal cord has the capacity to "learn" and execute motor tasks in quadrupedal animals.
In further research, Edgerton's group set out to determine whether this learning was task-specific or more generalized and could improve motor performance on other behavioral tasks.69 Animals with complete transection of the spinal cord were trained to step or stand until performance plateaued, then they were tested on the opposite task (eg, step training followed by stand training). Animals that were trained to step could not stand in a manner similar to that of animals that were trained to stand. They were unable to support themselves for any length of time without a large amount of cutaneous stimulation. Likewise, most animals that were trained to stand could not step. Two animals took only a few aberrant steps at extremely low treadmill speeds. Thus, the general observation that animals trained to step could not stand and animals trained to stand could not step is powerful evidence of task-specific learning. Further evidence was gleaned by cross-training these animals. Animals that learned to step or stand were later trained to perform the opposite task, although they lost the ability to perform the first task. That is, the isolated spinal cord acquires complex motor skills in a context-dependant manner and requires extensive training.
Recently, treatments based on CPGs have been successfully transferred to human subjects with SCI by several researchers.70–76 The methods of intervention are based on the principles identified in animals with SCI by Edgerton and colleagues.67–69 Initially, the individual is partially unweighted over a treadmill, and the lower extremities are manually assisted to step. With training, people with SCI can progress to full weight support and stepping independently while on the treadmill.70 Even individuals with long-standing, functionally complete lesions have been trained to step independently on the treadmill (see article by Behrman and Harkema77 in this special series). Furthermore, training at increased tread-mill speeds and greater loads across the legs over time facilitated greater angular excursion of the joints, increased amplitudes of muscle activity (measured via electromyography), and facilitated appropriate muscle activation patterns relative to other muscles and to the phases of gait.70 These findings serve as a dramatic example of the inherent neuroplasticity of the spinal cord. In addition, training can trigger this plasticity several years after the SCI, suggesting that the potential for recovery is somehow preserved in the spinal cord over time.
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TopAbstractIntroductionLesion Development After SCIRelationship of Lesion Size...Identification of CNS Systems...Justification for Locomotor...SummaryReferences |
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Clinical Implications
Basic science research has contributed dramatically to our understanding of SCI; however, important clinical questions remain. First, we do not know whether motor skill learning after anatomically complete SCI is the same as when the lesion is incomplete, the condition most frequently encountered in the clinic. Perhaps when tissue is spared, less training specificity will be needed to induce learning because more of the CNS can participate. Second, we have a general understanding of training paradigms that facilitate skill acquisition after SCI, but we do not yet know the effect of specific components on learning. For example, there are at least 2 primary paradigms involved in body weight-supported treadmill step training: rhythmicity and loading of the limbs. We currently do not know whether one, both, or none of these paradigms play a primary role in learning to step. Third, it remains to be shown whether treadmill training can reduce the hyperreflexia that often accompanies SCI. Fourth, and perhaps most importantly, there is little data on how to transfer treadmill-induced locomotion to more functionally relevant tasks such as overground locomotion.
My list of questions is meant to illustrate the importance and necessity of clinically based studies. Some of the most important, valuable, and relevant questions concerning advances in the treatment of people with SCI may be posed by physical therapists. Therefore, it is imperative that physical therapists contribute to clinically based research and the development of new treatment approaches.
| Footnotes |
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The work was supported by NIH grant NS-32000, American Paralysis Association grant BB-2-9302-2, and USPHS grants NS-25095 and NS-10165.
Portions of this work were presented at the 1993–1996 Annual Meetings of the Society for Neuroscience and at the 1998 Neuroplasticity Symposium of the Section on Research, American Physical Therapy Association.
* Fluorochrome, Englewood, CO 80110. 
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TopAbstractIntroductionLesion Development After SCIRelationship of Lesion Size...Identification of CNS Systems...Justification for Locomotor...SummaryReferences |
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