Anatomical and behavioral outcomes following a graded hemi-contusive cervical spinal cord injury model in mice.

BACKGROUND: A graded hemi-contusion spinal cord injury produces complex anatomical deformation of the spinal cord parenchyma. The relationship between lesion severity and behavioral consequences in a novel contusion mouse model remains unknown. PURPOSE: We aimed to establish a graded cervical hemi-contusion spinal cord injury model in mice and investigate the correlation between graded anatomical damage to the spinal cord and resulting behavioral impairments. METHODS: Thirty-two mice were divided into groups of 1.2 mm, 1.5 mm and sham. The tip of an impactor with a diameter of 1 mm was utilized to compress the left dorsal cord of C5 by 1.2 mm or 1.5 mm at a speed of 300 mm/s. Forelimb motor function was evaluated using rearing, grooming and grip-strength tests before and after the injuries. Histologically the area of white matter sparing, gray matter sparing and lesion area were quantified at 6-week-post-injury. RESULTS: Behavioral assessments showed a more severe forelimb functional deficit in 1.5 mm contusion displacements relative to 1.2 mm contusion displacements after injury. The 1.2 mm hemi-contusion mainly caused damage to the dorsal fasciculus, ventral and dorsal horn, while the 1.5 mm hemi-contusion lead to additional damage extending to ventral fasciculus. Sparing of the gray and white matter at the epicenter was 36.8 ± 2.4% and 12.4 ± 2.6% in the 1.2 mm group, and 27.6 ± 4.0% and 4.1 ± 2.2% in the 1.5 mm group, respectively. Furthermore, the lesion area was 20.8 ± 3.0% and 36.0 ± 2.1% in the 1.2 mm and 1.5 mm groups, respectively. There was a significant correlation between the performance in the grooming test and white matter sparing, and between grip-test strength and gray matter sparing. CONCLUSION: The present study demonstrates that a hemi-contusion cervical spinal cord injury in mice can be graded by contusion displacement and that there is a correlation between anatomical and behavioral outcomes. This study provides a means for determining the severity of lesions in a contusion mouse model.

A Cervical Spinal Cord Hemi-Contusion Injury Model Based on Displacement Control in Non-Human Primates (Macaca fascicularis).

Non-human primate (NHP) spinal cord injury (SCI) models can be informative in the evaluation of treatments that show promise in rodent models prior to translation to humans. In the present study, we aimed to establish a cervical spinal hemi-contusion model with controlled displacement and evaluate the abnormalities in behavior, electrophysiology, histology, and magnetic resonance imaging. Twelve adult NHPs were divided into an SCI group (n = 8, 24 and 48 weeks) and a control group (n = 4). An impactor (Φ = 4 mm) was driven to compress the left C5 cord at 800 mm/sec. The contusion displacement and peak force was 4.08 ± 0.17 mm and 19.8 ± 4.6 N. The behavioral assessment showed a consistent dysfunction below the wrist and spontaneous recovery of limb function after injury. Lesion length and lesion area at the epicenter based on T2 hyperintensity were 5.68 ± 0.47 mm and 5.99 ± 0.24 mm2 at 24 weeks post-injury (wpi), and 5.29 ± 0.17 mm and 5.95 ± 0.24 mm2 at 48 wpi. The spared spinal cord area immuno-positive for glial fibrillary acidic protein was significantly reduced, while the staining intensity increased at 24 wpi and 48 wpi, compared with the sham group. Ipsilateral somatosensory and motor evoked potentials were dynamic, increasing in latency and decreasing in amplitude compared with pre-operative values or the contralateral values, and correlated to varying degrees with behavioral outcomes. A shift in size-frequency distribution of sensory neurons of the dorsal root ganglia (DRG) was consistent with a loss of large-diameter cells. The present study demonstrated that the NHP SCI model resulted in consistent unilateral limb dysfunction and potential plasticity in the face of loss of spinal cord and DRG tissue.

Three-Dimensional Changes in Cervical Spinal Cord Microvasculature During the Chronic Phase of Hemicontusion Spinal Cord Injury in Rats.

BACKGROUND: The angioarchitecture of the spinal cord and microvascular changes after acute and subacute spinal cord injury (SCI) have been reported in rodents. Microvascular changes after chronic SCI have not been explored. We characterized three-dimensional microvascular changes during the chronic phase of cervical hemicontusion SCI in rats. METHODS: At 12 weeks after 1.2-mm hemicontusion injury, microvascular parameters, including vascular volume, ratio of vascular volume to tissue volume, vascular number, and vascular separation, were measured at the epicenter and each cord segment, and the percentage and volume of spinal vessels with different diameters were measured by micro computed tomography at the injury segment. RESULTS: The 1.2-mm hemicontusion injury applied a compressive force of 1.050 ± 0.103 N to the cord, resulting in a cavity and a significant decrease in microvasculature at the epicenter. The vascular volume, ratio of vascular volume to tissue volume, and vascular number of the C5 cord decreased by 40%, 38%, and 36% at 12 weeks after SCI, whereas vascular separation increased by 54% compared with the control group. In the chronic phase after SCI, the percentage and volume of spinal microvessels at the contusion segment decreased significantly (especially vessels with diameters <40 µm). CONCLUSIONS: Blood supply to the cervical spinal cord is insufficient during the chronic phase of cervical hemicontusion SCI, especially in microvessels with diameters <40 µm. These results may provide a basis to explore microvascular changes of SCI during the chronic phase.

Longitudinal electrophysiological changes after cervical hemi-contusion spinal cord injury in rats.

OBJECTIVE: To evaluate the longitudinal somatosensory evoked potentials (SEPs) and motor evoked potentials (MEPs) characterization from acute to chronic injury following cervical hemi-contusion spinal cord injury (SCI) in rats, and correlate the MEPs & SEPs to the behavioral outcomes. METHODS: Fifteen adult male Sprague-Dawley rats were subjected to the hemi-contusion spinal cord injury at C5. Forelimb MEPs & SEPs were applied to 5 animals before injury and 3h, 1d, 3d, 1w, 2w, 4w and 8w after injury respectively. Forelimb functional assessments, including Montoya staircase task and cylinder rearing test, were conducted on another 10 animals before injury and at 2w, 4w and 8w after injury respectively, as well as histological analysis of the cord at 8w after injury. A group correlation was performed between the MEPs & SEPs and behavioral outcomes. RESULTS: The hemi-contusion injury resulted in unilateral tissue damage at the epicenter with loss of the ventral horns and lateral funiculus. Both ipsilateral and contralateral forelimb MEPs showed latency prolongation and amplitude reduction at 3h after injury. The MEPs amplitude increased with time after injury, but the ipsilateral amplitude was persistently lower than the contralateral amplitude. The ipsilateral MEPs latency increased with time after injury and was significantly longer than the contralateral MEPs latency. The ipsilateral SEPs amplitude dropped after injury and stayed at a lower level up to 8 weeks. There was no difference in the SEPs latency among time points and between sides. At 8 weeks after injury, the ipsilateral forelimb grasped 30% pellets while the contralateral forelimb close to 81%. An obvious decreased usage of the ipsilateral paw and increased usage of the contralateral paw were observed in rearing test after injury. The MEPs latency and amplitude correlated significantly with the forelimb motor function. CONCLUSION: Cervical hemi-contusion SCI led to persistent changes in MEPs & SEPs of the ipsilateral forelimb, ipsilateral impairment in motor function and unilateral cord tissue damage. Reliable electrophysiology assessment was obtained in chronic phase due to unstable MEPs & SEPs of bilateral forelimb immediately after injury, which might reflect the underlying pathological processes. The present study further confirmed the link of the MEPs to the behavioral outcomes, supporting the longitudinal electrophysiology assessment for neurological impairment after SCI.

Anatomical and functional effects of lateral cervical hemicontusion in adult rats.

PURPOSE: Cervical injuries are the most common form of spinal cord injury (SCI), and are often complicated by pathological secondary damage. Therefore, cervical SCI is of great clinical importance for understanding pathology and potential therapies. Here we utilize a weight drop cervical hemi-contusion injury model using a NYU/MASCIS impactor that produced graded anatomical and functional deficits. METHODS: Three groups of rats were established: 1) Sham (laminectomy only) (n = 6), 12.5 mm weight drop (n = 10), and 25 mm weight drop (n = 10) SCI groups. Forelimb functional assessments of grooming ability, cereal manipulation, and forepaw adhesive removal were performed weekly after injury. Using transcranial magnetic motor evoked potentials (tcMMEPs), supraspinal motor stimulations were recorded in both forelimbs and hindlimbs at 5 and 28d post-injury. Lesion volume and myelinated tissue area were assessed through histological analysis. RESULTS: A 12.5 mm weight drop height produced considerable tissue damage compared to Sham animals, while a 25 mm drop induced even greater damage than the 12.5 mm drop (p < 0.05). Forelimb functional assessments showed that increased injury severity and tissue damage was correlated to the degree of forelimb functional deficits. Interestingly, the hindlimbs showed little to no motor function loss. Upon tcMMEP stimulation, surprisingly little motor signal was recorded in the hindlimbs despite outward evidence of hindlimb motor recovery. CONCLUSIONS: Our findings highlight a correlation between anatomical damage and functional outcome in a graded cervical hemi-contusion model, and support a loss of descending motor control from supraspinal inputs and intraspinal plasticity that promote spontaneous hindlimb functional recovery in this model.