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Significant interest exists in strategies for improving forelimb function following spinal cord injury. We investigated the effect of enriched housing combined with skilled training on the recovery of skilled and automatic forelimb function after a cervical spinal cord injury in adult rats. All animals were pretrained in skilled reaching, gridwalk crossing, and overground locomotion. Some received a cervical over-hemisection lesion at C4-5, interrupting the right side of the spinal cord and dorsal columns bilaterally, and were housed in standard housing alone or enriched environments with daily training. A subset of animals received rolipram to promote neuronal plasticity. Animals were tested weekly for 4 weeks to measure reaching, errors on the gridwalk, locomotion, and vertical exploration. Biotinylated dextran amine was injected into the cortex to label the corticospinal tract. Enriched environments/daily training significantly increased the number and success of left reaches compared to standard housing. Animals also made fewer errors on the gridwalk, a measure of coordinated forelimb function. However, there were no significant improvements in forelimb use during vertical exploration or locomotion. Likewise, rolipram did not improve any of the behaviors tested. Both enriched housing and rolipram increased plasticity of the corticospinal tract rostral to the lesion. These studies indicate that skilled training after a cervical spinal cord injury improves recovery of skilled forelimb use (reaching) and coordinated limb function (gridwalk) but does not improve automatic forelimb function (locomotion and vertical exploration). These studies suggest that rehabilitating forelimb function after spinal cord injury will require separate strategies for descending and segmental pathways.

Gait analysis plays an important role in the assessment of neurological function in many disease models. In this review, we focus on the newly developed CatWalk system for gait analysis. CatWalk was originally developed as a tool to enhance assessment of functional outcome in spinal cord injury(SCI) models. Although it is also of value in models of among others (neuropathic) pain and peripheral nerve damage, we will limit ourselves to its use in SCI models in this review. The system is positioned against well-established locomotor function tests, and it is indicated how CatWalk can enhance the usefulness of such tests. Development of the system started with the idea that it should enable objective assessment of coordination, and powerful measures of coordination are nowadays included in the analysis options provided by CatWalk. Therefore, a major part of this review is devoted to the history and meaning of these coordination measures.

Refsum disease is caused by a deficiency of phytanoyl-CoA hydroxylase (PHYH), the first enzyme of the peroxisomal α-oxidation system, resulting in the accumulation of the branched-chain fatty acid phytanic acid. The main clinical symptoms are polyneuropathy, cerebellar ataxia, and retinitis pigmentosa. To study the pathogenesis of Refsum disease, we generated and characterized a Phyh knockout mouse. We studied the pathological effects of phytanic acid accumulation in Phyh⁻/⁻ mice fed a diet supplemented with phytol, the precursor of phytanic acid. Phytanic acid accumulation caused a reduction in body weight, hepatic steatosis, and testicular atrophy with loss of spermatogonia. Phenotype assessment using the SHIRPA protocol and subsequent automated gait analysis using the CatWalk system revealed unsteady gait with strongly reduced paw print area for both fore- and hindpaws and reduced base of support for the hindpaws. Histochemical analyses in the CNS showed astrocytosis and up-regulation of calcium-binding proteins. In addition, a loss of Purkinje cells in the cerebellum was observed. No demyelination was present in the CNS. Motor nerve conduction velocity measurements revealed a peripheral neuropathy. Our results show that, in the mouse, high phytanic acid levels cause a peripheral neuropathy and ataxia with loss of Purkinje cells. These findings provide important insights in the pathophysiology of Refsum disease.

Most experimental studies of spinal cord injury (SCI) in rats damage the thoracic cord, with the consequent functional loss being due to interruption of long tracts connecting the caudal spinal cord to the rostral nervous system. Less work has been done evaluating injury to the cervical cord, even though it is the most common level of human SCI. In addition to the long tracts, the cervical spinal cord contains the sensory and motor neurons responsible for upper extremity function. The purpose of this study was to further develop a rat model of cervical spinal cord contusion injury using a modified NYU/MASCIS weight drop device. Mild (6.25 mm) and moderate (12.5 mm) C5 unilateral injuries were produced. Behavioral recovery was examined using a grooming test, a paw preference test, a walkway test (The Catwalk), and a horizontal ladder test. Histological outcome measures included sparing at the lesion epicenter, sparing throughout the extent of the lesion, quantification of myelin loss rostral and caudal to the lesion, and motor neuron counts. Compared to controls, animals receiving SCI exhibited injury severity-specific deficits in forelimb, locomotor, and hindlimb function persisting for 6-weeks post-SCI. Histological analysis revealed ipsilateral containment of the injury, and differentiation between groups on all measures except motor neuron counts. This model has many advantages: (1) minimal animal care requirements post-SCI, (2) within subject controls, (3) functional loss involves primarily the ipsilateral forelimb, and (4) it is a behavioral and histological model for both gray and white matter damage caused by contusive SCI.

The Basso, Beattie and Bresnahan (BBB) locomotor rating scale is the most widely used open field test and has been accepted as a valid way to assess locomotor function after spinal cord contusion injury in the rat. A limitation within the BBB locomotor rating scale is the correct assessment of forelimb (FL)–hindlimb (HL) coordination. This limitation can have major implications for the final assessment of locomotor function. In the present study, we show an objective method to assess coordination based on the regularity index (RI), achieved through the use of the CatWalk method. The RI grades the degree of coordination as the result of the number of normal step sequence patterns multiplied by four and divided by the total amount of paw placements. Using the RI, single walkway crossings can be objectively analyzed on coordination. Integration of the CatWalk based coordination into the BBB scale indicates that objective analysis of coordination results in reliable and more sensitive assessment of locomotor function. This new method has been tested successfully in determination of positive effects of enriched housing on functional recovery after spinal cord injury(SCI).

Analysis of locomotion is an important tool in the study of peripheral and central nervous system damage. Most locomotor scoring systems in rodents are based either upon open field locomotion assessment, for example, the BBB score or upon foot print analysis. The former yields a semiquantitative description of locomotion as a whole, whereas the latter generates quantitative data on several selected gait parameters. In this paper, we describe the use of a newly developed gait analysis method that allows easy quantitation of a large number of locomotion parameters during walkway crossing. We were able to extract data on interlimb coordination, swing duration, paw print areas (total over stance, and at 20-msec time resolution), stride length, and base of support: Similar data can not be gathered by any single previously described method. We compare changes in gait parameters induced by two different models of spinal cord injury in rats, transection of the dorsal half of the spinal cord and spinal cord contusion injury induced by the NYU or MASCIS device. Although we applied this method to rats with spinal cord injury, the usefulness of this method is not limited to rats or to the investigation of spinal cord injuries alone.

The purpose of this study was to compare spontaneous functional recovery after different spinal motor tract lesions in the rat spinal cord using three methods of analysis, the BBB, the rope test, and the CatWalk. We transected the dorsal corticospinal tract (CSTx) or the rubrospinal tract(RSTx) or the complete dorsal half of the spinal cord (Hx) at thoracic level T8. Functional recovery was monitored for 31 weeks. We found no recovery of consistent inter limb coordination in any experimental group over time using the BBB locomotor rating scale. Quantitative CatWalk analysis revealed significant differences between experimental groups for inter limb coordination (RI). RSTx and Hx animals showed a significant decrease in the RI, and only in the RSTx group did the RI improve from 6 weeks post-lesion onward. Significant differences between experimental groups in step sequence patterns and base of support were also observed. In the rope test all experimental groups had significantly higher error percentages compared to control animals. Tracing of the CST revealed enhanced collateral formation rostral to the lesion in the CSTx group, not in other groups. The results presented here show that locomotor function in all, but CSTx groups gradually improved over time. This is important for studies that employ pharmacological, cell-, and/or gene therapy– based interventions to improve axonal regeneration and functional recovery after spinal cord injury.

We have recently shown that enriched environment (EE) housing significantly enhances locomotor recovery following spinal cord contusion injury (SCI) in rats. As the type and intensity of locomotor training with EE housing are rather poorly characterized, we decided to compare the effectiveness of EE housing with that of voluntary wheel running, the latter of which is both well characterized and easily quantified. Female Wistar rats were made familiar with three types of housing conditions, social housing (nine together) in an EE (EHC), individual housing in a running wheel cage (RUN, n = 8), and standard housing two together (CON, n = 10). Subsequently, a 12.5 gcm SCI at Th8 was produced and animals were randomly divided over the three housing conditions. Locomotor function was measured regularly, once a week by means of the BBB score, BBB sub score, TLH test, Gridwalk test, and CatWalk test. In the RUN group, daily distance covered was also measured. Locomotor recovery in the EHC and the RUN groups was equal and significantly better than in the CON group. The extent of recovery at 8 weeks post injury in the RUN group did not correlate with distance covered. We conclude that locomotor training needs to exceed a given threshold in order to be effective in enhancing locomotor recovery in this experimental model, but that once this threshold is exceeded no further improvement occurs, and that the specificity of locomotor training plays little role.

Traumatic spinal cord injury (SCI) results in partial or complete paralysis and is characterized by a loss of neurons and oligodendrocytes, axonal injury, and demyelination/dysmyelination of spared axons. Approximately 1,250,000 individuals have chronic SCI in the U.S.; therefore treatment in the chronic stages is highly clinically relevant. Human neural stem cells (hCNS-SCns) were prospectively isolated based on fluorescence-activated cell sorting for a CD133(+) and CD24(-/lo) population from fetal brain, grown as neurospheres, and lineage restricted to generate neurons, oligodendrocytes and astrocytes. hCNS-SCns have recently been transplanted sub-acutely following spinal cord injury and found to promote improved locomotor recovery. We tested the ability of hCNS-SCns transplanted 30 days post SCI to survive, differentiate, migrate, and promote improved locomotor recovery. hCNS-SCns were transplanted into immunodeficient NOD-scid mice 30 days post spinal cord contusion injury. hCNS-SCns transplanted mice demonstrated significantly improved locomotor recovery compared to vehicle controls using open field locomotor testing and CatWalk gait analysis. Transplanted hCNS-SCns exhibited long-term engraftment, migration, limited proliferation, and differentiation predominantly to oligodendrocytes and neurons. Astrocytic differentiation was rare and mice did not exhibit mechanical allodynia. Furthermore, differentiated hCNS-SCns integrated with the host as demonstrated by co-localization of human cytoplasm with discrete staining for the paranodal marker contactin-associated protein. The results suggest that hCNS-SCns are capable of surviving, differentiating, and promoting improved locomotor recovery when transplanted into an early chronic injury microenvironment. These data suggest that hCNS-SCns transplantation has efficacy in an early chronic SCI setting and thus expands the \"window of opportunity\" for intervention.

To date, most research performed in the area of spinal cord injury focuses on treatments designed to either prevent spreading lesion (secondary injury) or to enhance outgrowth of long descending and ascending fiber tracts around or through the lesion. In the last decade, however, several authors have shown that it is possible to enhance locomotor function after spinal cord injury in both animals and patients using specific training paradigms. As a first step towards combining such training paradigms with pharmacotherapy, we evaluated recovery of function in adult rats sustaining a spinal cord contusion injury(MASCIS device, 12.5 mm at T8), either housed in an enriched environment or in standard cages (n = 15 in both groups). The animals in the enriched environment were stimulated to increase their locomotor activity by placing water and food on opposite sides of the cage. As extra stimuli, a running wheel and several other objects were added to the cage. We show that exposure to the enriched environment improves gross and fine locomotor recovery as measured by the Basso, Beattie, and Bresnahan (BBB) locomotor rating scale, the BBB subscale, the Gridwalk, and the Thoracolumbar height test. However, no group differences were found on our electrophysiological parameters nor on the amount of spared white matter. These data justify further studies on enriched housing and more controlled exercise training, with their use as potential additive to pharmacological intervention.